Author: "Jacob Gratten" / Topic: 0301 basic medicine - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"Jacob Gratten"' showing total 29 results

Start Over Author "Jacob Gratten" Topic 0301 basic medicine

29 results on '"Jacob Gratten"'

1. Analysis of DNA methylation associates the cystine–glutamate antiporter SLC7A11 with risk of Parkinson’s disease

Author: Anjali K. Henders, Marta F. Nabais, Steven R. Bentley, Ting Qi, John C. Dalrymple-Alford, Jacob Gratten, Glenda M. Halliday, Qian Zhang, Leanne Wallace, Allan F. McRae, Costanza L. Vallerga, Peter A. Silburn, Yu-Hsuan Chuang, Steve Horvath, Tim J. Anderson, Futao Zhang, Jian Yang, Grant W. Montgomery, George D. Mellick, Beate Ritz, Naomi R. Wray, John F. Pearson, Irfahan Kassam, Martin A. Kennedy, John B.J. Kwok, Simon J.G. Lewis, Javed Fowdar, Peter M. Visscher, Ian B. Hickie, and Toni L. Pitcher
Subjects: Epigenomics, Male, 0301 basic medicine, Parkinson's disease, General Physics and Astronomy, SLC7A11, 0302 clinical medicine, Gene expression, lcsh:Science, Aged, 80 and over, Genetics, DNA methylation, Multidisciplinary, biology, Parkinson Disease, Environmental exposure, Middle Aged, Glutathione, Healthy Volunteers, 3. Good health, CpG site, Female, Chromosomes, Human, Pair 4, Adult, Amino Acid Transport System y+, Science, Down-Regulation, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, medicine, Humans, Gene, Aged, Australia, General Chemistry, Mendelian Randomization Analysis, medicine.disease, 030104 developmental biology, Risk factors, Case-Control Studies, biology.protein, CpG Islands, lcsh:Q, 030217 neurology & neurosurgery, New Zealand
Abstract: An improved understanding of etiological mechanisms in Parkinson’s disease (PD) is urgently needed because the number of affected individuals is projected to increase rapidly as populations age. We present results from a blood-based methylome-wide association study of PD involving meta-analysis of 229 K CpG probes in 1,132 cases and 999 controls from two independent cohorts. We identify two previously unreported epigenome-wide significant associations with PD, including cg06690548 on chromosome 4. We demonstrate that cg06690548 hypermethylation in PD is associated with down-regulation of the SLC7A11 gene and show this is consistent with an environmental exposure, as opposed to medications or genetic factors with effects on DNA methylation or gene expression. These findings are notable because SLC7A11 codes for a cysteine-glutamate anti-porter regulating levels of the antioxidant glutathione, and it is a known target of the environmental neurotoxin β-methylamino-L-alanine (BMAA). Our study identifies the SLC7A11 gene as a plausible biological target in PD., Parkinson’s disease (PD) is a common neurodegenerative disorder with a complex etiology involving genetics and the environment. Here, Vallerga et al. identify two CpG probes associated with PD in a blood cell type-corrected epigenome-wide meta-analysis, implicating the SLC7A11 gene as a plausible biological target.
Published: 2020

2. Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders

Author: Gabriëlla A.M. Blokland, Jakob Grove, Chia-Yen Chen, Chris Cotsapas, Stuart Tobet, Robert Handa, David St Clair, Todd Lencz, Bryan J. Mowry, Sathish Periyasamy, Murray J. Cairns, Paul A. Tooney, Jing Qin Wu, Brian Kelly, George Kirov, Patrick F. Sullivan, Aiden Corvin, Brien P. Riley, Tõnu Esko, Lili Milani, Erik G. Jönsson, Aarno Palotie, Hannelore Ehrenreich, Martin Begemann, Agnes Steixner-Kumar, Pak C. Sham, Nakao Iwata, Daniel R. Weinberger, Pablo V. Gejman, Alan R. Sanders, Joseph D. Buxbaum, Dan Rujescu, Ina Giegling, Bettina Konte, Annette M. Hartmann, Elvira Bramon, Robin M. Murray, Michele T. Pato, Jimmy Lee, Ingrid Melle, Espen Molden, Roel A. Ophoff, Andrew McQuillin, Nicholas J. Bass, Rolf Adolfsson, Anil K. Malhotra, Nicholas G. Martin, Janice M. Fullerton, Philip B. Mitchell, Peter R. Schofield, Andreas J. Forstner, Franziska Degenhardt, Sabrina Schaupp, Ashley L. Comes, Manolis Kogevinas, José Guzman-Parra, Andreas Reif, Fabian Streit, Lea Sirignano, Sven Cichon, Maria Grigoroiu-Serbanescu, Joanna Hauser, Jolanta