Author: "Kristel R van Eijk" - Searchworks@Jio Institute Digital Library Search Results

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1. Enrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders

Author: Jonathan Gilley, Oscar Jackson, Menelaos Pipis, Mehrdad A Estiar, Ammar Al-Chalabi, Matt C Danzi, Kristel R van Eijk, Stephen A Goutman, Matthew B Harms, Henry Houlden, Alfredo Iacoangeli, Julia Kaye, Leandro Lima, Queen Square Genomics, John Ravits, Guy A Rouleau, Rebecca Schüle, Jishu Xu, Stephan Züchner, Johnathan Cooper-Knock, Ziv Gan-Or, Mary M Reilly, and Michael P Coleman
Subjects: SARM1, NADase, ALS, risk allele, Medicine, Science, Biology (General), QH301-705.5
Abstract: SARM1, a protein with critical NADase activity, is a central executioner in a conserved programme of axon degeneration. We report seven rare missense or in-frame microdeletion human SARM1 variant alleles in patients with amyotrophic lateral sclerosis (ALS) or other motor nerve disorders that alter the SARM1 auto-inhibitory ARM domain and constitutively hyperactivate SARM1 NADase activity. The constitutive NADase activity of these seven variants is similar to that of SARM1 lacking the entire ARM domain and greatly exceeds the activity of wild-type SARM1, even in the presence of nicotinamide mononucleotide (NMN), its physiological activator. This rise in constitutive activity alone is enough to promote neuronal degeneration in response to otherwise non-harmful, mild stress. Importantly, these strong gain-of-function alleles are completely patient-specific in the cohorts studied and show a highly significant association with disease at the single gene level. These findings of disease-associated coding variants that alter SARM1 function build on previously reported genome-wide significant association with ALS for a neighbouring, more common SARM1 intragenic single nucleotide polymorphism (SNP) to support a contributory role of SARM1 in these disorders. A broad phenotypic heterogeneity and variable age-of-onset of disease among patients with these alleles also raises intriguing questions about the pathogenic mechanism of hyperactive SARM1 variants.
Published: 2021
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2. Associations of autozygosity with a broad range of human phenotypes

Author: David W Clark, Yukinori Okada, Kristjan H S Moore, Dan Mason, Nicola Pirastu, Ilaria Gandin, Hannele Mattsson, Catriona L K Barnes, Kuang Lin, Jing Hua Zhao, Patrick Deelen, Rebecca Rohde, Claudia Schurmann, Xiuqing Guo, Franco Giulianini, Weihua Zhang, Carolina Medina-Gomez, Robert Karlsson, Yanchun Bao, Traci M Bartz, Clemens Baumbach, Ginevra Biino, Matthew J Bixley, Marco Brumat, Jin-Fang Chai, Tanguy Corre, Diana L Cousminer, Annelot M Dekker, David A Eccles, Kristel R van Eijk, Christian Fuchsberger, He Gao, Marine Germain, Scott D Gordon, Hugoline G de Haan, Sarah E Harris, Edith Hofer, Alicia Huerta-Chagoya, Catherine Igartua, Iris E Jansen, Yucheng Jia, Tim Kacprowski, Torgny Karlsson, Marcus E Kleber, Shengchao Alfred Li, Ruifang Li-Gao, Anubha Mahajan, Koichi Matsuda, Karina Meidtner, Weihua Meng, May E Montasser, Peter J van der Most, Matthias Munz, Teresa Nutile, Teemu Palviainen, Gauri Prasad, Rashmi B Prasad, Tallapragada Divya Sri Priyanka, Federica Rizzi, Erika Salvi, Bishwa R Sapkota, Daniel Shriner, Line Skotte, Melissa C Smart, Albert Vernon Smith, Ashley van der Spek, Cassandra N Spracklen, Rona J Strawbridge, Salman M Tajuddin, Stella Trompet, Constance Turman, Niek Verweij, Clara Viberti, Lihua Wang, Helen R Warren, Robyn E Wootton, Lisa R Yanek, Jie Yao, Noha A Yousri, Wei Zhao, Adebowale A Adeyemo, Saima Afaq, Carlos Alberto Aguilar-Salinas, Masato Akiyama, Matthew L Albert, Matthew A Allison, Maris Alver, Tin Aung, Fereidoun Azizi, Amy R Bentley, Heiner Boeing, Eric Boerwinkle, Judith B Borja, Gert J de Borst, Erwin P Bottinger, Linda Broer, Harry Campbell, Stephen Chanock, Miao-Li Chee, Guanjie Chen, Yii-Der I Chen, Zhengming Chen, Yen-Feng Chiu, Massimiliano Cocca, Francis S Collins, Maria Pina Concas, Janie Corley, Giovanni Cugliari, Rob M van Dam, Anna Damulina, Maryam S Daneshpour, Felix R Day, Graciela E Delgado, Klodian Dhana, Alexander S F Doney, Marcus Dörr, Ayo P Doumatey, Nduna Dzimiri, S Sunna Ebenesersdóttir, Joshua Elliott, Paul Elliott, Ralf Ewert, Janine F Felix, Krista Fischer, Barry I Freedman, Giorgia Girotto, Anuj Goel, Martin Gögele, Mark O Goodarzi, Mariaelisa Graff, Einat Granot-Hershkovitz, Francine Grodstein, Simonetta Guarrera, Daniel F Gudbjartsson, Kamran Guity, Bjarni Gunnarsson, Yu Guo, Saskia P Hagenaars, Christopher A Haiman, Avner Halevy, Tamara B Harris, Mehdi Hedayati, David A van Heel, Makoto Hirata, Imo Höfer, Chao Agnes Hsiung, Jinyan Huang, Yi-Jen Hung, M Arfan Ikram, Anuradha Jagadeesan, Pekka Jousilahti, Yoichiro Kamatani, Masahiro Kanai, Nicola D Kerrison, Thorsten Kessler, Kay-Tee Khaw, Chiea Chuen Khor, Dominique P V de Kleijn, Woon-Puay Koh, Ivana Kolcic, Peter Kraft, Bernhard K Krämer, Zoltán Kutalik, Johanna Kuusisto, Claudia Langenberg, Lenore J Launer, Deborah A Lawlor, I-Te Lee, Wen-Jane Lee, Markus M Lerch, Liming Li, Jianjun Liu, Marie Loh, Stephanie J London, Stephanie Loomis, Yingchang Lu, Jian’an Luan, Reedik Mägi, Ani W Manichaikul, Paolo Manunta, Gísli Másson, Nana Matoba, Xue W Mei, Christa Meisinger, Thomas Meitinger, Massimo Mezzavilla, Lili Milani, Iona Y Millwood, Yukihide Momozawa, Amy Moore, Pierre-Emmanuel Morange, Hortensia Moreno-Macías, Trevor A Mori, Alanna C Morrison, Taulant Muka, Yoshinori Murakami, Alison D Murray, Renée de Mutsert, Josyf C Mychaleckyj, Mike A Nalls, Matthias Nauck, Matt J Neville, Ilja M Nolte, Ken K Ong, Lorena Orozco, Sandosh Padmanabhan, Gunnar Pálsson, James S Pankow, Cristian Pattaro, Alison Pattie, Ozren Polasek, Neil Poulter, Peter P Pramstaller, Lluis Quintana-Murci, Katri Räikkönen, Sarju Ralhan, Dabeeru C Rao, Wouter van Rheenen, Stephen S Rich, Paul M Ridker, Cornelius A Rietveld, Antonietta Robino, Frank J A van Rooij, Daniela Ruggiero, Yasaman Saba, Charumathi Sabanayagam, Maria Sabater-Lleal, Cinzia Felicita Sala, Veikko Salomaa, Kevin Sandow, Helena Schmidt, Laura J Scott, William R Scott, Bahareh Sedaghati-Khayat, Bengt Sennblad, Jessica van Setten, Peter J Sever, Wayne H-H Sheu, Yuan Shi, Smeeta Shrestha, Sharvari Rahul Shukla, Jon K Sigurdsson, Timo Tonis Sikka, Jai Rup Singh, Blair H Smith, Alena Stančáková, Alice Stanton, John M Starr, Lilja Stefansdottir, Leon Straker, Patrick Sulem, Gardar Sveinbjornsson, Morris A Swertz, Adele M Taylor, Kent D Taylor, Natalie Terzikhan, Yih-Chung Tham, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Annika Tillander, Russell P Tracy, Teresa Tusié-Luna, Ioanna Tzoulaki, Simona Vaccargiu, Jagadish Vangipurapu, Jan H Veldink, Veronique Vitart, Uwe Völker, Eero Vuoksimaa, Salma M Wakil, Melanie Waldenberger, Gurpreet S Wander, Ya Xing Wang, Nicholas J Wareham, Sarah Wild, Chittaranjan S Yajnik, Jian-Min Yuan, Lingyao Zeng, Liang Zhang, Jie Zhou, Najaf Amin, Folkert W Asselbergs, Stephan J L Bakker, Diane M Becker, Benjamin Lehne, David A Bennett, Leonard H van den Berg, Sonja I Berndt, Dwaipayan Bharadwaj, Lawrence F Bielak, Murielle Bochud, Mike Boehnke, Claude Bouchard, Jonathan P Bradfield, Jennifer A Brody, Archie Campbell, Shai Carmi, Mark J Caulfield, David Cesarini, John C Chambers, Giriraj Ratan Chandak, Ching-Yu Cheng, Marina Ciullo, Marilyn Cornelis, Daniele Cusi, George Davey Smith, Ian J Deary, Rajkumar Dorajoo, Cornelia M van Duijn, David Ellinghaus, Jeanette Erdmann, Johan G Eriksson, Evangelos Evangelou, Michele K Evans, Jessica D Faul, Bjarke Feenstra, Mary Feitosa, Sylvain Foisy, Andre Franke, Yechiel Friedlander, Paolo Gasparini, Christian Gieger, Clicerio Gonzalez, Philippe Goyette, Struan F A Grant, Lyn R Griffiths, Leif Groop, Vilmundur Gudnason, Ulf Gyllensten, Hakon Hakonarson, Anders Hamsten, Pim van der Harst, Chew-Kiat Heng, Andrew A Hicks, Hagit Hochner, Heikki Huikuri, Steven C Hunt, Vincent W V Jaddoe, Philip L De Jager, Magnus Johannesson, Åsa Johansson, Jost B Jonas, J Wouter Jukema, Juhani Junttila, Jaakko Kaprio, Sharon L. R. Kardia, Fredrik Karpe, Meena Kumari, Markku Laakso, Sander W van der Laan, Jari Lahti, Matthias Laudes, Rodney A Lea, Wolfgang Lieb, Thomas Lumley, Nicholas G Martin, Winfried März, Giuseppe Matullo, Mark I McCarthy, Sarah E Medland, Tony R Merriman, Andres Metspalu, Brian F Meyer, Karen L Mohlke, Grant W Montgomery, Dennis Mook-Kanamori, Patricia B Munroe, Kari E North, Dale R Nyholt, Jeffery R O’connell, Carole Ober, Albertine J Oldehinkel, Walter Palmas, Colin Palmer, Gerard G Pasterkamp, Etienne Patin, Craig E Pennell, Louis Perusse, Patricia A Peyser, Mario Pirastu, Tinca J. C. Polderman, David J Porteous, Danielle Posthuma, Bruce M Psaty, John D Rioux, Fernando Rivadeneira, Charles Rotimi, Jerome I Rotter, Igor Rudan, Hester M Den Ruijter, Dharambir K Sanghera, Naveed Sattar, Reinhold Schmidt, Matthias B Schulze, Heribert Schunkert, Robert A Scott, Alan R Shuldiner, Xueling Sim, Neil Small, Jennifer A Smith, Nona Sotoodehnia, E-Shyong Tai, Alexander Teumer, Nicholas J Timpson, Daniela Toniolo, David-Alexandre Tregouet, Tiinamaija Tuomi, Peter Vollenweider, Carol A Wang, David R Weir, John B Whitfield, Cisca Wijmenga, Tien-Yin Wong, John Wright, Jingyun Yang, Lei Yu, Babette S Zemel, Alan B Zonderman, Markus Perola, Patrik K. E. Magnusson, André G Uitterlinden, Jaspal S Kooner, Daniel I Chasman, Ruth J. F. Loos, Nora Franceschini, Lude Franke, Chris S Haley, Caroline Hayward, Robin G Walters, John R. B. Perry, Tōnu Esko, Agnar Helgason, Kari Stefansson, Peter K Joshi, Michiaki Kubo, and James F Wilson
Subjects: Science
Abstract: Inbreeding depression has been observed in many different species, but in humans a systematic analysis has been difficult so far. Here, analysing more than 1.3 million individuals, the authors show that a genomic inbreeding coefficient (FROH) is associated with disadvantageous outcomes in 32 out of 100 traits tested.
Published: 2019
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3. Whole blood transcriptome analysis in amyotrophic lateral sclerosis: A biomarker study.

Author: Wouter van Rheenen, Frank P Diekstra, Oliver Harschnitz, Henk-Jan Westeneng, Kristel R van Eijk, Christiaan G J Saris, Ewout J N Groen, Michael A van Es, Hylke M Blauw, Paul W J van Vught, Jan H Veldink, and Leonard H van den Berg
Subjects: Medicine, Science
Abstract: The biological pathways involved in amyotrophic lateral sclerosis (ALS) remain elusive and diagnostic decision-making can be challenging. Gene expression studies are valuable in overcoming such challenges since they can shed light on differentially regulated pathways and may ultimately identify valuable biomarkers. This two-stage transcriptome-wide study, including 397 ALS patients and 645 control subjects, identified 2,943 differentially expressed transcripts predominantly involved in RNA binding and intracellular transport. When batch effects between the two stages were overcome, three different models (support vector machines, nearest shrunken centroids, and LASSO) discriminated ALS patients from control subjects in the validation stage with high accuracy. The models' accuracy reduced considerably when discriminating ALS from diseases that mimic ALS clinically (N = 75), nor could it predict survival. We here show that whole blood transcriptome profiles are able to reveal biological processes involved in ALS. Also, this study shows that using these profiles to differentiate between ALS and mimic syndromes will be challenging, even when taking batch effects in transcriptome data into account.
Published: 2018
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4. Characterization of genome-methylome interactions in 22 nuclear pedigrees.

Author: Nongluk Plongthongkum, Kristel R van Eijk, Simone de Jong, Tina Wang, Jae Hoon Sul, Marco P M Boks, René S Kahn, Ho-Lim Fung, Roel A Ophoff, and Kun Zhang
Subjects: Medicine, Science
Abstract: Genetic polymorphisms can shape the global landscape of DNA methylation, by either changing substrates for DNA methyltransferases or altering the DNA binding affinity of cis-regulatory proteins. The interactions between CpG methylation and genetic polymorphisms have been previously investigated by methylation quantitative trait loci (mQTL) and allele-specific methylation (ASM) analysis. However, it remains unclear whether these approaches can effectively and comprehensively identify all genetic variants that contribute to the inter-individual variation of DNA methylation levels. Here we used three independent approaches to systematically investigate the influence of genetic polymorphisms on variability in DNA methylation by characterizing the methylation state of 96 whole blood samples in 52 parent-child trios from 22 nuclear pedigrees. We performed targeted bisulfite sequencing with padlock probes to quantify the absolute DNA methylation levels at a set of 411,800 CpG sites in the human genome. With mid-parent offspring analysis (MPO), we identified 10,593 CpG sites that exhibited heritable methylation patterns, among which 70.1% were SNPs directly present in methylated CpG dinucleotides. We determined the mQTL analysis identified 49.9% of heritable CpG sites for which regulation occurred in a distal cis-regulatory manner, and that ASM analysis was only able to identify 5%. Finally, we identified hundreds of clusters in the human genome for which the degree of variation of CpG methylation, as opposed to whether or not CpG sites were methylated, was associated with genetic polymorphisms, supporting a recent hypothesis on the genetic influence of phenotypic plasticity. These results show that cis-regulatory SNPs identified by mQTL do not comprise the full extent of heritable CpG methylation, and that ASM appears overall unreliable. Overall, the extent of genome-methylome interactions is well beyond what is detectible with the commonly used mQTL and ASM approaches, and is likely to include effects on plasticity.
Published: 2014
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5. Author Correction: Integrative genetic analysis illuminates ALS heritability and identifies risk genes

Author: Salim Megat, Natalia Mora, Jason Sanogo, Olga Roman, Alberto Catanese, Najwa Ouali Alami, Axel Freischmidt, Xhuljana Mingaj, Hortense De Calbiac, François Muratet, Sylvie Dirrig-Grosch, Stéphane Dieterle, Nick Van Bakel, Kathrin Müller, Kirsten Sieverding, Jochen Weishaupt, Peter Munch Andersen, Markus Weber, Christoph Neuwirth, Markus Margelisch, Andreas Sommacal, Kristel R. Van Eijk, Jan H. Veldink, Project Mine Als Sequencing Consortium, Géraldine Lautrette, Philippe Couratier, Agnès Camuzat, Isabelle Le Ber, Maurizio Grassano, Adriano Chio, Tobias Boeckers, Albert C. Ludolph, Francesco Roselli, Deniz Yilmazer-Hanke, Stéphanie Millecamps, Edor Kabashi, Erik Storkebaum, Chantal Sellier, and Luc Dupuis
Subjects: Science
Published: 2023
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6. Integrative genetic analysis illuminates ALS heritability and identifies risk genes

Author: Salim Megat, Natalia Mora, Jason Sanogo, Olga Roman, Alberto Catanese, Najwa Ouali Alami, Axel Freischmidt, Xhuljana Mingaj, Hortense De Calbiac, François Muratet, Sylvie Dirrig-Grosch, Stéphane Dieterle, Nick Van Bakel, Kathrin Müller, Kirsten Sieverding, Jochen Weishaupt, Peter Munch Andersen, Markus Weber, Christoph Neuwirth, Markus Margelisch, Andreas Sommacal, Kristel R. Van Eijk, Jan H. Veldink, Project Mine Als Sequencing Consortium, Géraldine Lautrette, Philippe Couratier, Agnès Camuzat, Isabelle Le Ber, Maurizio Grassano, Adriano Chio, Tobias Boeckers, Albert C. Ludolph, Francesco Roselli, Deniz Yilmazer-Hanke, Stéphanie Millecamps, Edor Kabashi, Erik Storkebaum, Chantal Sellier, and Luc Dupuis
Subjects: Science
Abstract: Abstract Amyotrophic lateral sclerosis (ALS) has substantial heritability, in part shared with fronto-temporal dementia (FTD). We show that ALS heritability is enriched in splicing variants and in binding sites of 6 RNA-binding proteins including TDP-43 and FUS. A transcriptome wide association study (TWAS) identified 6 loci associated with ALS, including in NUP50 encoding for the nucleopore basket protein NUP50. Independently, rare variants in NUP50 were associated with ALS risk (P = 3.71.10−03; odds ratio = 3.29; 95%CI, 1.37 to 7.87) in a cohort of 9,390 ALS/FTD patients and 4,594 controls. Cells from one patient carrying a NUP50 frameshift mutation displayed a decreased level of NUP50. Loss of NUP50 leads to death of cultured neurons, and motor defects in Drosophila and zebrafish. Thus, our study identifies alterations in splicing in neurons as critical in ALS and provides genetic evidence linking nuclear pore defects to ALS.
Published: 2023
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7. Childhood maltreatment mediates the effect of the genetic background on psychosis risk in young adults

Author: Mattia Marchi, Laurent Elkrief, Anne Alkema, Willemijn van Gastel, Chris D. Schubart, Kristel R. van Eijk, Jurjen J. Luykx, Susan Branje, Stefanos Mastrotheodoros, Gian M. Galeazzi, Jim van Os, Charlotte A. Cecil, Patricia J. Conrod, and Marco P. Boks
Subjects: Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Abstract Childhood maltreatment (CM) and genetic vulnerability are both risk factors for psychosis, but the relations between them are not fully understood. Guided by the recent identification of genetic risk to CM, this study investigates the hypothesis that genetic risk to schizophrenia also increases the risk of CM and thus impacts psychosis risk. The relationship between schizophrenia polygenetic risk, CM, and psychotic-like experiences (PLE) was investigated in participants from the Utrecht Cannabis Cohort (N = 1262) and replicated in the independent IMAGEN cohort (N = 1740). Schizophrenia polygenic risk score (SZ-PRS) were calculated from the most recent GWAS. The relationship between CM, PRS, and PLE was first investigated using multivariate linear regression. Next, mediation of CM in the pathway linking SZ-PRS and PLE was examined by structural equation modeling, while adjusting for a set of potential mediators including cannabis use, smoking, and neuroticism. In agreement with previous studies, PLE were strongly associated with SZ-PRS (B = 0.190, p = 0.009) and CM (B = 0.575, p
Published: 2022
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8. Telomere length analysis in amyotrophic lateral sclerosis using large-scale whole genome sequence data

Author: Ahmad Al Khleifat, Alfredo Iacoangeli, Ashley R. Jones, Joke J. F. A. van Vugt, Matthieu Moisse, Aleksey Shatunov, Ramona A. J. Zwamborn, Rick A. A. van der Spek, Johnathan Cooper-Knock, Simon Topp, Wouter van Rheenen, Brendan Kenna, Kristel R. Van Eijk, Kevin Kenna, Ross Byrne, Victoria López, Sarah Opie-Martin, Atay Vural, Yolanda Campos, Markus Weber, Bradley Smith, Isabella Fogh, Vincenzo Silani, Karen E. Morrison, Richard Dobson, Michael A. van Es, Russell L. McLaughlin, Patrick Vourc’h, Adriano Chio, Philippe Corcia, Mamede de Carvalho, Marc Gotkine, Monica Povedano Panades, Jesus S. Mora, Pamela J. Shaw, John E. Landers, Jonathan D. Glass, Christopher E. Shaw, Nazli Basak, Orla Hardiman, Wim Robberecht, Philip Van Damme, Leonard H. van den Berg, Jan H. Veldink, and Ammar Al-Chalabi
Subjects: amyotrophic lateral sclerosis (ALS), telomere–genetics, whole genome sequence (WGS), genomics, bigdata, MND–motor neuron disorders, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: BackgroundAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of upper and lower motor neurons, leading to progressive weakness of voluntary muscles, with death following from neuromuscular respiratory failure, typically within 3 to 5 years. There is a strong genetic contribution to ALS risk. In 10% or more, a family history of ALS or frontotemporal dementia is obtained, and the Mendelian genes responsible for ALS in such families have now been identified in about 50% of cases. Only about 14% of apparently sporadic ALS is explained by known genetic variation, suggesting that other forms of genetic variation are important. Telomeres maintain DNA integrity during cellular replication, differ between sexes, and shorten naturally with age. Sex and age are risk factors for ALS and we therefore investigated telomere length in ALS.MethodsSamples were from Project MinE, an international ALS whole genome sequencing consortium that includes phenotype data. For validation we used donated brain samples from motor cortex from people with ALS and controls. Ancestry and relatedness were evaluated by principal components analysis and relationship matrices of DNA microarray data. Whole genome sequence data were from Illumina HiSeq platforms and aligned using the Isaac pipeline. TelSeq was used to quantify telomere length using whole genome sequence data. We tested the association of telomere length with ALS and ALS survival using Cox regression.ResultsThere were 6,580 whole genome sequences, reducing to 6,195 samples (4,315 from people with ALS and 1,880 controls) after quality control, and 159 brain samples (106 ALS, 53 controls). Accounting for age and sex, there was a 20% (95% CI 14%, 25%) increase of telomere length in people with ALS compared to controls (p = 1.1 × 10−12), validated in the brain samples (p = 0.03). Those with shorter telomeres had a 10% increase in median survival (p = 5.0×10−7). Although there was no difference in telomere length between sporadic ALS and familial ALS (p=0.64), telomere length in 334 people with ALS due to expanded C9orf72 repeats was shorter than in those without expanded C9orf72 repeats (p = 5.0×10−4).DiscussionAlthough telomeres shorten with age, longer telomeres are a risk factor for ALS and worsen prognosis. Longer telomeres are associated with ALS.
Published: 2022
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9. Phenome-wide and genome-wide analyses of quality of life in schizophrenia – ERRATUM

Author: Raha Pazoki, Bochao Danae Lin, Kristel R. van Eijk, Dick Schijven, Sonja de Zwarte, Sinan Guloksuz, and Jurjen J. Luykx
Subjects: Quality of life, schizophrenia, phenome, genome, polygenic, erratum, Psychiatry, RC435-571
Published: 2021
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10. Age- and sex-specific associations between risk scores for schizophrenia and self-reported health in the general population

Author: Vincent Paquin, Lotta-Katrin Pries, Margreet ten Have, Maarten Bak, Nicole Gunther, Ron de Graaf, Saskia van Dorsselaer, Bochao D. Lin, Kristel R. van Eijk, Gunter Kenis, Alexander Richards, Michael C. O’Donovan, Jurjen J. Luykx, Bart P. F. Rutten, Jim van Os, Jai L. Shah, Sinan Guloksuz, RS: MHeNs - R2 - Mental Health, Psychiatry 1, RS: MHeNs - R3 - Neuroscience, MUMC+: MA Niet Med Staf Psychiatrie (9), Basic Neuroscience 1, Psychiatrie & Neuropsychologie, MUMC+: MA Psychiatrie (3), MUMC+: Hersen en Zenuw Centrum (3), RS-Research Line Clinical psychology (part of UHC program), and Department of Clinical Psychology
Subjects: Quality of life, Psychiatry and Mental health, Exposome, Health (social science), Social Psychology, Genes, Epidemiology, ONSET, Schizophrenia, Sex characteristics, CHILDHOOD, TWIN, POLYGENIC RISK
Abstract: Purpose The health correlates of polygenic risk (PRS-SCZ) and exposome (ES-SCZ) scores for schizophrenia may vary depending on age and sex. We aimed to examine age- and sex-specific associations of PRS-SCZ and ES-SCZ with self-reported health in the general population. Methods Participants were from the population-based Netherlands Mental Health Survey and Incidence Study–2 (NEMESIS-2). Mental and physical health were measured with the 36-item Short Form Survey 4 times between 2007 and 2018. The PRS-SCZ and ES-SCZ were respectively calculated from common genetic variants and exposures (cannabis use, winter birth, hearing impairment, and five childhood adversity categories). Moderation by age and sex was examined in linear mixed models. Results For PRS-SCZ and ES-SCZ analyses, we included 3099 and 6264 participants, respectively (age range 18–65 years; 55.7–56.1% female). Age and sex did not interact with PRS-SCZ. Age moderated the association between ES-SCZ and mental (interaction: p = 0.02) and physical health (p = 0.0007): at age 18, + 1.00 of ES-SCZ was associated with − 0.10 of mental health and − 0.08 of physical health, whereas at age 65, it was associated with − 0.21 and − 0.23, respectively (all units in standard deviations). Sex moderated the association between ES-SCZ and physical health (p Conclusion There were larger associations between higher ES-SCZ and poorer health among female and older individuals. Accounting for these interactions may increase ES-SCZ precision and help uncover populational determinants of environmental influences on health.
Published: 2023

11. Structural variation analysis of 6,500 whole genome sequences in amyotrophic lateral sclerosis

Author: Ahmad Al Khleifat, Alfredo Iacoangeli, Joke J. F. A. van Vugt, Harry Bowles, Matthieu Moisse, Ramona A. J. Zwamborn, Rick A. A. van der Spek, Aleksey Shatunov, Johnathan Cooper-Knock, Simon Topp, Ross Byrne, Cinzia Gellera, Victoria López, Ashley R. Jones, Sarah Opie-Martin, Atay Vural, Yolanda Campos, Wouter van Rheenen, Brendan Kenna, Kristel R. Van Eijk, Kevin Kenna, Markus Weber, Bradley Smith, Isabella Fogh, Vincenzo Silani, Karen E. Morrison, Richard Dobson, Michael A. van Es, Russell L. McLaughlin, Patrick Vourc’h, Adriano Chio, Philippe Corcia, Mamede de Carvalho, Marc Gotkine, Monica P. Panades, Jesus S. Mora, Pamela J. Shaw, John E. Landers, Jonathan D. Glass, Christopher E. Shaw, Nazli Basak, Orla Hardiman, Wim Robberecht, Philip Van Damme, Leonard H. van den Berg, Jan H. Veldink, Ammar Al-Chalabi, Wellcome Trust, Unión Europea. Comisión Europea. 7 Programa Marco, Unión Europea. Comisión Europea. H2020, Unión Europea. Fondo Social Europeo (ESF/FSE), Research Foundation - Flanders, KU Leuven (Bélgica), Science Foundation Ireland, Amyotrophic Lateral Sclerosis Association (Estados Unidos), NIH - National Institute of Neurological Disorders and Stroke (NINDS) (Estados Unidos), Repositório da Universidade de Lisboa, Vural, Atay (ORCID 0000-0003-3222-874X & YÖK ID 182369), Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512), Ahmad Al, Khleifat, Alfredo, Iacoangeli, Joke J F A van, Vugt, Harry, Bowles, Matthieu, Moisse, Ramona A J, Zwamborn, Rick A A van, der Spek, Aleksey, Shatunov, Johnathan, Cooper-Knock, Simon, Topp, Ross, Byrne, Cinzia, Gellera, Victoria, Lopez, Ashley R, Jones, Sarah, Opie-Martin, Yolanda, Campos, Wouter van, Rheenen, Brendan, Kenna, Kristel R Van, Eijk, Kevin, Kenna, Markus, Weber, Bradley, Smith, Isabella, Fogh, Vincenzo, Silani, Karen E., Morrison, Richard, Dobson, Michael A van, Es, Russell L., McLaughlin, Patrick, Vourc’h, Adriano, Chio, Philippe, Corcia, Mamede, de Carvalho, Marc, Gotkine, Monica, P Panades, Jesus ,S Mora, Pamela, J Shaw, John, E Landers, Jonathan, D Glass, Christopher, E Shaw, Orla, Hardiman, Wim, Robberecht, Philip Van, Damme, Leonard H van, den Berg, Jan, H Veldink, Ammar, Al-Chalabi, Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), and School of Medicine
Subjects: Genetics and heredity, C9ORF72, VARIANTS, QH426-470, Article, 03 medical and health sciences, 0302 clinical medicine, Human genetics, Genetics, INCLUSION-BODY MYOPATHY, Amyotrophic lateral sclerosis (ALS), Molecular Biology, Genetics (clinical), COPY NUMBER VARIATION, 030304 developmental biology, Genetics & Heredity, 0303 health sciences, Science & Technology, Genètica humana, HERITABILITY, Comparative genomics, Amyotrophic lateral sclerosis, Disease progression, Advanced launch system (STS), ASSOCIATION, HEXANUCLEOTIDE REPEAT EXPANSION, Genome sequences, PAGET-DISEASE, Medicine, BONE, Life Sciences & Biomedicine, FAMILIAL FRONTOTEMPORAL DEMENTIA, 030217 neurology & neurosurgery, Esclerosi lateral amiotròfica
Abstract: © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/., There is a strong genetic contribution to Amyotrophic lateral sclerosis (ALS) risk, with heritability estimates of up to 60%. Both Mendelian and small effect variants have been identified, but in common with other conditions, such variants only explain a little of the heritability. Genomic structural variation might account for some of this otherwise unexplained heritability. We therefore investigated association between structural variation in a set of 25 ALS genes, and ALS risk and phenotype. As expected, the repeat expansion in the C9orf72 gene was identified as associated with ALS. Two other ALS-associated structural variants were identified: inversion in the VCP gene and insertion in the ERBB4 gene. All three variants were associated both with increased risk of ALS and specific phenotypic patterns of disease expression. More than 70% of people with respiratory onset ALS harboured ERBB4 insertion compared with 25% of the general population, suggesting respiratory onset ALS may be a distinct genetic subtype., This research was funded in whole, or in part, by the Wellcome Trust [Grant number]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. The authors acknowledge use of the research computing facility at King’s College London, Rosalind (https://rosalind.kcl.ac.uk), which is delivered in partnership with the National Institute for Health Research (NIHR) Biomedical Research Centres at South London & Maudsley and Guy’s & St. Thomas’ NHS Foundation Trusts, and part-funded by capital equipment grants from the Maudsley Charity (award 980) and Guy’s & St. Thomas’ Charity (TR130505). The views expressed are those of the author (s) and not necessarily those of the NHS, the NIHR, King’s College London, or the Department of Health and Social Care. National. The authors acknowledge Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The authors acknowledge Health Data Research UK, which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation and Wellcome Trust. A.A.K. is funded by The Motor Neurone Disease Association (MNDA), NIHR Maudsley Biomedical Research Centre and and ALS Association Milton Safenowitz Research Fellowship. This project was funded by the MND Association and the Wellcome Trust. This is an EU Joint Programme-Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organisations under the aegis of JPND - www.jpnd.eu (United Kingdom, Medical Research Council (MR/L501529/1 and MR/R024804/1) and Economic and Social Research Council (ES/L008238/1)). A.A.C. is an NIHR Senior Investigator. C.E.S. and A.A.C. receive salary support from the National Institute for Health Research (NIHR) Dementia Biomedical Research Unit at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The work leading up to this publication was funded by the European Community’s Health Seventh Framework Program (FP7/2007–2013; grant agreement number 259867) and Horizon 2020 Program (H2020-PHC-2014-two-stage; grant agreement number 633413). This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 772376 - EScORIAL. The collaboration project is co-funded by the PPP Allowance made available by Health~Holland, Top Sector Life Sciences & Health, to stimulate public-private partnerships. Project MinE Belgium was supported by a grant from IWT, the Belgian ALS Liga and a grant from Opening the Future Fund (KU Leuven). PVD holds a senior clinical investigatorship of FWO-Vlaanderen and is supported by E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders, the ALS Liga België and the KU Leuven funds “Een Hart voor ALS”, “Laeversfonds voor ALS Onderzoek” and the “Valéry Perrier Race against ALS Fund”. R.L.McL. is supported by Science Foundation Ireland (17/CDA/4737). MinE USA is funded by the US ALS Association. We thank the patients and families from the Emory ALS Clinic participating in this research. Funding was provided by US National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS) (R01NS073873, J.E.L.) and the American ALS Association (J.E.L.).
Published: 2022

12. Whole genome sequencing analysis reveals post-zygotic mutation variability in monozygotic twins discordant for amyotrophic lateral sclerosis

Author: Gijs H.P. Tazelaar, Paul J. Hop, Meinie Seelen, Joke J.F.A. van Vugt, Wouter van Rheenen, Lindy Kool, Kristel R. van Eijk, Marleen Gijzen, Dennis Dooijes, Matthieu Moisse, Andrea Calvo, Cristina Moglia, Maura Brunetti, Antonio Canosa, Angelica Nordin, Jesus S. Mora Pardina, John Ravits, Ammar Al-Chalabi, Adriano Chio, Russell L. McLaughlin, Orla Hardiman, Philip Van Damme, Mamede de Carvalho, Christoph Neuwirth, Markus Weber, Peter M Andersen, Leonard H. van den Berg, Jan H. Veldink, Michael A. van Es, and Repositório da Universidade de Lisboa
Subjects: Genetic modifiers, Aging, Geriatrics & Gerontology, Neurologi, GALACTOCEREBROSIDE, REPEAT, AGE, Repeat expansions, RISK, Science & Technology, General Neuroscience, Amyotrophic Lateral Sclerosis, Post-zygotic mutations, MULTISTEP PROCESS, Neurosciences, EXPANSIONS, Neurology, DE-NOVO MUTATIONS, PATTERNS, Neurology (clinical), Neurosciences & Neurology, Geriatrics and Gerontology, ALS, Life Sciences & Biomedicine, Neurovetenskaper, Developmental Biology
Abstract: © 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license., Amyotrophic lateral sclerosis is a heterogeneous, fatal neurodegenerative disease, characterized by motor neuron loss and in 50% of cases also by cognitive and/or behavioral changes. Mendelian forms of ALS comprise approximately 10-15% of cases. The majority is however considered sporadic, but also with a high contribution of genetic risk factors. To explore the contribution of somatic mutations and/or epigenetic changes to disease risk, we performed whole genome sequencing and methylation analyses using samples from multiple tissues on a cohort of 26 monozygotic twins discordant for ALS, followed by in-depth validation and replication experiments. The results of these analyses implicate several mechanisms in ALS pathophysiology, which include a role for de novo mutations, defects in DNA damage repair and accelerated aging., This study was funded by the Thierry Latran Foundation and the Dutch ALS foundation. Project MinE Belgium was supported by a grant from IWT (n° 140935), the ALS Liga België, the National Lottery of Belgium and the KU Leuven Opening the Future Fund. M.A.v.E. is additionally supported by the Rudolf Magnus Brain Center Talent Fellowship. P.V.D. holds a senior clinical investigatorship of FWO-Vlaanderen and is supported by the E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders, the ALS Liga België and the KU Leuven funds “Een Hart voor ALS,” “Laeversfonds voor ALS Onderzoek” and the “Valéry Perrier Race against ALS Fund.” Several authors of this publication are member of the European Reference Network for Rare Neuromuscular Diseases (ERN-NMD). A.A.-C. receives salary support from the National Institute for Health Research (NIHR) Dementia Biomedical Research Unit and Biomedical Research Centre in Mental Health at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. O.H. is funded by the Health Research Board Clinician Scientist Programme and Science Foundation Ireland. R.L.M is also supported by the Thierry Latran Foundation (ALSIBD) and the ALS Association (2284). The Swedish Brain Foundation (grants nr. 2012-0262, 2012-0305, 2013-0279, 2016-0303), the Swedish Science Council (grants nr 2012-3167, 2017-03100), the Knut and Alice Wallenberg Foundation (grants nr. 2012.0091, 2014.0305), the Bertil Hållsten Foundation, the Ulla-Carin Lindquist Foundation, the Neuroförbundet Association, the Torsten and Ragnar Söderberg Foundation, Umeå University Insamlingsstiftelsen (223-2808-12, 223-1881-13, 2.1.12-1605-14), Västerbotten County Council, Swedish Brain Power, King Gustaf V:s and Queen Victoria's Freemason's Foundation.
Published: 2023