Lissowska, Fermin Mayoral, Bertram Müller-Myhsok, Beata Świątkowska, Thomas G. Schulze, Markus M. Nöthen, Marcella Rietschel, John Kelsoe, Marion Leboyer, Stéphane Jamain, Bruno Etain, Frank Bellivier, John B. Vincent, Martin Alda, Claire O’Donovan, Pablo Cervantes, Joanna M. Biernacka, Mark Frye, Susan L. McElroy, Laura J. Scott, Eli A. Stahl, Mikael Landén, Marian L. Hamshere, Olav B. Smeland, Srdjan Djurovic, Arne E. Vaaler, Ole A. Andreassen, Bernhard T. Baune, Tracy Air, Martin Preisig, Rudolf Uher, Douglas F. Levinson, Myrna M. Weissman, James B. Potash, Jianxin Shi, James A. Knowles, Roy H. Perlis, Susanne Lucae, Dorret I. Boomsma, Brenda W.J.H. Penninx, Jouke-Jan Hottenga, Eco J.C. de Geus, Gonneke Willemsen, Yuri Milaneschi, Henning Tiemeier, Hans J. Grabe, Alexander Teumer, Sandra Van der Auwera, Uwe Völker, Steven P. Hamilton, Patrik K.E. Magnusson, Alexander Viktorin, Divya Mehta, Niamh Mullins, Mark J. Adams, Gerome Breen, Andrew M. McIntosh, Cathryn M. Lewis, David M. Hougaard, Merete Nordentoft, Ole Mors, Preben B. Mortensen, Thomas Werge, Thomas D. Als, Anders D. Børglum, Tracey L. Petryshen, Jordan W. Smoller, Jill M. Goldstein, Stephan Ripke, Benjamin M. Neale, James T.R. Walters, Kai-How Farh, Peter A. Holmans, Phil Lee, Brendan Bulik-Sullivan, David A. Collier, Hailiang Huang, Tune H. Pers, Ingrid Agartz, Esben Agerbo, Margot Albus, Madeline Alexander, Farooq Amin, Silviu A. Bacanu, Richard A. Belliveau, Judit Bene, Sarah E. Bergen, Elizabeth Bevilacqua, Tim B. Bigdeli, Donald W. Black, Richard Bruggeman, Nancy G. Buccola, Randy L. Buckner, William Byerley, Wiepke Cahn, Guiqing Cai, Dominique Campion, Rita M. Cantor, Vaughan J. Carr, Noa Carrera, Stanley V. Catts, Kimberly D. Chambert, Raymond C.K. Chan, Ronald Y.L. Chen, Eric Y.H. Chen, Wei Cheng, Eric F.C. Cheung, Siow Ann Chong, C. Robert Cloninger, David Cohen, Nadine Cohen, Paul Cormican, Nick Craddock, James J. Crowley, David Curtis, Michael Davidson, Kenneth L. Davis, Jurgen Del Favero, Ditte Demontis, Dimitris Dikeos, Timothy Dinan, Gary Donohoe, Elodie Drapeau, Jubao Duan, Frank Dudbridge, Naser Durmishi, Peter Eichhammer, Johan Eriksson, Valentina Escott-Price, Laurent Essioux, Ayman H. Fanous, Martilias S. Farrell, Josef Frank, Lude Franke, Robert Freedman, Nelson B. Freimer, Marion Friedl, Joseph I. Friedman, Menachem Fromer, Giulio Genovese, Lyudmila Georgieva, Paola Giusti-Rodríguez, Stephanie Godard, Jacqueline I. Goldstein, Vera Golimbet, Srihari Gopal, Jacob Gratten, Lieuwe de Haan, Christian Hammer, Mark Hansen, Thomas Hansen, Vahram Haroutunian, Frans A. Henskens, Stefan Herms, Joel N. Hirschhorn, Per Hoffmann, Andrea Hofman, Mads V. Hollegaard, Masashi Ikeda, Inge Joa, Antonio Julià, René S. Kahn, Luba Kalaydjieva, Sena Karachanak-Yankova, Juha Karjalainen, David Kavanagh, Matthew C. Keller, James L. Kennedy, Andrey Khrunin, Yunjung Kim, Janis Klovins, Vaidutis Kucinskas, Zita Ausrele Kucinskiene, Hana Kuzelova-Ptackova, Anna K. Kähler, Claudine Laurent, Jimmy Lee Chee Keong, S. Hong Lee, Sophie E. Legge, Bernard Lerer, Miaoxin Li, Tao Li, Kung-Yee Liang, Jeffrey Lieberman, Svetlana Limborska, Carmel M. Loughland, Jan Lubinski, Jouko Lönnqvist, Milan Macek, Brion S. Maher, Wolfgang Maier, Jacques Mallet, Sara Marsal, Manuel Mattheisen, Morten Mattingsdal, Robert W. McCarley, Colm McDonald, Sandra Meier, Carin J. Meijer, Bela Melegh, Raquelle I. Mesholam-Gately, Andres Metspalu, Patricia T. Michie, Vihra Milanova, Younes Mokrab, Derek W. Morris, Kieran C. Murphy, Inez Myin-Germeys, Mari Nelis, Igor Nenadic, Deborah A. Nertney, Gerald Nestadt, Kristin K. Nicodemus, Liene Nikitina-Zake, Laura Nisenbaum, Annelie Nordin, Eadbhard O’Callaghan, Colm O’Dushlaine, F. Anthony O’Neill, Sang-Yun Oh, Ann Olincy, Line Olsen, Jim Van Os, Christos Pantelis, George N. Papadimitriou, Sergi Papiol, Elena Parkhomenko, Tiina Paunio, Milica Pejovic-Milovancevic, Diana O. Perkins, Olli Pietiläinen, Jonathan Pimm, Andrew J. Pocklington, John Powell, Alkes Price, Ann E. Pulver, Shaun M. Purcell, Digby Quested, Henrik B. Rasmussen, Abraham Reichenberg, Mark A. Reimers, Alexander L. Richards, Joshua L. Roffman, Panos Roussos, Douglas M. Ruderfer, Veikko Salomaa, Ulrich Schall, Christian R. Schubert, Sibylle G. Schwab, Edward M. Scolnick, Rodney J. Scott, Larry J. Seidman, Engilbert Sigurdsson, Teimuraz Silagadze, Jeremy M. Silverman, Kang Sim, Petr Slominsky, Hon-Cheong So, Chris C.A. Spencer, Hreinn Stefansson, Stacy Steinberg, Elisabeth Stogmann, Richard E. Straub, Eric Strengman, Jana Strohmaier, T. Scott Stroup, Mythily Subramaniam, Jaana Suvisaari, Dragan M. Svrakic, Jin P. Szatkiewicz, Erik Söderman, Srinivas Thirumalai, Draga Toncheva, Sarah Tosato, Juha Veijola, John Waddington, Dermot Walsh, Dai Wang, Qiang Wang, Bradley T. Webb, Mark Weiser, Dieter B. Wildenauer, Nigel M. Williams, Stephanie Williams, Stephanie H. Witt, Aaron R. Wolen, Emily H.M. Wong, Brandon K. Wormley, Hualin Simon Xi, Clement C. Zai, Xuebin Zheng, Fritz Zimprich, Naomi R. Wray, Kari Stefansson, Peter M. Visscher, Douglas H.R. Blackwood, Ariel Darvasi, Enrico Domenici, Michael Gill, Hugh Gurling, Christina M. Hultman, Assen V. Jablensky, Kenneth S. Kendler, Jo Knight, Qingqin S. Li, Jianjun Liu, Steven A. McCarroll, Jennifer L. Moran, Michael J. Owen, Carlos N. Pato, Danielle Posthuma, Pamela Sklar, Jens R. Wendland, Mark J. Daly, Michael C. O’Donovan, Peter Donnelly, Ines Barroso, Jenefer M. Blackwell, Matthew A. Brown, Juan P. Casas, Panos Deloukas, Audrey Duncanson, Janusz Jankowski, Hugh S. Markus, Christopher G. Mathew, Colin N.A. Palmer, Robert Plomin, Anna Rautanen, Stephen J. Sawcer, Richard C. Trembath, Ananth C. Viswanathan, Nicholas W. Wood, Gavin Band, Céline Bellenguez, Colin Freeman, Eleni Giannoulatou, Garrett Hellenthal, Richard Pearson, Matti Pirinen, Amy Strange, Zhan Su, Damjan Vukcevic, Cordelia Langford, Hannah Blackburn, Suzannah J. Bumpstead, Serge Dronov, Sarah Edkins, Matthew Gillman, Emma Gray, Rhian Gwilliam, Naomi Hammond, Sarah E. Hunt, Alagurevathi Jayakumar, Jennifer Liddle, Owen T. McCann, Simon C. Potter, Radhi Ravindrarajah, Michelle Ricketts, Avazeh Tashakkori-Ghanbaria, Matthew Waller, Paul Weston, Pamela Whittaker, Sara Widaa, Mark I. McCarthy, Maria J. Arranz, Steven Bakker, Stephan Bender, Benedicto Crespo-Facorro, Jeremy Hall, Conrad Iyegbe, Stephen Lawrie, Kuang Lin, Don H. Linszen, Ignacio Mata, Muriel Walshe, Matthias Weisbrod, Durk Wiersma, Vassily Trubetskoy, Yunpeng Wang, Jonathan R.I. Coleman, Héléna A. Gaspar, Christiaan A. de Leeuw, Jennifer M. Whitehead Pavlides, Maciej Trzaskowski, Enda M. Byrne, Liam Abbott, Huda Akil, Diego Albani, Ney Alliey-Rodriguez, Adebayo Anjorin, Verneri Antilla, Swapnil Awasthi, Judith A. Badner, Marie Bækvad-Hansen, Jack D. Barchas, Nicholas Bass, Michael Bauer, Richard Belliveau, Carsten Bøcker Pedersen, Erlend Bøen, Marco P. Boks, James Boocock, Monika Budde, William Bunney, Margit Burmeister, Jonas Bybjerg-Grauholm, Miquel Casas, Felecia Cerrato, Kimberly Chambert, Alexander W. Charney, Danfeng Chen, Claire Churchhouse, Toni-Kim Clarke, William Coryell, David W. Craig, Cristiana Cruceanu, Piotr M. Czerski, Anders M. Dale, Simone de Jong, Jurgen Del-Favero, J. Raymond DePaulo, Amanda L. Dobbyn, Ashley Dumont, Torbjørn Elvsåshagen, Chun Chieh Fan, Sascha B. Fischer, Matthew Flickinger, Tatiana M. Foroud, Liz Forty, Christine Fraser, Katrin Gade, Diane Gage, Julie Garnham, Claudia Giambartolomei, Marianne Giørtz Pedersen, Jaqueline Goldstein, Scott D. Gordon, Katherine Gordon-Smith, Elaine K. Green, Melissa J. Green, Tiffany A. Greenwood, Weihua Guan, Martin Hautzinger, Urs Heilbronner, Maria Hipolito, Dominic Holland, Laura Huckins, Jessica S. Johnson, Radhika Kandaswamy, Robert Karlsson, Sarah Kittel-Schneider, Anna C. Koller, Ralph Kupka, Catharina Lavebratt, Jacob Lawrence, William B. Lawson, Markus Leber, Phil H. Lee, Shawn E. Levy, Jun Z. Li, Chunyu Liu, Anna Maaser, Donald J. MacIntyre, Pamela B. Mahon, Lina Martinsson, Steve McCarroll, Peter McGuffin, Melvin G. McInnis, James D. McKay, Helena Medeiros, Sarah E. Medland, Fan Meng, Grant W. Montgomery, Thomas W. Mühleisen, Hoang Nguyen, Caroline M. Nievergelt, Annelie Nordin Adolfsson, Evaristus A. Nwulia, Claire O'Donovan, Loes M. Olde Loohuis, Anil P.S. Ori, Lilijana Oruc, Urban Ösby, Amy Perry, Andrea Pfennig, Eline J. Regeer, Céline