13. Associations between genetic liabilities to smoking behavior and schizophrenia symptoms in patients with a psychotic disorder, their siblings and healthy controls

Author: Bochao Danae Lin, Jentien M. Vermeulen, K. Bolhuis, Xiao Chang, Frederike Schirmbeck, Kristel R van Eijk, Sinan Guloksuz, Matthijs Blankers, W. van den Brink, Lieuwe de Haan, Jurjen J. Luykx, Behrooz Z. Alizadeh, Agna A. Bartels-Velthuis, Therese van Amelsvoort, Richard Bruggeman, Wiepke Cahn, Bart P.F. Rutten, Jim van Os, Claudia J.P. Simons, Ruud van Winkel, RS: MHeNs - R2 - Mental Health, RS: MHeNs - R3 - Neuroscience, Psychiatry 1, Psychiatry 3, MUMC+: MA Med Staf Spec Psychiatrie (9), Psychiatrie & Neuropsychologie, MUMC+: MA Psychiatrie (3), RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Child and Adolescent Psychiatry / Psychology, Adult Psychiatry, APH - Mental Health, ANS - Complex Trait Genetics, ANS - Compulsivity, Impulsivity & Attention, ANS - Mood, Anxiety, Psychosis, Stress & Sleep, CCA - Cancer Treatment and Quality of Life, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism
Subjects: RISK, Psychiatry and Mental health, SDG 3 - Good Health and Well-being, WORLDWIDE, Smoking, Schizophrenia, Polygenic, Negative symptoms, Psychosis, Positive symptoms, METAANALYSIS, Biological Psychiatry
Abstract: It is unknown how smoking behavior polygenic scores (PRS) relate to psychosis and psychotic symptoms. To elucidate this, genotype and phenotype data were collected from patients with schizophrenia, their unaffected siblings, and healthy controls in a six-year follow-up prospective cohort study. Associations between smoking behaviors, PRS and schizophrenia symptoms were explored using linear mixed-effect models. The mean number of cigarettes smoked per day were 18 for patients, 13 for siblings and 12 for controls. In the overall sample, PRSs-smoking initiation (i.e., ever smoking as a binary phenotype, PRS-SI) were positively associated with positive symptoms, negative symptoms, and depressive symptoms, whereas PRSs-AI (age at regular smoking initiation) were negatively associated with all symptom dimensions, with similar effect sizes. When considering groups separately, PRS were only associated with psychotic symptoms in siblings and controls. In conclusion, unaffected siblings show smoking behaviors at an intermediate level between patients and healthy controls. Additionally, PRS-SI and PRS-AI are associated with all symptom dimensions only in unaffected siblings and healthy controls, possibly owing to the dominant role of other (genetic) risk factors in patients. Future studies may examine mechanisms via which genetic risk for smoking affects mental health symptoms.
Published: 2023

14. Association of Recent Stressful Life Events With Mental and Physical Health in the Context of Genomic and Exposomic Liability for Schizophrenia

Author: Sinan Guloksuz, Kristel R. van Eijk, Ron de Graaf, Michael Conlon O'Donovan, Saskia van Dorsselaer, Gunter Kenis, Maarten Bak Bak, Lotta-Katrin Pries, Jurjen J. Luykx, Alexander Richards, Margreet ten Have, Bochao D. Lin, Jim van Os, Bart P. F. Rutten, Psychiatrie & Neuropsychologie, RS: MHeNs - R2 - Mental Health, MUMC+: MA Psychiatrie (3), MUMC+: Hersen en Zenuw Centrum (3), MUMC+: MA Niet Med Staf Psychiatrie (9), and RS: MHeNs - R3 - Neuroscience
Subjects: Male, Health Status, CHILDHOOD, 0302 clinical medicine, ANXIETY, Longitudinal Studies, Prospective Studies, POLYGENIC RISK, Prospective cohort study, Original Investigation, Netherlands, education.field_of_study, Incidence (epidemiology), Incidence, Middle Aged, EXPERIENCES, Causality, Psychiatry and Mental health, Mental Health, Schizophrenia, DEPRESSIVE SYMPTOMS, Anxiety, Female, medicine.symptom, Adult, Psychosis, medicine.medical_specialty, DISORDERS, Population, Context (language use), Life Change Events, 03 medical and health sciences, PSYCHOSIS, ADVERSITY, medicine, Humans, Genetic Predisposition to Disease, education, Psychiatry, ABUSE, business.industry, ADULTS, medicine.disease, Mental health, Health Surveys, 030227 psychiatry, Case-Control Studies, business, 030217 neurology & neurosurgery, Stress, Psychological
Abstract: This cohort study assesses whether recent stressful life events interact with genetic and environmental liability for schizophrenia in models of mental and physical health in the Dutch adult population.Key PointsQuestionIs the association of adulthood life stress with mental and physical health moderated by polygenic risk and exposome scores for schizophrenia? FindingsThis population-based cohort study of 6646 participants provides novel evidence of the associations of genetic and environmental liability for schizophrenia with mental health in the general population. Both genetic and environmental liability were associated with poor outcomes, particularly mental health, and the association between stressful life events and health outcomes was moderated by exposome score but not polygenic risk score for schizophrenia. MeaningThese findings showing an interaction between adulthood stressful life events and lifetime exposomic liability lend further support to the diathesis-stress model.ImportanceBoth adulthood stressful life events (SLEs) and liability for schizophrenia have been associated with poor mental and physical health in the general population, but their interaction remains to be elucidated to improve population-based health outcomes. ObjectiveTo test whether recent SLEs interact with genetic and environmental liability for schizophrenia in models of mental and physical health. Design, Setting, and ParticipantsThe Netherlands Mental Health Survey and Incidence Study-2 is a population-based prospective cohort study designed to investigate the prevalence, incidence, course, and consequences of mental disorders in the Dutch general population. Participants were enrolled from November 5, 2007, to July 31, 2009, and followed up with 3 assessments during 9 years. Follow-up was completed on June 19, 2018, and data were analyzed from September 1 to November 1, 2019. ExposuresRecent SLEs assessed at each wave and aggregate scores of genetic and environmental liability for schizophrenia: polygenic risk score for schizophrenia (PRS-SCZ) trained using the Psychiatric Genomics Consortium analysis results and exposome score for schizophrenia (ES-SCZ) trained using an independent data set. Main Outcomes and MeasuresIndependent and interacting associations of SLEs with ES-SCZ and PRS-SCZ on mental and physical health assessed at each wave using regression coefficients. ResultsOf the 6646 participants included at baseline, the mean (SD) age was 44.26 (12.54) years, and 3672 (55.25%) were female. The SLEs were associated with poorer physical health (B=-3.22 [95% CI, -3.66 to -2.79]) and mental health (B=-3.68 [95% CI, -4.05 to -3.32]). Genetic and environmental liability for schizophrenia was associated with poorer mental health (ES-SCZ: B=-3.07 [95% CI, -3.35 to -2.79]; PRS-SCZ: B=-0.93 [95% CI, -1.31 to -0.54]). Environmental liability was also associated with poorer physical health (B=-3.19 [95% CI, -3.56 to -2.82]). The interaction model showed that ES-SCZ moderated the association of SLEs with mental (B=-1.08 [95% CI, -1.47 to -0.69]) and physical health (B=-0.64 [95% CI, -1.11 to -0.17]), whereas PRS-SCZ did not. Several sensitivity analyses confirmed these results. Conclusions and RelevanceIn this study, schizophrenia liability was associated with broad mental health outcomes at the population level. Consistent with the diathesis-stress model, exposure to SLEs, particularly in individuals with high environmental liability for schizophrenia, was associated with poorer health. These findings underline the importance of modifiable environmental factors during the life span for population-based mental health outcomes.
Published: 2020

15. Structural variation analysis of 6,500 whole genome sequences in amyotrophic lateral sclerosis

Author: Vural, Atay (ORCID 0000-0003-3222-874X & YÖK ID 182369); Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512), Ahmad Al, Khleifat; Alfredo, Iacoangeli; Joke J F A van, Vugt; Harry, Bowles; Matthieu, Moisse; Ramona A J, Zwamborn; Rick A A van, der Spek; Aleksey, Shatunov; Johnathan, Cooper-Knock; Simon, Topp; Ross, Byrne; Cinzia, Gellera; Victoria, Lopez; Ashley R, Jones; Sarah, Opie-Martin; Yolanda, Campos; Wouter van, Rheenen; Brendan, Kenna; Kristel R Van, Eijk; Kevin, Kenna; Markus, Weber; Bradley, Smith; Isabella, Fogh; Vincenzo, Silani; Karen E., Morrison; Richard, Dobson; Michael A van, Es; Russell L., McLaughlin; Patrick, Vourc’h; Adriano, Chio; Philippe, Corcia; Mamede, de Carvalho; Marc, Gotkine; Monica, P Panades; Jesus ,S Mora; Pamela, J Shaw; John, E Landers; Jonathan, D Glass; Christopher, E Shaw; Orla, Hardiman; Wim, Robberecht; Philip Van, Damme; Leonard H van, den Berg; Jan, H Veldink; Ammar, Al-Chalabi, Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine, Vural, Atay (ORCID 0000-0003-3222-874X & YÖK ID 182369); Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512), Ahmad Al, Khleifat; Alfredo, Iacoangeli; Joke J F A van, Vugt; Harry, Bowles; Matthieu, Moisse; Ramona A J, Zwamborn; Rick A A van, der Spek; Aleksey, Shatunov; Johnathan, Cooper-Knock; Simon, Topp; Ross, Byrne; Cinzia, Gellera; Victoria, Lopez; Ashley R, Jones; Sarah, Opie-Martin; Yolanda, Campos; Wouter van, Rheenen; Brendan, Kenna; Kristel R Van, Eijk; Kevin, Kenna; Markus, Weber; Bradley, Smith; Isabella, Fogh; Vincenzo, Silani; Karen E., Morrison; Richard, Dobson; Michael A van, Es; Russell L., McLaughlin; Patrick, Vourc’h; Adriano, Chio; Philippe, Corcia; Mamede, de Carvalho; Marc, Gotkine; Monica, P Panades; Jesus ,S Mora; Pamela, J Shaw; John, E Landers; Jonathan, D Glass; Christopher, E Shaw; Orla, Hardiman; Wim, Robberecht; Philip Van, Damme; Leonard H van, den Berg; Jan, H Veldink; Ammar, Al-Chalabi, Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), and School of Medicine
Abstract: There is a strong genetic contribution to Amyotrophic lateral sclerosis (ALS) risk, with heritability estimates of up to 60%. Both Mendelian and small effect variants have been identified, but in common with other conditions, such variants only explain a little of the heritability. Genomic structural variation might account for some of this otherwise unexplained heritability. We therefore investigated association between structural variation in a set of 25 ALS genes, and ALS risk and phenotype. As expected, the repeat expansion in the C9orf72 gene was identified as associated with ALS. Two other ALS-associated structural variants were identified: inversion in the VCP gene and insertion in the ERBB4 gene. All three variants were associated both with increased risk of ALS and specific phenotypic patterns of disease expression. More than 70% of people with respiratory onset ALS harboured ERBB4 insertion compared with 25% of the general population, suggesting respiratory onset ALS may be a distinct genetic subtype., Motor Neurone Disease Association (MNDA); Wellcome Trust; Medical Research Council; University of Manchester Centre for Integrated Genomic Medical Research (CIGMR); National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care South London at King's College Hospital NHS Foundation Trust; Dementia Biomedical Research Unit; Maudsley Biomedical Research Centre; King's Health Partners (Guy's and St Thomas' NHS Foundation Trust, King's College Hospital NHS Foundation Trust, King's College London and South London and Maudsley NHS Foundation Trust; Guy's and St Thomas' Charity; Health Data Research UK (HDR UK); ALS Association Milton Safenowitz Research Fellowship; European Research Council (ERC); EU Joint Programme-Neurodegenerative Disease Research (JPND); European Community's Health Seventh Framework Programme (FP7/2007-2013); European Union (EU); Horizon 2020; H2020-PHC-2014-two-stage; PPP Allowance; KU Leuven Opening the Future Fund; ALS Liga Belgie; Science Foundation Ireland; Project MinE; American ALS Association; National Institutes of Health (NIH); National Institute of Neurological Disorders and Stroke (NINDS)
Published: 2022

16. The Distinct Traits of the UNC13A Polymorphism in Amyotrophic Lateral Sclerosis

Author: Jan H. Veldink, Harold H G Tan, Michael A. van Es, Henk-Jan Westeneng, Kevin van Veenhuijzen, Kristel R. van Eijk, Hannelore K. van der Burgh, Ruben P A van Eijk, Leonhard A Bakker, and Leonard H. van den Berg
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, Vital capacity, Genotype, Nerve Tissue Proteins, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, C9orf72, Internal medicine, Genetic model, medicine, Humans, Amyotrophic lateral sclerosis, Allele, 10. No inequality, Research Articles, Aged, business.industry, Amyotrophic Lateral Sclerosis, Middle Aged, medicine.disease, Phenotype, 030104 developmental biology, Neurology, Female, Neurology (clinical), business, 030217 neurology & neurosurgery, Research Article, Frontotemporal dementia
Abstract: OBJECTIVE The rs12608932 single nucleotide polymorphism in UNC13A is associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) susceptibility, and may underlie differences in treatment response. We aimed to characterize the clinical, cognitive, behavioral, and neuroimaging phenotype of UNC13A in patients with ALS. METHODS We included 2,216 patients with ALS without a C9orf72 mutation to identify clinical characteristics associated with the UNC13A polymorphism. A subcohort of 428 patients with ALS was used to study cognitive and behavioral profiles, and 375 patients to study neuroimaging characteristics. Associations were analyzed under an additive genetic model. RESULTS Genotyping rs12608932 resulted in 854 A/A, 988 A/C, and 374 C/C genotypes. The C allele was associated with a higher age at symptom onset (median years A/A 63.5, A/C 65.6, and C/C 65.5; p
Published: 2020

17. Enrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders

Author: Leandro Lima, Stephen A. Goutman, Oscar Jackson, Henry Houlden, Menelaos Pipis, Mehrdad Asghari Estiar, Ziv Gan-Or, Kristel R. van Eijk, Rebecca Schüle, Ammar Al-Chalabi, Julia Kaye, Mary M. Reilly, Matthew B. Harms, Stephan Züchner, John Ravits, Jishu Xu, Johnathan Cooper-Knock, Queen Square Genomics, Jonathan Gilley, Matt C. Danzi, Alfredo Iacoangeli, Michael P. Coleman, Guy A. Rouleau, Gilley, Jonathan [0000-0002-9510-7956], Jackson, Oscar [0000-0002-1825-9331], Gan-Or, Ziv [0000-0003-0332-234X], Coleman, Michael [0000-0002-9354-532X], and Apollo - University of Cambridge Repository
Subjects: Male, SARM1, metabolism [Nicotinamide Mononucleotide], neuroscience, Mice, Missense mutation, genetics, Biology (General), Amyotrophic lateral sclerosis, metabolism [NAD+ Nucleosidase], Nicotinamide Mononucleotide, Nicotinamide mononucleotide, Genetics, General Neuroscience, General Medicine, Middle Aged, metabolism [Motor Neuron Disease], genetics [Amyotrophic Lateral Sclerosis], Medicine, Female, genetics [Motor Neuron Disease], Research Article, Human, Adult, SARM1 protein, human, QH301-705.5, Science, Single-nucleotide polymorphism, Biology, NADase, General Biochemistry, Genetics and Molecular Biology, NAD+ Nucleosidase, genomics, medicine, Animals, Humans, SNP, human, Motor Neuron Disease, Allele, Alleles, Aged, risk allele, Armadillo Domain Proteins, General Immunology and Microbiology, Genetic heterogeneity, Activator (genetics), metabolism [Amyotrophic Lateral Sclerosis], Amyotrophic Lateral Sclerosis, Genetics and Genomics, medicine.disease, Cytoskeletal Proteins, ALS, ddc:600, Neuroscience
Abstract: SARM1, a protein with critical NADase activity, is a central executioner in a conserved programme of axon degeneration. We report seven rare missense or in-frame microdeletion human SARM1 variant alleles in patients with amyotrophic lateral sclerosis (ALS) or other motor nerve disorders that alter the SARM1 auto-inhibitory ARM domain and constitutively hyperactivate SARM1 NADase activity. The constitutive NADase activity of these seven variants is similar to that of SARM1 lacking the entire ARM domain and greatly exceeds the activity of wild-type SARM1, even in the presence of nicotinamide mononucleotide (NMN), its physiological activator. This rise in constitutive activity alone is enough to promote neuronal degeneration in response to otherwise non-harmful, mild stress. Importantly, these strong gain-of-function alleles are completely patient-specific in the cohorts studied and show a highly significant association with disease at the single gene level. These findings of disease-associated coding variants that alter SARM1 function build on previously reported genome-wide significant association with ALS for a neighbouring, more common SARM1 intragenic single nucleotide polymorphism (SNP) to support a contributory role of SARM1 in these disorders. A broad phenotypic heterogeneity and variable age-of-onset of disease among patients with these alleles also raises intriguing questions about the pathogenic mechanism of hyperactive SARM1 variants.
Published: 2021

18. Loss of nucleoporin Nup50 is a risk factor for amyotrophic lateral sclerosis

Author: Jan H. Veldink, Edor Kabashi, Sylvie Dirrig-Grosch, Peter M Andersen, Najwa Ouali Alami, Luc Dupuis, Kirsten Sieverding, Axel Freischmidt, Natalia Mora, Albert C. Ludolph, Tobias M. Boeckers, Markus Margelisch, Philippe Couratier, Francesco Roselli, François Muratet, Andreas Sommacal, Chantal Sellier, Géraldine Lautrette, Erik Storkebaum, Markus Weber, Nick H.M. van Bakel, Stéphane Dieterlé, Stéphanie Millecamps, Kristel R. van Eijk, Jochen H. Weishaupt, Alberto Catanese, Kathrin Muller, Salim Megat, Xhuljana Mingaj, Christoph Neuwirth, Jason Sanogo, Hortense de Calbiac, and Deniz Yilmazer-Hanke
Subjects: Genetics, BCS1L, RNA splicing, Gene expression, medicine, RNA-binding protein, Genome-wide association study, Nucleoporin, Amyotrophic lateral sclerosis, Biology, medicine.disease, Gene
Abstract: The genetic basis of amyotrophic lateral sclerosis (ALS) is still incompletely understood. Using two independent genetic strategies, we show here that a large part of ALS heritability lies in genes expressed in inhibitory and excitatory neurons, especially at splicing sites regulated by a defined set of RNA binding proteins including TDP-43 and FUS. We conducted a transcriptome wide association study (TWAS) and identified 59 loci associated with ALS, including 14 previously identified genes, some of them not previously reaching significance in genome wide association studies. Among the 45 novel genes, several genes are involved in pathways known to be affected in ALS such as mitochondrial metabolism (including ATP5H, ATP5D, BCS1L), proteostasis (including COPS7A, G2E3, TMEM175, USP35) or gene expression and RNA metabolism (including ARID1B, ATXN3, PTBP2, TAF10). Interestingly, decreased expression of NUP50, a constrained gene encoding a nuclear pore basket protein, was associated with ALS in TWAS (Zscore = −4, FDR = 0.034). 11 potentially pathogenic variants (CADD score > 20) in 23 patients were identified in the NUP50 gene, most of them in the region of the protein mediating interaction with Importin alpha, and including 2 frameshift mutations. In cells from two patients carrying NUP50 variants, we showed decreased levels of NUP50 protein. Importantly, knocking down Nup50 led to increased neuronal death associated with p62 and nucleoporin inclusions in cultured neurons, and motor defects in Drosophila and zebrafish models. In all, our study identifies alterations in splicing in neurons as a critical pathogenic process in ALS, uncovers several new loci potentially contributing to ALS missing heritability, and provides genetic evidence linking nuclear pore defects to ALS.
Published: 2021

19. Enrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders

Author: Stephen A. Goutman, Leandro Lima, Menelaos Pipis, Matthew B. Harms, Julia Kaye, Johnathan Cooper-Knock, Queen Square Genomics, Ziv Gan-Or, Kristel R. van Eijk, Oscar Jackson, Matt C. Danzi, Jishu Xu, Rebecca Schüle, Ammar Al-Chalabi, Mehrdad Asghari Estiar, Henry Houlden, Jonathan Gilley, Stephan Züchner, Mary M. Reilly, Alfredo Iacoangeli, Michael P. Coleman, John Ravits, and Guy A. Rouleau
Subjects: Genetics, Activator (genetics), Genetic heterogeneity, medicine, SNP, Missense mutation, Single-nucleotide polymorphism, Amyotrophic lateral sclerosis, Biology, Allele, medicine.disease, Nicotinamide mononucleotide
Abstract: SARM1, a protein with critical NADase activity, is a central executioner in a conserved programme of axon degeneration. We report seven rare missense or in-frame microdeletion human SARM1 variant alleles in patients with amyotrophic lateral sclerosis (ALS) or other motor nerve disorders that alter the SARM1 auto-inhibitory ARM domain and constitutively hyperactivate SARM1 NADase activity. The constitutive NADase activity of these seven variants is similar to that of SARM1 lacking the entire ARM domain and greatly exceeds the activity of wild-type SARM1, even in the presence of nicotinamide mononucleotide (NMN), its physiological activator. This rise in constitutive activity alone is enough to promote neuronal degeneration in response to otherwise non-harmful, mild stress. Importantly, these strong gain-of-function alleles are completely patient-specific in the cohorts studied and show a highly significant association with disease at the single gene level. These findings of disease-associated coding variants that alter SARM1 function build on previously reported genome-wide significant association with ALS for a neighbouring, more common SARM1 intragenic single nucleotide polymorphism (SNP) to support a contributory role of SARM1 in these disorders. A broad phenotypic heterogeneity and variable age-of-onset of disease among patients with these alleles also raises intriguing questions about the pathogenic mechanism of hyperactive SARM1 variants.
Published: 2021

20. A polygenic-informed approach to a predictive EEG signature empowers stratified antidepressant treatment

Author: Bieke De Wilde, Guido van Wingen, Pieter Niemegeers, Kristel R. van Eijk, Hannah Meijs, Bochao Lin, Jurjen J. Luykx, Evian Gordon, Jan Van Hecke, Martijn Arns, and Damiaan Denys
Subjects: Text mining, medicine.diagnostic_test, business.industry, Computer science, medicine, Antidepressant, Artificial intelligence, Electroencephalography, business, Machine learning, computer.software_genre, computer, Signature (logic)
Abstract: The treatment of major depressive disorder (MDD) is hampered by low chances of treatment response in each treatment step, which is partly due to a lack of firmly established outcome-predictive biomarkers. Here, we hypothesize that polygenic-informed EEG signatures may help predict differential antidepressant treatment response. Using a polygenic-informed electroencephalography (EEG) data-driven, data-reduction approach, we identify a functional brain network in a large cohort of predominantly psychiatric patients (N=1,123), and discover that this network is sex-specifically associated with polygenic liability to psychiatric illness. Subsequently, we demonstrate the utility of this network in predicting response to repetitive transcranial magnetic stimulation (rTMS) and antidepressant medication in two independent datasets (N=196 and N=1,008). A stratification model aimed at stratifying patients to rTMS or sertraline based on only this EEG component yields improved remission rates varying from 22% to 39%. Overall, our findings highlight the power and utility of a combined polygenic and neurophysiological approach in the search for clinically-relevant biomarkers in psychiatric disorders.
Published: 2021

21. Can polygenic-informed EEG biomarkers predict differential antidepressant treatment response? An EEG stratification marker for rTMS and sertraline

Author: Evian Gordon, Kristel R. van Eijk, Jan Van Hecke, Bochao Lin, Bieke De Wilde, Damiaan Denys, Martijn Arns, Hannah Meijs, Guido van Wingen, Jurjen J. Luykx, and Pieter Niemegeers
Subjects: Oncology, Treatment response, Sertraline, medicine.medical_specialty, medicine.diagnostic_test, business.industry, Internal medicine, medicine, Antidepressant, Electroencephalography, business, Stratification (mathematics), medicine.drug
Abstract: The treatment of major depressive disorder (MDD) is hampered by low chances of treatment response in each treatment step, which is partly due to a lack of firmly established outcome-predictive biomarkers. Here, we hypothesize that polygenic-informed EEG biomarkers may help predict differential antidepressant treatment response. Using a polygenic-informed electroencephalography (EEG) data-driven, data-reduction approach, we identify a functional brain network that is sex-specifically associated with polygenic risk for MDD in psychiatric patients (N=1,123). Subsequently, we demonstrate the utility of this network in predicting response to transcranial magnetic stimulation (TMS) and antidepressant medication in two independent datasets (N=196 and N=1,008). A simulation aimed at stratifying patients to TMS, sertraline or escitalopram/venlafaxine based on only this EEG component yields up to >30% improved remission rates. Overall, our findings highlight the power and utility of a combined polygenic and neurophysiological approach in the search for clinically-relevant biomarkers in psychiatric disorders.
Published: 2021

22. Genetic underpinnings of schizophrenia-related electroencephalographical intermediate phenotypes: A systematic review and meta-analysis

Author: Dirk J.A. Smit, Bob Oranje, Jure Hederih, Jurjen J. Luykx, Jasper O. Nuninga, Edwin van Dellen, and Kristel R. van Eijk
Subjects: Mismatch negativity, SNP, Single-nucleotide polymorphism, Genome-wide association study, Biology, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Electroencephalography (EEG), Biological Psychiatry, Genetic Association Studies, Pharmacology, Electroencephalography, medicine.disease, Genetic architecture, 030227 psychiatry, Electrophysiology, Phenotype, Schizophrenia, Meta-analysis, Intermediate phenotypes, ERP, rs4680
Abstract: Although substantial research into genetics of psychotic disorders has been conducted, a large proportion of their genetic architecture has remained unresolved. Electroencephalographical intermediate phenotypes (EIP) have the potential to constitute a valuable tool when studying genetic risk loci for schizophrenia, in particular P3b amplitude, P50 suppression, mismatch negativity (MMN) and resting state power spectra of the electroencephalogram (EEG). Here, we systematically reviewed studies investigating the association of single nucleotide polymorphisms (SNPs) with these EIPs and meta-analysed them when appropriate. We retrieved 45 studies (N = 34,971 study participants). Four SNPs investigated in more than one study were genome-wide significant for an association with schizophrenia and three were genome-wide suggestive, based on a lookup in the influential 2014 GWAS (Ripke et al., 2014). However, in our meta-analyses, rs1625579 failed to reach a statistically significant association with p3b amplitude decrease and rs4680 risk allele carrier status was not associated with p3b amplitude decrease or with impaired p50 suppression. In conclusion, evidence for SNP associations with EIPs remains limited to individual studies. Careful selection of EIPs and SNPs, combined with consistent reporting of effect sizes, directions of effect and p-values would aid future meta-analyses.
Published: 2021

23. The effect of SMN gene dosage on ALS risk and disease severity

Author: Vincenzo Silani, Mamede de Carvalho, Nicola Ticozzi, Joke J.F.A. van Vugt, Kristel R. van Eijk, Patrick Vourc'h, Markus Weber, Wouter van Rheenen, Kevin P. Kenna, Christopher Shaw, Wim Robberecht, Philippe Couratier, Mònica Povedano, Jonathan D. Glass, Pamela J. Shaw, Ramona A. J. Zwamborn, Ammar Al-Chalabi, John Landers, Michael A. Eberle, Michael A. van Es, Xiao Chen, Leonard H. van den Berg, Brendan J. Kenna, Philippe Corcia, Karen E. Morrison, Marc Gotkine, Russell McLaughin, Peter M. Andersen, Matthieu Moisse, Philip Van Damme, Rick A.A. van der Spek, Jesus S. Mora Pardina, Orla Hardiman, Vivian E. Drory, Jan H. Veldink, Nazli Basak, Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512), Moisse, Matthieu, Zwamborn, Ramona A. J., van Vugt, Joke, van Der Spek, Rick, van Rheenen, Wouter, Kenna, Brendan, Van Eijk, Kristel, Kenna, Kevin, Corcia, Philippe, Couratier, Philippe, Vourc'h, Patrick, Hardiman, Orla, McLaughin, Russell, Gotkine, Marc, Drory, Vivian, Ticozzi, Nicola, Silani, Vincenzo, de Carvalho, Mamede, Mora Pardina, Jesus S., Povedano, Monica, Andersen, Peter M., Weber, Markus, Chen, Xiao, Eberle, Michael A., Al-Chalabi, Ammar, Shaw, Chris, Shaw, Pamela J., Morrison, Karen E., Landers, John E., Glass, Jonathan D., Robberecht, Wim, van Es, Michael, van den Berg, Leonard, Veldink, Jan, Van Damme, Philip, Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine, Université de Leuven, Katholiek Universiteit Leuven, Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Centre de compétence de la Sclérose Latérale Amyotrophique [CHRU Tours] (SLA CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Neuroépidémiologie Tropicale (NET), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Service de Neurologie [CHU Limoges], CHU Limoges, UMR U 1253, Department of Neurology, The Adelaide and Meath Hospital, Trinity College Dublin, Trinity College, Trinity College Dublin, Tel Aviv Sourasky Medical Center [Te Aviv], Department of Neurology, IRCCS San Raffaele, Milano, Université de Lisbonne, Sant Rafael Hospital, Umeå University Hospital, Umea University Hospital, Illumina Incorporated [San Diego, CA, USA], Maurice Wohl Clinical Neuroscience Institut, King‘s College London, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield [Sheffield], Queen's University [Belfast] (QUB), University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Emory University School of Medicine, Emory University [Atlanta, GA], University Hospitals Leuven [Leuven], Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM), Grelier, Elisabeth, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-CHU Limoges-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST)
Subjects: 0301 basic medicine, Male, Neurologi, Survival of Motor Neuron 2 Protein/genetics, Clinical Neurology, Gene Dosage, SMN1, Bioinformatics, Logistic regression, Severity of Illness Index, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, medicine, Survival of Motor Neuron 1 Protein/genetics, Humans, Amyotrophic lateral sclerosis, Gene, Research Articles, Whole genome sequencing, Science & Technology, Whole Genome Sequencing, business.industry, Project MinE, Amyotrophic Lateral Sclerosis, Neurosciences, Case-control study, Reproducibility of Results, Survival of motor neuron, Amyotrophic Lateral Sclerosis/genetics, medicine.disease, Survival of Motor Neuron 1 Protein, 3. Good health, nervous system diseases, Survival of Motor Neuron 2 Protein, 030104 developmental biology, Neurology, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Case-Control Studies, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Medicine, Clinical neurology, Neurosciences & Neurology, Neurology (clinical), business, Life Sciences & Biomedicine, 030217 neurology & neurosurgery, Research Article
Abstract: Objective: the role of the survival of motor neuron (SMN) gene in amyotrophic lateral sclerosis (ALS) is unclear, with several conflicting reports. A decisive result on this topic is needed, given that treatment options are available now for SMN deficiency. Methods: in this largest multicenter case control study to evaluate the effect of SMN1 and SMN2 copy numbers in ALS, we used whole genome sequencing data from Project MinE data freeze 2. SMN copy numbers of 6,375 patients with ALS and 2,412 controls were called from whole genome sequencing data, and the reliability of the calls was tested with multiplex ligation-dependent probe amplification data. Results: the copy number distribution of SMN1 and SMN2 between cases and controls did not show any statistical differences (binomial multivariate logistic regression SMN1 p = 0.54 and SMN2 p = 0.49). In addition, the copy number of SMN did not associate with patient survival (Royston-Parmar; SMN1 p = 0.78 and SMN2 p = 0.23) or age at onset (Royston-Parmar; SMN1 p = 0.75 and SMN2 p = 0.63). Interpretation: in our well-powered study, there was no association of SMN1 or SMN2 copy numbers with the risk of ALS or ALS disease severity. This suggests that changing SMN protein levels in the physiological range may not modify ALS disease course. This is an important finding in the light of emerging therapies targeted at SMN deficiencies., European Union (EU); Horizon 2020; European Research Council (ERC); Research and Innovation Programme; EScORIAL; IWT; FWO-Vlaanderen; United Kingdom Medical Research Council; Neurodegenerative Disease Research (JPND); Netherlands; ZONMW; BRAIN-MEND; NIH/NINDS; Italian Ministry of Health; Fondazione Regionale per la Ricerca Biomedica Regione Lombardia; Science Foundation Ireland; ALS Liga Belgie; National Lottery of Belgium; KU Leuven Opening the Future Fund; E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders; ALS Foundation Netherlands; PPP Allowance; Motor Neurone Disease Association; National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre; Fondazione Italiana di Ricerca per la SLA - AriSLA; Exomefals; Novals; ALS Association; E-RARE JTC Project Repetomics
Published: 2021

24. Genomic and phenomic insights from an atlas of genetic effects on DNA methylation

Author: Carol A. Wang, Simonetta Guarrera, Avshalom Caspi, Eilis Hannon, Marta E. Alarcón-Riquelme, P. Eline Slagboom, Pooja R. Mandaviya, Koen F. Dekkers, Cheng-Jian Xu, Jari Lahti, Juan E. Castillo-Fernandez, Dan Mason, Dylan Aïssi, Jan H. Veldink, Mariona Bustamante, Melissa C. Smart, Guillermo Barturen, Zdenka Pausova, Jenny van Dongen, Jordi Jimenez-Conde, Craig E. Pennell, Gibran Hemani, Tom R. Gaunt, Camilla Schmidt Morgen, Ken K. Ong, Toni-Kim Clarke, Alexia Cardona, Susanne Lucae, René Luijk, T.J. Gorrie-Stone, Phillip E. Melton, Thorkild I. A. Sørensen, André G. Uitterlinden, Jordana T. Bell, Jouke-Jan Hottenga, Meena Kumari, Francesc Català-Moll, Jonathan Mill, Tõnu Esko, Sailalitha Bollepalli, Dorret I. Boomsma, Torben Hansen, Hongmei Zhang, Yanni Zeng, John Wright, Wilfried Karmaus, Martin Kerick, Carolina Soriano-Tárraga, Jaakko Kaprio, Miina Ollikainen, Eco J. C. de Geus, Jordi Sunyer, Therese Tillin, Juan R. González, Yvonne Awaloff, Faisal I. Rezwan, Karen Sugden, Nicholas G. Martin, Karen M Ho, Andres Metspalu, Marine Germain, Kristel R. van Eijk, Ramona A. J. Zwamborn, George Davey Smith, Judith M. Vonk, Tian Lin, Henning Tiemeier, Grant W. Montgomery, Naomi R. Wray, Rae-Chi Huang, Alfredo Iacoangeli, Wendy L. McArdle, Jean Shin, Michael Lerro, Darina Czamara, Valentina Iotchkova, David-Alexandre Trégouët, Johanna Klughammer, Elena Carnero-Montoro, Pierre-Emmanuel Morange, Andrew M. McIntosh, Gemma C Sharp, Alun D. Hughes, Carlos Ruiz-Arenas, John M. Starr, Riccardo E. Marioni, Peter M. Visscher, Nabila Kazmi, Ian J. Deary, Kathryn L. Evans, Terrie E. Moffitt, Janine F. Felix, Tomáš Paus, Ashok Kumar, Jaume Roquer, Christopher Shaw, Hannah R Elliott, Susan M. Ring, Nish Chaturvedi, Giovanni Cugliari, Ahmad Al Khleifat, Joyce B. J. van Meurs, Kimberley Burrows, Bert Brunekreef, Debbie A Lawlor, Clara Viberti, Louise Arseneault, Silva Kasela, Cilla Söderhäll, Idil Yet, Manon Bernard, Christoph Bock, Vincent W. V. Jaddoe, Felix R. Day, Diana van Heemst, Alison D. Murray, Nicholas J. Wareham, Giuseppe Matullo, John R. B. Perry, Gerard H. Koppelman, M. Arfan Ikram, Ammar Al Chalabi, Gonneke Willemsen, Richie Poulton, Daniel Lawson, Andrew D. Bretherick, Vanessa Schmoll, Carlotta Sacerdote, Annelot M. Dekker, Lili Milani, Fernando Rivadeneira, Erik Melén, John W. Holloway, Gareth E. Davies, Tom G. Richardson, Caroline L Relton, Josine L. Min, Göran Pershagen, Elisabeth B. Binder, Marian Beekman, Chris Haley, Richa Gupta, Bastiaan T. Heijmans, Ellen A. Nohr, Allan F. McRae, Matthew Suderman, Rosie M. Walker, David L. Corcoran, Katri Räikkönen, Marinus H. van IJzendoorn, Eva Giralt-Steinhauer, Leonard C. Schalkwyk, Aleksey Shatunov, and Tim D. Spector
Subjects: Genetics, Regulation of gene expression, 0303 health sciences, Natural selection, dNaM, Biology, Genetic architecture, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, chemistry, Genetic variation, DNA methylation, Trait, 030217 neurology & neurosurgery, DNA, 030304 developmental biology
Abstract: Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. Here we describe results of DNA methylation-quantitative trait loci (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTL of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We reveal that the genetic architecture of DNAm levels is highly polygenic and DNAm exhibits signatures of negative and positive natural selection. Using shared genetic control between distal DNAm sites we construct networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic factors are associated with both blood DNAm levels and complex diseases but in most cases these associations do not reflect causal relationships from DNAm to trait or vice versa indicating a more complex genotype-phenotype map than has previously been hypothesised.
Published: 2020

25. The role of rare compound heterozygous events in autism spectrum disorder

Author: Thomas Bourgeron, Alistair T. Pagnamenta, Jeremy R. Parr, Louise Gallagher, Christine M. Freitag, Jacob A. S. Vorstman, Sean Ennis, Isaac J. Nijman, Fabrice Colas, Kristel R. van Eijk, Bochao Danae Lin, Jurjen J. Luykx, Jelena Medic, Sabine M. Klauck, Elena Maestrini, Astrid M. Vicente, Richard Anney, Guiomar Oliveira, Elena Bacchelli, Hilary Coon, Andreas G. Chiocchetti, William J. Brands, Utrecht University [Utrecht], Henan University, Kaifeng, Newcastle University [Newcastle], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Goethe-Universität Frankfurt am Main, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), University of Utah School of Medicine [Salt Lake City], Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal] (INSA), Centro Hospitalar e Universitário [Coimbra], University of Oxford [Oxford], Trinity College Dublin, University College Dublin [Dublin] (UCD), Cardiff University, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), GGNet Mental Health [Apeldoorn, The Netherlands], The Hospital for sick children [Toronto] (SickKids), University of Toronto, This study has been funded by the Dutch Brain Foundation (Hersenstichting Nederland) to JV., Lin B.D., Colas F., Nijman I.J., Medic J., Brands W., Parr J.R., van Eijk K.R., Klauck S.M., Chiocchetti A.G., Freitag C.M., Maestrini E., Bacchelli E., Coon H., Vicente A., Oliveira G., Pagnamenta A.T., Gallagher L., Ennis S., Anney R., Bourgeron T., Luykx J.J., Vorstman J., Henan University, University of Oxford, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
Subjects: 0301 basic medicine, Proband, DNA Copy Number Variations, Autism Spectrum Disorder, Autism, Biology, Compound heterozygosity, ASD, Article, lcsh:RC321-571, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, medicine, Humans, Genetic Predisposition to Disease, Allele, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Gene, Biological Psychiatry, Alleles, MESH: Autism Spectrum Disorder, Genetics, Comparative genomics, MESH: Humans, MESH: Alleles, [SCCO.NEUR]Cognitive science/Neuroscience, MESH: Genetic Predisposition to Disease, Autism spectrum disorders, medicine.disease, Penetrance, Autism Spectrum Disorders, Autism, CNVs, Deletions, SNVs, Compound Heterozygosity, Targeted Sequencing, Psychiatry and Mental health, 030104 developmental biology, Autism spectrum disorder, Perturbações do Desenvolvimento Infantil e Saúde Mental, MESH: DNA Copy Number Variations, 030217 neurology & neurosurgery
Abstract: The identification of genetic variants underlying autism spectrum disorders (ASDs) may contribute to a better understanding of their underlying biology. To examine the possible role of a specific type of compound heterozygosity in ASD, namely, the occurrence of a deletion together with a functional nucleotide variant on the remaining allele, we sequenced 550 genes in 149 individuals with ASD and their deletion-transmitting parents. This approach allowed us to identify additional sequence variants occurring in the remaining allele of the deletion. Our main goal was to compare the rate of sequence variants in remaining alleles of deleted regions between probands and the deletion-transmitting parents. We also examined the predicted functional effect of the identified variants using Combined Annotation-Dependent Depletion (CADD) scores. The single nucleotide variant-deletion co-occurrence was observed in 13.4% of probands, compared with 8.1% of parents. The cumulative burden of sequence variants (n = 68) in pooled proband sequences was higher than the burden in pooled sequences from the deletion-transmitting parents (n = 41, X2 = 6.69, p = 0.0097). After filtering for those variants predicted to be most deleterious, we observed 21 of such variants in probands versus 8 in their deletion-transmitting parents (X2 = 5.82, p = 0.016). Finally, cumulative CADD scores conferred by these variants were significantly higher in probands than in deletion-transmitting parents (burden test, β = 0.13; p = 1.0 × 10−5). Our findings suggest that the compound heterozygosity described in the current study may be one of several mechanisms explaining variable penetrance of CNVs with known pathogenicity for ASD.
Published: 2020

26. Age-dependent genetic variants associated with longitudinal changes in brain structure across the lifespan

Author: Philip R. Jansen, Erlend Bøen, Erin Burke Quinlan, Javier Vázquez-Bourgon, Celso Arango, Sonja M C de Zwarte, Andrea Parolin Jackowski, Mohammad Arfan Ikram, Dennis van der Meer, Clara Alloza, Matthew S. Panizzon, Ryan L. Muetzel, Vidar M. Steen, Lars T. Westlye, Joanna Bright, Walter Heindel, Marcella Rietschel, Wei Wen, Frauke Nees, Daniel Keeser, Sintia Iole Belangero, Philip Shaw, Tiago Reis Marques, Neda Jahanshad, Jiyang Jiang, Benedicto Crespo Facorro, Tilo Kircher, David Ames, Dan J. Stein, Ulrik Fredrik Malt, Axel Krug, Kang Sim, Gaia Bonfiglio, Nhat Trung Doan, Katrin Amunts, John B.J. Kwok, Pedro Mario Pan, Udo Dannlowski, Markus M. Nöthen, Elena Shumskaya, Simon R. Cox, Sarah J. Heany, Perminder S. Sachdev, Aad van der Lugt, Mark E. Bastin, Brenda W.J.H. Penninx, Catherine Morgan, Elizabeth E.L. Buimer, Henrik Walter, Dara M. Cannon, Hugo G. Schnack, Sarah Hohmann, Evangelos Vassos, Shun Takahashi, Gloria Roberts, Simone Ciufolini, Loes M. Olde Loohuis, Penny A. Gowland, Joost Janssen, Michael N. Smolka, Temmuz Karali, Robin M. Murray, Herve Lemaitre, Karen A. Mather, Dennis van 't Ent, Derek W. Morris, William S. Kremen, Peter Falkai, Berend Malchow, Tim Hahn, Dag Alnæs, Ronny Redlich, Ingrid Agartz, Fabian Streit, João P.O.F.T. Guimarães, Nils Opel, Bernhard T. Baune, Marie-Laure Paillère Martinot, Catharina A. Hartman, Alexander Teumer, Frederike Stein, André Zugman, Nikita Setiaman, Jalmar Teeuw, Isabella A. Breukelaar, Vicente Medel, Stephanie H. Witt, Christienne G. Damatac, Nicolas Crossley, Luise Poustka, Hieab H.H. Adams, Linda Ding, Jonathan Repple, Jacqueline Hoare, Eric Artiges, Manon H.J. Hillegers, Andreas Heinz, Susanne Meinert, Tianye Jia, Diana Tordesillas-Gutiérrez, Marieke Klein, Herta Flor, Joanna M. Wardlaw, Roel A. Ophoff, Rodrigo A. Bressan, Antoine Grigis, Marcos L. Santoro, Javier González-Peñas, Thomas Espeseth, Torbjørn Elvsåshagen, Kristel R. van Eijk, Hilleke E. Hulshoff Pol, Sophia I. Thomopoulos, Gustavo Sudre, Juliane H. Fröhner, Rhoshel K. Lenroot, Bernd Ittermann, René S. Kahn, Gareth J. Barker, Wiepke Cahn, Yuri Milaneschi, Margaret J. Wright, Janita Bralten, Gail Davies, Elisabet Blok, Janice M. Fullerton, Jouke-Jan Hottenga, Paola Dazzan, Andreas J. Forstner, Leila Nabulsi, Christopher D. Whelan, Katharina Wittfeld, Mathew A. Harris, Julian N. Trollor, Mayuresh S. Korgaonkar, Igor Nenadic, Nitin Gogtay, Laura K.M. Han, Robin Bülow, Moji Aghajani, Leonard H. van den Berg, Marta Di Forti, Bronwyn Overs, Paul M. Thompson, Rick M. Tankard, Sven Cichon, Jason L. Stein, Jaap Oosterlaan, Jan K. Buitelaar, Jean-Luc Martinot, René C.W. Mandl, Victor Ortiz-García de la Foz, Robert Whelan, Svenja Caspers, Rosa Ayesa-Arriola, Sylvane Desrivières, Covadonga M. Díaz-Caneja, Ole A. Andreassen, Gunter Schumann, Arun L.W. Bokde, Alyssa H. Zhu, Henk-Jan Westeneng, Emma Sprooten, Sergi Papiol, Giovanni Abrahão Salum, Neeltje E.M. van Haren, Simon E. Fisher, Dominik Grotegerd, Casper L. de Mol, Alzheimer’s Disease Neuroimaging Initiative, Dorret I. Boomsma, Gennady V. Roshchupkin, Pieter J. Hoekstra, Andreas Jansen, Peter R. Schofield, Tonya White, Maria J. Knol, Rachel M. Brouwer, Martijn G.J.C. Koevoets, Thomas W. Mühleisen, Katharina Dohm, Barbara Franke, Philip B. Mitchell, Colm McDonald, Anbupalam Thalamuthu, Henry Brodaty, Gary Donohoe, Stephanie Le Hellard, Shareefa Dalvie, Georg Homuth, Jan H. Veldink, Nicola J. Armstrong, Christiane Jockwitz, Sarah E. Medland, Katrina L. Grasby, Tobias Banaschewski, Hans J. Grabe, Hugh Garavan, Dirk J. Heslenfeld, Erik G. Jönsson, Carol E. Franz, and Janik Goltermann
Subjects: 2. Zero hunger, Apolipoprotein E, 0303 health sciences, Brain morphometry, Human brain, Biology, medicine.disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Atrophy, Schizophrenia, Ageing, medicine, Cognitive skill, Neuroscience, 030217 neurology & neurosurgery, Depression (differential diagnoses), 030304 developmental biology
Abstract: SummaryHuman brain structure changes throughout our lives. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental, and neurodegenerative diseases. Here, we identified common genetic variants that affect rates of brain growth or atrophy, in the first genome-wide association meta-analysis of changes in brain morphology across the lifespan. Longitudinal MRI data from 15,640 individuals were used to compute rates of change for 15 brain structures. The most robustly identified genesGPR139, DACH1andAPOEare associated with metabolic processes. We demonstrate global genetic overlap with depression, schizophrenia, cognitive functioning, insomnia, height, body mass index and smoking. Gene-set findings implicate both early brain development and neurodegenerative processes in the rates of brain changes. Identifying variants involved in structural brain changes may help to determine biological pathways underlying optimal and dysfunctional brain development and ageing.
Published: 2020

27. Whole-genome sequencing reveals that variants in the Interleukin 18 Receptor Accessory Protein 3'UTR protect against ALS

Author: Chen, Eitan, Aviad, Siany, Elad, Barkan, Tsviya, Olender, Kristel R, van Eijk, Matthieu, Moisse, Sali M K, Farhan, Yehuda M, Danino, Eran, Yanowski, Hagai, Marmor-Kollet, Natalia, Rivkin, Nancy Sarah, Yacovzada, Shu-Ting, Hung, Johnathan, Cooper-Knock, Chien-Hsiung, Yu, Cynthia, Louis, Seth L, Masters, Kevin P, Kenna, Rick A A, van der Spek, William, Sproviero, Ahmad, Al Khleifat, Alfredo, Iacoangeli, Aleksey, Shatunov, Ashley R, Jones, Yael, Elbaz-Alon, Yahel, Cohen, Elik, Chapnik, Daphna, Rothschild, Omer, Weissbrod, Gilad, Beck, Elena, Ainbinder, Shifra, Ben-Dor, Sebastian, Werneburg, Dorothy P, Schafer, Robert H, Brown, Pamela J, Shaw, Philip, Van Damme, Leonard H, van den Berg, Hemali, Phatnani, Eran, Segal, Justin K, Ichida, Ammar, Al-Chalabi, Jan H, Veldink, and Eran, Hornstein
Subjects: Motor Neurons, Amyotrophic Lateral Sclerosis, Induced Pluripotent Stem Cells, Humans, Interleukin-18 Receptor beta Subunit, 3' Untranslated Regions
Abstract: The noncoding genome is substantially larger than the protein-coding genome but has been largely unexplored by genetic association studies. Here, we performed region-based rare variant association analysis of25,000 variants in untranslated regions of 6,139 amyotrophic lateral sclerosis (ALS) whole genomes and the whole genomes of 70,403 non-ALS controls. We identified interleukin-18 receptor accessory protein (IL18RAP) 3' untranslated region (3'UTR) variants as significantly enriched in non-ALS genomes and associated with a fivefold reduced risk of developing ALS, and this was replicated in an independent cohort. These variants in the IL18RAP 3'UTR reduce mRNA stability and the binding of double-stranded RNA (dsRNA)-binding proteins. Finally, the variants of the IL18RAP 3'UTR confer a survival advantage for motor neurons because they dampen neurotoxicity of human induced pluripotent stem cell (iPSC)-derived microglia bearing an ALS-associated expansion in C9orf72, and this depends on NF-κB signaling. This study reveals genetic variants that protect against ALS by reducing neuroinflammation and emphasizes the importance of noncoding genetic association studies.
Published: 2020

28. Genetic Susceptibility to Clozapine-Induced Agranulocytosis/Neutropenia Across Ethnicities: Results From a New Cohort of Turkish and Other Caucasian Participants, and Meta-Analysis

Author: Berna B Kıvırcık Akdede, Alp Üçok, Kristel R. van Eijk, Evelien Van Assche, Edwin Beld, Dan Cohen, Yasemin Görgülü, Jelena Medic, Vesile Altınyazar, Erwin Bekema, Cynthia Okhuijsen-Pfeifer, Jurjen J. Luykx, Gökhan Yoca, Yavuz Ayhan, Jan P.A.M. Bogers, Memduha Aydin, Mustafa Çelik, A Elif Anıl Yağcıoğlu, Hasret Ozan, Fatma Özlem Orhan, Ayşen Esen Danacı, Bilge Çetin İlhan, Semra Ulusoy, Hatice Özdemir, İsmet Kaygısız, Haldun Soygür, Hanneke van Beek, Annemieke A M de Jonge, Köksal Alptekin, Ahmet Muderrisoglu, Lindy J G B Kool, Melih O. Babaoglu, Bochao D. Lin, and Selene R. T. Veerman
Subjects: 0301 basic medicine, medicine.medical_specialty, HLA-DQB1, business.industry, Single-nucleotide polymorphism, Genome-wide association study, Neutropenia, medicine.disease, 03 medical and health sciences, Psychiatry and Mental health, 030104 developmental biology, 0302 clinical medicine, Internal medicine, Meta-analysis, Cohort, medicine, Genetic predisposition, business, 030217 neurology & neurosurgery, Clozapine, medicine.drug
Abstract: Clozapine (CLZ) is considered the most effective antipsychotic, but its use is associated with neutropenia (CIN) and agranulocytosis (CIA). Although the exact etiology of these hazardous side effects is unknown, 4 genetic polymorphisms have been implicated by genome-wide association studies (GWAS), mostly performed in North-Western Europeans. These polymorphisms are rs113332494 (HLA-DQB1), rs41549217 (HLA-B), and rs1546308/rs149104283 (SLCO1B3/7), several of which were not directly genotyped but imputed. To test whether these 4 single-nucleotide polymorphisms (SNPs) are associated with CIN/CIA in a Turkish population and in a more extensive group of Caucasians, we directly genotyped these polymorphisms using Taqman and Sanger sequencing and performed logistic regression. We divided our participants (234 CLZ-using participants of whom 31 CIN/CIA cases) into (1) North-Western European, (2) Turkish, (3) Caucasian (=1 + 2); and (4) a total group (Caucasian + other ethnicities). Rs113332494 (HLA-DQB1) was significantly associated with CIN/CIA in the total group (P = 3.5 × 10−8), in the Caucasian group (P = 9.3 × 10−6) and in the Turkish group (P = 2.8 × 10−5). Rs41549217 (HLA-B) was nominally significant in the Caucasian group (P = .018). In meta-analysis of our results and the previously reported genome-wide results, 3 SNPs were significantly associated with CIN/CIA in participants with Caucasian ancestry: rs113332494 (P = 2.05 × 10−8), rs41549217 (P = 7.19 × 10−9), and rs149104283 (P = 5.54 × 10−9), with the result for rs1546308 (SCLO1B3/SCLO1B7) being significantly heterogeneous across studies. Our results hint at ethnicity-dependent and clinically relevant effects of genetic polymorphisms on the risk to develop CIN/CIA. Pharmacogenetic testing can complement clinical decision making and thus empower appropriate CLZ prescribing, but ancestry should be taken into account when performing such testing for CLZ.
Published: 2020

29. Genome-wide association meta-analysis of age at first cannabis use

Author: Albertine J. Oldehinkel, Dorret I. Boomsma, Camelia C. Minică, Marco P. Boks, Jacqueline M. Vink, Iryna O. Fedko, Tamara L. Wall, Nicholas G. Martin, Michael C. Stallings, Andrew C. Heath, Michael C. Neale, Abdel Abdellaoui, Marcus R. Munafò, Kristel R. van Eijk, Christian J. Hopfer, Hans M. Koot, Tellervo Korhonen, Jean Shin, Lindsay A. Farrer, Kenneth Krauter, Joel Gelernter, Josep Antoni Ramos-Quiroga, Eske M. Derks, Vanesa Richarte, Gareth E. Davies, Ian B. Hickie, Michelle Taylor, René S. Kahn, Dominique F. Maciejewski, Iris Garcia-Martínez, Teemu Palviainen, Catharina A. Hartman, Marta Ribasés, Karin J. H. Verweij, Timothy B. Bigdeli, Margaret J. Wright, Hongyu Zhao, Ilja M. Nolte, Pamela A. F. Madden, Anu Loukola, Susan Branje, Mengzhen Liu, Richard J. Rose, Richard Sherva, Harold Snieder, Scott D. Gordon, Jennifer J. Ware, Raymond K. Walters, John K. Hewitt, Jaakko Kaprio, Manon Bernard, Hamdi Mbarek, Sandra A. Brown, Pol A. C. van Lier, Miguel Casas, Wim Meeus, Robin P. Corley, Grant W. Montgomery, Cristina Sánchez-Mora, Nathan A. Gillespie, Henry R. Kranzler, Sarah E. Medland, Zdenka Pausova, Jouke-Jan Hottenga, Penelope A. Lind, Peter J. van der Most, George Davey-Smith, Matthew Hickman, Tomáš Paus, and Erik A. Ehli
Subjects: 0301 basic medicine, biology, business.industry, Medicine (miscellaneous), Single-nucleotide polymorphism, Genome-wide association study, Heritability, biology.organism_classification, Confidence interval, 3. Good health, 03 medical and health sciences, Psychiatry and Mental health, 030104 developmental biology, 0302 clinical medicine, Meta-analysis, SNP, Medicine, Cannabis, Young adult, business, 030217 neurology & neurosurgery, Demography
Abstract: Background and aims: Cannabis is one of the most commonly used substances among adolescents and young adults. Earlier age at cannabis initiation is linked to adverse life outcomes, including multi-substance use and dependence. This study estimated the heritability of age at first cannabis use and identified associations with genetic variants. Methods: A twin-based heritability analysis using 8055 twins from three cohorts was performed. We then carried out a genome-wide association meta-analysis of age at first cannabis use in a discovery sample of 24 953 individuals from nine European, North American and Australian cohorts, and a replication sample of 3735 individuals. Results: The twin-based heritability for age at first cannabis use was 38% [95% confidence interval (CI) = 19–60%]. Shared and unique environmental factors explained 39% (95% CI = 20–56%) and 22% (95% CI = 16–29%). The genome-wide association meta-analysis identified five single nucleotide polymorphisms (SNPs) on chromosome 16 within the calcium-transporting ATPase gene (ATP2C2) at P 0.8), with the strongest association at the intronic variant rs1574587 (P = 4.09E-09). Gene-based tests of association identified the ATP2C2 gene on 16q24.1 (P = 1.33e-06). Although the five SNPs and ATP2C2 did not replicate, ATP2C2 has been associated with cocaine dependence in a previous study. ATP2B2, which is a member of the same calcium signalling pathway, has been associated previously with opioid dependence. SNP-based heritability for age at first cannabis use was non-significant. Conclusion: Age at cannabis initiation appears to be moderately heritable in western countries, and individual differences in onset can be explained by separate but correlated genetic liabilities. The significant association between age of initiation and ATP2C2 is consistent with the role of calcium signalling mechanisms in substance use disorders.
Published: 2018