S. Reinbold, John P. Rice, Fabio Rivas, Margarita Rivera, Euijung Ryu, Cristina Sánchez-Mora, Alan F. Schatzberg, William A. Scheftner, Nicholas J. Schork, Cynthia Shannon Weickert, Tatyana Shehktman, Paul D. Shilling, Claire Slaney, Janet L. Sobell, Christine Søholm Hansen, Anne T. Spijker, Michael Steffens, John S. Strauss, Szabolcs Szelinger, Robert C. Thompson, Thorgeir E. Thorgeirsson, Jens Treutlein, Helmut Vedder, Weiqing Wang, Stanley J. Watson, Thomas W. Weickert, Simon Xi, Wei Xu, Allan H. Young, Peter Zandi, Peng Zhang, Sebastian Zöllner, Abdel Abdellaoui, Tracy M. Air, Till F.M. Andlauer, Silviu-Alin Bacanu, Aartjan T.F. Beekman, Elisabeth B. Binder, Julien Bryois, Henriette N. Buttenschøn, Na Cai, Enrique Castelao, Jane Hvarregaard Christensen, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Gregory E. Crawford, Gail Davies, Ian J. Deary, Eske M. Derks, Nese Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Jerome C. Foo, Fernando S. Goes, Lynsey S. Hall, Thomas F. Hansen, Ian B. Hickie, Georg Homuth, Carsten Horn, David M. Howard, Marcus Ising, Rick Jansen, Ian Jones, Lisa A. Jones, Eric Jorgenson, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Zoltán Kutalik, Yihan Li, Penelope A. Lind, Dean F. MacKinnon, Robert M. Maier, Jonathan Marchini, Hamdi Mbarek, Patrick McGrath, Christel M. Middeldorp, Evelin Mihailov, Francis M. Mondimore, Sara Mostafavi, Matthias Nauck, Bernard Ng, Michel G. Nivard, Dale R. Nyholt, Paul F. O'Reilly, Hogni Oskarsson, Jodie N. Painter, Roseann E. Peterson, Wouter J. Peyrot, Giorgio Pistis, Jorge A. Quiroz, Per Qvist, Saira Saeed Mirza, Robert Schoevers, Eva C. Schulte, Ling Shen, Stanley I. Shyn, Grant C.B. Sinnamon, Johannes H. Smit, Daniel J. Smith, Katherine E. Tansey, Henning Teismann, Wesley Thompson, Pippa A. Thomson, Matthew Traylor, André G. Uitterlinden, Daniel Umbricht, Albert M. van Hemert, Shantel Marie Weinsheimer, Jürgen Wellmann, Yang Wu, Hualin S. Xi, Jian Yang, Futao Zhang, Volker Arolt, Klaus Berger, Udo Dannlowski, Katharina Domschke, Caroline Hayward, Andrew C. Heath, Stefan Kloiber, Glyn Lewis, Pamela AF. Madden, Patrik K. Magnusson, Preben Bo Mortensen, Michael C. O'Donovan, Sara A. Paciga, Nancy L. Pedersen, David J. Porteous, Catherine Schaefer, Henry Völzke, Marco Bortolato, Janita Bralten, Cynthia M. Bulik, Christie L. Burton, Caitlin E. Carey, Lea K. Davis, Laramie E. Duncan, Howard J. Edenberg, Lauren Erdman, Stephen V. Faraone, Slavina B. Goleva, Wei Guo, Christopher Hübel, Laura M. Huckins, Ekaterina A. Khramtsova, Joanna Martin, Carol A. Mathews, Elise Robinson, Eli Stahl, Barbara E. Stranger, Michela Traglia, Raymond K. Walters, Lauren A. Weiss, Stacey J. Winham, Yin Yao, Kristjar Skajaa, Markus Nöthen, Michael Owen, Robert H. Yolken, Niels Plath, Jonathan Mill, Daniel Geschwind, Psychiatry 1, RS: MHeNs - R2 - Mental Health, Psychiatrie & Neuropsychologie, Centre of Excellence in Complex Disease Genetics, Research Programme of Molecular Medicine, Research Programs Unit, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Functional Genomics, Biological Psychology, APH - Mental Health, APH - Methodology, Sociology and Social Gerontology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Blokland, Gabriella AM, Grove, Jakob, Chen, Chia Yen, Cotsapas, Chris, Tobet, Stuart, Handa, Robert, Lee, Sang Hong, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium, iPSYCH, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), Child and Adolescent Psychiatry / Psychology, Adult Psychiatry, ANS - Complex Trait Genetics, and ANS - Mood, Anxiety, Psychosis, Stress & Sleep