30. Associations of autozygosity with a broad range of human phenotypes

Author: Dennis O. Mook-Kanamori, Salma M. Wakil, Lisa R. Yanek, Dominique P.V. de Kleijn, Gert J. de Borst, Alison D. Murray, Kamran Guity, Vincent W. V. Jaddoe, Mario Pirastu, Carole Ober, Giuseppe Matullo, Charles N. Rotimi, Daniela Ruggiero, Teresa Tusié-Luna, Wolfgang Lieb, Chew-Kiat Heng, John R. B. Perry, Hortensia Moreno-Macías, Jie Zhou, John M. Starr, Juhani Junttila, Lei Yu, Danielle Posthuma, Marcus Dörr, Yingchang Lu, Jonathan P. Bradfield, Einat Granot-Hershkovitz, Karina Meidtner, Wouter van Rheenen, T Esko, Maris Alver, Wen-Jane Lee, Zhengming Chen, Jennifer A. Brody, Paolo Gasparini, Yii-Der Ida Chen, Cinzia Sala, Peter P. Pramstaller, Gauri Prasad, Nana Matoba, Natalie Terzikhan, Simonetta Guarrera, Bjarke Feenstra, Peter Vollenweider, Smeeta Shrestha, Yi-Jen Hung, Lilja Stefansdottir, David R. Weir, Felix R. Day, Antonietta Robino, Liang Zhang, Lluis Quintana-Murci, Nicholas J. Timpson, Robyn E Wootton, Xue W. Mei, Dharambir K. Sanghera, Gisli Masson, Debbie A Lawlor, Thomas Meitinger, Sharon L.R. Kardia, Peter K. Joshi, Frank J. A. van Rooij, Claude Bouchard, Cassandra N. Spracklen, Ken K. Ong, Taulant Muka, Guanjie Chen, Laura J. Scott, Walter Palmas, Daniel I. Chasman, Sarah E. Medland, Krista Fischer, Blair H. Smith, Jon K. Sigurdsson, Leon Straker, Clara Viberti, Yuan Shi, Louis Pérusse, Peter J. van der Most, Timo Tõnis Sikka, Chris Haley, Kuang Lin, Leif Groop, Hester M. den Ruijter, Hakon Hakonarson, Masato Akiyama, Stephan J. L. Bakker, Sonja I. Berndt, Jeffery R. O'Connell, Cisca Wijmenga, Daniele Cusi, Lorena Orozco, Kristjan H. S. Moore, Kevin Sandow, Stephen S. Rich, Stephanie J. Loomis, George Davey Smith, Cornelia M. van Duijn, Sharvari Rahul Shukla, Agnar Helgason, Thorsten Kessler, Anuj Goel, Dan Mason, David W. Clark, James S. Pankow, Simona Vaccargiu, Uwe Völker, Tamara B. Harris, Matthew A. Allison, Clicerio Gonzalez, Sarju Ralhan, I-Te Lee, Matthias Laudes, Yen-Feng Chiu, Neil Poulter, Benjamin Lehne, John Wright, Lawrence F. Bielak, Philip L. De Jager, Reinhold Schmidt, Ya Xing Wang, Matthias Nauck, Diana L. Cousminer, Patrick Deelen, Ani Manichaikul, Stephen J. Chanock, Anders Hamsten, Barry I. Freedman, Gudmar Thorleifsson, Peter Kraft, Ozren Polasek, Jie Yao, Yoshinori Murakami, Paul M. Ridker, Anubha Mahajan, Struan F.A. Grant, Claudia Schurmann, Bjarni Gunnarsson, Catriona L. K. Barnes, Jessica van Setten, Sandosh Padmanabhan, Alena Stančáková, Markus M. Lerch, Anuradha Jagadeesan, Franco Giulianini, Daniel F. Gudbjartsson, Dwaipayan Bharadwaj, Shengchao Alfred Li, Peter S. Sever, Trevor A. Mori, Albertine J. Oldehinkel, Koichi Matsuda, Xueling Sim, Evangelos Evangelou, André G. Uitterlinden, Pekka Jousilahti, Yukihide Momozawa, Ioanna Tzoulaki, Chao A. Hsiung, Ginevra Biino, Murielle Bochud, Hannele Mattsson, Ilja M. Nolte, Sarah H. Wild, Patricia B. Munroe, Jianjun Liu, Bruce M. Psaty, Giriraj R. Chandak, Masahiro Kanai, Tony R. Merriman, Teemu Palviainen, Rodney A. Lea, Janie Corley, Nicholas J. Wareham, Alan B. Zonderman, Makoto Hirata, Matthew J. Bixley, Caroline Hayward, Nora Franceschini, Kristel R van Eijk, Etienne Patin, Daniel Shriner, Niek Verweij, Xiuqing Guo, Fredrik Karpe, Ruth J. F. Loos, Tiinamaija Tuomi, Ashley van der Spek, Patricia A. Peyser, Jessica D. Faul, Christian Fuchsberger, David Cesarini, Alex S. F. Doney, Janine F. Felix, Cornelius A. Rietveld, Jagadish Vangipurapu, Tanguy Corre, Line Skotte, Rajkumar Dorajoo, Catherine Igartua, Meena Kumari, Nona Sotoodehnia, Leonard H. van den Berg, Najaf Amin, Dale R. Nyholt, Harry Campbell, Massimiliano Cocca, Scott D. Gordon, Patrik K. E. Magnusson, John C. Chambers, Traci M. Bartz, Mike A. Nalls, Tin Aung, Nduna Dzimiri, Colin N. A. Palmer, Rob M. van Dam, Johanna Kuusisto, Russell P. Tracy, Anna Damulina, Pierre-Emmanuel Morange, Sylvain Foisy, Jing Hua Zhao, Nicholas G. Martin, Ching-Yu Cheng, Mariaelisa Graff, Rashmi B. Prasad, Alice Stanton, David-Alexandre Trégouët, Yu Guo, Helen R. Warren, Lyn R. Griffiths, Weihua Meng, Annika Tillander, Christa Meisinger, Albert V. Smith, Mark I. McCarthy, Jingyun Yang, Marine Germain, Neil Small, Linda Broer, Vilmundur Gudnason, Gunnar K. Pálsson, Michele K. Evans, Alexander Teumer, Mark J. Caulfield, Giorgia Girotto, Thomas Lumley, Tinca J. C. Polderman, Wei Zhao, Carlos A. Aguilar-Salinas, Jari Lahti, Matthew L. Albert, Yechiel Friedlander, Veikko Salomaa, Iona Y Millwood, Jan H. Veldink, Archie Campbell, Andres Metspalu, Ulf Gyllensten, Grant W. Montgomery, Veronique Vitart, Jai Rup Singh, Saima Afaq, Alan R. Shuldiner, Miao-Li Chee, Adebowale Adeyemo, Jennifer A. Smith, David A. van Heel, Jaspal S. Kooner, Daniela Toniolo, Cristian Pattaro, Jerome I. Rotter, John Whitfield, Melissa C. Smart, Kari E. North, Salman M. Tajuddin, Tallapragada Divya Sri Priyanka, Christopher A. Haiman, Diane M. Becker, Bernhard K. Krämer, Paul Elliott, Lihua Wang, He Gao, Patrick Sulem, Jinyan Huang, Chiea Chuen Khor, Ruifang Li-Gao, Åsa Johansson, Winfried März, Shai Carmi, Ilaria Gandin, Eric Boerwinkle, Gardar Sveinbjornsson, Saskia P. Hagenaars, Sander W. van der Laan, Gerard Pasterkamp, E-Shyong Tai, Hagit Hochner, Yih Chung Tham, Kent D. Taylor, Kari Stefansson, Matt J. Neville, Craig E. Pennell, Yanchun Bao, Annelot M. Dekker, Helena Schmidt, Mehdi Hedayati, Joshua Elliott, Ian J. Deary, Iris E. Jansen, Judith B. Borja, Edith Hofer, Martin Gögele, Igor Rudan, Lude Franke, Matthias Munz, Folkert W. Asselbergs, Bengt Sennblad, Imo Hofer, John D. Rioux, Pim van der Harst, Bahareh Sedaghati-khayat, Giovanni Cugliari, Morris A. Swertz, Francine Grodstein, Erwin P. Bottinger, Carol A. Wang, Andre Franke, Brian F. Meyer, Adele M. Taylor, Klodian Dhana, Jian'an Luan, Constance Turman, Robert A. Scott, May E. Montasser, Alison Pattie, Marco Brumat, Liming Li, Heiner Boeing, Karen L. Mohlke, Clemens Baumbach, Bishwa Raj Sapkota, Unnur Thorsteinsdottir, Naveed Sattar, Amy R. Bentley, Matthias B. Schulze, Ivana Kolcic, Stella Trompet, Sarah E. Harris, Ayo P. Doumatey, Charumathi Sabanayagam, David Eccles, Mary F. Feitosa, Jost B. Jonas, Massimo Mezzavilla, Mark O. Goodarzi, David Ellinghaus, Heribert Schunkert, Christian Gieger, Heikki V. Huikuri, Lingyao Zeng, Johan G. Eriksson, Woon-Puay Koh, Yucheng Jia, Gurpreet Singh Wander, James F. Wilson, Torgny Karlsson, Steven C. Hunt, Weihua Zhang, Maria Pina Concas, Zoltán Kutalik, Rebecca Rohde, Chittaranjan S. Yajnik, Yasaman Saba, Dabeeru C. Rao, Robin G. Walters, Reedik Mägi, Marie Loh, Eero Vuoksimaa, Josyf C. Mychaleckyj, Katri Räikkönen, Philippe Goyette, M. Arfan Ikram, Alicia Huerta-Chagoya, David J. Porteous, Teresa Nutile, J. Wouter Jukema, Noha A. Yousri, Yoichiro Kamatani, Maryam S. Daneshpour, Babette S. Zemel, Rona J. Strawbridge, Tien Yin Wong, Claudia Langenberg, Amy Moore, Marcus E. Kleber, Fereidoun Azizi, Avner Halevy, Erika Salvi, Francis S. Collins, Markku Laakso, Tim Kacprowski, S. Sunna Ebenesersdóttir, William R. Scott, Michael Boehnke, Jin-Fang Chai, Markus Perola, Nicola Pirastu, Wayne Huey-Herng Sheu, Robert Karlsson, Lenore J. Launer, Lili Milani, Renée de Mutsert, Fernando Rivadeneira, David A. Bennett, Nicola D. Kerrison, Paolo Manunta, Graciela E. Delgado, Magnus Johannesson, Carolina Medina-Gomez, Alanna C. Morrison, Kay-Tee Khaw, Jian-Min Yuan, Jaakko Kaprio, Melanie Waldenberger, Ralf Ewert, Hugoline G. de Haan, Andrew A. Hicks, Yukinori Okada, Maria Sabater-Lleal, Marilyn C. Cornelis, Stephanie J. London, Federica Rizzi, Jeanette Erdmann, Marina Ciullo, Michiaki Kubo, University of Edinburgh, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Osaka University Graduate School of Medicine, Laboratory for Cardiovascular Genomics and Informatics [Yokohama] (RIKEN IMS), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN)-RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), deCODE genetics [Reykjavik], Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK (BIHR), Area Science Park, Università degli studi di Trieste = University of Trieste, MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, Harbor UCLA Medical Center [Torrance, Ca.], Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, Department of Electrical and Computer Engineering [Waterloo] (ECE), University of Waterloo [Waterloo], Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Institute of Pop. Genetics, CNR, Sassari, Shardna life science Pula Cagliari, Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL), Medstar Research Institute, Florida State University [Tallahassee] (FSU), University Medical Center [Utrecht], Centre for Population Health Sciences, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), California State University [Sacramento], Department of Thrombosis and Haemostasis, Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Medical University Graz, Department of Neurology, Alzheimer Centre, VU Medical Centre, Amsterdam, Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Heidelberg, Frederick National Laboratory for Cancer Research (FNLCR), Wellcome Trust Centre of Human Genetics, University of Oxford, Department of Epidemiology, German Institute of Human Nutrition, University Medical Center Groningen [Groningen] (UMCG), Institute of Genetics and Biophysics, National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), Department of Medicine, Surgery, and Dentistry, University of Milano, Icelandic Heart Association, Kopavogur, Iceland., Department of Epidemiology [Rotterdam], Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Glasgow, Department of Cardiology, Leiden University Medical Center, Leiden, Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, Queen Mary University of London (QMUL), General Internal Medicine, Johns Hopkins School of Medicine, Johns Hopkins University School of Medicine [Baltimore], Institut de biologie moléculaire des plantes (IBMP), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Genentech, Inc., Genentech, Inc. [San Francisco], University of Tartu, Duke-NUS Medical School [Singapore], Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke (DifE), Leibniz Association, Human Genome Sequencing Center, Baylor College of Medicine, Baylor College of Medicine (BCM), Baylor University-Baylor University, University of San Carlos, Office of Population Studies Foundation, Icahn School of Medicine at Mount Sinai [New York] (MSSM), King‘s College London, Division of Cancer Epidemiology and Genetics, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), University of Oxford, Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Department of Internal Medicine B, University Medicine Greifswald, Greifswald, University of Chicago, University of Huddersfield, Infectious diseases division, Department of internal medicine, Washington University in Saint Louis (WUSTL), Section on Nephrology [Winston-Salem, NC, USA] (Department of Internal Medicine), Wake Forest School of Medicine [Winston-Salem], Wake Forest Baptist Medical Center-Wake Forest Baptist Medical Center, Radcliffe Department of Medicine [Oxford], Harvard School of Public Health, Kunming University of Science and Technology (KMUST), Sans affiliation, University of Southern California (USC), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), MRC Centrer for Nutritional Epidemiology and Cancer Prevention and Survival, University of Cambridge [UK] (CAM), National University of Singapore (NUS), Experimental Cardiology Laboratory (ECL), Unirversity Medical Center, Department of Medical Statistics, Epidemiology and Medical Informatics, University of Zagreb, Department of Medical Genetics, Department of Medicine, University of Eastern Finland-Kuopio University Hospital, MRC Epidemiology Unit, University of Cambridge [UK] (CAM)-Institute of Metabolic Science, Capital Normal University [Beijing], Saw Swee Hock School of Public Health, National Institute for Environmental Health Sciences Research Triangle Park, Brown University, MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, Toyota Research Institute, Helmholtz Zentrum München = German Research Center for Environmental Health, Department of Chemistry and Biochemistry [Boulder], University of Colorado [Boulder], Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital de la Timone [CHU - APHM] (TIMONE), Metacohorts Consortium, Universiteit Leiden, Institute of Clinical Chemistry and Laboratory Medicine, University of Groningen [Groningen], Medical Research Concil Epidemiology Unit, Institute of Medical Science, Faculty of Medicine, Genetics and Pathology, Imperial College London, Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Brigham and Women's Hospital [Boston], Erasmus University Rotterdam, Department of Chronic Disease Prevention, National Institute for Health and Welfare [Helsinki], Department of Biostatistics and Center for Statistical Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU), Stockholm Bioinformatics Center (SBC), Stockholm University, Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, INRH, Department of Genetics, Los Angeles Biomedical Research Institute (LA BioMed), Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán - National Institute of Medical Science and Nutrition Salvador Zubiran [Mexico], Western General Hospital, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Medical Research Council, Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute-University of Pittsburgh Graduate School of Public Health, Zhengzhou University of Light Industry, Department of Electrical and Electronic Engineering [Niigata Univ.], Niigata University, Genetic Epidemiology Unit, University College of London [London] (UCL), Aston Business School, Aston University [Birmingham], Division of Cancer Epidemiology and Genetics [Bethesda, MD, États-Unis], Centre Hospitalier Universitaire Vaudois (CHUV), Pennington Biomedical Research Center, University of Washington [Seattle], Guy's and St Thomas' Hospitals, Northwestern Polytechnical University [Xi'an] (NPU), Department of Social Medicine, University of Bristol [Bristol], Department of Genomics of Common Disease [London, UK], Imperial College London-Hammersmith Hospital NHS Imperial College Healthcare, Department of Internal Medicine, Institute of Clinical Molecular Biology, Kiel University, Medizinische Klinik II, Universität zu Lübeck = University of Lübeck [Lübeck], Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, University of Ioannina, Institute for Social Research, University of Michigan System-University of Michigan System, Division of Statistical Genomics, Washington University School of Medicine, Institute for Clinical Molecular Biology, Christian-Albrechts-Universität zu Kiel (CAU), Department of Physics, RISSC-Lab-University of Naples Federico II = Università degli studi di Napoli Federico II, Lund University [Lund], Icelandic Heart Association, Heart Preventive Clinic and Research Institute, The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Génétique moléculaire de la neurotransmission et des processus neurodégénératifs (LGMNPN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Medical Research Center Oulu, University of Oulu, University of Utah School of Medicine [Salt Lake City], The Generation R Study, Pediatrics, Epidemiology, Center for Translational and Computational Neuroimmunology [New York, NY, États-Unis] (CTCN), Department of Neurology [New York, NY, États-Unis], Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York]-Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York], Universität Heidelberg [Heidelberg] = Heidelberg University, Interuniversity Cardiology Institute Netherlands, School of Public Health, University of Michigan [Dearborn], Department of Epidemiology and Public Health, University of Kuopio, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Institute of Epidemiology and Biobank PopGen, Department of Biostatistics, University of Washington, Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Clinical Institute of Medical and Chemical Laboratory Diagnostics, Karl-Franzens-Universität Graz, Department of Genetics, Biology and Biochemistry, Università degli studi di Torino = University of Turin (UNITO), Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), QIMR Berghofer Medical Research Institute, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC)-UNC Gillings School of Global Public Health-Carolina Center for Genome Sciences, University of Illinois [Chicago] (UIC), University of Illinois System, Experimental Cardiology Laboratory, Genetic Epidemiology and Clinical Research Group, Umea University Hospital, Functional Genomics, Erasmus Medical Centre, National Human Genome Research Institute (NHGRI), School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), Department of Pathological Biochemistry, Royal Infirmary, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Institute of Metabolic Science, MRC, University of Maryland School of Medicine [Baltimore, MD, USA], Centre for Molecular Epidemiology, Centre for Causal Analyses in Translational Epidemiology, University of Bristol [Bristol]-Medical Research Council, IRCCS San Raffaele Scientific Institute [Milan, Italie], U937, Génomique cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), University of Michigan System, HMNC Brain Health, Singapore Eye Research Institute, Partenaires INRAE, Institut d'Électronique et des Technologies du numéRique (IETR), Université de Nantes (UN)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Department of Psychiatry and Psychotherapy, Rheinische Friedrich-Wilhelms-Universität Bonn, University of Groningen, Department of Genomics of Common Disease, Department of Microbiology, The Freeman Hospital, Department Biostatistics University of North Carolina, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Clark, D. W., Okada, Y., Moore, K. H. S., Mason, D., Pirastu, N., Gandin, I., Mattsson, H., Barnes, C. L. K., Lin, K., Zhao, J. H., Deelen, P., Rohde, R., Schurmann, C., Guo, X., Giulianini, F., Zhang, W., Medina-Gomez, C., Karlsson, R., Bao, Y., Bartz, T. M., Baumbach, C., Biino, G., Bixley, M. J., Brumat, M., Chai, J. -F., Corre, T., Cousminer, D. L., Dekker, A. M., Eccles, D. A., van Eijk, K. R., Fuchsberger, C., Gao, H., Germain, M., Gordon, S. D., de Haan, H. G., Harris, S. E., Hofer, E., Huerta-Chagoya, A., Igartua, C., Jansen, I. E., Jia, Y., Kacprowski, T., Karlsson, T., Kleber, M. E., Li, S. A., Li-Gao, R., Mahajan, A., Matsuda, K., Meidtner, K., Meng, W., Montasser, M. E., van der Most, P. J., Munz, M., Nutile, T., Palviainen, T., Prasad, G., Prasad, R. B., Priyanka, T. D. S., Rizzi, F., Salvi, E., Sapkota, B. R., Shriner, D., Skotte, L., Smart, M. C., Smith, A. V., van der Spek, A., Spracklen, C. N., Strawbridge, R. J., Tajuddin, S. M., Trompet, S., Turman, C., Verweij, N., Viberti, C., Wang, L., Warren, H. R., Wootton, R. E., Yanek, L. R., Yao, J., Yousri, N. A., Zhao, W., Adeyemo, A. A., Afaq, S., Aguilar-Salinas, C. A., Akiyama, M., Albert, M. L., Allison, M. A., Alver, M., Aung, T., Azizi, F., Bentley, A. R., Boeing, H., Boerwinkle, E., Borja, J. B., de Borst, G. J., Bottinger, E. P., Broer, L., Campbell, H., Chanock, S., Chee, M. -L., Chen, G., Chen, Y. -D. I., Chen, Z., Chiu, Y. -F., Cocca, M., Collins, F. S., Concas, M. P., Corley, J., Cugliari, G., van Dam, R. M., Damulina, A., Daneshpour, M. S., Day, F. R., Delgado, G. E., Dhana, K., Doney, A. S. F., Dorr, M., Doumatey, A. P., Dzimiri, N., Ebenesersdottir, S. S., Elliott, J., Elliott, P., Ewert, R., Felix, J. F., Fischer, K., Freedman, B. I., Girotto, G., Goel, A., Gogele, M., Goodarzi, M. O., Graff, M., Granot-Hershkovitz, E., Grodstein, F., Guarrera, S., Gudbjartsson, D. F., Guity, K., Gunnarsson, B., Guo, Y., Hagenaars, S. P., Haiman, C. A., Halevy, A., Harris, T. B., Hedayati, M., van Heel, D. A., Hirata, M., Hofer, I., Hsiung, C. A., Huang, J., Hung, Y. -J., Ikram, M. A., Jagadeesan, A., Jousilahti, P., Kamatani, Y., Kanai, M., Kerrison, N. D., Kessler, T., Khaw, K. -T., Khor, C. C., de Kleijn, D. P. V., Koh, W. -P., Kolcic, I., Kraft, P., Kramer, B. K., Kutalik, Z., Kuusisto, J., Langenberg, C., Launer, L. J., Lawlor, D. A., Lee, I. -T., Lee, W. -J., Lerch, M. M., Li, L., Liu, J., Loh, M., London, S. J., Loomis, S., Lu, Y., Luan, J., Magi, R., Manichaikul, A. W., Manunta, P., Masson, G., Matoba, N., Mei, X. W., Meisinger, C., Meitinger, T., Mezzavilla, M., Milani, L., Millwood, I. Y., Momozawa, Y., Moore, A., Morange, P. -E., Moreno-Macias, H., Mori, T. A., Morrison, A. C., Muka, T., Murakami, Y., Murray, A. D., de Mutsert, R., Mychaleckyj, J. C., Nalls, M. A., Nauck, M., Neville, M. J., Nolte, I. M., Ong, K. K., Orozco, L., Padmanabhan, S., Palsson, G., Pankow, J. S., Pattaro, C., Pattie, A., Polasek, O., Poulter, N., Pramstaller, P. P., Quintana-Murci, L., Raikkonen, K., Ralhan, S., Rao, D. C., van Rheenen, W., Rich, S. S., Ridker, P. M., Rietveld, C. A., Robino, A., van Rooij, F. J. A., Ruggiero, D., Saba, Y., Sabanayagam, C., Sabater-Lleal, M., Sala, C. F., Salomaa, V., Sandow, K., Schmidt, H., Scott, L. J., Scott, W. R., Sedaghati-Khayat, B., Sennblad, B., van Setten, J., Sever, P. J., Sheu, W. H. -H., Shi, Y., Shrestha, S., Shukla, S. R., Sigurdsson, J. K., Sikka, T. T., Singh, J. R., Smith, B. H., Stancakova, A., Stanton, A., Starr, J. M., Stefansdottir, L., Straker, L., Sulem, P., Sveinbjornsson, G., Swertz, M. A., Taylor, A. M., Taylor, K. D., Terzikhan, N., Tham, Y. -C., Thorleifsson, G., Thorsteinsdottir, U., Tillander, A., Tracy, R. P., Tusie-Luna, T., Tzoulaki, I., Vaccargiu, S., Vangipurapu, J., Veldink, J. H., Vitart, V., Volker, U., Vuoksimaa, E., Wakil, S. M., Waldenberger, M., Wander, G. S., Wang, Y. X., Wareham, N. J., Wild, S., Yajnik, C. S., Yuan, J. -M., Zeng, L., Zhang, L., Zhou, J., Amin, N., Asselbergs, F. W., Bakker, S. J. L., Becker, D. M., Lehne, B., Bennett, D. A., van den Berg, L. H., Berndt, S. I., Bharadwaj, D., Bielak, L. F., Bochud, M., Boehnke, M., Bouchard, C., Bradfield, J. P., Brody, J. A., Campbell, A., Carmi, S., Caulfield, M. J., Cesarini, D., Chambers, J. C., Chandak, G. R., Cheng, C. -Y., Ciullo, M., Cornelis, M., Cusi, D., Smith, G. D., Deary, I. J., Dorajoo, R., van Duijn, C. M., Ellinghaus, D., Erdmann, J., Eriksson, J. G., Evangelou, E., Evans, M. K., Faul, J. D., Feenstra, B., Feitosa, M., Foisy, S., Franke, A., Friedlander, Y., Gasparini, P., Gieger, C., Gonzalez, C., Goyette, P., Grant, S. F. A., Griffiths, L. R., Groop, L., Gudnason, V., Gyllensten, U., Hakonarson, H., Hamsten, A., van der Harst, P., Heng, C. -K., Hicks, A. A., Hochner, H., Huikuri, H., Hunt, S. C., Jaddoe, V. W. V., De Jager, P. L., Johannesson, M., Johansson, A., Jonas, J. B., Jukema, J. W., Junttila, J., Kaprio, J., Kardia, S. L. R., Karpe, F., Kumari, M., Laakso, M., van der Laan, S. W., Lahti, J., Laudes, M., Lea, R. A., Lieb, W., Lumley, T., Martin, N. G., Marz, W., Matullo, G., Mccarthy, M. I., Medland, S. E., Merriman, T. R., Metspalu, A., Meyer, B. F., Mohlke, K. L., Montgomery, G. W., Mook-Kanamori, D., Munroe, P. B., North, K. E., Nyholt, D. R., O'Connell, J. R., Ober, C., Oldehinkel, A. J., Palmas, W., Palmer, C., Pasterkamp, G. G., Patin, E., Pennell, C. E., Perusse, L., Peyser, P. A., Pirastu, M., Polderman, T. J. C., Porteous, D. J., Posthuma, D., Psaty, B. M., Rioux, J. D., Rivadeneira, F., Rotimi, C., Rotter, J. I., Rudan, I., Den Ruijter, H. M., Sanghera, D. K., Sattar, N., Schmidt, R., Schulze, M. B., Schunkert, H., Scott, R. A., Shuldiner, A. R., Sim, X., Small, N., Smith, J. A., Sotoodehnia, N., Tai, E. -S., Teumer, A., Timpson, N. J., Toniolo, D., Tregouet, D. -A., Tuomi, T., Vollenweider, P., Wang, C. A., Weir, D. R., Whitfield, J. B., Wijmenga, C., Wong, T. -Y., Wright, J., Yang, J., Yu, L., Zemel, B. S., Zonderman, A. B., Perola, M., Magnusson, P. K. E., Uitterlinden, A. G., Kooner, J. S., Chasman, D. I., Loos, R. J. F., Franceschini, N., Franke, L., Haley, C. S., Hayward, C., Walters, R. G., Perry, J. R. B., Esko, T., Helgason, A., Stefansson, K., Joshi, P. K., Kubo, M., Wilson, J. F., Læknadeild (HÍ), Faculty of Medicine (UI), Félagsfræði-, mannfræði- og þjóðfræðideild (HÍ), Faculty of Sociology, Anthropology and Folkloristics (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), School of Engineering and Natural Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), Félagsvísindasvið (HÍ), School of Social Sciences (UI), Háskóli Íslands, University of Iceland, Clark, David W [0000-0002-1025-9185], Okada, Yukinori [0000-0002-0311-8472], Moore, Kristjan H S [0000-0002-9579-4362], Mason, Dan [0000-0002-0026-9216], Pirastu, Nicola [0000-0002-5363-3886], Gandin, Ilaria [0000-0003-3196-2491], Deelen, Patrick [0000-0002-5654-3966], Schurmann, Claudia [0000-0003-4158-9192], Medina-Gomez, Carolina [0000-0001-7999-5538], Karlsson, Robert [0000-0002-8949-2587], Bao, Yanchun [0000-0002-6102-5098], Biino, Ginevra [0000-0002-9936-946X], Brumat, Marco [0000-0003-3268-039X], Chai, Jin-Fang [0000-0003-3770-1137], Eccles, David A [0000-0003-4634-4995], Gordon, Scott 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Mark J [0000-0001-9295-3594], Smith, George Davey [0000-0002-1407-8314], Dorajoo, Rajkumar [0000-0001-6608-2051], Ellinghaus, David [0000-0002-4332-6110], Erdmann, Jeanette [0000-0002-4486-6231], Evangelou, Evangelos [0000-0002-5488-2999], Feenstra, Bjarke [0000-0003-1478-649X], Feitosa, Mary [0000-0002-0933-2410], Franke, Andre [0000-0003-1530-5811], Grant, Struan F A [0000-0003-2025-5302], Griffiths, Lyn R [0000-0002-6774-5475], Groop, Leif [0000-0002-0187-3263], Gudnason, Vilmundur [0000-0001-5696-0084], van der Harst, Pim [0000-0002-2713-686X], Heng, Chew-Kiat [0000-0002-7309-9473], Hicks, Andrew A [0000-0001-6320-0411], Jaddoe, Vincent W V [0000-0003-2939-0041], De Jager, Philip L [0000-0002-8057-2505], Johannesson, Magnus [0000-0001-8759-6393], Johansson, Åsa [0000-0002-2915-4498], Jonas, Jost B [0000-0003-2972-5227], Jukema, J Wouter [0000-0002-3246-8359], Kaprio, Jaakko [0000-0002-3716-2455], Laakso, Markku [0000-0002-3394-7749], van der Laan, Sander W [0000-0001-6888-1404], Lahti, Jari [0000-0002-4310-5297], Martin, Nicholas G [0000-0003-4069-8020], Medland, Sarah E [0000-0003-1382-380X], Merriman, Tony R [0000-0003-0844-8726], Metspalu, Andres [0000-0002-3718-796X], Mohlke, Karen L [0000-0001-6721-153X], Montgomery, Grant W [0000-0002-4140-8139], Munroe, Patricia B [0000-0002-4176-2947], Nyholt, Dale R [0000-0001-7159-3040], Ober, Carole [0000-0003-4626-9809], Oldehinkel, Albertine J [0000-0003-3925-3913], Palmer, Colin [0000-0002-6415-6560], Perusse, Louis [0000-0001-6440-9698], Polderman, Tinca J. C. [0000-0001-5564-301X], Porteous, David J [0000-0003-1249-6106], Rioux, John D [0000-0001-7560-8326], Rivadeneira, Fernando [0000-0001-9435-9441], Rotimi, Charles [0000-0001-5759-053X], Rotter, Jerome I [0000-0001-7191-1723], Rudan, Igor [0000-0001-6993-6884], Sattar, Naveed [0000-0002-1604-2593], Sim, Xueling [0000-0002-1233-7642], Smith, Jennifer A [0000-0002-3575-5468], Teumer, Alexander [0000-0002-8309-094X], Timpson, Nicholas J [0000-0002-7141-9189], Tuomi, Tiinamaija [0000-0002-8306-6202], Wang, Carol A [0000-0002-4301-3974], Weir, David R [0000-0002-1661-2402], Whitfield, John B [0000-0002-1103-0876], Magnusson, Patrik K. E. [0000-0002-7315-7899], Uitterlinden, André G [0000-0002-7276-3387], Loos, Ruth J. F. [0000-0002-8532-5087], Franke, Lude [0000-0002-5159-8802], Haley, Chris S [0000-0002-9811-0210], Hayward, Caroline [0000-0002-9405-9550], Walters, Robin G [0000-0002-9179-0321], Joshi, Peter K [0000-0002-6361-5059], Wilson, James F [0000-0001-5751-9178], Apollo - University of Cambridge Repository, Moore, Kristjan HS [0000-0002-9579-4362], Luan, Jian'an [0000-0003-3137-6337], Grant, Struan FA [0000-0003-2025-5302], Jaddoe, Vincent WV [0000-0003-2939-0041], Polderman, Tinca JC [0000-0001-5564-301X], Magnusson, Patrik KE [0000-0002-7315-7899], Loos, Ruth JF [0000-0002-8532-5087], Neurology, Human genetics, Amsterdam Reproduction & Development (AR&D), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Stem Cell Aging Leukemia and Lymphoma (SALL), Institute for Molecular Medicine Finland, Department of Psychology and Logopedics, University Management, Developmental Psychology Research Group, Staff Services, Cognitive and Brain Aging, Research Programs Unit, Diabetes and Obesity Research Program, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Clinicum, University of Helsinki, Centre of Excellence in Complex Disease Genetics, Department of Public Health, Genetic Epidemiology, Helsinki Collegium for Advanced Studies, HUS Abdominal Center, Endokrinologian yksikkö, Bradford Teaching Hospitals NHS Foundation Trust [Bradford, UK] (BTHFT), University of Trieste, Université de Lausanne (UNIL), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Consiglio Nazionale delle Ricerche (CNR), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Institut Pasteur [Paris], University of Oxford [Oxford], Medical Genetics, Dept. RSD and Public Health, IRCCS-Burlo Garofolo/University of Trieste, sans affiliation, Helmholtz-Zentrum München (HZM), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institute of Cardiovascular Science, University College London, Hammersmith Hospital NHS Imperial College Healthcare-Imperial College London, Universität zu Lübeck [Lübeck], University of Ioannina Medical School, Università degli studi di Napoli Federico II-RISSC-Lab, Universität Heidelberg [Heidelberg], University of Turin, University of California-University of California, Nantes Université (NU)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), University of Helsinki-University of Helsinki, Université de Nantes (UN)-Université de Rennes 1 (UR1), Erasmus MC other, Internal Medicine, and Applied Economics
Subjects: 0301 basic medicine, 631/208/1397, Chemistry(all), Health Status, [SDV]Life Sciences [q-bio], LOCI, General Physics and Astronomy, MESH: Haplotype, MESH: Cognition, 030105 genetics & heredity, Runs of Homozygosity, Biochemistry, Consanguinity, Cognition, Inbreeding depression, 2.1 Biological and endogenous factors, Body Size, Inbreeding, Skyldleikarækt, Aetiology, Human phenotypes, lcsh:Science, MESH: Health Status, Genetics, Multidisciplinary, Inbreeding Depression, Confounding, Homozygote, RUNS, 631/208/205, 631/208/721, 3. Good health, genomic inbreeding coefficients, MESH: Risk-Taking, 631/208/730, Autozygosit, homozygosity, Erfðarannsóknir, Medical Genetics, genomic inbreeding coefficient, MESH: Homozygote, Offspring, Science, Autozygosity, Blóðsifjar, 610 Medicine & health, Biology, INBREEDING DEPRESSION, HOMOZYGOSITY, FERTILITY, QUANTIFICATION, Physics and Astronomy(all), General Biochemistry, Genetics and Molecular Biology, Article, Association, 03 medical and health sciences, Risk-Taking, 360 Social problems & social services, Journal Article, Humans, ddc:610, Allele, Alleles, Medicinsk genetik, Genetic association study, MESH: Consanguinity, MESH: Body Size, MESH: Humans, Biochemistry, Genetics and Molecular Biology(all), MESH: Alleles, Haplotype, MESH: Fertility, General Chemistry, Brain Disorders, MESH: Inbreeding Depression, 030104 developmental biology, Fertility, Haplotypes, Genetic markers, lcsh:Q, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 3111 Biomedicine, Genetics and Molecular Biology(all)
Abstract: Publisher's version (útgefin grein)., In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding., This paper is the work of the ROHgen consortium. We thank the Sigma T2D Consortium, whose members are detailed in Supplementary Note 3. We thank the UK Biobank Resource, approved under application 19655; we acknowledge funding from the UK Medical Research Council Human Genetics Unit and MRC Doctoral Training Programme in Precision Medicine. We also thank Neil Robertson, Wellcome Trust Centre for Human Genetics, Oxford, for use of his author details management software, Authorial. Finally, we thank all the participants, researchers and funders of ROHgen cohorts. Cohort-specific acknowledgements are in Supplementary Data 2; personal acknowledgements and disclosures are in Supplementary Note 2. We thank Rachel Edwards for administrative assistance.
Published: 2019

31. Cannabinoids and psychotic symptoms: A potential role for a genetic variant in the P2X purinoceptor 7 (P2RX7) gene

Author: Tomáš Paus, Patricia J. Conrod, Christiaan H. Vinkers, Elly M. Hol, Marco P. Boks, Lot de Witte, René S. Kahn, Guillaume Huguet, Willemijn A. van Gastel, Yujie He, C. D. Schubart, Kristel R. van Eijk, Laurent Elkrief, Psychiatry, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Anatomy and neurosciences, APH - Mental Health, and Netherlands Institute for Neuroscience (NIN)
Subjects: 0301 basic medicine, Psychosis, Immunology, Single-nucleotide polymorphism, Genome-wide association study, Bioinformatics, 03 medical and health sciences, Behavioral Neuroscience, 0302 clinical medicine, Medicine, Cannabidiol, Humans, Dronabinol, Tetrahydrocannabinol, biology, Endocrine and Autonomic Systems, business.industry, Cannabinoids, P2RX7, biology.organism_classification, medicine.disease, 030104 developmental biology, Psychotic Disorders, Schizophrenia, Receptors, Purinergic P2X, Cannabis, Receptors, Purinergic P2X7, business, 030217 neurology & neurosurgery, medicine.drug
Abstract: To investigate the biological mechanisms underlying the higher risk for psychosis in those that use cannabis, we conducted a genome-wide environment-interaction study (GWEIS). In a sample of individuals without a psychiatric disorder (N = 1262), we analyzed the interactions between regular cannabis use and genotype with psychotic-like experiences (PLE) as outcome. PLE were measured using the Community Assessment of Psychic Experiences (CAPE). The sample was enriched for those at the extremes of both cannabis use and PLE to increase power. A single nucleotide polymorphism in the P2RX7 gene (rs7958311) was associated with risk for a high level of psychotic experiences in regular cannabis users (p = 1.10 x10-7) and in those with high levels of lifetime cannabis use (p = 4.5 × 10-6). This interaction was replicated in individuals with high levels of lifetime cannabis use in the IMAGEN cohort (N = 1217, p = 0.020). Functional relevance of P2RX7 in cannabis users was suggested by in vitro experiments on activated monocytes. Exposure of these cells to tetrahydrocannabinol (THC) or cannabidiol (CBD) reduced the immunological response of the P2X7 receptor, which was dependent on the identified genetic variant. P2RX7 variants have been implicated in psychiatric disorders before and the P2X7 receptor is involved in pathways relevant to psychosis, such as neurotransmission, synaptic plasticity and immune regulation. We conclude that P2RX7 plays a role in vulnerability to develop psychotic symptoms when using cannabis and point to a new pathway that can potentially be targeted by newly developed P2X7 antagonists.
Published: 2019

32. Pharmacogenetic interactions in amyotrophic lateral sclerosis: a step closer to a cure?

Author: Jan H. Veldink, Rick A.A. van der Spek, Kristel R. van Eijk, Sanne Piepers, Stavros Nikolakopoulos, Marc D. Jansen, Geert-Jan Groeneveld, Joke J.F.A. van Vugt, Leonard H. van den Berg, Michael A. van Es, Marinus J.C. Eijkemans, Henk-Jan Westeneng, and Ruben P A van Eijk
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Nerve Tissue Proteins, Creatine, 030226 pharmacology & pharmacy, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Double-Blind Method, C9orf72, Internal medicine, Genotype, Genetics, medicine, Humans, Allele, Amyotrophic lateral sclerosis, Netherlands, Pharmacology, Valproic Acid, C9orf72 Protein, business.industry, Amyotrophic Lateral Sclerosis, Epistasis, Genetic, medicine.disease, Pharmacogenomic Testing, Clinical trial, 030104 developmental biology, chemistry, Pharmacogenetics, Mutation, Molecular Medicine, business, Myelin Proteins, medicine.drug
Abstract: Genetic mutations related to amyotrophic lateral sclerosis (ALS) act through distinct pathophysiological pathways, which may lead to varying treatment responses. Here we assess the genetic interaction between C9orf72, UNC13A, and MOBP with creatine and valproic acid treatment in two clinical trials. Genotypic data was available for 309 of the 338 participants (91.4%). The UNC13A genotype affected mortality (p = 0.012), whereas C9orf72 repeat-expansion carriers exhibited a faster rate of decline in overall (p = 0.051) and bulbar functioning (p = 0.005). A dose-response pharmacogenetic interaction was identified between creatine and the A allele of the MOBP genotype (p = 0.027), suggesting a qualitative interaction in a recessive model (HR 3.96, p = 0.015). Not taking genetic information into account may mask evidence of response to treatment or be an unrecognized source of bias. Incorporating genetic data could help investigators to identify critical treatment clues in patients with ALS.
Published: 2019

33. Analysis of FUS, PFN2, TDP-43, and PLS3 as potential disease severity modifiers in spinal muscular atrophy

Author: Jelena Medic, Camiel A. Wijngaarde, Ewout J N Groen, Joyce van Kuik, W. Ludo van der Pol, Leonard H. van den Berg, Peter Sodaar, Marc D. Jansen, Renske I. Wadman, Henny H. Lemmink, Jan H. Veldink, Marloes Stam, Chantall A.D. Curial, Manon M. H. Huibers, Wouter van Rheenen, and Kristel R. van Eijk
Subjects: PLASTIN 3 EXPRESSION, 0301 basic medicine, Biology, Article, 03 medical and health sciences, symbols.namesake, Exon, 0302 clinical medicine, medicine, splice, Enhancer, SMN PROTEIN, Gene, Genetics (clinical), Sanger sequencing, Genetics, IDENTIFICATION, MUTATIONS, MOTOR-NEURON PROTEIN, Spinal muscular atrophy, medicine.disease, SMA, GENE, 030104 developmental biology, RNA splicing, symbols, Neurology (clinical), 030217 neurology & neurosurgery
Abstract: ObjectiveTo investigate mutations in genes that are potential modifiers of spinal muscular atrophy (SMA) severity.MethodsWe performed a hypothesis-based search into the presence of variants in fused in sarcoma (FUS), transactive response DNA-binding protein 43 (TDP-43), plastin 3 (PLS3), and profilin 2 (PFN2) in a cohort of 153 patients with SMA types 1–4, including 19 families. Variants were detected with targeted next-generation sequencing and confirmed with Sanger sequencing. Functional effects of the identified variants were analyzed in silico and for PLS3, by analyzing expression levels in peripheral blood.ResultsWe identified 2 exonic variants in FUS exons 5 and 6 (p.R216C and p.S135N) in 2 unrelated patients, but clinical effects were not evident. We identified 8 intronic variants in PLS3 in 33 patients. Five PLS3 variants (c.1511+82T>C; c.748+130 G>A; c.367+182C>T; c.891-25T>C (rs145269469); c.1355+17A>G (rs150802596)) potentially alter exonic splice silencer or exonic splice enhancer sites. The variant c.367+182C>T, but not RNA expression levels, corresponded with a more severe phenotype in 1 family. However, this variant or level of PLS3 expression did not consistently correspond with a milder or more severe phenotype in other families or the overall cohort. We found 3 heterozygous, intronic variants in PFN2 and TDP-43 with no correlation with clinical phenotype or effects on splicing.ConclusionsPLS3 and FUS sequence variants do not modify SMA severity at the population level. Specific variants in individual patients or families do not consistently correlate with disease severity.
Published: 2020

34. Human genetics and neuropathology suggest a link between miR-218 and amyotrophic lateral sclerosis pathophysiology

Author: Amitai D. Mandelbaum, Jesus S. Mora, Giancarlo Costaguta, Timothy M. Miller, Guy Haim, Revital Ravid, Ofer Yizhar, Cristiane de Araújo Martins Moreno, Irit Reichenstein, Tsviya Olender, Nicole M. Bode, Smita Saxena, Karen E. Morrison, Hemali Phatnani, Natali Rivkin, Orla Hardiman, Robert H. Brown, Matthew B. Harms, Kim A. Lennox, Kristel R. van Eijk, Jing Liang, Sandra Diaz-Garcia, A. Nazli Basak, Gilad Beck, Samuel L. Pfaff, John Ravits, Chen Eitan, Thomas Möller, Beáta Tóth, Jan H. Veldink, Eran Yanowski, Sali M.K. Farhan, Pamela J. Shaw, Ammar Al-Chalabi, Iddo Magen, Mark A. Behlke, Leonard H. van den Berg, John Landers, Rivka Levy, Elena Ainbinder, Jeffrey K. Rymer, Eran Hornstein, Christina Gross, Aviad Siany, Mariah L. Hoye, Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512), Reichenstein,I., Eitan, C., Diaz-Garcia, S., Haim, G., Magen, I., Siany, A., Hoye, M.L., Rivkin, N., Olender, T., Toth, B., Ravid, R., Mandelbaum, A.D., Yanowski, E., Liang, J., Rymer, J.K., Levy, R., Beck, G., Ainbinder, E., Farhan,S.M.K., Lennox, K.A., Bode, N.M., Behlke, M.A., Möller, T., Saxena, S., Moreno, C.A.M., Costaguta, G., van Eijk, K.R., Phatnani, H., Al-Chalabi, A., van den Berg, L.H., Hardiman, O., Landers, J.E., Mora, J.S., Morrison, K.E., Shaw, P.J., Veldink, J.H., Pfaff S.L., Yizhar, O., Gross, C., Brown, R.H. Jr., Ravits, J.M., Harms, M.B., Miller, T.M., Hornstein, E., and Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM)
Subjects: Neuropathology, Article, 03 medical and health sciences, Mice, 0302 clinical medicine, medicine, Journal Article, Premovement neuronal activity, Animals, Humans, Amyotrophic lateral sclerosis, 610 Medicine & health, Gene, 030304 developmental biology, Motor Neurons, Neurons, 0303 health sciences, biology, Amyotrophic Lateral Sclerosis, General Medicine, Motor neuron, medicine.disease, Transgenic mouse model, In-situ detection, Motor-neurons, RNA interference, Rare variants, Microrna, ALS, Motoneurons, Disease, Excitability, Human genetics, Ether-A-Go-Go Potassium Channels, MicroRNAs, medicine.anatomical_structure, nervous system, biology.protein, 570 Life sciences, Cell biology, Medicine, research and experimental, Neuron, Neuroscience, 030217 neurology & neurosurgery, Dicer
Abstract: Motor neuron–specific microRNA-218 (miR-218) has recently received attention because of its roles in mouse development. However, miR-218 relevance to human motor neuron disease was not yet explored. Here, we demonstrate by neuropathology that miR-218 is abundant in healthy human motor neurons. However, in amyotrophic lateral sclerosis (ALS) motor neurons, miR-218 is down-regulated and its mRNA targets are reciprocally up-regulated (derepressed). We further identify the potassium channel Kv10.1 as a new miR-218 direct target that controls neuronal activity. In addition, we screened thousands of ALS genomes and identified six rare variants in the human miR-218-2 sequence. miR-218 gene variants fail to regulate neuron activity, suggesting the importance of this small endogenous RNA for neuronal robustness. The underlying mechanisms involve inhibition of miR-218 biogenesis and reduced processing by DICER. Therefore, miR-218 activity in motor neurons may be susceptible to failure in human ALS, suggesting that miR-218 may be a potential therapeutic target in motor neuron disease., Target ALS; European Union (European Union); Horizon 2020; European Research Council (ERC), European Union's Seventh Framework Programme (FP7/2007-2013); AFM Telethon; NIH; National Institute of Neurological Disorders and Stroke; NIH/NINDS; United Kingdom, Medical Research Council; Suna and İnan Kıraç Foundation; Legacy Heritage Fund; Bruno and Ilse Frick Foundation for Research on ALS; Teva Pharmaceutical Industries Ltd. as part of the Israeli National Network of Excellence in Neuroscience (NNE); Minna-James-Heineman Stiftung through Minerva; Israel Science Foundation; ALS-Therapy Alliance; Motor Neuron Disease Association (United Kingdom); Thierry Latran Foundation for ALS research; ERA-Net for Research Programmes on Rare Diseases (FP7); IsrALS, Yeda-Sela, Yeda-CEO, Israel Ministry of Trade and Industry; Y. Leon Benoziyo Institute for Molecular Medicine; Kekst Family Institute for Medical Genetics; David and Fela Shapell Family Center for Genetic Disorders Research; Crown Human Genome Center; Nathan, Shirley, Philip and Charlene Vener New Scientist Fund; Julius and Ray Charlestein Foundation; Fraida Foundation; Wolfson Family Charitable Trust; Adelis Foundation; Merck (United Kingdom); ALS Canada Tim E. Noel Postdoctoral Fellowship; Project5 for ALS; Robert Packard Center for ALS Research; University of Missouri Spinal Cord Injury/Disease Research Program; Hope Center for Neurological Disorders; ALS Association ; Biogen; ALS Finding a Cure; Angel Fund; ALS-One; Cellucci Fund; Motor Neurone Disease Association; National Institute for Health Research (NIHR) Biomedical Research Centre
Published: 2018

35. The Project MinE databrowser: bringing large-scale whole-genome sequencing in ALS to researchers and the public

Author: Gijs H.P. Tazelaar, Yolanda Campos, Pamela J. Shaw, Rick A.A. van der Spek, Ammar Al-Chalabi, Ian R. A. Mackenzie, John Landers, Mónica Povedano Panades, Ceren Tunca, Johnathan Cooper-Knock, Karen E. Morrison, Orla Hardiman, Janez Zidar, Vivian E. Drory, Atay Vural, Vera Fominyh, Kristel R. van Eijk, Raymond D. Schellevis, Ahmad Al Khleifat, Phillipe Corcia, Ersen Kavak, Stephan Newhouse, Mamede de Carvalho, Kevin P. Kenna, Sara L. Pulit, William J. Brands, Nazli Basak, Marc Gotkine, Gabriel Miltenberger-Miltenyi, Matthieu Moisse, Jesus S. Mora, Annelot M. Dekker, Joke J.F.A. van Vugt, Boris Rogelj, Philip Van Damme, Wim Robberecht, Ervina Bilić, Maarten Kooyman, William Sproviero, Nicolas Dupré, Blaz Koritnik, Tuncay Seker, Leonard H. van den Berg, Jan H. Veldink, Ross P. Byrne, Brendan J. Kenna, Naomi R. Wray, P. Couratier, Perry T.C. van Doormaal, Jonathan D. Glass, Johnathan Mill, Russell L. McLaughlin, Bas Middelkoop, Lev Brylev, Alberto Garcia Redondo, Nicola Ticozzi, Markus Weber, Wouter van Rheenen, Mayana Zatz, Christopher Shaw, Cemile Kocoglu, Ivana Munitic, Ekaterina Rogaeva, Miguel Mitne-Neto, Peter M. Andersen, Vincenzo Silani, Michael A. van Es, Fulya Akçimen, Aleksey Shatunov, Matthew C. Kiernan, Ian P. Blair, Guy A. Rouleau, Adriano Chiò, Alfredo Iacoangeli, and Victoria Lopez Alonso
Subjects: Whole genome sequencing, Resource (project management), Computer science, Project MinE, Scale (social sciences), Genetic variation, Genomics, Biostatistics, Set (psychology), Data science
Abstract: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive fatal neurodegenerative disease affecting 1 in 350 people. The aim of Project MinE is to elucidate the pathophysiology of ALS through whole-genome sequencing at least 15,000 ALS patients and 7,500 controls at 30X coverage. Here, we present the Project MinE data browser (databrowser.projectmine.com). a unique and intuitive one-stop, open-access server that provides detailed information on genetic variation analyzed in a new and still growing set of 4,366 ALS cases and 1,832 matched controls. Through its visual components and interactive design, the browser specifically aims to be a resource to those without a biostatistics background and allow clinicians and preclinical researchers to integrate Project MinE data into their own research. The browser allows users to query a transcript and immediately access a unique combination of detailed (meta)data, annotations and association statistics that would otherwise require analytic expertise and visits to scattered resources.
Published: 2018

36. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

Author: Aude Nicolas, Kevin P. Kenna, Alan E. Renton, Nicola Ticozzi, Faraz Faghri, Ruth Chia, Janice A. Dominov, Brendan J. Kenna, Mike A. Nalls, Pamela Keagle, Alberto M. Rivera, Wouter van Rheenen, Natalie A. Murphy, Joke J.F.A. van Vugt, Joshua T. Geiger, Rick A. Van der Spek, Hannah A. Pliner, null Shankaracharya, Bradley N. Smith, Giuseppe Marangi, Simon D. Topp, Yevgeniya Abramzon, Athina Soragia Gkazi, John D. Eicher, Aoife Kenna, Gabriele Mora, Andrea Calvo, Letizia Mazzini, Nilo Riva, Jessica Mandrioli, Claudia Caponnetto, Stefania Battistini, Paolo Volanti, Vincenzo La Bella, Francesca L. Conforti, Giuseppe Borghero, Sonia Messina, Isabella L. Simone, Francesca Trojsi, Fabrizio Salvi, Francesco O. Logullo, Sandra D’Alfonso, Lucia Corrado, Margherita Capasso, Luigi Ferrucci, Cristiane de Araujo Martins Moreno, Sitharthan Kamalakaran, David B. Goldstein, Aaron D. Gitler, Tim Harris, Richard M. Myers, Hemali Phatnani, Rajeeva Lochan Musunuri, Uday Shankar Evani, Avinash Abhyankar, Michael C. Zody, Julia Kaye, Steven Finkbeiner, Stacia K. Wyman, Alex LeNail, Leandro Lima, Ernest Fraenkel, Clive N. Svendsen, Leslie M. Thompson, Jennifer E. Van Eyk, James D. Berry, Timothy M. Miller, Stephen J. Kolb, Merit Cudkowicz, Emily Baxi, Michael Benatar, J. Paul Taylor, Evadnie Rampersaud, Gang Wu, Joanne Wuu, Giuseppe Lauria, Federico Verde, Isabella Fogh, Cinzia Tiloca, Giacomo P. Comi, Gianni Sorarù, Cristina Cereda, Philippe Corcia, Hannu Laaksovirta, Liisa Myllykangas, Lilja Jansson, Miko Valori, John Ealing, Hisham Hamdalla, Sara Rollinson, Stuart Pickering-Brown, Richard W. Orrell, Katie C. Sidle, Andrea Malaspina, John Hardy, Andrew B. Singleton, Janel O. Johnson, Sampath Arepalli, Peter C. Sapp, Diane McKenna-Yasek, Meraida Polak, Seneshaw Asress, Safa Al-Sarraj, Andrew King, Claire Troakes, Caroline Vance, Jacqueline de Belleroche, Frank Baas, Anneloor L.M.A. ten Asbroek, José Luis Muñoz-Blanco, Dena G. Hernandez, Jinhui Ding, J. Raphael Gibbs, Sonja W. Scholz, Mary Kay Floeter, Roy H. Campbell, Francesco Landi, Robert Bowser, Stefan M. Pulst, John M. Ravits, Daniel J.L. MacGowan, Janine Kirby, Erik P. Pioro, Roger Pamphlett, James Broach, Glenn Gerhard, Travis L. Dunckley, Christopher B. Brady, Neil W. Kowall, Juan C. Troncoso, Isabelle Le Ber, Kevin Mouzat, Serge Lumbroso, Terry D. Heiman-Patterson, Freya Kamel, Ludo Van Den Bosch, Robert H. Baloh, Tim M. Strom, Thomas Meitinger, Aleksey Shatunov, Kristel R. Van Eijk, Mamede de Carvalho, Maarten Kooyman, Bas Middelkoop, Matthieu Moisse, Russell L. McLaughlin, Michael A. Van Es, Markus Weber, Kevin B. Boylan, Marka Van Blitterswijk, Rosa Rademakers, Karen E. Morrison, A. Nazli Basak, Jesús S. Mora, Vivian E. Drory, Pamela J. Shaw, Martin R. Turner, Kevin Talbot, Orla Hardiman, Kelly L. Williams, Jennifer A. Fifita, Garth A. Nicholson, Ian P. Blair, Guy A. Rouleau, Jesús Esteban-Pérez, Alberto García-Redondo, Ammar Al-Chalabi, Ekaterina Rogaeva, Lorne Zinman, Lyle W. Ostrow, Nicholas J. Maragakis, Jeffrey D. Rothstein, Zachary Simmons, Johnathan Cooper-Knock, Alexis Brice, Stephen A. Goutman, Eva L. Feldman, Summer B. Gibson, Franco Taroni, Antonia Ratti, Cinzia Gellera, Philip Van Damme, Wim Robberecht, Pietro Fratta, Mario Sabatelli, Christian Lunetta, Albert C. Ludolph, Peter M. Andersen, Jochen H. Weishaupt, William Camu, John Q. Trojanowski, Vivianna M. Van Deerlin, Robert H. Brown, Leonard H. van den Berg, Jan H. Veldink, Matthew B. Harms, Jonathan D. Glass, David J. Stone, Pentti Tienari, Vincenzo Silani, Adriano Chiò, Christopher E. Shaw, Bryan J. Traynor, John E. Landers, Isabella Simone, Giancarlo Logroscino, Ilaria Bartolomei, Maria Rita Murru, Emanuela Costantino, Carla Pani, Roberta Puddu, Carla Caredda, Valeria Piras, Stefania Tranquilli, Stefania Cuccu, Daniela Corongiu, Maurizio Melis, Antonio Milia, Francesco Marrosu, Maria Giovanna Marrosu, Gianluca Floris, Antonino Cannas, Gianluigi Mancardi, Paola Origone, Paola Mandich, Sebastiano Cavallaro, Kalliopi Marinou, Riccardo Sideri, Silvana Penco, Lorena Mosca, Giuseppe Lauria Pinter, Massimo Corbo, Paola Carrera, Nicola Fini, Antonio Fasano, Lucio Tremolizzo, Alessandro Arosio, Carlo Ferrarese, Gioacchino Tedeschi, Maria Rosaria Monsurrò, Giovanni Piccirillo, Cinzia Femiano, Anna Ticca, Enzo Ortu, Rossella Spataro, Tiziana Colletti, Marcella Zollino, Amelia Conte, Marco Luigetti, Serena Lattante, Marialuisa Santarelli, Antonio Petrucci, Maura Pugliatti, Angelo Pirisi, Leslie D. Parish, Patrizia Occhineri, Fabio Giannini, Claudia Ricci, Michele Benigni, Tea B. Cau, Daniela Loi, Cristina Moglia, Maura Brunetti, Marco Barberis, Gabriella Restagno, Federico Casale, Giuseppe Marrali, Giuseppe Fuda, Irene Ossola, Stefania Cammarosano, Antonio Canosa, Antonio Ilardi, Umberto Manera, Maurizio Grassano, Raffaella Tanel, Fabrizio Pisano, Neil A. Shneider, Stephen Goutman, Siddharthan Chandran, Suvankar Pal, George Manousakis, Stanley H. Appel, Ericka Simpson, Leo Wang, Summer Gibson, Richard Bedlack, David Lacomis, Dhruv Sareen, Alexander Sherman, Lucie Bruijn, Michelle Penny, Andrew S. Allen, Stanley Appel, Richard S. Bedlack, Braden E. Boone, Robert Brown, John P. Carulli, Alessandra Chesi, Wendy K. Chung, Elizabeth T. Cirulli, Gregory M. Cooper, Julien Couthouis, Aaron G. Day-Williams, Patrick A. Dion, Yujun Han, Sebastian D. Hayes, Angela L. Jones, Jonathan Keebler, Brian J. Krueger, Brittany N. Lasseigne, Shawn E. Levy, Yi-Fan Lu, Tom Maniatis, Slavé Petrovski, Alya R. Raphael, Zhong Ren, Katherine B. Sims, John F. Staropoli, Lindsay L. Waite, Quanli Wang, Jack R. Wimbish, Winnie W. Xin, Justin Kwan, James R. Broach, Ximena Arcila-Londono, Edward B. Lee, Noah Zaitlen, Gregory A. Cox, Steve Finkbeiner, Efthimios Dardiotis, Eran Hornstein, Daniel J. MacGowan, Terry Heiman-Patterson, Molly G. Hammell, Nikolaos A. Patsopoulos, Joshua Dubnau, Avindra Nath, Stacia Wyman, Alexander LeNail, Jenny Van Eyk, Stephan Züchner, Rebecca Schule, Jacob McCauley, Sumaira Hussain, Anne Cooley, Marielle Wallace, Christine Clayman, Richard Barohn, Jeffrey Statland, John Ravits, Andrea Swenson, Carlayne Jackson, Jaya Trivedi, Shaida Khan, Jonathan Katz, Liberty Jenkins, Ted Burns, Kelly Gwathmey, James Caress, Corey McMillan, Lauren Elman, Erik Pioro, Jeannine Heckmann, Yuen So, David Walk, Samuel Maiser, Jinghui Zhang, Fabiola De Marchi, Stefania Corti, Mauro Ceroni, Gabriele Siciliano, Massimiliano Filosto, Maurizio Inghilleri, Silvia Peverelli, Claudia Colombrita, Barbara Poletti, Luca Maderna, Roberto Del Bo, Stella Gagliardi, Giorgia Querin, Cinzia Bertolin, Viviana Pensato, Barbara Castellotti, Vincent Meininger, Gérard Besson, Emmeline Lagrange, Pierre Clavelou, Nathalie Guy, Philippe Couratier, Patrick Vourch, Véronique Danel, Emilien Bernard, Gwendal Lemasson, Ahmad Al Kheifat, Peter Andersen, Adriano Chio, Jonathan Cooper-Knock, Annelot Dekker, Vivian Drory, Alberto Garcia Redondo, Marc Gotkine, Winston Hide, Alfredo Iacoangeli, Jonathan Glass, Kevin Kenna, Matthew Kiernan, John Landers, Russell McLaughlin, Jonathan Mill, Miguel Mitne Neto, Mattieu Moisse, Jesus Mora Pardina, Karen Morrison, Stephen Newhouse, Susana Pinto, Sara Pulit, Pamela Shaw, Chris Shaw, William Sproviero, Gijs Tazelaar, Philip van Damme, Leonard van den Berg, Rick van der Spek, Kristel van Eijk, Michael van Es, Joke van Vugt, Jan Veldink, Mayana Zatz, Denis C. Bauer, Natalie A. Twine, Department of Neurosciences, Pentti Tienari / Principal Investigator, Neurologian yksikkö, Research Programs Unit, Clinicum, Research Programme for Molecular Neurology, University of Helsinki, Medicum, Department of Pathology, HUS Neurocenter, Nicolas A., Kenna K.P., Renton A.E., Ticozzi N., Faghri F., Chia R., Dominov J.A., Kenna B.J., Nalls M.A., Keagle P., Rivera A.M., van Rheenen W., Murphy N.A., van Vugt J.J.F.A., Geiger J.T., Van der Spek R.A., Pliner H.A., Shankaracharya, Smith B.N., Marangi G., Topp S.D., Abramzon Y., Gkazi A.S., Eicher J.D., Kenna A., Logullo F.O., Simone I.L., Logroscino G., Salvi F., Bartolomei I., Borghero G., Murru M.R., Costantino E., Pani C., Puddu R., Caredda C., Piras V., Tranquilli S., Cuccu S., Corongiu D., Melis M., Milia A., Marrosu F., Marrosu M.G., Floris G., Cannas A., Capasso M., Caponnetto C., Mancardi G., Origone P., Mandich P., Conforti F.L., Cavallaro S., Mora G., Marinou K., Sideri R., Penco S., Mosca L., Lunetta C., Pinter G.L., Corbo M., Riva N., Carrera P., Volanti P., Mandrioli J., Fini N., Fasano A., Tremolizzo L., Arosio A., Ferrarese C., Trojsi F., Tedeschi G., Monsurro M.R., Piccirillo G., Femiano C., Ticca A., Ortu E., La Bella V., Spataro R., Colletti T., Sabatelli M., Zollino M., Conte A., Luigetti M., Lattante S., Santarelli M., Petrucci A., Pugliatti M., Pirisi A., Parish L.D., Occhineri P., Giannini F., Battistini S., Ricci C., Benigni M., Cau T.B., Loi D., Calvo A., Moglia C., Brunetti M., Barberis M., Restagno G., Casale F., Marrali G., Fuda G., Ossola I., Cammarosano S., Canosa A., Ilardi A., Manera U., Grassano M., Tanel R., Pisano F., Mazzini L., Messina S., D'Alfonso S., Corrado L., Ferrucci L., Harms M.B., Goldstein D.B., Shneider N.A., Goutman S.A., Simmons Z., Miller T.M., Chandran S., Pal S., Manousakis G., Appel S.H., Simpson E., Wang L., Baloh R.H., Gibson S.B., Bedlack R., Lacomis D., Sareen D., Sherman A., Bruijn L., Penny M., Moreno C.D.A.M., Kamalakaran S., Allen A.S., Boone B.E., Brown R.H., Carulli J.P., Chesi A., Chung W.K., Cirulli E.T., Cooper G.M., Couthouis J., Day-Williams A.G., Dion P.A., Gitler A.D., Glass J.D., Han Y., Harris T., Hayes S.D., Jones A.L., Keebler J., Krueger B.J., Lasseigne B.N., Levy S.E., Lu Y.-F., Maniatis T., McKenna-Yasek D., Myers R.M., Petrovski S., Pulst S.M., Raphael A.R., Ravits J.M., Ren Z., Rouleau G.A., Sapp P.C., Sims K.B., Staropoli J.F., Waite L.L., Wang Q., Wimbish J.R., Xin W.W., Phatnani H., Kwan J., Broach J., Arcila-Londono X., Lee E.B., Van Deerlin V.M., Fraenkel E., Ostrow L.W., Baas F., Zaitlen N., Berry J.D., Malaspina A., Fratta P., Cox G.A., Thompson L.M., Finkbeiner S., Dardiotis E., Hornstein E., MacGowan D.J.L., Heiman-Patterson T., Hammell M.G., Patsopoulos N.A., Dubnau J., Nath A., Musunuri R.L., Evani U.S., Abhyankar A., Zody M.C., Kaye J., Wyman S.K., LeNail A., Lima L., Rothstein J.D., Svendsen C.N., Van Eyk J.E., Maragakis N.J., Kolb S.J., Cudkowicz M., Baxi E., Benatar M., Taylor J.P., Wu G., Rampersaud E., Wuu J., Rademakers R., Zuchner S., Schule R., McCauley J., Hussain S., Cooley A., Wallace M., Clayman C., Barohn R., Statland J., Swenson A., Jackson C., Trivedi J., Khan S., Katz J., Jenkins L., Burns T., Gwathmey K., Caress J., McMillan C., Elman L., Pioro E.P., Heckmann J., So Y., Walk D., Maiser S., Zhang J., Silani V., Gellera C., Ratti A., Taroni F., Lauria G., Verde F., Fogh I., Tiloca C., Comi G.P., Soraru G., Cereda C., De Marchi F., Corti S., Ceroni M., Siciliano G., Filosto M., Inghilleri M., Peverelli S., Colombrita C., Poletti B., Maderna L., Del Bo R., Gagliardi S., Querin G., Bertolin C., Pensato V., Castellotti B., Camu W., Mouzat K., Lumbroso S., Corcia P., Meininger V., Besson G., Lagrange E., Clavelou P., Guy N., Couratier P., Vourch P., Danel V., Bernard E., Lemasson G., Laaksovirta H., Myllykangas L., Jansson L., Valori M., Ealing J., Hamdalla H., Rollinson S., Pickering-Brown S., Orrell R.W., Sidle K.C., Hardy J., Singleton A.B., Johnson J.O., Arepalli S., Polak M., Asress S., Al-Sarraj S., King A., Troakes C., Vance C., de Belleroche J., ten Asbroek A.L.M.A., Munoz-Blanco J.L., Hernandez D.G., Ding J., Gibbs J.R., Scholz S.W., Floeter M.K., Campbell R.H., Landi F., Bowser R., Kirby J., Pamphlett R., Gerhard G., Dunckley T.L., Brady C.B., Kowall N.W., Troncoso J.C., Le Ber I., Heiman-Patterson T.D., Kamel F., Van Den Bosch L., Strom T.M., Meitinger T., Shatunov A., Van Eijk K.R., de Carvalho M., Kooyman M., Middelkoop B., Moisse M., McLaughlin R.L., Van Es M.A., Weber M., Boylan K.B., Van Blitterswijk M., Morrison K.E., Basak A.N., Mora J.S., Drory V.E., Shaw P.J., Turner M.R., Talbot K., Hardiman O., Williams K.L., Fifita J.A., Nicholson G.A., Blair I.P., Esteban-Perez J., Garcia-Redondo A., Al-Chalabi A., Al Kheifat A., Andersen P.M., Chio A., Cooper-Knock J., Dekker A., Redondo A.G., Gotkine M., Hide W., Iacoangeli A., Kiernan M., Landers J.E., Mill J., Neto M.M., Pardina J.M., Newhouse S., Pinto S., Pulit S., Robberecht W., Shaw C., Sproviero W., Tazelaar G., Van Damme P., van den Berg L.H., van Vugt J., Veldink J.H., Zatz M., Bauer D.C., Twine N.A., Rogaeva E., Zinman L., Brice A., Feldman E.L., Ludolph A.C., Weishaupt J.H., Trojanowski J.Q., Stone D.J., Tienari P., Shaw C.E., Traynor B.J., ITALSGEN Consortium, Genomic Translation ALS Care GTAC, ALS Sequencing Consortium, NYGC ALS Consortium, Answer ALS Fdn, Clinical Res ALS Related Disorders, SLAGEN Consortium, French ALS Consortium, Project MinE ALS Sequencing Consor, Medical Research Council (MRC), ANS - Complex Trait Genetics, Human Genetics, ARD - Amsterdam Reproduction and Development, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Università cattolica del Sacro Cuore [Roma] (Unicatt), Centre référent Sclérose Latérale Amyotrophique [CHRU Montpellier] (SLA CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1), Lunar and Planetary Laboratory [Tucson] (LPL), University of Arizona, Università degli studi di Torino (UNITO), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), New York Genome Center [New York], New York Genome Center, Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), St Jude Children's Research Hospital, Howard Hughes Medical Institute [Chevy Chase] (HHMI), Howard Hughes Medical Institute (HHMI), Centre de compétence de la Sclérose Latérale Amyotrophique [CHRU Tours] (SLA CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), University College of London [London] (UCL), Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS), King‘s College London, University of New Haven [Connecticut], Princeton University, Laboratoire de Biochimie [CHRU Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Helmholtz-Zentrum München (HZM), University Medical Center [Utrecht], Deutsches Forschungszentrum für Künstliche Intelligenz GmbH = German Research Center for Artificial Intelligence (DFKI), Mayo Clinic [Jacksonville], Trinity College Dublin, Maurice Wohl Clinical Neuroscience Institut, Tanz Center Research in Neurodegenerative Diseases [Toronto], University of Toronto, Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Repositório da Universidade de Lisboa, Nicolas, A, Kenna, K, Renton, A, Ticozzi, N, Faghri, F, Chia, R, Dominov, J, Kenna, B, Nalls, M, Keagle, P, Rivera, A, van Rheenen, W, Murphy, N, van Vugt, J, Geiger, J, van der Spek, R, Pliner, H, Shankaracharya, N, Smith, B, Marangi, G, Topp, S, Abramzon, Y, Gkazi, A, Eicher, J, Kenna, A, Logullo, F, Simone, I, Logroscino, G, Salvi, F, Bartolomei, I, Borghero, G, Murru, M, Costantino, E, Pani, C, Puddu, R, Caredda, C, Piras, V, Tranquilli, S, Cuccu, S, Corongiu, D, Melis, M, Milia, A, Marrosu, F, Marrosu, M, Floris, G, Cannas, A, Capasso, M, Caponnetto, C, Mancardi, G, Origone, P, Mandich, P, Conforti, F, Cavallaro, S, Mora, G, Marinou, K, Sideri, R, Penco, S, Mosca, L, Lunetta, C, Pinter, G, Corbo, M, Riva, N, Carrera, P, Volanti, P, Mandrioli, J, Fini, N, Fasano, A, Tremolizzo, L, Arosio, A, Ferrarese, C, Trojsi, F, Tedeschi, G, Monsurrò, M, Piccirillo, G, Femiano, C, Ticca, A, Ortu, E, La Bella, V, Spataro, R, Colletti, T, Sabatelli, M, Zollino, M, Conte, A, Luigetti, M, Lattante, S, Santarelli, M, Petrucci, A, Pugliatti, M, Pirisi, A, Parish, L, Occhineri, P, Giannini, F, Battistini, S, Ricci, C, Benigni, M, Cau, T, Loi, D, Calvo, A, Moglia, C, Brunetti, M, Barberis, M, Restagno, G, Casale, F, Marrali, G, Fuda, G, Ossola, I, Cammarosano, S, Canosa, A, Ilardi, A, Manera, U, Grassano, M, Tanel, R, Pisano, F, Mazzini, L, Messina, S, D'Alfonso, S, Corrado, L, Ferrucci, L, Harms, M, Goldstein, D, Shneider, N, Goutman, S, Simmons, Z, Miller, T, Chandran, S, Pal, S, Manousakis, G, Appel, S, Simpson, E, Wang, L, Baloh, R, Gibson, S, Bedlack, R, Lacomis, D, Sareen, D, Sherman, A, Bruijn, L, Penny, M, Moreno, C, Kamalakaran, S, Allen, A, Boone, B, Brown, R, Carulli, J, Chesi, A, Chung, W, Cirulli, E, Cooper, G, Couthouis, J, Day-Williams, A, Dion, P, Gitler, A, Glass, J, Han, Y, Harris, T, Hayes, S, Jones, A, Keebler, J, Krueger, B, Lasseigne, B, Levy, S, Lu, Y, Maniatis, T, McKenna-Yasek, D, Myers, R, Petrovski, S, Pulst, S, Raphael, A, Ravits, J, Ren, Z, Rouleau, G, Sapp, P, Sims, K, Staropoli, J, Waite, L, Wang, Q, Wimbish, J, Xin, W, Phatnani, H, Kwan, J, Broach, J, Arcila-Londono, X, Lee, E, Van Deerlin, V, Fraenkel, E, Ostrow, L, Baas, F, Zaitlen, N, Berry, J, Malaspina, A, Fratta, P, Cox, G, Thompson, L, Finkbeiner, S, Dardiotis, E, Hornstein, E, Macgowan, D, Heiman-Patterson, T, Hammell, M, Patsopoulos, N, Dubnau, J, Nath, A, Musunuri, R, Evani, U, Abhyankar, A, Zody, M, Kaye, J, Wyman, S, Lenail, A, Lima, L, Rothstein, J, Svendsen, C, Van Eyk, J, Maragakis, N, Kolb, S, Cudkowicz, M, Baxi, E, Benatar, M, Taylor, J, Wu, G, Rampersaud, E, Wuu, J, Rademakers, R, Züchner, S, Schule, R, Mccauley, J, Hussain, S, Cooley, A, Wallace, M, Clayman, C, Barohn, R, Statland, J, Swenson, A, Jackson, C, Trivedi, J, Khan, S, Katz, J, Jenkins, L, Burns, T, Gwathmey, K, Caress, J, Mcmillan, C, Elman, L, Pioro, E, Heckmann, J, So, Y, Walk, D, Maiser, S, Zhang, J, Silani, V, Gellera, C, Ratti, A, Taroni, F, Lauria, G, Verde, F, Fogh, I, Tiloca, C, Comi, G, Sorarù, G, Cereda, C, De Marchi, F, Corti, S, Ceroni, M, Siciliano, G, Filosto, M, Inghilleri, M, Peverelli, S, Colombrita, C, Poletti, B, Maderna, L, Del Bo, R, Gagliardi, S, Querin, G, Bertolin, C, Pensato, V, Castellotti, B, Camu, W, Mouzat, K, Lumbroso, S, Corcia, P, Meininger, V, Besson, G, Lagrange, E, Clavelou, P, Guy, N, Couratier, P, Vourch, P, Danel, V, Bernard, E, Lemasson, G, Laaksovirta, H, Myllykangas, L, Jansson, L, Valori, M, Ealing, J, Hamdalla, H, Rollinson, S, Pickering-Brown, S, Orrell, R, Sidle, K, Hardy, J, Singleton, A, Johnson, J, Arepalli, S, Polak, M, Asress, S, Al-Sarraj, S, King, A, Troakes, C, Vance, C, de Belleroche, J, ten Asbroek, A, Muñoz-Blanco, J, Hernandez, D, Ding, J, Gibbs, J, Scholz, S, Floeter, M, Campbell, R, Landi, F, Bowser, R, Kirby, J, Pamphlett, R, Gerhard, G, Dunckley, T, Brady, C, Kowall, N, Troncoso, J, Le Ber, I, Kamel, F, Van Den Bosch, L, Strom, T, Meitinger, T, Shatunov, A, Van Eijk, K, de Carvalho, M, Kooyman, M, Middelkoop, B, Moisse, M, Mclaughlin, R, Van Es, M, Weber, M, Boylan, K, Van Blitterswijk, M, Morrison, K, Basak, A, Mora, J, Drory, V, Shaw, P, Turner, M, Talbot, K, Hardiman, O, Williams, K, Fifita, J, Nicholson, G, Blair, I, Esteban-Pérez, J, García-Redondo, A, Al-Chalabi, A, Al Kheifat, A, Andersen, P, Chio, A, Cooper-Knock, J, Dekker, A, Redondo, A, Gotkine, M, Hide, W, Iacoangeli, A, Kiernan, M, Landers, J, Mill, J, Neto, M, Pardina, J, Newhouse, S, Pinto, S, Pulit, S, Robberecht, W, Shaw, C, Sproviero, W, Tazelaar, G, van Damme, P, van den Berg, L, van Eijk, K, van Es, M, Veldink, J, Zatz, M, Bauer, D, Twine, N, Rogaeva, E, Zinman, L, Brice, A, Feldman, E, Ludolph, A, Weishaupt, J, Trojanowski, J, Stone, D, Tienari, P, Chiò, A, Traynor, B, Nicolas, Aude, Kenna, Kevin P, Renton, Alan E, Ticozzi, Nicola, Faghri, Faraz, Chia, Ruth, Dominov, Janice A, Kenna, Brendan J, Nalls, Mike A, Keagle, Pamela, Rivera, Alberto M, van Rheenen, Wouter, Murphy, Natalie A, van Vugt, Joke J F A, Geiger, Joshua T, Van der Spek, Rick A, Pliner, Hannah A, Shankaracharya, Null, Smith, Bradley N, Marangi, Giuseppe, Topp, Simon D, Abramzon, Yevgeniya, Gkazi, Athina Soragia, Eicher, John D, Kenna, Aoife, Mora, Gabriele, Calvo, Andrea, Mazzini, Letizia, Riva, Nilo, Mandrioli, Jessica, Caponnetto, Claudia, Battistini, Stefania, Volanti, Paolo, La Bella, Vincenzo, Conforti, Francesca L, Borghero, Giuseppe, Messina, Sonia, Simone, Isabella L, Trojsi, Francesca, Salvi, Fabrizio, Logullo, Francesco O, D'Alfonso, Sandra, Corrado, Lucia, Capasso, Margherita, Ferrucci, Luigi, Logullo, Fo, Murru, Mr, Marrosu, Mg, Conforti, Fl, Pinter, Gl, Tedeschi, Gioacchino, Monsurrò, Maria Rosaria, Parish, Ld, Cau, Tb, Moreno, Cristiane de Araujo Martin, Kamalakaran, Sitharthan, Goldstein, David B, Gitler, Aaron D, Harris, Tim, Myers, Richard M, Phatnani, Hemali, Musunuri, Rajeeva Lochan, Evani, Uday Shankar, Abhyankar, Avinash, Zody, Michael C, Kaye, Julia, Finkbeiner, Steven, Wyman, Stacia K, Lenail, Alex, Lima, Leandro, Fraenkel, Ernest, Svendsen, Clive N, Thompson, Leslie M, Van Eyk, Jennifer E, Berry, James D, Miller, Timothy M, Kolb, Stephen J, Cudkowicz, Merit, Baxi, Emily, Benatar, Michael, Taylor, J Paul, Rampersaud, Evadnie, Wu, Gang, Wuu, Joanne, Lauria, Giuseppe, Verde, Federico, Fogh, Isabella, Tiloca, Cinzia, Comi, Giacomo P, Sorarù, Gianni, Cereda, Cristina, Corcia, Philippe, Laaksovirta, Hannu, Myllykangas, Liisa, Jansson, Lilja, Valori, Miko, Ealing, John, Hamdalla, Hisham, Rollinson, Sara, Pickering-Brown, Stuart, Orrell, Richard W, Sidle, Katie C, Malaspina, Andrea, Hardy, John, Singleton, Andrew B, Johnson, Janel O, Arepalli, Sampath, Sapp, Peter C, McKenna-Yasek, Diane, Polak, Meraida, Asress, Seneshaw, Al-Sarraj, Safa, King, Andrew, Troakes, Claire, Vance, Caroline, de Belleroche, Jacqueline, Baas, Frank, Ten Asbroek, Anneloor L M A, Muñoz-Blanco, José Lui, Hernandez, Dena G, Ding, Jinhui, Gibbs, J Raphael, Scholz, Sonja W, Floeter, Mary Kay, Campbell, Roy H, Landi, Francesco, Bowser, Robert, Pulst, Stefan M, Ravits, John M, Macgowan, Daniel J L, Kirby, Janine, Pioro, Erik P, Pamphlett, Roger, Broach, Jame, Gerhard, Glenn, Dunckley, Travis L, Brady, Christopher B, Kowall, Neil W, Troncoso, Juan C, Le Ber, Isabelle, Mouzat, Kevin, Lumbroso, Serge, Heiman-Patterson, Terry D, Kamel, Freya, Van Den Bosch, Ludo, Baloh, Robert H, Strom, Tim M, Meitinger, Thoma, Shatunov, Aleksey, Van Eijk, Kristel R, de Carvalho, Mamede, Kooyman, Maarten, Middelkoop, Ba, Moisse, Matthieu, Mclaughlin, Russell L, Van Es, Michael A, Weber, Marku, Boylan, Kevin B, Van Blitterswijk, Marka, Rademakers, Rosa, Morrison, Karen E, Basak, A Nazli, Mora, Jesús S, Drory, Vivian E, Shaw, Pamela J, Turner, Martin R, Talbot, Kevin, Hardiman, Orla, Williams, Kelly L, Fifita, Jennifer A, Nicholson, Garth A, Blair, Ian P, Rouleau, Guy A, Esteban-Pérez, Jesú, García-Redondo, Alberto, Al-Chalabi, Ammar, Rogaeva, Ekaterina, Zinman, Lorne, Ostrow, Lyle W, Maragakis, Nicholas J, Rothstein, Jeffrey D, Simmons, Zachary, Cooper-Knock, Johnathan, Brice, Alexi, Goutman, Stephen A, Feldman, Eva L, Gibson, Summer B, Taroni, Franco, Ratti, Antonia, Gellera, Cinzia, Van Damme, Philip, Robberecht, Wim, Fratta, Pietro, Sabatelli, Mario, Lunetta, Christian, Ludolph, Albert C, Andersen, Peter M, Weishaupt, Jochen H, Camu, William, Trojanowski, John Q, Van Deerlin, Vivianna M, Brown, Robert H, van den Berg, Leonard H, Veldink, Jan H, Harms, Matthew B, Glass, Jonathan D, Stone, David J, Tienari, Pentti, Silani, Vincenzo, Chiò, Adriano, Shaw, Christopher E, Traynor, Bryan J, Landers, John E, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: Male, Als gene, Genome-wide association study, FAMILIAL ALS, ALS, axonal transport, cargo, GWAS, KIF5A, WES, WGS, 0302 clinical medicine, 80 and over, Psychology, Aetiology, Aged, 80 and over, 0303 health sciences, French ALS Consortium, Kinesin, KINESIN HEAVY-CHAIN, Cognitive Sciences, Human, Hereditary spastic paraplegia, Neuroscience(all), Single-nucleotide polymorphism, TARGETED DISRUPTION, Article, 03 medical and health sciences, Genetics, Humans, Amino Acid Sequence, Loss function, Aged, HEXANUCLEOTIDE REPEAT, Neuroscience (all), MUTATIONS, Amyotrophic Lateral Sclerosis, 3112 Neurosciences, 1702 Cognitive Science, medicine.disease, ITALSGEN Consortium, Answer ALS Foundation, 030104 developmental biology, ALS Sequencing Consortium, Human medicine, 1109 Neurosciences, 030217 neurology & neurosurgery, 0301 basic medicine, [SDV]Life Sciences [q-bio], Kinesins, Neurodegenerative, Genetic analysis, Genome, AMYOTROPHIC-LATERAL-SCLEROSIS, 3124 Neurology and psychiatry, Cohort Studies, Pathogenesis, Loss of Function Mutation, Missense mutation, 2.1 Biological and endogenous factors, Amyotrophic lateral sclerosis, NYGC ALS Consortium, General Neuroscience, ALS, axonal transport, cargo, GWAS, KIF5A, WES, WGS, Middle Aged, Phenotype, Settore MED/26 - NEUROLOGIA, Neurological, Project MinE ALS Sequencing Consortium, Female, Adult, Biology, GENOTYPE IMPUTATION, Genome-Wide Association Study, Young Adult, NO, Rare Diseases, medicine, SLAGEN Consortium, Gene, 030304 developmental biology, Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium, Neurology & Neurosurgery, Human Genome, Neurosciences, AXONAL-TRANSPORT, Brain Disorders, Family member, DNA-DAMAGE, MOTOR-NEURONS, 3111 Biomedicine, Cohort Studie, Genomic Translation for ALS Care (GTAC) Consortium, Amyotrophic Lateral Sclerosi
Abstract: © 2018 Elsevier Inc., To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.
Published: 2018

37. A Nonsynonymous Mutation in PLCG2 Reduces the Risk of Alzheimer's Disease, Dementia with Lewy-Bodies and Frontotemporal Dementia, and Increases the Likelihood of Longevity