Subjects: 0301 basic medicine, Male, Bipolar Disorder, Schizophrenia/genetics, LD SCORE REGRESSION, Genome-wide association study, 0302 clinical medicine, Receptors, SCHIZOPHRENIA, Psychotic Disorders/genetics, KYNURENINE PATHWAY METABOLISM, Genetics, RISK, Sex Characteristics, Vascular Endothelial Growth Factor, Bipolar Disorder/genetics, Major/genetics, Single Nucleotide, AFFECTIVE STIMULI IMPACT, Schizophrenia, Sulfurtransferases, Major depressive disorder, Female, Depressive Disorder, Major/genetics, Bipolar disorder, Locus (genetics), Genomics, Biology, Polymorphism, Single Nucleotide, Article, DYSPHORIC MOOD, 03 medical and health sciences, Sex differences, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Polymorphism, GENOME-WIDE ASSOCIATION, Genotype-by-sex interaction, Biological Psychiatry, Depressive Disorder, Major, Depressive Disorder, GENDER-DIFFERENCES, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], PARAVENTRICULAR NUCLEUS, 3112 Neurosciences, Endothelial Cells, MAJOR DEPRESSION, medicine.disease, Genetic architecture, 030104 developmental biology, Mood, Receptors, Vascular Endothelial Growth Factor, Psychotic Disorders, 3111 Biomedicine, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Contains fulltext : 248656.pdf (Publisher’s version ) (Closed access) BACKGROUND: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10(-8)), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10(-6)) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10(-7); rs73033497, p = 8.8 × 10(-7); rs7914279, p = 6.4 × 10(-7)), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10(-7)) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10(-7)), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10(-7)) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
Published: 2022

3. The genetic relationship between female reproductive traits and six psychiatric disorders

Author: Xuan Zhou, Natalie T. Mills, Jacob Gratten, Guiyan Ni, Azmeraw T. Amare, Sang Hong Lee, Ni, Guiyan, Amare, Azmeraw T, Zhou, Xuan, Mills, Natalie, Gratten, Jacob, and Lee, S Hong
Subjects: Male, 0301 basic medicine, Multifactorial Inheritance, lcsh:Medicine, 0302 clinical medicine, Risk Factors, Databases, Genetic, Young adult, lcsh:Science, Reproductive health, 0303 health sciences, Multidisciplinary, Mental Disorders, Reproduction, bipolar affective-disorder, health, Genomics, Middle Aged, 3. Good health, Schizophrenia, Major depressive disorder, Female, Adult, medicine.medical_specialty, Adolescent, Offspring, Biology, Genetic correlation, Article, Young Adult, 03 medical and health sciences, Quantitative Trait, Heritable, medicine, Humans, Genetic Predisposition to Disease, Psychiatry, Genetic Association Studies, 030304 developmental biology, Genetic association study, Aged, Reproductive success, business.industry, lcsh:R, medicine.disease, Genetic architecture, schizophrenia, Sexual intercourse, 030104 developmental biology, maternal age, mendelian randomization, lcsh:Q, business, 030217 neurology & neurosurgery
Abstract: Female reproductive behaviors have an important implication in evolutionary fitness and health of offspring. Previous studies have shown that age at first birth of women (AFB) is genetically associated with schizophrenia (SCZ). However, for most other psychiatric disorders and reproductive traits, the latent shared genetic architecture is largely unknown. Here we used the second wave of UK Biobank data (N=220,685) to evaluate the association between five female reproductive traits and polygenetic risk scores (PRS) projected from genome-wide association study summary statistics of six psychiatric disorders (N=429,178). We found that the PRS of attention-deficit/hyperactivity disorder (ADHD) were strongly associated with AFB (genetic correlation of −0.68 ± 0.03 with p-value = 1.86E-89), age at first sexual intercourse (AFS) (−0.56 ± 0.03 with p-value = 3.42E-60), number of live births (NLB) (0.36 ± 0.04 with p-value = 4.01E-17) and age at menopause (−0.27 ± 0.04 with p-value = 5.71E-13). There were also robustly significant associations between the PRS of eating disorder (ED) and AFB (genetic correlation of 0.35 ± 0.06), ED and AFS (0.19 0.06), Major depressive disorder (MDD) and AFB (−0.27 ± 0.07), MDD and AFS (− 0.27 ± 0.03) and SCZ and AFS (−0.10 ± 0.03). Our findings reveal the shared genetic architecture between the five reproductive traits in women and six psychiatric disorders, which have a potential implication that helps to improve reproductive health in women, hence better child outcomes. Our findings may also explain, at least in part, an evolutionary hypothesis that causal mutations underlying psychiatric disorders have positive effects on reproductive success.