Author: Bart N.M. van Berckel, Begoña Indakoetxea, Estrella Morenas-Rodríguez, Cornelis Blauwendraat, Christopher Morris, Patrick F. Chinnery, Iris E. Jansen, Danielle Posthuma, Eliezer Masliah, Ingmar Skoog, Heinz Wiendl, Jordi Clarimón, Adela Orellana, Carmen Lage, Neill R. Graff-Radford, Monica Diez-Fairen, Michael Wagner, Rosa Rademakers, Tanis J. Ferman, Daniel Alcolea, Henne Holstege, Zbigniew K. Wszolek, Alfredo Ramirez, Marcel J. T. Reinders, Itziar de Rojas, Kristel R. van Eijk, Erik B. van den Akker, Bradley F. Boeve, Jay A. van Gerpen, Marian Beekman, Agustín Ruiz, Jeanne E. Savage, Modifying factors in Fronto-Temporal Dementia, James W. Ironside, Najada Stringa, Ronald C. Petersen, Lluís Tárraga, Minerva M. Carrasquillo, Adolfo López de Munain, Pascual Sanchez-Juan, Fermin Moreno, Martin Scherer, Afina W. Lemstra, Giovanni Coppola, Henrik Zetterberg, RiMod-FTD Rsk, Nilufer Ertekin-Taner, Ignacio Illán-Gala, Owen A. Ross, Thorkild Ingvor Arrild Sørensen, Alexander Pantelyat, Eline Slagboom, Wiesje M. van der Flier, Till F. M. Andlauer, Amit Kawalia, Bernard Jeune, Wolfgang Maier, Sonia Moreno-Grau, Sven J. van der Lee, Olivia J. Conway, Mariet Allen, Marianne Nygaard, Marc Hulsman, Alberto Lleó, Uwe K. Zettl, Ellen A. Nohr, Philip Scheltens, Jonas Mengel-From, Luca Kleineidam, Yolande A.L. Pijnenburg, Samantha L. Strickland, Isabel Hernández, Olga Pletnikova, Niccolò Tesi, Michael J. Keogh, Juan C. Troncoso, Natasja M. van Schoor, Steffi G. Riedel-Heller, Wei Wei, Oriol Dols-Icardo, David S. Knopman, Ryan J. Uitti, Pau Pastor, Nina Beker, Javier Simón-Sánchez, Kaare Christensen, Anna Zettergren, Miren Zulaica, Eloy Rodríguez Rodríguez, Bernhard Hemmer, Martijn A. Huisman, Thomas Gasser, Peter Heutink, Jason A. Chen, Mercè Boada, Maria Carolina Dalmasso, Xue Wang, Dennis W. Dickson, Florian Then Bergh, Lyduine Collij, Kaj Blennow, Manuel A. Friese, Juan Fortea, Netherlands Brain Bank, and Sonja W. Scholz
Subjects: medicine.medical_specialty, Parkinson's disease, business.industry, Dementia with Lewy bodies, Odds ratio, Disease, medicine.disease, Progressive supranuclear palsy, Internal medicine, Cohort, Medicine, Dementia, business, Frontotemporal dementia
Abstract: Background: PLCG2 plays an important role in immune system signaling, and is expressed in several immune cell types including microglia in the brain. In 2017, the genetic variant rs72824905 (p.Pro522Arg) in the PLCG2 gene (Phospholipase C Gamma 2) was associated with a reduced risk of Alzheimer's disease (AD). Here we investigated whether the rs72824905 variant had a similar protective effect on six other brain diseases. We further tested if rs72824905 increases the likelihood of longevity, since a reduced risk of neurodegenerative diseases might associate with general survival. Methods: We investigated the effect of carrying rs72824905 on disease risk in a total of 53,627 patients with one of seven brain diseases. We studied AD (N = 4,985), frontotemporal dementia (FTD) (N = 2,437), dementia with Lewy-bodies (DLB) (N = 1,446), progressive supranuclear palsy (PSP) (N = 882), Parkinson's disease (PD) (N = 28,448) amyotrophic lateral sclerosis (ALS) (N = 10,953) and multiple sclerosis (MS) (N = 4,476) by comparing them with in total 149,290 controls using logistic regression models. Next, we studied the effect of carrying rs72824905 on longevity by comparing individuals who reached at least 90 years (N = 3,516) with individuals who died before age 90 years or were last screened before 90 years (N = 9,677). In addition, we studied the association of rs72824905 with survival after the age of 90 in a subset of long-lived individuals followed until death. Finally, we supported our findings by studying by-proxy phenotypes in the ~450.000 participants of the UK Biobank. We associated the rs72824905 genotypes of UK Biobank participants with parental history of dementia as proxy for dementia and as a proxy for longevity we studied parental age over 90 as well as parental age over 95 years of age. All individuals were of European ancestry. Results: The rs72824905-G allele associated with a reduced AD risk (Odds ratio (OR) = 0·57, p = 4·7×10-4), a reduced DLB risk (OR = 0·54, p = 4·5×10-2) and reduced FTD risk (OR = 0·61, p = 1·0×10 2). We did not find evidence for association of rs72824905 with the risks of PSP (OR = 1·46, p = 0·19), PD (OR = 1·18, p = 0·10), ALS (OR = 1·07, p = 0·26) or MS (OR = 0·99, p = 0·95). The rs72824905-G allele was associated with a 1·49 increased likelihood of reaching >90 years (p = 6.4×10-3): variant carriers lived longer after the age of 90 years, median 4.7 (inter quartile range = 1·9 - 7·4) years compared to non-carriers 3.3 (IQR = 1·4 - 5·8) (Hazard ratio = 0·75, p = 0·07). By-proxy analyses supported the associations of rs728824905 with dementia as well as longevity. Variant carriers had a lower likelihood of having a parent with dementia (OR = 0·88, p = 1·8×10 3) and had a significantly increased likelihood of having a parent aged >95 years (OR = 1·19, p = 2·1×10-2). Conclusions: Our results show that rs72824905 in PLCG2 protects from AD, DLB and FTD and increases the likelihood of longevity. Together, our findings highlight a central role for PLCG2 related immune signaling in the brain, which should be the subject of future studies as a drug target for multiple brain diseases. Funding Statement: The authors present a short description of 16 cohorts, often including multiple sites or studies, that contributed to this manuscript and their funding sources in Supplementary Table 1: Amsterdam dementia Cohort (ADC), 100-Plus study, German Study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe), Brain compendium, Clinical AD, Sweden, Danish data, Fundacio ACE (FACE), Genetics of Healthy Ageing Study (GEHA – NL), Gothenburg Birth Cohort (GBC) Studies, International FTD-Genomics Consortium (IFGC), Kompetenznetz Multiple Sklerose (KKNMS), Longitudinal Aging Study Amsterdam (LASA), Leiden Longevity Study, Maria Carolina Dalmasso, Mayo Clinic AD, DLB, PD, PSP, NDRU cohort, Oviedo, Pascual Sanchez-Juan, Project MinE, Risk and modifying factors in Fronto Temporal Dementia (RiMoD-FTD): follows The SPIN cohort, San Sebastian, UK Biobank analysis, IPDGC (The International Parkinson Disease Genomics Consortium). Declaration of Interests: The authors declare no competing interest related to this work. Ethics Approval Statement: Studies were approved by corresponding ethics committees and informed consent was obtained for all participants.
Published: 2018

38. Relating C-reactive Protein to Psychopathology after Cardiac Surgery and Intensive Care Unit Admission: A Mendelian Randomization Study

Author: Bochao Danae Lin, Kristel R. van Eijk, Erwin Bekema, Jelena Medic, Juliette L. Broersen, Manon H.J. Hillegers, Lotte Kok, Jurjen J. Luykx, and Dieuwke S. Veldhuijzen
Subjects: medicine.medical_specialty, biology, business.industry, C-reactive protein, Single-nucleotide polymorphism, Logistic regression, Intensive care unit, law.invention, law, Internal medicine, Mendelian randomization, Cohort, biology.protein, Medicine, business, Psychopathology, Genetic association
Abstract: Patients admitted to an intensive care unit (ICU) are subjected to a high burden of stress, rendering them prone to develop stress-related psychopathology. Dysregulation of inflammation and, more specifically, upregulation of inflammatory markers such as C-reactive protein (CRP) is potentially key in development of post-ICU psychopathology.To investigate the effects of state-independent CRP on symptoms of post-traumatic stress disorder (PTSD) and depression after ICU admission, we analysed the three leading single nucleotide polymorphisms (SNPs) of loci most strongly associated with blood CRP levels (i.e. rs2794520, rs4420638, and rs1183910) in an ICU survivor cohort. Genetic association was estimated by linear and logistical regression models of individual SNPs and genetic risk score (GRS) profiling. Mendelian Randomization (MR) was used to investigate potential causal relationships.Single-SNP analyses were non-significant for both quantitative and binary trait analyses after correction for multiple testing. In addition, GRS results were non-significant and explained little variance in psychopathology. Moreover, MR analysis did not reveal any causality and MR-Egger regression showed no evidence of pleiotropic effects (p-pleiotropy >0.05). Furthermore, estimation of causality between these loci and other psychiatric disorders was similarly non-significant.In conclusion, by applying a range of statistical models we demonstrate that the strongest plasma CRP-influencing genetic loci are not associated with post-ICU PTSD and depressive symptoms. Our findings add to an expanding body of literature on the absence of associations between trait CRP and neuropsychiatric phenotypes.
Published: 2017

39. Genetic Architecture of Subcortical Brain Structures in Over 40,000 Individuals Worldwide

Author: Arvin Saremi, Tomas Axelsson, Kristel R. van Eijk, Tonya White, Elena Shumskaya, Christine Macare, Christopher Chen, Neeltje E.M. van Haren, K Hegenscheid, Ingrid Melle, Benjamin S. Aribisala, Clyde Francks, Lisa R. Yanek, Konstantinos Arfanakis, Lars Nyberg, Nina Romanczuk-Seiferth, Clifford R. Jack, Thomas H. Wassink, Norman Delanty, Oscar L. Lopez, Jennifer S. Richards, Philippe Amouyel, William T. Longstreth, Michael W. Weiner, Maria J. Knol, Ralph Burkhardt, Ching-Yu Cheng, Wolfgang Hoffmann, Norbert Hosten, Alexander Teumer, Simone Reppermund, Markus M. Nöthen, Tien Yin Wong, Maria del C. Valdés Hernández, Bernd Kraemer, Murali Sargurupremraj, Amelia A. Assareh, Jessika E. Sussmann, Gabriel Cuellar-Partida, Ian J. Deary, Ganesh Chauhan, Christopher R.K. Ching, Arno Villringer, Dalia Kasperaviciute, Han G. Brunner, Srdjan Djurovic, Lachlan T. Strike, Albert V. Smith, Lars T. Westlye, Paul A. Nyquist, Bertram Müller-Myhsok, Phil Lee, Qiong Yang, Herve Lemaitre, Andreas Meyer-Lindenberg, Vidar M. Steen, Marc M. Bohlken, Rachel M. Brouwer, Charles DeCarli, Mar Matarin, Fabrice Crivello, Henry Völzke, Manuel Mattheisen, Bruno Vellas, Loes M. Olde Loohuis, Sudha Seshadri, Claudia L. Satizabal, Sebastian Mohnke, David C. Liewald, Li Shen, Kwangsik Nho, Simon E. Fisher, Deborah Janowitz, Wiro J. Niessen, Matthew J. Huentelman, Sylvane Desrivières, Ole A. Andreassen, Evan Fletcher, Christiane Wolf, Vilmundur Gudnason, Alejandro Arias-Vasquez, Charles C. White, Joshua C. Bis, Pauline Maillard, Ingrid Agartz, Oliver Grimm, Matthias Nauck, Andrew M. McIntosh, Iryna O. Fedko, Gianpiero L. Cavalleri, Andreas Heinz, Tulio Guadalupe, Andrew D. Johnson, Daan van Rooij, Thomas W. Mühleisen, Jessica A. Turner, Marieke Klein, Jia Yu Koh, Avram J. Holmes, Saud Alhusaini, Douglas N. Greve, Roberto Roiz-Santiañez, Nic J.A. van der Wee, Irina Filippi, Hans van Bokhoven, Miguel E. Rentería, Andrew J. Saykin, Marjolein M.J. van Donkelaar, Dan J. Stein, Randy L. Gollub, Sanjay M. Sisodiya, Honghuang Lin, Aaron Goldman, Patrizia Mecocci, Thomas Espeseth, Barbara Franke, Unn K. Haukvik, Theo G.M. van Erp, Venkata S. Mattay, Jonathan C Ipser, Catharina A. Hartman, Florian Holsboer, Saskia P. Hagenaars, Benedicto Crespo-Facorro, Manon Bernard, Jerome I. Rotter, Louis N. Vinke, Nastassja Koen, Vince D. Calhoun, Anders M. Dale, Dennis van der Meer, Jordan W. Smoller, Debra A. Fleischman, Janita Bralten, Hannah J. Jones, Lavinia Athanasiu, Hilleke E. Hulshoff Pol, Brenda W.J.H. Penninx, Peter R. Schofield, Roel A. Ophoff, J Wardlaw, Sven J. van der Lee, Katie L. McMahon, Esther Walton, Nicholas G. Martin, Gunter Schumann, Katharina Wittfeld, Perminder S. Sachdev, André G. Uitterlinden, Christophe Tzourio, Pieter J. Hoekstra, Roberto Toro, Henry Brodaty, Marcella Rietschel, David Ames, George Davey Smith, G. Bruce Pike, Alexa S. Beiser, Zdenka Pausova, Simon Lovestone, Robert C. Green, Greig I. de Zubicaray, Stephen M. Lawrie, Mark E. Bastin, Marco P. Boks, M. Mallar Chakravarty, Magda Tsolaki, Myriam Fornage, Nanda Rommelse, Andre F. Marquand, Anbupalam Thalamuthu, Helena Schmidt, Jason L. Stein, Bruce M. Psaty, Jan K. Buitelaar, Jean-Luc Martinot, Kazima B. Bulayeva, Henrik Walter, Xueqiu Jian, Yasaman Saba, Saima Hilal, Paul M. Thompson, Tamara B. Harris, Jaap Oosterlaan, Marie-José van Tol, Joshua L. Roffman, Bernard Mazoyer, Shuo Li, Nhat Trung Doan, Qiang Chen, John B.J. Kwok, Najaf Amin, Diana Tordesillas-Gutiérrez, Eco J. C. de Geus, Meike W. Vernooij, Andrew J. Schork, Susanne Erk, Daniel R. Weinberger, Grant W. Montgomery, Jean Shin, James T. Becker, Martine Hoogman, Philip L. De Jager, Dirk J. Heslenfeld, Derrek P. Hibar, Narelle K. Hansell, Andrew Simmons, Micael Andersson, Lucija Abramovic, Dorret I. Boomsma, Allison Stevens, Wei Wen, A. Veronica Witte, Owen Carmichael, Jayandra J. Himali, Asta Håberg, Hieab H.H. Adams, Nynke A. Groenewold, Sven Cichon, Wiepke Cahn, Lianne Schmaal, Shannon L. Risacher, Erik G. Jönsson, Shahrzad Kharabian Masouleh, Oliver Gruber, Tianye Jia, Hilkka Soininen, M. Kamran Ikram, Markus Loeffler, Philipp G. Sämann, Sungeun Kim, Jingyun Yang, Iwona Kłoszewska, Ryota Kanai, Christopher D. Whelan, Massimo Pandolfo, Dick J. Veltman, Diane M. Becker, Anouk den Braber, Hans J. Grabe, Neda Jahanshad, Yanhui Hu, Anita L. DeStefano, Beng-Choon Ho, Stephanie Le Hellard, Cornelia M. van Duijn, Georg Homuth, Tomáš Paus, Stéphanie Debette, Nicola J. Armstrong, Jouke-Jan Hottenga, Eric Westman, Tom V. Lee, Sarah E. Medland, Randy L. Buckner, Benno Pütz, Edith Hofer, Steven G. Potkin, Albert Hofman, Dennis van 't Ent, Sudheer Giddaluru, Tatiana Foroud, Guillén Fernández, John D. Eicher, Gareth E. Davies, Thomas H. Mosley, Michelle Luciano, Lenore J. Launer, Joshua W. Cheung, Markus Scholz, D. Höhn, Thomas Wolfers, Reinhold Schmidt, Arthur W. Toga, René S. Kahn, Nazanin Karbalai, Yuri Milaneschi, Margaret J. Wright, Martina Papmeyer, David A. Bennett, M. Arfan Ikram, Stefan Ehrlich, Marcel P. Zwiers, Karen A. Mather, and Joshua M. Shulman
Subjects: Candidate gene, Globus pallidus, nervous system, Putamen, Thalamus, Caudate nucleus, Synaptic signaling, Nucleus accumbens, Biology, Bioinformatics, Neuroscience, Genetic architecture
Abstract: Subcortical brain structures are integral to motion, consciousness, emotions, and learning. We identified common genetic variation related to the volumes of nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen, and thalamus, using genome-wide association analyses in over 40,000 individuals from CHARGE, ENIGMA and the UK-Biobank. We show that variability in subcortical volumes is heritable, and identify 25 significantly associated loci (20 novel). Annotation of these loci utilizing gene expression, methylation, and neuropathological data identified 62 candidate genes implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
Published: 2017

40. Project MinE: study design and pilot analyses of a large-scale whole genome sequencing study in amyotrophic lateral sclerosis

Author: Matthieu Moisse, Jesus S. Mora, Philip Van Damme, Annelot M. Dekker, Michael A. van Es, Gijs H.P. Tazelaar, William Sproviero, Pamela J. Shaw, Ammar Al-Chalabi, Leonard H. van den Berg, Christopher Shaw, Sara L. Pulit, Bas M. Middelkoop, Orla Hardiman, Kristel R. van Eijk, Wouter van Rheenen, A. Nazli Basak, Perry T.C. van Doormaal, Raymond D. Schellevis, Ahmad Al Khleifat, Ersen Kavak, Wim Robberecht, Karen E. Morrison, Jonathan D. Glass, Maarten Kooyman, Alfredo Iacoangeli, John E. Landers, William J. Brands, Russell L. McLaughlin, Jan H. Veldink, Stephen Newhouse, Kevin P. Kenna, Aleksey Shatunov, Winston Hide, Rick A.A. van der Spek, and Joke J.F.A. van Vugt
Subjects: Whole genome sequencing, 0303 health sciences, Project MinE, Computational biology, Biology, Bioinformatics, medicine.disease, 3. Good health, Minor allele frequency, 03 medical and health sciences, 0302 clinical medicine, Data sequences, Genetic variation, Genetic predisposition, medicine, Amyotrophic lateral sclerosis, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: The most recent genome-wide association study in amyotrophic lateral sclerosis (ALS) demonstrates a disproportionate contribution from low-frequency variants to genetic susceptibility of disease. We have therefore begun Project MinE, an international collaboration that seeks to analyse whole-genome sequence data of at least 15,000 ALS patients and 7,500 controls. Here, we report on the design of Project MinE and pilot analyses of newly whole-genome sequenced 1,264 ALS patients and 611 controls drawn from the Netherlands. As has become characteristic of sequencing studies, we find an abundance of rare genetic variation (minor allele frequency < 0.1 %), the vast majority of which is absent in public data sets. Principal component analysis reveals local geographical clustering of these variants within The Netherlands. We use the whole-genome sequence data to explore the implications of poor geographical matching of cases and controls in a sequence-based disease study and to investigate how ancestry-matched, externally sequenced controls can induce false positive associations. Also, we have publicly released genome-wide minor allele counts in cases and controls, as well as results from genic burden tests.
Published: 2017

41. Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

Author: Cristina Cereda, Jurjen J. Luykx, Sandra Meier, Derek W. Morris, Douglas M. Ruderfer, Mythily Subramaniam, Paul Cormican, Lyudmila Georgieva, John Landers, Silvana Penco, Marian L. Hamshere, Frank Dudbridge, Mari Nelis, Dick Schijven, Jimmy Lee, Sarah E. Bergen, Alessandro Padovani, Nicholas W. Wood, Meraida Polak, Hannelore Ehrenreich, Nancy G. Buccola, Noa Carrera, Stefan Herms, Panos Roussos, Marion Friedl, Teimuraz Silagadze, Jim van Os, Annette M. Hartmann, Ole A. Andreassen, R. Jeroen Pasterkamp, Sibylle G. Schwab, Aleksey Shatunov, Eli A. Stahl, David A. Collier, Farooq Amin, Michael Conlon O'Donovan, Guiqing Cai, Kung-Yee Liang, Denis C. Bauer, Charles Curtis, Brion S. Maher, Ashley R. Jones, Sara L. Pulit, Sarah Tosato, Milan Macek, Vivianna M. Van Deerlin, Vincenzo Silani, Pietro Fratta, Bettina Konte, Rosanna Tortelli, Dan Rujescu, T. Scott Stroup, Elizabeth Bevilacqua, Christian Lunetta, Bradley T. Webb, Christophe Tzourio, Patrick Vourc'h, Joel N. Hirschhorn, Gilbert Bensimon, Timothy G. Dinan, Thomas G. Schulze, Richard A. Belliveau, Daniel R. Weinberger, Andrew McQuillin, Qingqin S. Li, Orla Hardiman, Claudine Laurent, Masashi Ikeda, Tim Kahlke, Rodney J. Scott, Frans Henskens, Tune H. Pers, Wolfgang Lieb, Christian Hammer, Elvira Bramon, Hana Kuzelova-Ptackova, Raquelle I. Mesholam-Gately, Ingrid Melle, Nadine Cohen, David Cohen, Nazli Basak, Elisabeth Stögmann, Nelson B. Freimer, Peter Eichhammer, J. Mallet, Preben Bo Mortensen, Robert H. Brown, Wouter van Rheenen, Roberto Del Bo, Dai Wang, Laurent Essioux, Larry J. Seidman, Hreinn Stefansson, Erik G. Jönsson, Mads V. Hollegaard, Raymond C.K. Chan, Susana Pinto, Alexander Richards, Jubao Duan, Peter Holmans, George Kirov, Pablo V. Gejman, Philippe Amouyel, Stephanie Godard, Dieter B. Wildenauer, Martina Wiedau-Pazos, Stacy Steinberg, Ole Mors, Andres Metspalu, Rolf Adolfsson, Shaun Purcell, Hugh Gurling, Joseph I. Friedman, Erik Söderman, Mark Weiser, Giacomo P. Comi, James A. Knowles, Peter M. Andersen, Brien P. Riley, Nakao Iwata, Jeremy M. Silverman, Mark J. Daly, Elena Parkhomenko, Digby Quested, Srinivas Thirumalai, Ulrich Schall, Jan Lubinski, Dragan M. Svrakic, Aaron R. Wolen, S. Hong Lee, Andrew Pocklington, Bernard Lerer, Vahram Haroutunian, Matthew C. Kiernan, Kenneth L. Davis, Assen Jablensky, William Byerley, Karol Estrada, Aarno Palotie, Cinzia Tiloca, Eadbhard O'Callaghan, Perry T.C. van Doormaal, Colm McDonald, Federico Casale, Thomas Meitinger, Robert Freedman, Gerome Breen, Milena Blagojevic-Radivojkov, Ian P. Blair, Ann E. Pulver, Jan H. Veldink, Giancarlo Logroscino, Miaoxin Li, Abraham Reichenberg, Esben Agerbo, Siddharthan Chandran, Patrik K. E. Magnusson, Andrew M. McIntosh, Gianni Sorarù, Maura Brunetti, Xuebin Zheng, Madeline Alexander, James L. Kennedy, Douglas Blackwood, Menachem Fromer, Martilias S. Farrell, Alan R. Sanders, Dominic B. Rowe, Alexis Brice, Jonathan Pimm, Emily H. M. Wong, Jana Strohmaier, André G. Uitterlinden, Andrea Calvo, Carsten Drepper, John Q. Trojanowski, Marcella Rietschel, Siow Ann Chong, Karen E. Morrison, Sang-Yun Oh, Laura Nisenbaum, Margaret O'Brien, Alkes L. Price, Carin J. Meijer, Michael Davidson, John Powell, Petr Slominsky, Wiepke Cahn, Cinzia Gellera, Vihra Milanova, Peter M. Visscher, Patricia T. Michie, Dimitris Dikeos, Jianxin Shi, Veikko Salomaa, Philip Van Damme, James J. Crowley, Younes Mokrab, Valentina Escott-Price, Jesus S. Mora, Stanley V. Catts, David St Clair, Bernhard Landwehrmeyer, John Hardy, Kristin K. Nicodemus, Dominique Campion, Juha Veijola, Wim Robberecht, Thomas Meyer, Peter Lichtner, Christos Pantelis, Markus Weber, Nilo Riva, Jin P. Szatkiewicz, Michele T. Pato, Cinzia Bertolin, Frank P. Diekstra, Simon Arcuti, Bryan J. Mowry, Hon-Cheong So, Adriano Chiò, Viviana Pensato, Yunjung Kim, Jean-François Dartigues, Zita Ausrele Kucinskiene, Inez Myin-Germeys, Jaana Suvisaari, Sophie E. Legge, Roel A. Ophoff, Philippe Corcia, Gerald Nestadt, Stephan Ripke, Kuang Lin, Paola Giusti-Rodríguez, Michael John Owen, Chris C. A. Spencer, Safa Saker-Delye, Robert W. McCarley, Kimberley D. Chambert, Brandon Wormley, Isabella Fogh, Mamede de Carvalho, Pamela J. Shaw, Tõnu Esko, Ronald Y. L. Chan, Jianjun Liu, Tim B. Bigdeli, Christian R. Andres, David M. Hougaard, Michael Gill, Ammar Al-Chalabi, Colm O'Dushlaine, Rick A.A. van der Spek, Gary Donohoe, Tao Li, Jonathan D. Glass, Christopher Shaw, Draga Toncheva, Leonard H. van den Berg, Liene Nikitina-Zake, Morten Mattingsdal, François Salachas, Andrey Khrunin, Line Olsen, Jochen H. Weishaupt, Jo Knight, Katie Sidle, Filip Eftimov, Massimiliano Filosto, Russell L. McLaughlin, Pak C. Sham, Joshua L. Roffman, Thomas Hansen, Naser Durmishi, Deborah A. Nertney, Juha Karjalainen, Robert Swingler, Ditte Demontis, Vaidutis Kučinskas, Jennifer L. Moran, Leo McCluskey, Donald W. Black, Eric F.C. Cheung, Qiang Wang, Olli Pietilainen, Vera Golimbet, Anna K. Kähler, Clement C. Zai, Nigel Williams, Annelie Nordin, Wolfgang Maier, Bradley N. Smith, Ettore Beghi, Rosa Capozzo, Garth A. Nicholson, Markus M. Nöuthen, Jordan W. Smoller, Eric Y.H. Chen, Joseph D. Buxbaum, Letizia Mazzini, Andrea Malaspina, Antonio Julià, Stephanie Williams, Tracey L. Petryshen, Christine Payan, Johan G. Eriksson, Carmel M. Loughland, Elodie Drapeau, Lieuwe de Haan, Martin Begemann, Lukas Tittmann, Franziska Degenhardt, Mark Reimers, Jurgen Del Favero, Jacqueline I. Goldstein, Annelot M. Dekker, Sergi Papiol, Svetlana A. Limborska, René S. Kahn, Shuna Colville, Kelly L. Williams, Pamela Sklar, Diana O. Perkins, Lili Milani, Ayman H. Fanous, Nicola Ticozzi, Fernando Rivadeneira, Marianne de Visser, P. Nigel Leigh, James T.R. Walters, Josef Frank, Aiden Corvin, Silviu Alin Bacanu, John L. Waddington, Stephanie H. Witt, Tiina Paunio, Margot Albus, Catherine Lomen-Hoerth, Sara Marsal, Per Hoffmann, David Curtis, Cindy Maurel, Todd Lencz, Orietta Pansarasa, Manuel Mattheisen, Anneke J. van der Kooi, A. Hofman, Dermot Walsh, Hailiang Huang, Ann Olincy, Anders D. Børglum, Ricardo Rojas-García, William Sproviero, Albert C. Ludolph, Edward M. Scolnick, Danielle Posthuma, George N. Papadimitriou, Michael A. van Es, Fritz Zimprich, F. Anthony O'Neill, Lude Franke, Jouko Lönnqvist, Daniel G. Bradley, Sven Cichon, Susanna Abdulla, Kristel R. van Eijk, Ingrid Agartz, Elisabetta Pupillo, Milica Pejovic-Milovancevic, Antonia Ratti, Henrik B. Rasmussen, Kari Stefansson, Brendan Bulik-Sullivan, Béla Melegh, Stéphanie Millecamps, Janis Klovins, Enrico Domenici, Michael Sendtner, Kai-How Farh, Randy L. Buckner, Albert Hofman, Benjamin M. Neale, Naomi R. Wray, An Goris, Kang Sim, Lauren Elman, Giulio Genovese, Jens R. Wendland, Rita M. Cantor, Ariel Darvasi, Christina M. Hultman, Sandra D'Alfonso, Cristina Moglia, Carlos N. Pato, Sena Karachanak-Yankova, Nicholas John Craddock, Richard W. Orrell, Richard Bruggeman, Kenneth S. Kendler, Alan M. Pittman, Robin M. Murray, Richard E. Straub, Cathryn M. Lewis, Srdjan Djurovic, Vincent Meininger, Jeffrey A. Lieberman, Bertram Müller-Myhsok, Phil Lee, David J. Kavanagh, Srihari Gopal, Igor Nenadic, Matthew C. Keller, Christian R. Schubert, Jacob Gratten, Alexandra Durr, Roger Pamphlett, Douglas F. Levinson, Luba Kalaydjieva, Chiara Zecca, Anil K. Malhotra, Andre Franke, Vaughan J. Carr, Steven A. McCarroll, C. Robert Cloninger, Judit Bene, Ina Giegling, Wei Cheng, Hualin Simon Xi, Thomas Werge, Eric Strengman, Susanne Petri, Engilbert Sigurdsson, Mark Hansen, Patrick F. Sullivan, Kieran C. Murphy, Inge Joa, Complex Trait Genetics, McLaughlin, Russell L, Schijven, Dick, Van Rheenen, Wouter, Van Eijk, Kristel R, O'Brien, Margaret, Kahn, René S, Ophoff, Roel A, Goris, An, Bradley, Daniel G, Al-Chalabi, Ammar, Van Den Berg, Leonard H, Luykx, Jurjen J, Hardiman, Orla, Veldink, Jan H, Lee, S Hong, Project MinE GWAS Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Kučinskas, Vaidutis, Kučinskienė, Zita Aušrelė, Other departments, Neurology, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Adult Psychiatry, Schizophrenia Working Group of the Psychiatric Genomics Consortiumz, Germeys, Inez, Robberecht, Wim, and Van Damme, Philip
Subjects: 0301 basic medicine, Oncology, Genetics and Molecular Biology (all), Linkage disequilibrium, Multifactorial Inheritance, General Physics and Astronomy, Genome-wide association study, Comorbidity, VARIANTS, Neurodegenerative, Biochemistry, DISEASE, 3124 Neurology and psychiatry, Linkage Disequilibrium, Cohort Studies, 0302 clinical medicine, Genetics research, Odds Ratio, 2.1 Biological and endogenous factors, Amyotrophic lateral sclerosis, Aetiology, ARCHITECTURE, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Multidisciplinary, Chemistry (all), Motor neuron disease, Schizophrenia, BIPOLAR DISORDER, Single Nucleotide, Serious Mental Illness, 3. Good health, Mental Health, RC0346, motor neuron disease, Project MinE GWAS Consortium, medicine.medical_specialty, SUSCEPTIBILITY LOCI, Science, European Continental Ancestry Group, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, White People, 03 medical and health sciences, Physics and Astronomy (all), Rare Diseases, SDG 3 - Good Health and Well-being, Clinical Research, Internal medicine, MD Multidisciplinary, mental disorders, medicine, Genetics, Journal Article, Humans, Genetic Predisposition to Disease, Family, Bipolar disorder, GENOME-WIDE ASSOCIATION, Polymorphism, Biology, METAANALYSIS, business.industry, Amyotrophic Lateral Sclerosis, Human Genome, Case-control study, 3112 Neurosciences, Neurosciences, General Chemistry, Odds ratio, medicine.disease, R1, Brain Disorders, 030104 developmental biology, genetics research, Case-Control Studies, RC0321, Linear Models, PLEIOTROPY, Human medicine, 3111 Biomedicine, Biochemistry, Genetics and Molecular Biology (all), ALS, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05–21.6; P=1 × 10−4) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10−7). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08–1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies., Relatives of patients with amyotrophic lateral sclerosis have an unexpectedly high incidence of schizophrenia. Here, the authors show a genetic link between the two conditions, suggesting shared neurobiological mechanisms.
Published: 2017

42. Novel genetic loci associated with hippocampal volume

Author: Benjamin S. Aribisala, Marjolein M.J. van Donkelaar, Randy L. Gollub, Rachel M. Brouwer, Norman Delanty, Tomas Axelsson, Oscar L. Lopez, Thomas Espeseth, Alejandro Arias-Vasquez, Kristel R. van Eijk, Tien Yin Wong, Jeroen van der Grond, Georg Homuth, James T. Becker, Sebastian Guelfi, Anton J. M. de Craen, Bruno Vellas, Christopher R.K. Ching, Charles C. DeCarli, Janita Bralten, Lars T. Westlye, Ryota Hashimoto, Sampath Arepalli, Bertram Müller-Myhsok, Loes M. Olde Loohuis, Sudha Seshadri, Simon E. Fisher, K Hegenscheid, Konstantinos Arfanakis, Zdenka Pausova, Robert C. Green, Simone Reppermund, Katie L. McMahon, Ashley Beecham, Daan van Rooij, Marcel P. Zwiers, Karen A. Mather, Randy L. Buckner, Edith Hofer, Marcella Rietschel, Fabrice Crivello, Ronald H. Zielke, G. Bruce Pike, Thomas W. Mühleisen, Myriam Fornage, Kazutaka Ohi, Gareth E. Davies, Chantal Depondt, Gabriel Cuellar-Partida, Iryna O. Fedko, Peter R. Schofield, Steven G. Potkin, Albert Hofman, Paul M. Thompson, Wiro J. Niessen, Deborah Janowitz, Nicholas G. Martin, Li Shen, Mina Ryten, Meike W. Vernooij, Michael E. Weale, Tonya White, Dennis van 't Ent, Sudheer Giddaluru, Nanda Rommelse, Wei Wen, Sven J. van der Lee, Eco J. C. de Geus, Aaron Goldman, Joanne E. Curran, Qiang Chen, Jean Shin, Wayne C. Drevets, Thomas H. Mosley, Matthias Nauck, Massimo Pandolfo, Anders M. Dale, Paul A. Nyquist, Girma Woldehawariat, Francis J. McMahon, Najaf Amin, Emma J. Rose, Norbert Hosten, David J. Stott, Sigurdur Sigursson, Andrew J. Saykin, M. Kamran Ikram, Pieter J. Hoekstra, Neda Jahanshad, Grant W. Montgomery, Michael Weiner, Aad van der Lugt, Esther Walton, Gunter Schumann, Clyde Francks, Narelle K. Hansell, Xinmin Liu, Herve Lemaitre, Cornelia M. van Duijn, Ralph L. Sacco, Clinton B. Wright, Arvin Saremi, Clifford R. Jack, Andre G. Uitterlinden, G. Donohoe, Tomáš Paus, Michael Griswold, Peter T. Fox, Alan B. Zonderman, Lukas Pirpamer, Christiane Wolf, Aiden Corvin, Shannon L. Risacher, Ian Ford, Philippe Amouyel, Henrik Walter, Beng-Choon Ho, William T. Longstreth, M. Arfan Ikram, Hieab H.H. Adams, Colin Smith, Sungeun Kim, Simon Lovestone, Stefan Ehrlich, Benno Pütz, Markus M. Nöthen, Susana Muñoz Maniega, Ian J. Deary, Elena Shumskaya, Susan H. Blanton, Jerome I. Rotter, Neeltje E.M. van Haren, Mar Matarin, I. Kloszewska, Ganesh Chauhan, Anita L. DeStefano, Barbara Franke, Lars Nyberg, Tatiana Foroud, Tianye Jia, Manon Bernard, Unn K. Haukvik, Rebecca F. Gottesman, Srdjan Djurovic, Ching-Yu Cheng, Lachlan T. Strike, Alex P. Zijdenbos, Jouke-Jan Hottenga, Vince D. Calhoun, Yuri Milaneschi, David C. Glahn, Phil Lee, Amelia A. Assareh, Adaikalavan Ramasamy, Emma Sprooten, Debra A. Fleischman, David R. McKay, J. Raphael Gibbs, Bruce M. Psaty, Kazima B. Bulayeva, Bryan J. Traynor, Vilmundur Gudnason, Jessika E. Sussmann, Alexander Teumer, Guillén Fernández, Katharina Wittfeld, Christophe Tzourio, Dennis van der Meer, Wolfgang Hoffmann, Sebastian Mohnke, David C. Liewald, Jordan W. Smoller, Theo G.M. van Erp, Marcel Van Der Brug, Dara M. Cannon, Lenore J. Launer, D. Ames, Juan C. Troncoso, Brenda W.J.H. Penninx, Dhananjay Vaidya, Thomas D. Dyer, Marie-José van Tol, Han G. Brunner, Andrew Singleton, Lavinia Athanasiu, Adam M. Brickman, Eric Westman, P. Mecocci, Sandra Barral, Dick J. Veltman, Catharina A. Hartman, Benedicto Crespo-Facorro, Alexa S. Beiser, Vincent Chouraki, Nhat Trung Doan, Marieke Klein, Jaap Oosterlaan, Natalie A. Royle, John B.J. Kwok, Saud Alhusaini, Ingrid Melle, Roberto Toro, Ravi Duggirala, Allissa Dillman, Reinhold Schmidt, Lisa R. Yanek, Anbupalam Thalamuthu, Helena Schmidt, Derrek P. Hibar, Albert V. Smith, Jean-Luc Martinot, Thomas H. Wassink, Jennifer S. Richards, Oliver Martinez, Joshua L. Roffman, Sylvane Desrivières, Hilkka Soininen, Rene L. Olvera, Ole A. Andreassen, Diana Tordesillas-Gutiérrez, Claudia L. Satizabal, Owen Carmichael, Lianne Schmaal, Bernd Kraemer, Martine Hoogman, Daniah Trabzuni, Oliver Grimm, Andrew M. McIntosh, René S. Kahn, Nazanin Karbalai, Margaret J. Wright, Harald H.H. Göring, Martina Papmeyer, Roberto Roiz-Santiañez, Luigi Ferrucci, David A. Bennett, Kwangsik Nho, Gianpiero L. Cavalleri, Andreas Meyer-Lindenberg, Masashi Ikeda, Avram J. Holmes, Greig I. de Zubicaray, Andreas Heinz, Tatjana Rundek, Maria del C. Valdés Hernández, Dalia Kasperaviciute, Dan L. Longo, Matthew J. Huentelman, Wiepke Cahn, Beverly G. Windham, Michael A. Nalls, Philipp G. Sämann, Stella Trompet, Vidar M. Steen, Marc M. Bohlken, Christopher D. Whelan, Hilleke E. Hulshoff Pol, Susanne Erk, Dorret I. Boomsma, Dirk J. Heslenfeld, Masaki Fukunaga, D. Hoehn, Stephen M. Lawrie, Mark E. Bastin, Marco P. Boks, M. Mallar Chakravarty, M. R. Cookson, C. McDonald, Magda Tsolaki, Badri N. Vardarajan, Jason L. Stein, Jan K. Buitelaar, Erik G. Jönsson, Oliver Gruber, Robert Johnson, Jingyun Yang, Joshua C. Bis, J. Wouter Jukema, Tulio Guadalupe, Nina Romanczuk-Seiferth, Kjetil Nordbø Jørgensen, Henry Brodaty, Diane M. Becker, Anouk den Braber, Allison C. Nugent, Thomas Wolfers, John Hardy, Joanna M. Wardlaw, Michelle Luciano, Christine Macare, Dena G. Hernandez, D. Morris, John Blangero, Andrew J. Schork, Daniel R. Weinberger, Johanna Hass, Andrew Simmons, Micael Andersson, Lucija Abramovic, David S. Knopman, Mark Jenkinson, Roel A. Ophoff, Sanjay M. Sisodiya, Boris A. Gutman, Asta Håberg, Stephanie Le Hellard, Stéphanie Debette, Nicola J. Armstrong, Sarah E. Medland, Hans J. Grabe, Henry Völzke, Thomas E. Nichols, Manuel Mattheisen, Sven Cichon, Venkata S. Mattay, Ingrid Agartz, Stefan Ropele, Lorna M. Lopez, Hans van Bokhoven, Philip L. De Jager, Miguel E. Rentería, Laura Almasy, Arthur W. Toga, Michael Czisch, Florian Holsboer, Ryota Kanai, Nic J.A. van der Wee, Peter Kochunov, Perminder S. Sachdev, Andre F. Marquand, Christian Enzinger, Anderson M. Winkler, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, Metacohorts Consortium, Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique, Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), INSERM Research Center for Epidemiology and Biostatistics (U897) Team Neuroepidemiology, Bordeaux, France College of Health Sciences, University of Bordeaux, Bordeaux, France, sans affiliation, QIMR Berghofer Medical Research Institute, University of Washington [Seattle], Department of Psychiatry, Donders Centre for Neuroscience, Radboud University Medical Center [Nijmegen]-Radboud university [Nijmegen]-Radboud University Medical Center [Nijmegen]-Radboud university [Nijmegen], Department of Human Genetics, Radboud University Medical Center [Nijmegen], Institute of Psychiatry, Psychology & Neuroscience, King's College London, King‘s College London, University Medical Center [Utrecht], Department of Neurology and Neurosurgery [Montreal], Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada]-McGill University = Université McGill [Montréal, Canada], Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland (RCSI), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Sahlgrenska University Hospital [Gothenburg], Department of Biomedical Engineering, Illinois Institute of Technology (IIT), Rush University Medical Center [Chicago], University of Edinburgh, Lagos State University (LASU), Assistance Publique - Hôpitaux de Marseille (APHM), University of Oslo (UiO), Department of medical sciences, Uppsala University-Molecular Medicine-Science for Life Laboratory, John P. Hussman Institute for Human Genomics, University of Miami Leonard M. Miller School of Medicine (UMMSM), Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], Neurology Department, University of California, Davis (UCDavis-Neuro), University of California [Davis] (UC Davis), Douglas Mental Health University Institute, McGill University = Université McGill [Montréal, Canada], Université Lille Nord de France (COMUE), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Groupe d'imagerie neurofonctionnelle (GIN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), MetaGenoPolis, Institut National de la Recherche Agronomique (INRA), Haukeland University Hospital, University of Bergen (UiB), Ames Laboratory [Ames, USA], Iowa State University (ISU)-U.S. Department of Energy [Washington] (DOE), Johns Hopkins University School of Medicine [Baltimore], Language and Genetics Department [Nijmegen], Max Planck Institute for Psycholinguistics, Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, International Max Planck Research School for Language Sciences (IMPRS ), Laboratory of Neuro Imaging [Los Angeles] (LONI), Department of Mathematics [UCLA], Georgia Institute of Technology [Atlanta], Medizinische Klinik, Universitätsklinikum Heidelberg, Heidelberg, Germany, Greifswald University Hospital, Beijing Normal University (BNU), Aalborg University [Denmark] (AAU), UCL Institute of Neurology and Epilepsy Society, Department of Medicine, Imperial College London, Service d'Endocrinologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Center for Translational Research in Systems Neuroscience and Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center, Goettingen 37075, Germany, Medstar Research Institute, Clinical And Experimental Epilepsy, Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia, Department of Genomics, Life and Brain Center, University of Bonn, Institute of Human Genetics, Department of Biomedicine and the Centre for Integrative Sequencing, Aarhus University [Aarhus], VU University Medical Center [Amsterdam], Indiana University School of Medicine, Indiana University System, Indiana Alzheimer Disease Center, Indiana University System-Indiana University System, Institute of Food & Health, University College Dublin, University College Dublin [Dublin] (UCD), Department of Neurology, Statistical Genetics Group, Respiratory Epidemiology and Public Health, Imperial College London-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU)-MRC-HPA Centre for Environment and Health, Centro de Investigación Biomédica en Red Salud Mental [Madrid] (CIBER-SAM), Karakter Child and Adolescent Psychiatry University Centre [Nijmegen], Department of Neurology [Austria], Medical University Graz, Institut Parisien de Chimie Moléculaire (IPCM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, INSERM, Neuroepidemiology U708, Bordeaux, France, Department of Neurosciences [San Diego], University of California [San Diego] (UC San Diego), Department of Cognitive Sciences [San Diego], Wuhan University [China], Plymouth University, Dpt of Psychiatry [New Haven], Yale University School of Medicine, Queensland Institute of Medical Research, School of Psychology, University of Queensland, Brisbane 4072, Australia, University of Queensland [Brisbane], Centre for Advanced Imaging, University of Queensland, Brisbane 4072, Australia, Gènes, Synapses et Cognition (CNRS - UMR3571 ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL, Institute of Neurology [London], Department of Genetics, King Faisal Specialist Hospital and Research Centre, Depts of Radiology, Leiden University Medical Center (LUMC), University of Twente [Netherlands], Department of Psychiatry and Human Behavior [Irvine], University of California [Irvine] (UCI), RCMG Ghent, Universiteit Gent = Ghent University [Belgium] (UGENT), Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Department of Psychology [Oslo], Faculty of Social Sciences [Oslo], University of Oslo (UiO)-University of Oslo (UiO), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), National Institutes of Health [Bethesda] (NIH), Biospective [Montréal], KG Jebsen Centre for Psychosis Research, University of Oslo (UiO)-Institute of Clinical Medicine-Oslo University Hospital [Oslo], Southwest Foundation for Biomedical Research, Department of Psychiatry and National Ageing Research Institute, University of Melbourne, Université de Lille, Department of Clinical Genetics, Department of Experimental Physics, National University of Ireland Maynooth (Maynooth University), Texas Biomedical Research Institute [San Antonio, TX], The University of Texas Health Science Center at Houston (UTHealth), 849 Department of Human Genetics, Centre for Healthy Brain Ageing, University of New South Wales [Sydney] (UNSW), Dementia Collaborative Research Centre, Brain Center Rudolf Magnus, Department of Psychiatry, UMC Utrecht, Utrecht 3584 CX, The Netherlands, Department of Psychiatry [Boston], Massachusetts General Hospital [Boston], N.I. Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow 119333, Russia, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Department of Electrical and Computer Engineering [Albuquerque] (ECE Department), The University of New Mexico [Albuquerque], The Mind Research Network, Human Genetics Branch, National Institutes of Health [Bethesda] (NIH)-National Institute of Mental Health (NIMH), Division of Molecular and Cellular Therapeutics, Northwestern Polytechnical University [Xi'an] (NPU), Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Division of Medical Genetics, University of Basel (Unibas), Cell Biology and Gene Expression Section, National Institute of Health, Bethesda, Trinity College Dublin-St. James's Hospital, Neuropsychiatric Genetics Research Group, Trinity College Dublin, Bijvoet Center of Biomolecular Research [Utrecht], Utrecht University [Utrecht], York Structural Biology Laboratory, Department of Chemistry, University of York [York, UK], Harvard Medical School [Boston] (HMS), Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Program in Translational NeuroPsychiatric Genomics, Brigham and Women's Hospital [Boston], School of Psychology, University of Queensland, Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurology Division, Beaumont Hospital, Dublin 9, Ireland, Beaumont Hospital, Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Laboratory of Neurogenetics, Department of Genomics, Biological Psychology, Neuroscience Campus Amsterdam & EMGO Institute for Health and Care Research, VU University & VU Medical Center, Amsterdam 1081 BT, The Netherlands, Institut des Sciences du Mouvement Etienne Jules Marey (ISM), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), École des hautes études en sciences sociales (EHESS), Department of Radiology, Mayo Clinic, Robertson Centre for Biostatistics, University of Glasgow, Human Genetics Center, Department of Medical and Molecular Genetics, Rensselaer Polytechnic Institute (RPI), Department of Physics, Okayama University, Okayama University, University of New Haven [Connecticut], Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS), Public Health Genomics Unit, Department of Mathematics, University of Colorado, University of Colorado [Boulder], Faculty of Medicine, University of Iceland [Reykjavik], Icelandic Heart Association, Kopavogur, Iceland., University of Science, VNU-HCM, University Medical Center Groningen [Groningen] (UMCG), Neuronal Plasticity / Mouse Behaviour, Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, Department of Medical Genetics, HMNC Brain Health, University of Oxford [Oxford], University of Florida [Gainesville] (UF), Göteborgs Universitet (GU), Department of Medicine, Clinical Pharmacology Unit, Karolinska University Hospital [Stockholm], Brain Centre Rudolf Magnus [Utrecht], School of Psychology, University of Sussex, Brighton BN1 9QH, UK, University of Sussex, Institute of Cognitive Neuroscience, University College of London [London] (UCL), Medical University of Łódź (MUL), Mayo Clinic [Rochester], University of Maryland School of Medicine, University of Maryland System-University of Maryland System-University of Maryland [Baltimore County] (UMBC), University of Maryland System, School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Université de Cergy Pontoise (UCP), Université Paris-Seine, Lymphocyte Cell Biology Unit, Laboratory of Genetics, Psychiatry Institute, Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Department of Health and Human Services, Department of Life Sciences, Mathematical Sciences Institute (MSI), Australian National University (ANU), Centre for Advanced Imaging, Institute of Gerontology and Geriatrics, Università degli Studi di Perugia (UNIPG), Division of Mental Health and Addiction, Oslo University Hospital [Oslo], Institute of Clinical Medicine [Oslo], Faculty of Medicine [Oslo], Medical Faculty [Mannheim], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Genetic Epidemiology Unit, University of Mississippi Medical Center (UMMC), Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], Institute of Clinical Chemistry and Laboratory Medicine, Department of Statistics [Coventry], University of Warwick [Coventry], Delft University of Technology (TU Delft), Rheinische Friedrich-Wilhelms-Universität Bonn, Department of Health Science, Division of Health and Rehabilitation, Luleå University of Technology (LUT), Osaka University [Osaka], University Medical Center [Utrecht]-Brain Center Rudolf Magnus, University of Nottingham, UK (UON), McConnell Brain Imaging Centre (MNI), Departments of Physiology and Nutritional Sciences, University of Toronto, Toronto, Canada, Psychiatry and Human Behavior, University of California, Irvine, California 92617, USA, Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health [Mannheim], Medical Faculty [Mannheim]-Medical Faculty [Mannheim], Cedars-Sinai Medical Center, Politecnico di Milano [Milan] (POLIMI), University of Applied Sciences [Munich], Dpt of Pharmacology and Personalised Medicine [Maastricht], Maastricht University [Maastricht], Genetics of Mental Illness and Brain Function, Neuroscience Research Australia, Department of neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland, Department of neurology, University of Eastern Finland-University Hospital of Kuopio-University of Eastern Finland-University Hospital of Kuopio, Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney 2052, Australia, National Institute of Aging, 3rd Department of Neurology, Aristotle University of Thessaloniki-General Hospital of Thessaloniki George Papanikolaou, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Santé Publique, d'Epidémiologie et de Développement (ISPED), Université Bordeaux Segalen - Bordeaux 2, Genentech, Inc. [San Francisco], Psychiatry and Leiden Institute for Brain and Cognition, Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for Community Medicine, Berlin School of Mind and Brain [Berlin], Humboldt-Universität zu Berlin, Carver College of Medicine [Iowa City], University of Iowa [Iowa City]-University of Iowa [Iowa City], Centre for Population Health Sciences, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet [Stockholm], University of Pretoria [South Africa], University of Missouri [Columbia] (Mizzou), University of Missouri System, Department of Psychiatry and Psychotherapy, HELIOS Klinikum Stralsund Hanseatic-Greifswald University Hospital, Donders Center for Cognitive Neuroimaging, Donders Centre for Cognitive Neuroimaging, Radboud university [Nijmegen]-Radboud university [Nijmegen], University of Southern California (USC), University of California (UC)-University of California (UC), Sans affiliation, Radboud University [Nijmegen]-Radboud University Medical Center [Nijmegen]-Radboud University [Nijmegen]-Radboud University Medical Center [Nijmegen], University of Toronto, Radboud University [Nijmegen], Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Universität Bonn = University of Bonn, Department of Neurosciences [Univ California San Diego] (Neuro - UC San Diego), School of Medicine [Univ California San Diego] (UC San Diego), University of California (UC)-University of California (UC)-University of California [San Diego] (UC San Diego), Department of Cognitive Sciences [Univ California San Diego] (CogSci - UC San Diego), Yale School of Medicine [New Haven, Connecticut] (YSM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), King Faisal Specialist Hospital and Research Centre (KFSH & RC), Universiteit Leiden-Universiteit Leiden, University of Twente, University of California [Irvine] (UC Irvine), Universiteit Gent = Ghent University (UGENT), Centre épigénétique et destin cellulaire (EDC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], University of Oxford, University of Maryland [Baltimore County] (UMBC), University of Maryland System-University of Maryland System-University of Maryland School of Medicine, Università degli Studi di Perugia = University of Perugia (UNIPG), University Hospital Mannheim | Universitätsmedizin Mannheim, Universität Leipzig-Universität Leipzig, University Hospital Mannheim | Universitätsmedizin Mannheim-University Hospital Mannheim | Universitätsmedizin Mannheim, University of Eastern Finland, Universiteit Leiden, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Humboldt University Of Berlin, Radboud University [Nijmegen]-Radboud University [Nijmegen], School of Medicine / Clinical Medicine, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Other departments, Adult Psychiatry, ARD - Amsterdam Reproduction and Development, Radboud university [Nijmegen]-Radboud University Medical Center [Nijmegen]-Radboud university [Nijmegen]-Radboud University Medical Center [Nijmegen], McGill University-McGill University, Sahlgrenska University Hospital, McGill University, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement (Inserm U1167 - RID-AGE - Institut Pasteur), University of Bergen (UIB), Iowa State University (ISU)-U.S. Department of Energy (DOE), Beijing Normal University, Karakter Child and Adolescent Psychiatry University Center Nijmegen, Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Gènes, Synapses et Cognition, Ghent University [Belgium] (UGENT), National University of Ireland Maynooth (NUIM), Texas Biomedical Research Institute [San Antonio, Texas], Bijvoet Center of Biomolecular Research, Université Libre de Bruxelles [Bruxelles] (ULB)-Hôpital Erasme (Bruxelles), Okayama University [Okayama], University of Florida [Gainesville], Institut National de la Recherche Agronomique (INRA)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Aristotle University of Thessaloniki-G. Papanikolaou Hospital, Humboldt Universität zu Berlin, University of Missouri [Columbia], Epidemiology, Radiology & Nuclear Medicine, Medical Informatics, Internal Medicine, Neurology, Biological Psychology, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Health Behaviors & Chronic Diseases, Cognitive Psychology, IBBA, APH - Personalized Medicine, Amsterdam Neuroscience - Brain Imaging, MUMC+: DA Klinische Genetica (5), Klinische Genetica, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Anatomy and neurosciences, APH - Digital Health, Hal, GIN, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Universidad de Cantabria, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées
Subjects: Male, Netherlands Twin Register (NTR), Genome-wide association study, 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit, Spatial memory, 0302 clinical medicine, 610 Medicine & health, Child, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), Episodic memory, Aged, 80 and over, Subiculum, 220 Statistical Imaging Neuroscience, COMMON VARIANTS, ALZHEIMERS-DISEASE, ddc:500, Alzheimer's disease, genetics [Methionine Sulfoxide Reductases], Science, Locus (genetics), genetics [Protein-Serine-Threonine Kinases], Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Alzheimer Disease, ASTN2 protein, human, Humans, GENOME-WIDE ASSOCIATION, METAANALYSIS, Aged, Glycoproteins, Dentate gyrus, MEMORY, medicine.disease, R1, 030104 developmental biology, nervous system, Genetic Loci, MSRB3 protein, human, 030217 neurology & neurosurgery, 0301 basic medicine, General Physics and Astronomy, genetics [Alzheimer Disease], Hippocampal formation, Hippocampus, Genome-wide association studies, Taugasjúkdómar, Cohort Studies, DPP4 protein, human, TEMPORAL-LOBE EPILEPSY, BRAIN-REGIONS, genetics [Dipeptidyl Peptidase 4], genetics [Nerve Tissue Proteins], Genetics, Multidisciplinary, Neurodegenerative diseases, BIPOLAR DISORDER, Organ Size, Middle Aged, SUBFIELDS, Protein-Serine-Threonine Kinases, growth & development [Hippocampus], Female, genetics [Glycoproteins], Microtubule-Associated Proteins, Medical Genetics, Neuroinformatics, Adult, genetics [Microtubule-Associated Proteins], Adolescent, SUSCEPTIBILITY LOCI, Dipeptidyl Peptidase 4, genetics [Protein Serine-Threonine Kinases], Nerve Tissue Proteins, Bioinformatik och systembiologi, Protein Serine-Threonine Kinases, Biology, physiopathology [Alzheimer Disease], 150 000 MR Techniques in Brain Function, Young Adult, MAST4 protein, human, medicine, Journal Article, Erfðafræði, Genetic Predisposition to Disease, ddc:610, Medicinsk genetik, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Bioinformatics and Systems Biology, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, Rannsóknir, General Chemistry, Methionine Sulfoxide Reductases, 150 Psychology, Genome-Wide Association Study
Abstract: The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg=-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness., published version, peerReviewed
Published: 2017

43. Novel genetic loci underlying human intracranial volume identified through genome-wide association

Author: G. Bruce Pike, Marcel P. Zwiers, Andreas Meyer-Lindenberg, Jeroen van der Grond, Randy L. Gollub, Karen A. Mather, Andrew J. Schork, Vidar M. Steen, Marc M. Bohlken, Nhat Trung Doan, Derek W. Morris, John B.J. Kwok, Emma J. Rose, Johanna Hass, Andrew Simmons, Tian Ge, Reinhold Schmidt, Micael Andersson, Ian J. Deary, Christopher Chen, Derrek P. Hibar, Simon E. Fisher, Lucija Abramovic, Marcella Rietschel, Edith Hofer, Simon Lovestone, Clyde Francks, Christopher R.K. Ching, Srdjan Djurovic, Lachlan T. Strike, Lorna M. Lopez, Rene L. Olvera, Owen Carmichael, M. Arfan Ikram, Andre F. Marquand, Christine Macare, W.T. Longstreth, Philippe Amouyel, Aaron L. Goldman, Wolfgang Hoffmann, Philip L. De Jager, David C. Liewald, Harald H H Göring, Aad van der Lugt, David Ames, Neeltje E.M. van Haren, Lars Nyberg, Nina Romanczuk-Seiferth, Lukas Pirpamer, Stefan Ehrlich, Alexa S. Beiser, Lianne Schmaal, Hilkka Soininen, Mark Jenkinson, Kazima B. Bulayeva, Anderson M. Winkler, Mike A. Nalls, Diana Tordesillas-Gutiérrez, Martine Hoogman, Lars T. Westlye, Loes M. Olde Loohuis, Andrew Singleton, Gabriel Cuellar-Partida, Randy L. Buckner, Dorret I. Boomsma, Dena G. Hernandez, Steven G. Potkin, Sudha Seshadri, Bertram Müller-Myhsok, D. Hoehn, Gareth E. Davies, Chantal Depondt, Henrik Walter, Michael E. Weale, Deborah Janowitz, Susanne Erk, Iryna O. Fedko, Daniel R. Weinberger, Nic J A van der Wee, Jean-Luc Martinot, Jessica A. Turner, Marieke Klein, Sandra Barral, Sebastian Mohnke, Albert Hofman, Ingrid Melle, Saud Alhusaini, Vincent Chouraki, Stephen M. Lawrie, Mark E. Bastin, Juan C. Troncoso, Jean Shin, Wiro J. Niessen, Diane M. Becker, Laura Almasy, Anders M. Dale, Benjamin S. Aribisala, Dennis van 't Ent, Marco P. Boks, M. Mallar Chakravarty, Paul M. Thompson, David Reese McKay, Michael Griswold, John Blangero, Narelle K. Hansell, Eco J. C. de Geus, Paul A. Nyquist, Susana Muñoz Maniega, Sampath Arepalli, Tatjana Rundek, Dan L. Longo, Anton J. M. de Craen, Rebekah McWhirter, Nazanin Mirza-Schreiber, Henning Tiemeier, Girma Woldehawariat, Sven Cichon, Irene Pappa, Amelia A. Assareh, Sudheer Giddaluru, Pieter J. Hoekstra, Hieab H.H. Adams, Hilleke E. Hulshoff Pol, Grant W. Montgomery, Roel A. Ophoff, Markus M. Nöthen, Sara Pudas, Sigurdur Sigurdsson, Arthur W. Toga, Tien Yin Wong, Massimo Pandolfo, Corina U. Greven, Esther Walton, Tianye Jia, David J. Stott, Gunter Schumann, Marie-José van Tol, Dalia Kasperaviciute, Thomas Wolfers, Henry Völzke, Ian Ford, Shannon L. Risacher, Jessika E. Sussmann, Nicholas G. Martin, Wei Wen, Daniah Trabzuni, Iwona Kłoszewska, Kwangsik Nho, Gianpiero L. Cavalleri, Adam M. Brickman, Sungeun Kim, Andreas Heinz, Ralph L. Sacco, Neda Jahanshad, Velandai Srikanth, Elena Shumskaya, Susan H. Blanton, Katharina Wittfeld, Badri N. Vardarajan, Joshua C. Bis, Joanne E. Curran, Helena Schmidt, Peter T. Fox, Clifford R. Jack, Jason L. Stein, Laura M. E. Blanken, Thomas Espeseth, Dick J. Veltman, Sebastian Guelfi, Margaret J. Wright, Norman Delanty, Michael Czisch, Martina Papmeyer, Oscar L. Lopez, Marjolein M. J. Van Donkelaar, Bruce M. Psaty, Jan K. Buitelaar, Sven J. van der Lee, David A. Bennett, Beng-Choon Ho, Oliver Martinez, Wiepke Cahn, Li Shen, J. Wouter Jukema, Janita Bralten, Peter Kochunov, Greig I. Zubicaray, Marcel P. van der Brug, Ching-Yu Cheng, Philipp G. Sämann, Stella Trompet, Roberto Roiz-Santiañez, David C. Glahn, Allissa Dillman, Venkata S. Mattay, Dara M. Cannon, Michael W. Weiner, Christopher D. Whelan, Alexander Teumer, Sylvane Desrivières, Ole A. Andreassen, Thomas E. Nichols, Manuel Mattheisen, Matthias Nauck, René S. Kahn, Albert V. Smith, Colin Smith, Vilmundur Gudnason, Denis A. Evans, Anouk den Braber, Katie L. McMahon, Han G. Brunner, Florian Holsboer, Yuri Milaneschi, Andrew J. Saykin, Jiemin Liao, Vince D. Calhoun, Neelum T. Aggarwal, Dennis van der Meer, Hans J. Grabe, Anita L. DeStefano, Claudia L. Satizabal, Alan B. Zonderman, Alex P. Zijdenbos, Tulio Guadalupe, Ingrid Agartz, Jordan W. Smoller, Allison C. Nugent, Alejandro Arias-Vasquez, Masashi Ikeda, Avram J. Holmes, Brenda W.J.H. Penninx, John Hardy, Herve Lemaitre, Charles DeCarli, Patrizia Mecocci, Catharina A. Hartman, Tomas Axelsson, Oliver Grimm, Irina Filippi, Wayne C. Drevets, Hans van Bokhoven, Miguel E. Rentería, Aiden Corvin, Ryota Kanai, Kristel R. van Eijk, Andrew M. McIntosh, Jouke-Jan Hottenga, Roberto Toro, Lavinia Athanasiu, Joanna M. Wardlaw, Thomas H. Mosley, Mina Ryten, Meike W. Vernooij, Michelle Luciano, Joshua L. Roffman, Rebecca F. Gottesman, Dhananjay Vaidya, Ryota Hashimoto, Mar Matarin, Adaikalavan Ramasamy, Jerome I. Rotter, Ryan L. Muetzel, Konstantinos Arfanakis, Theo G.M. van Erp, Ganesh Chauhan, Xinmin Liu, Tomáš Paus, Emma Sprooten, Christiane Wolf, David S. Knopman, Manon Bernard, Zdenka Pausova, Bryan J. Traynor, Maria C. Valdés Hernández, Robert C. Green, Russell Thomson, Ravi Duggirala, Lisa R. Yanek, Luigi Ferrucci, Bing Xu, Thomas D. Dyer, Thomas H. Wassink, Eric Westman, Jennifer S. Richards, Phil H. Lee, Benno Pütz, Mark R. Cookson, Benedicto Crespo-Facorro, Natalie A. Royle, Bernd Kraemer, Katrin Hegenscheid, Francis J. McMahon, Tatiana Foroud, M. Kamran Ikram, Myriam Fornage, Nanda Rommelse, Saima Hilal, Perminder S. Sachdev, Qiang Chen, Najaf Amin, Lenore J. Launer, Norbert Hosten, Guillén Fernández, Simone Reppermund, Ashley Beecham, Dirk J. Heslenfeld, Masaki Fukunaga, Cornelia M. van Duijn, Clinton B. Wright, Erik G. Jönsson, Sanjay M. Sisodiya, Oliver Gruber, Christophe Tzourio, André G. Uitterlinden, Robert Johnson, Jaap Oosterlaan, Bernard Mazoyer, H. Ronald Zielke, Stephanie Le Hellard, Jingyun Yang, Georg Homuth, Stéphanie Debette, Nicola J. Armstrong, Sarah E. Medland, Henry Brodaty, Beverly G Windham, Gary Donohoe, Rachel M. Brouwer, James T. Becker, Kumar B. Rajan, Daan van Rooij, Thomas W. Mühleisen, Kazutaka Ohi, Peter R. Schofield, Tonya White, Barbara Franke, Unn K. Haukvik, Debra A. Fleischman, J. Raphael Gibbs, Colm McDonald, Anbupalam Thalamuthu, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Keck School of Medicine [Los Angeles], University of Southern California (USC), Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Johns Hopkins University (JHU), QIMR Berghofer Medical Research Institute, Leiden University Medical Center (LUMC), Radboud University Medical Center [Nijmegen], Institute of Psychiatry, Psychology & Neuroscience, King's College London, King‘s College London, University of Miami Leonard M. Miller School of Medicine (UMMSM), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Greifswald University Hospital, Department of Neurology and Neurosurgery [Montreal], Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada]-McGill University = Université McGill [Montréal, Canada], Royal College of Surgeons in Ireland (RCSI), Umeå University, Illinois Institute of Technology (IIT), Rush University Medical Center [Chicago], University of Edinburgh, Lagos State University (LASU), University of New South Wales [Sydney] (UNSW), Murdoch University, University of Oslo (UiO), Uppsala University, Framingham Heart Study, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), University of Toronto, University of Washington [Seattle], Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], Columbia University Medical Center (CUMC), Columbia University [New York], Pennington Biomedical Research Center, Louisiana State University (LSU), McGill University = Université McGill [Montréal, Canada], Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lieber Institute for Brain Development [Baltimore] (LIBD), University of California [Los Angeles] (UCLA), University of California, Vrije Universiteit Amsterdam [Amsterdam] (VU), Technische Universität Dresden = Dresden University of Technology (TU Dresden), Massachusetts General Hospital [Boston], Neuroimagerie en psychiatrie (U1000), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Sud - Paris 11 (UP11), Maison de Solenn [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], University of Bergen (UiB), Haukeland University Hospital, Johns Hopkins University School of Medicine [Baltimore], Universität Heidelberg [Heidelberg], University of Mississippi Medical Center (UMMC), International Max Planck Research School for Language Sciences (IMPRS ), Max Planck Institute for Psycholinguistics, Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, Language and Genetics Department [Nijmegen], National University of Singapore (NUS), Medical University Graz, Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, Yale University [New Haven], University College of London [London] (UCL), Imperial College London, Structure et Réactivité des Systèmes Moléculaires Complexes (SRSMC), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Center for Translational Research in Systems Neuroscience and Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center, Goettingen 37075, Germany, Medstar Research Institute, Clinical And Experimental Epilepsy, Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia, Department of Biomedicine and the Centre for Integrative Sequencing, Aarhus University [Aarhus], Institute of Human Genetics, University of Bonn, Department of Genomics, Life and Brain Center, Groupe d'imagerie neurofonctionnelle (GIN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Dpt of Psychiatry [New Haven], Yale University School of Medicine, Department of Psychiatry, VU University Medical Center [Amsterdam], Department of Psychology [Minneapolis], University of Minnesota [Twin Cities] (UMN), University of Minnesota System-University of Minnesota System, Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indiana University System-Indiana University System, Indiana University System, Institute of Food & Health, University College Dublin, University College Dublin [Dublin] (UCD), Statistical Genetics Group, Respiratory Epidemiology and Public Health, Imperial College London-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU)-MRC-HPA Centre for Environment and Health, Centro de Investigación Biomédica en Red Salud Mental [Madrid] (CIBER-SAM), Karakter Child and Adolescent Psychiatry University Centre [Nijmegen], Institut Parisien de Chimie Moléculaire (IPCM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), INSERM, Neuroepidemiology U708, Bordeaux, France, Department of Cognitive Sciences [San Diego], University of California [San Diego] (UC San Diego), University of California-University of California, Department of Neurosciences [San Diego], Centre for Advanced Imaging, University of Queensland, Brisbane 4072, Australia, School of Psychology, University of Queensland, Brisbane 4072, Australia, University of Queensland [Brisbane], Queensland Institute of Medical Research, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Department of Genetics, King Faisal Specialist Hospital and Research Centre, Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL, Institute of Neurology [London], Depts of Radiology, University of Twente [Netherlands], Department of Psychiatry and Human Behavior [Irvine], University of California [Irvine] (UCI), Donders Center for Cognitive Neuroimaging, Donders Centre for Cognitive Neuroimaging, Radboud university [Nijmegen]-Radboud university [Nijmegen], Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Department of Psychology [Oslo], Faculty of Social Sciences [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Deutsche Bundesbank, National Institutes of Health [Bethesda] (NIH), General Internal Medicine, Johns Hopkins School of Medicine, Biospective [Montréal], KG Jebsen Centre for Psychosis Research, University of Oslo (UiO)-Institute of Clinical Medicine-Oslo University Hospital [Oslo], Southwest Foundation for Biomedical Research, Department of Psychiatry and National Ageing Research Institute, University of Melbourne, Department of Clinical Genetics, Department of Medical Parasitology and Mycology, School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU)-Tehran University of Medical Siences, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Departments of Psychiatry, Neurology, and Psychology, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), The University of Texas Health Science Center at Houston (UTHealth), Texas Biomedical Research Institute [San Antonio, TX], 849 Department of Human Genetics, Dementia Collaborative Research Centre, Centre for Healthy Brain Ageing, Brain Center Rudolf Magnus, Department of Psychiatry, UMC Utrecht, Utrecht 3584 CX, The Netherlands, Université de Lausanne (UNIL), Department of Psychiatry [Boston], N.I. Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow 119333, Russia, Icahn School of Medicine at Mount Sinai [New York] (MSSM), The Mind Research Network, Department of Electrical and Computer Engineering [Albuquerque] (ECE Department), The University of New Mexico [Albuquerque], Human Genetics Branch, National Institutes of Health [Bethesda] (NIH)-National Institute of Mental Health (NIMH), Division of Molecular and Cellular Therapeutics, Metacohorts Consortium, Division of Medical Genetics, University of Basel (Unibas), Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Cell Biology and Gene Expression Section, National Institute of Health, Bethesda, Neuropsychiatric Genetics Research Group, Trinity College Dublin, Trinity College Dublin-St. James's Hospital, Department of Materials Science & Metallurgy, University of Cambridge [UK] (CAM), Bijvoet Center of Biomolecular Research [Utrecht], Utrecht University [Utrecht], VU University Amsterdam, Program in Translational NeuroPsychiatric Genomics, Brigham and Women's Hospital [Boston], Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA, Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), School of Psychology, University of Queensland, Neurology Division, Beaumont Hospital, Dublin 9, Ireland, Beaumont Hospital, Molecular and Cellular Therapeutics, Department of Neurology, Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Laboratory of Neurogenetics, Department of Genomics, Biological Psychology, Neuroscience Campus Amsterdam & EMGO Institute for Health and Care Research, VU University & VU Medical Center, Amsterdam 1081 BT, The Netherlands, Department of Radiology, Mayo Clinic, Department of Medical and Molecular Genetics, South Texas Veterans Health Care System, San Antonio, Texas 78229, USA, Department of Physics, Okayama University, Okayama University, National Institute of Aging, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS), Public Health Genomics Unit, Department of Psychiatry and Psychotherapy, HELIOS Klinikum Stralsund Hanseatic-Greifswald University Hospital, Department of Mathematics, University of Colorado, University of Colorado [Boulder], Icelandic Heart Association, Kopavogur, Iceland., Faculty of Medicine, University of Iceland [Reykjavik], Department of Molecular Neurosciences, Institute of Neurology, UCL, Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University [Osaka], Department of Psychiatry, University of Iowa, University of Iowa [Iowa City], University Medical Center Groningen [Groningen] (UMCG), Neuronal Plasticity / Mouse Behaviour, Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, Tohoku University [Sendai], Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Stony Brook University [SUNY] (SBU), State University of New York (SUNY), Department of Medicine, Clinical Pharmacology Unit, Karolinska University Hospital [Stockholm], Centre for Allergy Research, Karolinska Institutet [Stockholm], Interuniversity Cardiology Institute Netherlands, Institute of Cognitive Neuroscience, School of Psychology, University of Sussex, Brighton BN1 9QH, UK, University of Sussex, Medical University of Łódź (MUL), Mayo Clinic [Rochester], University of Maryland School of Medicine, University of Maryland System-University of Maryland System-University of Maryland [Baltimore County] (UMBC), University of Maryland System, Department of Civil and Structural Engineering, The Hong Kong Polytechnic University [Hong Kong] (POLYU)-The Hong Kong Polytechnic University [Hong Kong] (POLYU), Université de Cergy Pontoise (UCP), Université Paris-Seine, Lymphocyte Cell Biology Unit, Laboratory of Genetics, Laboratoire de Statistique Théorique et Appliquée (LSTA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Psychiatry Institute, Department of Health and Human Services, Department of Life Sciences, Mathematical Sciences Institute (MSI), Australian National University (ANU), Centre for Advanced Imaging, Institute of Gerontology and Geriatrics, Università degli Studi di Perugia (UNIPG), Division of Mental Health and Addiction, Oslo University Hospital [Oslo], Institute of Clinical Medicine [Oslo], Faculty of Medicine [Oslo], Medical Faculty [Mannheim], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Genetic Epidemiology Unit, Université de Toulon - UFR Lettres et Sciences Humaines (UTLN UFR LSH), Université de Toulon (UTLN), Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], Institute of Clinical Chemistry and Laboratory Medicine, Warwick Manufacturing Group [Coventry] (WMG), University of Warwick [Coventry], Department of Statistics [Warwick], Delft University of Technology (TU Delft), Rheinische Friedrich-Wilhelms-Universität Bonn, Department of Health Science, Division of Health and Rehabilitation, Luleå University of Technology (LUT), University Medical Center [Utrecht]-Brain Center Rudolf Magnus, McConnell Brain Imaging Centre (MNI), Departments of Physiology and Nutritional Sciences, University of Toronto, Toronto, Canada, Psychiatry and Human Behavior, University of California, Irvine, California 92617, USA, Group Health Research Institute, Group Health Cooperative, Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health [Mannheim], Medical Faculty [Mannheim]-Medical Faculty [Mannheim], Cedars-Sinai Medical Center, Centre for Healthy Brain Ageing [Sydney], The University of Sydney, Genetics of Mental Illness and Brain Function, Neuroscience Research Australia, Broad Institute [Cambridge], Harvard University [Cambridge]-Massachusetts Institute of Technology (MIT), Department of Medical Biochemistry and Microbiology, Department of Clinical and Experimental Epilepsy, Department of neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland, Department of neurology, University of Eastern Finland-University Hospital of Kuopio-University of Eastern Finland-University Hospital of Kuopio, Stroke and Ageing Research Centre, Southern Clinical School, Department of Medicine, Monash University, Monash University [Melbourne], Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia, University of Tasmania [Hobart, Australia] (UTAS), Institute of Cardiovascular and Medical Sciences [Glasgow], University of Glasgow, Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney 2052, Australia, Department of Epidemiology, Laboratory of Neuro Imaging [Los Angeles] (LONI), University of York [York, UK], Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Genentech, Inc. [San Francisco], Departments of Radiology and of Epidemiology [Rotterdam], Psychiatry and Leiden Institute for Brain and Cognition, Department of Neurology [Rotterdam], Institute for Community Medicine, Berlin School of Mind and Brain [Berlin], Humboldt-Universität zu Berlin, Carver College of Medicine [Iowa City], University of Iowa [Iowa City]-University of Iowa [Iowa City], Centre for Population Health Sciences, Department of Physics [Hong Kong University of Science and Technology], Hong Kong University of Science and Technology (HKUST), Department of Neurobiology, Care Sciences and Society, Research Laboratory for Archaeology & the History of Art, Singapore Eye Research Institute, Singapore National Eye Centre, School of Life Sciences, Arizona State University [Tempe] (ASU), Department of Neurology and Center for Neuroscience, University of California at Davis, Sacramento, University of California [Davis] (UC Davis), Dpt of Pharmacology and Personalised Medicine [Maastricht], Maastricht University [Maastricht], University of Missouri [Columbia] (Mizzou), University of Missouri System, Göttingen Zentrum Geowissenschaften, Georg-August-University [Göttingen], Human Genetics Center, Psychiatry, EMGO - Mental health, Amsterdam Neuroscience - Complex Trait Genetics, Anatomy and neurosciences, Klinische Genetica, MUMC+: DA Klinische Genetica (5), RS: FHML non-thematic output, RS: GROW - School for Oncology and Reproduction, RS: GROW - R4 - Reproductive and Perinatal Medicine, Genetica & Celbiologie, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie du CNRS (INC)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), University of Maryland [Baltimore County] (UMBC), University of Maryland System-University of Maryland System-University of Maryland School of Medicine, Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Universidad de Cantabria, Universiteit Leiden, Radboud University [Nijmegen], University of California (UC), Universität Heidelberg [Heidelberg] = Heidelberg University, Universität Bonn = University of Bonn, [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Yale School of Medicine [New Haven, Connecticut] (YSM), Department of Cognitive Sciences [Univ California San Diego] (CogSci - UC San Diego), University of California (UC)-University of California (UC), Department of Neurosciences [Univ California San Diego] (Neuro - UC San Diego), School of Medicine [Univ California San Diego] (UC San Diego), University of California (UC)-University of California (UC)-University of California [San Diego] (UC San Diego), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), King Faisal Specialist Hospital and Research Centre (KFSH & RC), Universiteit Leiden-Universiteit Leiden, University of Twente, University of California [Irvine] (UC Irvine), Radboud University [Nijmegen]-Radboud University [Nijmegen], Centre épigénétique et destin cellulaire (EDC), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Université de Lausanne = University of Lausanne (UNIL), Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Università degli Studi di Perugia = University of Perugia (UNIPG), University Hospital Mannheim | Universitätsmedizin Mannheim, Universität Leipzig-Universität Leipzig, University Hospital Mannheim | Universitätsmedizin Mannheim-University Hospital Mannheim | Universitätsmedizin Mannheim, Harvard University-Massachusetts Institute of Technology (MIT), University of Eastern Finland, Humboldt University Of Berlin, Georg-August-University = Georg-August-Universität Göttingen, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Epidemiology, Child and Adolescent Psychiatry / Psychology, Ophthalmology, Radiology & Nuclear Medicine, Internal Medicine, Neurosciences, Obstetrics & Gynecology, Neurology, EMGO+ - Mental Health, Biological Psychology, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement (Inserm U1167 - RID-AGE - Institut Pasteur), McGill University-McGill University, National Heart, Lung, and Blood Institute [Bethesda] (NHLBI)-Boston University [Boston] (BU), McGill University, Technische Universität Dresden (TUD), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], University of Bergen (UIB), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), University of Minnesota [Twin Cities], Karakter Child and Adolescent Psychiatry University Center Nijmegen, Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut Pasteur [Paris], Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Texas Biomedical Research Institute [San Antonio, Texas], Bijvoet Center of Biomolecular Research, Université Libre de Bruxelles [Bruxelles] (ULB)-Hôpital Erasme (Bruxelles), Okayama University [Okayama], Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Massachusetts Institute of Technology (MIT)-Harvard University [Cambridge], University of Tasmania (UTAS), Humboldt Universität zu Berlin, Department of Physics [Kowloon], University of Missouri [Columbia], Georg-August-Universität Göttingen, and the Alzheimer's Disease Neuroimaging Initiative, EPIGEN, IMAGEN, SYS
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), Genome-wide association study, Disease, methods [Genome-Wide Association Study], Genome-wide association studies, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, Cognition, PARKINSONS-DISEASE, pathology [Brain], genetics [Parkinson Disease], 610 Medicine & health, General Neuroscience, growth & development [Brain], physiology [Cognition], 220 Statistical Imaging Neuroscience, COMMON VARIANTS, Brain, Parkinson Disease, Phenotype, 17Q21.31 MICRODELETION, IGF-I, genetics [Oncogene Protein v-akt], Oncogene Protein v-akt, ALZHEIMERS-DISEASE, HEAD CIRCUMFERENCE, Brain size, genetics [Polymorphism, Single Nucleotide], Medical genetics, GROWTH, Neuroinformatics, medicine.medical_specialty, Neuroscience(all), European Continental Ancestry Group, genetics [Genetic Loci], Biology, Genetic correlation, Polymorphism, Single Nucleotide, 150 000 MR Techniques in Brain Function, Article, White People, 03 medical and health sciences, Image processing, SDG 3 - Good Health and Well-being, ddc:570, medicine, Journal Article, Humans, Genetic Predisposition to Disease, Gene, METAANALYSIS, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Neurology & Neurosurgery, Neuroscience (all), Height, [SCCO.NEUR]Cognitive science/Neuroscience, CONSORTIUM, Development of the nervous system, 1702 Cognitive Science, 030104 developmental biology, Genetic Loci, Human genome, BRAIN SIZE, 1109 Neurosciences, genetics [Phosphatidylinositol 3-Kinases], Neuroscience, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Contains fulltext : 165723pub.pdf (Publisher’s version ) (Closed access) Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (rhogenetic = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.
Published: 2016