Published: 2019

4. Improved precision of epigenetic clock estimates across tissues and its implication for biological ageing

Author: Riccardo E. Marioni, Peter A. Silburn, John B.J. Kwok, Ian J. Deary, Simon J.G. Lewis, Dongsheng Fan, Qian Zhang, David J. Porteous, Tian Lin, Alison D. Murray, Ji He, Glenda M. Halliday, Kathryn L. Evans, Sarah E. Harris, Tim J. Anderson, Grant W. Montgomery, John F. Pearson, Toni L. Pitcher, Peter M. Visscher, Chris Haley, Ian B. Hickie, Naomi R. Wray, Andrew M. McIntosh, Javed Fowdar, Anjali K. Henders, George D. Mellick, Costanza L. Vallerga, Allan F. McRae, Martin A. Kennedy, Jian Yang, Paul Redmond, Jacob Gratten, and Rosie M. Walker
Subjects: 0301 basic medicine, Oncology, Epigenomics, medicine.medical_specialty, Aging, Epigenetic clock, lcsh:QH426-470, Age prediction, lcsh:Medicine, Epigenesis, Genetic, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Genetics, Medicine, Humans, Genetic Predisposition to Disease, Epigenetics, Mortality, Saliva, Molecular Biology, Genetics (clinical), Proportional Hazards Models, DNA methylation, business.industry, Research, Confounding, lcsh:R, Reproducibility of Results, Small sample, Chronological age, 3. Good health, Ageing, lcsh:Genetics, 030104 developmental biology, Sample size determination, Organ Specificity, 030220 oncology & carcinogenesis, Molecular Medicine, business, Birth cohort, Genome-Wide Association Study
Abstract: Background DNA methylation changes with age. Chronological age predictors built from DNA methylation are termed ‘epigenetic clocks’. The deviation of predicted age from the actual age (‘age acceleration residual’, AAR) has been reported to be associated with death. However, it is currently unclear how a better prediction of chronological age affects such association. Methods In this study, we build multiple predictors based on training DNA methylation samples selected from 13,661 samples (13,402 from blood and 259 from saliva). We use the Lothian Birth Cohorts of 1921 (LBC1921) and 1936 (LBC1936) to examine whether the association between AAR (from these predictors) and death is affected by (1) improving prediction accuracy of an age predictor as its training sample size increases (from 335 to 12,710) and (2) additionally correcting for confounders (i.e., cellular compositions). In addition, we investigated the performance of our predictor in non-blood tissues. Results We found that in principle, a near-perfect age predictor could be developed when the training sample size is sufficiently large. The association between AAR and mortality attenuates as prediction accuracy increases. AAR from our best predictor (based on Elastic Net, https://github.com/qzhang314/DNAm-based-age-predictor) exhibits no association with mortality in both LBC1921 (hazard ratio = 1.08, 95% CI 0.91–1.27) and LBC1936 (hazard ratio = 1.00, 95% CI 0.79–1.28). Predictors based on small sample size are prone to confounding by cellular compositions relative to those from large sample size. We observed comparable performance of our predictor in non-blood tissues with a multi-tissue-based predictor. Conclusions This study indicates that the epigenetic clock can be improved by increasing the training sample size and that its association with mortality attenuates with increased prediction of chronological age. Electronic supplementary material The online version of this article (10.1186/s13073-019-0667-1) contains supplementary material, which is available to authorized users.
Published: 2019

5. Parkinson's disease age at onset genome‐wide association study: Defining heritability, genetic loci, and α‐synuclein mechanisms

Author: Lisa M. Shulman, Hirotaka Iwaki, David A. Hinds, Jacob Gratten, Huw R. Morris, Joseph Jankovic, Costanza L. Vallerga, J. Raphael Gibbs, John Hardy, Javier Simón-Sánchez, Johan Marinus, Thomas Gasser, Peter Heutink, Alexis Brice, Andrew B. Singleton, Dena G. Hernandez, Jean-Christophe Corvol, Karl Heilbron, Donald G. Grosset, Manu Sharma, Ari Siitonen, Peter M. Visscher, Sonja W. Scholz, Pentti J. Tienari, Lynne Krohn, Mathias Toft, Manuela Tan, Johanna Eerola-Rautio, Mike A. Nalls, Jacobus J. van Hilten, Lasse Pihlstrøm, Claudia Schulte, Ziv Gan-Or, Sara Bandres-Ciga, Cornelis Blauwendraat, Hampton L. Leonard, Alastair J. Noyce, Kari Majamaa, Rainer von Coelln, N Wood, Joshua M. Shulman, Suzanne Lesage, HUS Neurocenter, Pentti Tienari / Principal Investigator, Neurologian yksikkö, Research Programs Unit, Department of Neurosciences, STEMM - Stem Cells and Metabolism Research Program, University of Helsinki, and University Management
Subjects: Male, GLUCOCEREBROSIDASE, 0301 basic medicine, Parkinson's disease, EFFICIENT, Genome-wide association study, genetics [Glucosylceramidase], 3124 Neurology and psychiatry, 0302 clinical medicine, genetics [Parkinson Disease], STATISTICAL POWER, Databases, Genetic, TMEM175, Age of Onset, LONGEVITY, Aged, 80 and over, Genetics, Parkinson Disease, Middle Aged, 3. Good health, Neurology, alpha-Synuclein, genetics [alpha-Synuclein], Glucosylceramidase, Female, GBA, age at onset, APOE, Adult, EXPRESSION, PENETRANCE, Context (language use), Biology, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Polymorphism, Single Nucleotide, Article, Young Adult, 03 medical and health sciences, Genetic variation, Humans, Genetic Predisposition to Disease, ddc:610, Genetic variability, Allele, Alleles, METAANALYSIS, Aged, Genetic association, 3112 Neurosciences, Heritability, RISK LOCI, 030104 developmental biology, Genetic Loci, GBA MUTATIONS, genetics [Leucine-Rich Repeat Serine-Threonine Protein Kinase-2], SNCA, Neurology (clinical), Age of onset, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Background Increasing evidence supports an extensive and complex genetic contribution to PD. Previous genome-wide association studies (GWAS) have shed light on the genetic basis of risk for this disease. However, the genetic determinants of PD age at onset are largely unknown. Objectives To identify the genetic determinants of PD age at onset. Methods Using genetic data of 28,568 PD cases, we performed a genome-wide association study based on PD age at onset. Results We estimated that the heritability of PD age at onset attributed to common genetic variation was similar to 0.11, lower than the overall heritability of risk for PD (similar to 0.27), likely, in part, because of the subjective nature of this measure. We found two genome-wide significant association signals, one at SNCA and the other a protein-coding variant in TMEM175, both of which are known PD risk loci and a Bonferroni-corrected significant effect at other known PD risk loci, GBA, INPP5F/BAG3, FAM47E/SCARB2, and MCCC1. Notably, SNCA, TMEM175, SCARB2, BAG3, and GBA have all been shown to be implicated in alpha-synuclein aggregation pathways. Remarkably, other well-established PD risk loci, such as GCH1 and MAPT, did not show a significant effect on age at onset of PD. Conclusions Overall, we have performed the largest age at onset of PD genome-wide association studies to date, and our results show that not all PD risk loci influence age at onset with significant differences between risk alleles for age at onset. This provides a compelling picture, both within the context of functional characterization of disease-linked genetic variability and in defining differences between risk alleles for age at onset, or frank risk for disease. (c) 2019 International Parkinson and Movement Disorder Society
Published: 2019

6. A Comparison of Ten Polygenic Score Methods for Psychiatric Disorders Applied Across Multiple Cohorts