44. Genetic architecture of subcortical brain structures in 38,851 individuals

Author: Mar Matarin, Douglas N. Greve, Nic J.A. van der Wee, Evan Fletcher, Christiane Wolf, Arvin Saremi, Joshua W. Cheung, Randy L. Gollub, David Ames, Honghuang Lin, Nicholas G. Martin, Manon Bernard, Daniel R. Weinberger, Henry Völzke, Manuel Mattheisen, George Davey Smith, Dan J. Stein, Dorret I. Boomsma, John D. Eicher, Henrik Walter, Massimo Pandolfo, Andreas Meyer-Lindenberg, D. Hoehn, Louis N. Vinke, Wiro J. Niessen, G. Bruce Pike, Simon E. Fisher, Jerome I. Rotter, Neeltje E.M. van Haren, Neda Jahanshad, Stephen M. Lawrie, Mark E. Bastin, Sanjay M. Sisodiya, Marcella Rietschel, Jean Shin, Dirk J. Heslenfeld, Ingrid Agartz, Lars Nyberg, Nina Romanczuk-Seiferth, Clifford R. Jack, Markus Scholz, Baljeet Singh, Rachel M. Brouwer, Marco P. Boks, M. Mallar Chakravarty, Magda Tsolaki, André G. Uitterlinden, Amelia A. Assareh, Nastassja Koen, Beng-Choon Ho, Muralidharan Sargurupremraj, Perminder S. Sachdev, James T. Becker, Narelle K. Hansell, Katrin Hegenscheid, Zdenka Pausova, Irina Filippi, Hans van Bokhoven, Miguel E. Rentería, Robert C. Green, M. Kamran Ikram, Vidar M. Steen, Marc M. Bohlken, Iryna O. Fedko, Jayandra J. Himali, Hieab H.H. Adams, Erik G. Jönsson, Esther Walton, Gunter Schumann, Dennis van der Meer, Jordan W. Smoller, Ganesh Chauhan, Simon Lovestone, Kwangsik Nho, Gianpiero L. Cavalleri, Andrew Simmons, Shuo Li, Hannah J. Jones, Lavinia Athanasiu, Shahrzad Kharabian Masouleh, Micael Andersson, Andreas Heinz, Lucija Abramovic, Alexa S. Beiser, Vilmundur Gudnason, Oliver Gruber, Tianye Jia, Daan van Rooij, Philip L. De Jager, Allison Stevens, Thomas W. Mühleisen, Deborah Janowitz, Anita L. DeStefano, Gennady V. Roshchupkin, Maria C. Valdés Hernández, Nynke A. Groenewold, Vince D. Calhoun, Cornelia M. van Duijn, Roberto Toro, Wiepke Cahn, Florian Holsboer, Asta Håberg, Aaron Goldman, Lisa R. Yanek, Jingyun Yang, Matthias L. Schroeter, Patrizia Mecocci, Sven J. van der Lee, Gareth E. Davies, Elena Shumskaya, Jia Yu Koh, Thomas H. Wassink, Wei Wen, A. Veronica Witte, Anders M. Dale, Diana Tordesillas-Gutiérrez, Iwona Kłoszewska, Benedicto Crespo-Facorro, Sylvane Desrivières, Catharina A. Hartman, Saskia P. Hagenaars, Jennifer S. Richards, Martine Hoogman, Philipp G. Sämann, Andre F. Marquand, Stephanie Le Hellard, Christophe Tzourio, Sven Cichon, Tomáš Paus, Ole A. Andreassen, Pieter J. Hoekstra, Gabriel Cuellar-Partida, Joanna M. Wardlaw, Thomas H. Mosley, Bernd Kraemer, Barbara Franke, Joshua C. Bis, Katharina Wittfeld, Christopher D. Whelan, Christine Macare, Unn K. Haukvik, Lars T. Westlye, Loes M. Olde Loohuis, Sudha Seshadri, Michelle Luciano, Shannon L. Risacher, Diane M. Becker, Tamara B. Harris, Georg Homuth, Sungeun Kim, Lenore J. Launer, Debra A. Fleischman, Tulio Guadalupe, Joshua L. Roffman, Marie-José van Tol, Stéphanie Debette, Benno Pütz, Dick J. Veltman, Ching-Yu Cheng, Norman Delanty, Chantal Depondt, Jaap Oosterlaan, Nicola J. Armstrong, Myriam Fornage, Eric Westman, Anouk den Braber, Nanda Rommelse, Qiong Yang, Yasaman Saba, Tatiana Foroud, Susanne Erk, Saima Hilal, Paul M. Thompson, Eco J. C. de Geus, Paul A. Nyquist, Wolfgang Hoffmann, Alexander Teumer, Avram J. Holmes, Qiang Chen, Najaf Amin, Albert V. Smith, Tom V. Lee, Sarah E. Medland, Nazanin Mirza-Schreiber, Alejandro Arias-Vasquez, Grant W. Montgomery, Han G. Brunner, Meike W. Vernooij, Bernard Mazoyer, Guillén Fernández, Henry Brodaty, Claudia L. Satizabal, Thomas Wolfers, Herve Lemaitre, Li Shen, Greig I. de Zubicaray, Pauline Maillard, Hans J. Grabe, Ingrid Melle, Simone Reppermund, Charles DeCarli, Anbupalam Thalamuthu, Helena Schmidt, Peter R. Schofield, Marjolein M.J. van Donkelaar, Thomas Espeseth, Christopher Chen, Matthias Nauck, Norbert Hosten, Clyde Francks, Oliver Grimm, Tonya White, Andrew J. Saykin, Andrew M. McIntosh, Oscar L. Lopez, Philippe Amouyel, William T. Longstreth, Janita Bralten, Nhat Trung Doan, John B.J. Kwok, Charles C. White, Ralph Burkhardt, Jessika E. Sussmann, Michael W. Weiner, Markus M. Nöthen, Katie L. McMahon, Derrek P. Hibar, Dalia Kasperaviciute, Maria J. Knol, Hilleke E. Hulshoff Pol, Markus Loeffler, Bruno Vellas, Matthew J. Huentelman, Owen Carmichael, Jason L. Stein, Ryota Kanai, Lianne Schmaal, Hilkka Soininen, Bruce M. Psaty, Jan K. Buitelaar, Jean-Luc Martinot, Ian J. Deary, Venkata S. Mattay, Theo G.M. van Erp, Arno Villringer, Andrew D. Johnson, Srdjan Djurovic, Benjamin S. Aribisala, Lachlan T. Strike, Phil Lee, David C. Liewald, Tien Yin Wong, Tomas Axelsson, Jessica A. Turner, Marieke Klein, Kristel R. van Eijk, Saud Alhusaini, Konstantinos Arfanakis, M. Arfan Ikram, Stefan Ehrlich, Sebastian Mohnke, Marcel P. Zwiers, Karen A. Mather, Jonathan C Ipser, Joshua M. Shulman, Brenda W.J.H. Penninx, Reinhold Schmidt, Arthur W. Toga, Christopher R.K. Ching, René S. Kahn, Bertram Müller-Myhsok, Yuri Milaneschi, Margaret J. Wright, Martina Papmeyer, Fabrice Crivello, David A. Bennett, Randy L. Buckner, Edith Hofer, Roel A. Ophoff, Steven G. Potkin, Albert Hofman, Dennis van 't Ent, Sudheer Giddaluru, Roberto Roiz-Santiañez, Andrew J. Schork, Jouke-Jan Hottenga, Yanhui Hu, Kazima B. Bulayeva, Xueqiu Jian, Clinical Genetics, Epidemiology, Radiology & Nuclear Medicine, Medical Informatics, Neurology, Child and Adolescent Psychiatry / Psychology, Psychiatry, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Clinical Cognitive Neuropsychiatry Research Program (CCNP), APH - Mental Health, Pediatric surgery, Epidemiology and Data Science, Anatomy and neurosciences, Amsterdam Neuroscience - Brain Imaging, APH - Digital Health, General Paediatrics, ARD - Amsterdam Reproduction and Development, Psychiatrie & Neuropsychologie, Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA Klinische Genetica (5), RS: MHeNs - R2 - Mental Health, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Neurosciences cognitives et intégratives d'Aquitaine (INCIA), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-SFR Bordeaux Neurosciences-Centre National de la Recherche Scientifique (CNRS), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Stochastics, Biological Psychology, APH - Methodology, Clinical Neuropsychology, IBBA, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, and Cognitive Psychology
Subjects: Netherlands Twin Register (NTR), LD SCORE REGRESSION, Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13], Caudate nucleus, Genome-wide association study, Bio-Organic Chemistry, Language in Interaction, neuroscience, Cohort Studies, BASAL GANGLIA, 0302 clinical medicine, 130 000 Cognitive Neurology & Memory, metabolism [Drosophila melanogaster], Basal ganglia, Adult, Aged, Animals, Brain, Drosophila melanogaster, Humans, Magnetic Resonance Imaging, Middle Aged, Neurodevelopmental Disorders, Organ Size, Genetic Variation, Genome-Wide Association Study, genetics [Drosophila melanogaster], 0303 health sciences, genetics [Neurodevelopmental Disorders], Putamen, 220 Statistical Imaging Neuroscience, 3. Good health, ALZHEIMERS-DISEASE, DROSOPHILA, Globus pallidus, VINTAGE, epidemiology, Synaptic signaling, Neuroinformatics, EXPRESSION, Nucleus accumbens, Biology, 150 000 MR Techniques in Brain Function, Article, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, SDG 3 - Good Health and Well-being, ddc:570, PLASMA-PROTEIN, pathology [Neurodevelopmental Disorders], Genetics, GENOME-WIDE ASSOCIATION, HEALTHY, METAANALYSIS, 030304 developmental biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], RISK LOCI, Genetic architecture, ALKALINE-PHOSPHATASE, nervous system, metabolism [Brain], genome-wide association studies, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, growth & development [Drosophila melanogaster], anatomy & histology [Brain], Neuroscience, 030217 neurology & neurosurgery
Abstract: Aims/hypothesis MODY can be wrongly diagnosed as type 1 diabetes in children. We aimed to find the prevalence of MODY in a nationwide population-based registry of childhood diabetes. Methods Using next-generation sequencing, we screened the HNF1A, HNF4A, HNF1B, GCK and INS genes in all 469 children (12.1%) negative for both GAD and IA-2 autoantibodies and 469 antibody-positive matched controls selected from the Norwegian Childhood Diabetes Registry (3882 children). Variants were classified using clinical diagnostic criteria for pathogenicity ranging from class 1 (neutral) to class 5 (pathogenic). Results We identified 58 rare exonic and splice variants in cases and controls. Among antibody-negative patients, 6.5% had genetic variants of classes 3–5 (vs 2.4% in controls; p = 0.002). For the stricter classification (classes 4 and 5), the corresponding number was 4.1% (vs 0.2% in controls; p = 1.6 × 10−5). HNF1A showed the strongest enrichment of class 3–5 variants, with 3.9% among antibody-negative patients (vs 0.4% in controls; p = 0.0002). Antibody-negative carriers of variants in class 3 had a similar phenotype to those carrying variants in classes 4 and 5. Conclusions/interpretation This is the first study screening for MODY in all antibody-negative children in a nationwide population-based registry. Our results suggest that the prevalence of MODY in antibody-negative childhood diabetes may reach 6.5%. One-third of these MODY cases had not been recognised by clinicians. Since a precise diagnosis is important for treatment and genetic counselling, molecular screening of all antibody-negative children should be considered in routine diagnostics.
Published: 2019

45. The effect of childhood maltreatment and cannabis use on adult psychotic symptoms is modified by the COMT Val158Met polymorphism

Author: Marian Joëls, Christiaan H. Vinkers, Richard Bruggeman, Carin J. Meijer, Marco P. Boks, Christian D. Schubart, René S. Kahn, Roel A. Ophoff, Wiepke Cahn, Jurjen J. Luykx, Durk Wiersma, Inez Myin-Germeys, Willemijn A. van Gastel, Kristel R. van Eijk, Jim van Os, Ruud van Winkel, Lieuwe de Haan, Psychiatrie & Neuropsychologie, and RS: MHeNs School for Mental Health and Neuroscience
Subjects: Child abuse, medicine.medical_specialty, Psychosis, Population, Gene–environment, rs4680, Context (language use), 03 medical and health sciences, 0302 clinical medicine, medicine, Psychiatry, education, Biological Psychiatry, Cannabis, Psychic and psychic-like experiences, education.field_of_study, Catechol-O-methyl transferase, biology, biology.organism_classification, medicine.disease, COMT, Early life trauma, 3. Good health, 030227 psychiatry, Gene-environment, Psychiatry and Mental health, Schizophrenia, Psychology, 030217 neurology & neurosurgery
Abstract: Background Cannabis use and childhood maltreatment are independent risk factors for the development of psychotic symptoms. These factors have been found to interact in some but not all studies. One of the reasons may be that childhood maltreatment and cannabis primarily induce psychotic symptoms in genetically susceptible individuals. In this context, an extensively studied psychosis vulnerability gene is catechol-methyl-transferase ( COMT ). Therefore, we aimed to examine whether the COMT Val 158 Met polymorphism (rs4680) moderates the interaction between childhood maltreatment and cannabis use on psychotic symptoms in the general population. Method The discovery sample consisted of 918 individuals from a cross-sectional study. For replication we used an independent sample of 339 individuals from the general population. Results A significant three-way interaction was found between childhood maltreatment, cannabis use, and the COMT genotype (rs4680) in the discovery sample (P = 0.006). Val-homozygous individuals displayed increased psychotic experiences after exposure to both cannabis use and childhood maltreatment compared to Met-heterozygous and Met-homozygous individuals. Supportive evidence was found in the replication sample with similar effect and direction even though the results did not reach statistical significance (P = 0.25). Conclusions These findings suggest that a functional polymorphism in the COMT gene may moderate the interaction between childhood maltreatment and cannabis use on psychotic experiences in the general population. In conclusion, the COMT Val 158 Met polymorphism may constitute a genetic risk factor for psychotic symptoms in the context of combined exposure to childhood maltreatment and cannabis use.
Published: 2013

46. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis

Author: Aleksey Shatunov, An Goris, John Hardy, Thomas F. Meyer, Sandra D'Alfonso, Christian A. Hübner, Karol Estrada, Susana Pinto, Cristina Moglia, Perry T.C. van Doormaal, Simona Arcuti, Thomas Meitinger, Siddharthan Chandran, Kim A. Staats, Cinzia Bertolin, Peter M. Andersen, Ricardo Rojas-García, William Sproviero, Katie Sidle, François Salachas, Robert Swingler, Anna M. Blokhuis, Thomas M. Ringer, Emily P. McCann, Garth A. Nicholson, Lude Franke, Sven Cichon, Julian Grosskreutz, Markus M. Nöthen, Bernhard Landwehrmeyer, Lukas Tittmann, Jennifer A. Fifita, Christian R. Andres, Alice Vajda, Viviana Pensato, Lauren Elman, Gijs H.P. Tazelaar, Christian Lunetta, Patrick Vourc'h, Christopher Shaw, Gilbert Bensimon, Orla Hardiman, Kuang Lin, Pamela J. Shaw, Alessandro Padovani, Massimiliano Filosto, Jan H. Veldink, Boris Rogelj, Giacomo P. Comi, Matthew C. Kiernan, Philippe Corcia, Giancarlo Logroscino, Ammar Al-Chalabi, Blaž Koritnik, Safaa Saker-Delye, Ian P. Blair, Alexis Brice, Jochen H. Weishaupt, Gianni Sorarù, Maura Brunetti, Alan M. Pittman, Vincenzo Silani, Cindy Maurel, Alexandra Durr, Catherine Lomen-Hoerth, Matthew R. Robinson, Russell L. McLaughlin, Martina Wiedau-Pazos, Chiara Zecca, Nilo Riva, Ashley R. Jones, Andre Franke, Tune H. Pers, Roberto Del Bo, Dominic B. Rowe, Susanne Petri, Sara L. Pulit, John Q. Trojanowski, Wim Robberecht, Christine Payan, Otto W. Witte, Katharine Y. Zhang, Jesus S. Mora, Rick A.A. van der Spek, Urmo Võsa, Kevin P. Kenna, Marcella Rietschel, Milena Radivojkov-Blagojevic, Tino Prell, Philip Van Damme, Leja Dolenc Grošelj, Androniki Menelaou, Beatrice Stubendorff, Cristina Cereda, Kristel R. van Eijk, Leo McCluskey, Jean-François Dartigues, Rosa Capozzo, Markus Weber, Cinzia Tiloca, Michael A. van Es, Wouter van Rheenen, Paul I.W. de Bakker, Carsten Drepper, Bradley N. Smith, Ettore Beghi, Jian Yang, Peter M. Visscher, Hamid Hamzeiy, John Landers, A. Nazli Basak, Hylke M. Blauw, Annelot M. Dekker, Richard W. Orrell, Silvana Penco, Fernando Rivadeneira, Marianne de Visser, Ceren Tunca, Cathryn M. Lewis, Vincent Meininger, Andrea Malaspina, Raymond D. Schellevis, Leonard H. van den Berg, Rosanna Tortelli, Shuna Colville, Anneke J. van der Kooi, Ingo Kurth, Roger Pamphlett, Stéphanie Millecamps, Janez Zidar, Michael Sendtner, Simone de Jong, Roel A. Ophoff, Mamede de Carvalho, Karen E. Morrison, Robbert Jan Stuit, Letizia Mazzini, Jonathan D. Glass, Yesim Parman, Albert Hofman, Lea Leonardis, Naomi R. Wray, Meraida Polak, William J. Brands, Susanne Abdulla, Bernard Muller, Cinzia Gellera, Max Koppers, Pietro Fratta, John Powell, Charles Curtis, Peter Lichtner, Frank P. Diekstra, Adriano Chiò, Isabella Fogh, Federico Casale, Nicholas W. Wood, Katarina Vrabec, André G. Uitterlinden, Vivianna M. Van Deerlin, Gerome Breen, Wolfgang Lieb, Oliver Harschnitz, Nicola Ticozzi, P. Nigel Leigh, R. Jeroen Pasterkamp, Simon Topp, Metka Ravnik-Glavač, Christophe Tzourio, Robert H. Brown, Andrea Calvo, Orietta Pansarasa, Jelena Medic, Albert C. Ludolph, Elisabetta Pupillo, Antonia Ratti, Philippe Amouyel, Repositório da Universidade de Lisboa, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Erasmus MC other, Pediatric Surgery, Internal Medicine, Epidemiology, Neurology, and ANS - Neurodegeneration
Subjects: 0301 basic medicine, Population, EFFICIENT, Genome-wide association study, Locus (genetics), Biology, SUSCEPTIBILITY, SEQUENCE, Article, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Munc18 Proteins, medicine, Journal Article, Genetics, Humans, Genetic Predisposition to Disease, Comparative Study, Amyotrophic lateral sclerosis, education, POPULATION, Genetic association, Netherlands, PITFALLS, education.field_of_study, HEXANUCLEOTIDE REPEAT, COMPLEX, Project MinE, Amyotrophic Lateral Sclerosis, Proteins, PATHWAYS, FRONTOTEMPORAL DEMENTIA, medicine.disease, Genetic architecture, Cytoskeletal Proteins, 030104 developmental biology, Case-Control Studies, Mutation, ALS, 030217 neurology & neurosurgery, Imputation (genetics), Myelin Proteins, Genome-Wide Association Study
Abstract: Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved., To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
Published: 2016

47. Serotonin 2B receptor slows disease progression and prevents degeneration of spinal cord mononuclear phagocytes in amyotrophic lateral sclerosis

Author: Philip C. Wong, Dietmar Rudolf Thal, Jelena Scekic-Zahirovic, Leonard H. van den Berg, Yves Larmet, Sylvie Dirrig-Grosch, Roland Lawson, Hanna Bayer, Jérôme Sinniger, Luc Dupuis, Stéphane Dieterlé, Anke Witting, Albert C. Ludolph, Jochen H. Weishaupt, Jan H. Veldink, Kristel R. van Eijk, Laurent Monassier, Pauline Vercruysse, Hajer El Oussini, Wouter van Rheenen, Anne Roumier, Kathrin Muller, Luc Maroteaux, Andoni Echaniz-Laguna, Department of Neurology [Ulm], Universität Ulm - Ulm University [Ulm, Allemagne], University Medical Center [Utrecht], Laboratoire de neurobiologie et pharmacologie cardiovasculaire (LNPCV), Université de Strasbourg (UNISTRA), Institut du Fer à Moulin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Johns Hopkins University (JHU)
Subjects: 0301 basic medicine, Male, Motor neuron, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Mice, 0302 clinical medicine, Receptor, Serotonin, 5-HT2B, Amyotrophic lateral sclerosis, Receptor, Non-U.S. Gov't, Mononuclear Phagocyte System, Motor Neurons, Microglia, biology, Research Support, Non-U.S. Gov't, Neurodegeneration, SOD1, medicine.anatomical_structure, Integrin alpha M, Spinal Cord, Disease Progression, Female, Serotonin, Central nervous system, Mice, Transgenic, Research Support, Real-Time Polymerase Chain Reaction, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, Downregulation and upregulation, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, medicine, Journal Article, Animals, Humans, business.industry, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Disease Models, Animal, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, 030104 developmental biology, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Immunology, biology.protein, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: International audience; Microglia are the resident mononuclear phagocytes of the central nervous system and have been implicated in the pathogenesis of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). During neurodegeneration, microglial activation is accompanied by infiltration of circulating monocytes, leading to production of multiple inflammatory mediators in the spinal cord. Degenerative alterations in mononuclear phagocytes are commonly observed during neurodegenerative diseases, yet little is known concerning the mechanisms leading to their degeneration, or the consequences on disease progression. Here we observed that the serotonin 2B receptor (5-HT2B), a serotonin receptor expressed in microglia, is upregulated in the spinal cord of three different transgenic mouse models of ALS. In mutant SOD1 mice, this upregulation was restricted to cells positive for CD11b, a marker of mononuclear phagocytes. Ablation of 5-HT2B receptor in transgenic ALS mice expressing mutant SOD1 resulted in increased degeneration of mononuclear phagocytes, as evidenced by fragmentation of Iba1-positive cellular processes. This was accompanied by decreased expression of key neuroinflammatory genes but also loss of expression of homeostatic microglial genes. Importantly, the dramatic effect of 5-HT2B receptor ablation on mononuclear phagocytes was associated with acceleration of disease progression. To determine the translational relevance of these results, we studied polymorphisms in the human HTR2B gene, which encodes the 5-HT2B receptor, in a large cohort of ALS patients. In this cohort, the C allele of SNP rs10199752 in HTR2B was associated with longer survival. Moreover, patients carrying one copy of the C allele of SNP rs10199752 showed increased 5-HT2B mRNA in spinal cord and displayed less pronounced degeneration of Iba1 positive cells than patients carrying two copies of the more common A allele. Thus, the 5-HT2B receptor limits degeneration of spinal cord mononuclear phagocytes, most likely microglia, and slows disease progression in ALS. Targeting this receptor might be therapeutically useful.
Published: 2016

48. DRD2 schizophrenia-risk allele is associated with impaired striatal functioning in unaffected siblings of schizophrenia patients

Author: Matthijs Vink, Mariët van Buuren, Kristel R. van Eijk, Jurjen J. Luykx, Hanna E. van den Munkhof, Max de Leeuw, René S. Kahn, Clinical, Neuro- & Developmental Psychology, IBBA, and LEARN! - Educational neuroscience, learning and development
Subjects: Adult, Male, Risk, medicine.medical_specialty, striatum, Single-nucleotide polymorphism, Genome-wide association study, Executive Function, 03 medical and health sciences, 0302 clinical medicine, Dopamine, Dopamine receptor D2, Internal medicine, Basal ganglia, medicine, Journal Article, Humans, Allele, Alleles, siblings, Genetics, proactive inhibitory control, Reactive inhibition, Receptors, Dopamine D2, fMRI, Regular Article, medicine.disease, Magnetic Resonance Imaging, 030227 psychiatry, Neostriatum, schizophrenia, Inhibition, Psychological, Psychiatry and Mental health, Endocrinology, Schizophrenia, DRD2, Female, Psychology, 030217 neurology & neurosurgery, medicine.drug
Abstract: A recent Genome-Wide Association Study showed that the rs2514218 single nucleotide polymorphism (SNP) in close proximity to dopamine receptor D2 is strongly associated with schizophrenia. Further, an in silico experiment showed that rs2514218 has a cis expression quantitative trait locus effect in the basal ganglia. To date, however, the functional consequence of this SNP is unknown. Here, we used functional Magnetic resonance imaging to investigate the impact of this risk allele on striatal activation during proactive and reactive response inhibition in 45 unaffected siblings of schizophrenia patients. We included siblings to circumvent the illness specific confounds affecting striatal functioning independent from gene effects. Behavioral analyses revealed no differences between the carriers (n = 21) and noncarriers (n = 24). Risk allele carriers showed a diminished striatal response to increasing proactive inhibitory control demands, whereas overall level of striatal activation in carriers was elevated compared to noncarriers. Finally, risk allele carriers showed a blunted striatal response during successful reactive inhibition compared to the noncarriers. These data are consistent with earlier reports showing similar deficits in schizophrenia patients, and point to a failure to flexibly engage the striatum in response to contextual cues. This is the first study to demonstrate an association between impaired striatal functioning and the rs2514218 polymorphism. We take our findings to indicate that striatal functioning is impaired in carriers of the DRD2 risk allele, likely due to dopamine dysregulation at the DRD2 location.
Published: 2016

49. Using genome-wide pathway analysis to unravel the etiology of complex diseases

Author: Yvonne T. van der Schouw, Clara C. Elbers, Cisca Wijmenga, Kristel R. van Eijk, Lude Franke, Flip Mulder, N. Charlotte Onland-Moret, University of Groningen, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Stem Cell Aging Leukemia and Lymphoma (SALL)
Subjects: Risk, HAPLOTYPE MAP, Epidemiology, Concordance, Gene regulatory network, Single-nucleotide polymorphism, Genome-wide association study, pathway classification, VARIANTS, Biology, Polymorphism, Single Nucleotide, Genome, Humans, Genetic Predisposition to Disease, DGI, NETWORK, Genetics (clinical), Oligonucleotide Array Sequence Analysis, Genetic association, Inflammation, Genetics, Models, Statistical, WTCCC, Models, Genetic, Haplotype, Genetic Diseases, Inborn, Case-control study, Chromosome Mapping, ASSOCIATION, RISK LOCI, GENE, INSIGHTS, Diabetes Mellitus, Type 2, Haplotypes, Case-Control Studies, genome-wide association studies, REPLICATION, type 2 diabetes, Genome-Wide Association Study
Abstract: Several genome-wide association studies (GWAS) have been published on various complex diseases. Although, new loci are found to be associated with these diseases, still only very little of the genetic risk for these diseases can be explained. As GWAS are still underpowered to find small main effects, and gene-gene interactions are likely to play a role, the data might currently not be analyzed to its full potential. In this study, we evaluated alternative methods to study GWAS data. Instead of focusing on the single nucleotide polymorphisms (SNPs) with the highest statistical significance, we took advantage of prior biological information and tried to detect overrepresented pathways in the GWAS data. We evaluated whether pathway classification analysis can help prioritize the biological pathways most likely to be involved in the disease etiology. In this study, we present the various benefits and limitations of pathway-classification tools in analyzing GWAS data. We show multiple differences in outcome between pathway tools analyzing the same dataset. Furthermore, analyzing randomly selected SNPs always results in significantly overrepresented pathways, large pathways have a higher chance of becoming statistically significant and the bioinformatics tools used in this study are biased toward detecting well-defined pathways. As an example, we analyzed data from two GWAS on type 2 diabetes (T2D): the Diabetes Genetics Initiative (DGI) and the Wellcome Trust Case Control Consortium (WTCCC). Occasionally the results from the DGI and the WTCCC GWAS showed concordance in overrepresented pathways, but discordance in the corresponding genes. Thus, incorporating gene networks and pathway classification tools into the analysis can point toward significantly overrepresented molecular pathways, which cannot be picked up using traditional single-locus analyses. However, the limitations discussed in this study, need to be addressed before these methods can be widely used. Geriet. Epidemiol. 33:419-431, 2009. (C) 2009 Wiley-Liss, Inc.
Published: 2009

50. Identification of schizophrenia-associated loci by combining DNA methylation and gene expression data from whole blood

Author: Steve Horvath, René S. Kahn, Marco P. Boks, E. Strengman, Roel A. Ophoff, Kristel R. van Eijk, Simone de Jong, and Jacobine E. Buizer-Voskamp
Subjects: Male, medicine.medical_specialty, Clinical Sciences, Quantitative Trait Loci, Gene Expression, Genome-wide association study, Genomics, Single-nucleotide polymorphism, Locus (genetics), Biology, Research Support, Article, N.I.H, Epigenesis, Genetic, Promoter Regions, Rare Diseases, Genetic, Research Support, N.I.H., Extramural, Clinical Research, Molecular genetics, medicine, Genetics, Journal Article, 2.1 Biological and endogenous factors, Humans, Genetics(clinical), Genetic Predisposition to Disease, Epigenetics, Aetiology, Promoter Regions, Genetic, Genetics (clinical), Genetics & Heredity, Prevention, Human Genome, Extramural, Methylation, DNA Methylation, Serious Mental Illness, Brain Disorders, Mental Health, DNA methylation, Schizophrenia, Female, Epigenesis, Biotechnology, Genome-Wide Association Study
Abstract: Emerging evidence suggests that schizophrenia (SZ) susceptibility involves variation at genetic, epigenetic and transcriptome levels. We describe an integrated approach that leverages DNA methylation and gene expression data to prioritize genetic variation involved in disease. DNA methylation levels were obtained from whole blood of 260 SZ patients and 250 unaffected controls of which a subset with gene expression data was available. By assessing DNA methylation and gene expression in cases and controls, we identified 432 CpG sites with differential methylation levels that are associated with differential gene expression. We hypothesized that genetic factors involved in these methylation levels may be associated with the genetic risk of SZ susceptibility. To test this hypothesis, we used results from the Psychiatric Genomics Consortium SZ genome-wide association study (GWAS). We observe an enrichment of SZ-associated SNPs in the mQTLs of which the associated CpG site is also correlated with differential gene expression in SZ. While this enrichment was already apparent when using nominal significant thresholds, enrichment was even more pronounced when applying more stringent significance levels. One locus, previously identified as susceptibility locus in a SZ GWAS, involves SNP rs11191514:C>T, which regulates DNA methylation of calcium homeostasis modulator 1 that is also associated with differential gene expression in patients. Overall, our results suggest that epigenetic variation plays an important role in SZ susceptibility and that the integration of analyses of genetic, epigenetic and gene expression profiles may be a biologically meaningful approach for identifying disease susceptibility loci, even when using whole blood data in studies of brain-related disorders.
Published: 2014

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