Author: Guiyan Ni, Jian Zeng, Joana A. Revez, Ying Wang, Zhili Zheng, Tian Ge, Restuadi Restuadi, Jacqueline Kiewa, Dale R. Nyholt, Jonathan R.I. Coleman, Jordan W. Smoller, Jian Yang, Peter M. Visscher, Naomi R. Wray, Stephan Ripke, Benjamin M. Neale, Aiden Corvin, James T.R. Walters, Kai-How Farh, Peter A. Holmans, Phil Lee, Brendan Bulik-Sullivan, David A. Collier, Hailiang Huang, Tune H. Pers, Ingrid Agartz, Esben Agerbo, Margot Albus, Madeline Alexander, Farooq Amin, Silviu A. Bacanu, Martin Begemann, Richard A. Belliveau, Judit Bene, Sarah E. Bergen, Elizabeth Bevilacqua, Tim B. Bigdeli, Donald W. Black, Richard Bruggeman, Nancy G. Buccola, Randy L. Buckner, William Byerley, Wiepke Cahn, Guiqing Cai, Dominique Campion, Rita M. Cantor, Vaughan J. Carr, Noa Carrera, Stanley V. Catts, Kimberley D. Chambert, Raymond C.K. Chan, Ronald Y.L. Chen, Eric Y.H. Chen, Wei Cheng, Eric F.C. Cheung, Siow Ann Chong, C. Robert Cloninger, David Cohen, Nadine Cohen, Paul Cormican, Nick Craddock, James J. Crowley, Michael Davidson, Kenneth L. Davis, Franziska Degenhardt, Jurgen Del Favero, Ditte Demontis, Dimitris Dikeos, Timothy Dinan, Srdjan Djurovic, Gary Donohoe, Elodie Drapeau, Jubao Duan, Frank Dudbridge, Naser Durmishi, Peter Eichhammer, Johan Eriksson, Valentina Escott-Price, Laurent Essioux, Ayman H. Fanous, Martilias S. Farrell, Josef Frank, Lude Franke, Robert Freedman, Nelson B. Freimer, Marion Friedl, Joseph I. Friedman, Menachem Fromer, Giulio Genovese, Lyudmila Georgieva, Ina Giegling, Paola Giusti-Rodríguez, Stephanie Godard, Jacqueline I. Goldstein, Vera Golimbet, Srihari Gopal, Jacob Gratten, Lieuwe de Haan, Christian Hammer, Marian L. Hamshere, Mark Hansen, Thomas Hansen, Vahram Haroutunian, Annette M. Hartmann, Frans A. Henskens, Stefan Herms, Joel N. Hirschhorn, Per Hoffmann, Andrea Hofman, Mads V. Hollegaard, David M. Hougaard, Masashi Ikeda, Inge Joa, Antonio Julià, René S. Kahn, Luba Kalaydjieva, Sena Karachanak-Yankova, Juha Karjalainen, David Kavanagh, Matthew C. Keller, James L. Kennedy, Andrey Khrunin, Yunjung Kim, Janis Klovins, James A. Knowles, Bettina Konte, Vaidutis Kucinskas, Zita Ausrele Kucinskiene, Hana Kuzelova-Ptackova, Anna K. Kähler, Claudine Laurent, Jimmy Lee, S. Hong Lee, Sophie E. Legge, Bernard Lerer, Miaoxin Li, Tao Li, Kung-Yee Liang, Jeffrey Lieberman, Svetlana Limborska, Carmel M. Loughland, Jan Lubinski, Jouko Lönnqvist, Milan Macek, Patrik K.E. Magnusson, Brion S. Maher, Wolfgang Maier, Jacques Mallet, Sara Marsal, Manuel Mattheisen, Morten Mattingsdal, Robert W. McCarley, Colm McDonald, Andrew M. McIntosh, Sandra Meier, Carin J. Meijer, Bela Melegh, Ingrid Melle, Raquelle I. Mesholam-Gately, Andres Metspalu, Patricia T. Michie, Lili Milani, Vihra Milanova, Younes Mokrab, Derek W. Morris, Ole Mors, Kieran C. Murphy, Robin M. Murray, Inez Myin-Germeys, Bertram Müller-Myhsok, Mari Nelis, Igor Nenadic, Deborah A. Nertney, Gerald Nestadt, Kristin K. Nicodemus, Liene Nikitina-Zake, Laura Nisenbaum, Annelie Nordin, Eadbhard O’Callaghan, Colm O’Dushlaine, F. Anthony O’Neill, Sang-Yun Oh, Ann Olincy, Line Olsen, Jim Van Os, Psychosis Endophenotypes International Consortium, Christos Pantelis, George N. Papadimitriou, Sergi Papiol, Elena Parkhomenko, Michele T. Pato, Tiina Paunio, Milica Pejovic-Milovancevic, Diana O. Perkins, Olli Pietiläinen, Jonathan Pimm, Andrew J. Pocklington, John Powell, Alkes Price, Ann E. Pulver, Shaun M. Purcell, Digby Quested, Henrik B. Rasmussen, Abraham Reichenberg, Mark A. Reimers, Alexander L. Richards, Joshua L. Roffman, Panos Roussos, Douglas M. Ruderfer, Veikko Salomaa, Alan R. Sanders, Ulrich Schall, Christian R. Schubert, Thomas G. Schulze, Sibylle G. Schwab, Edward M. Scolnick, Rodney J. Scott, Larry J. Seidman, Jianxin Shi, Engilbert Sigurdsson, Teimuraz Silagadze, Jeremy M. Silverman, Kang Sim, Petr Slominsky, Hon-Cheong So, Chris C.A. Spencer, Eli A. Stahl, Hreinn Stefansson, Stacy Steinberg, Elisabeth Stogmann, Richard E. Straub, Eric Strengman, Jana Strohmaier, T. Scott Stroup, Mythily Subramaniam, Jaana Suvisaari, Dragan M. Svrakic, Jin P. Szatkiewicz, Erik Söderman, Srinivas Thirumalai, Draga Toncheva, Sarah Tosato, Juha Veijola, John Waddington, Dermot Walsh, Dai Wang, Qiang Wang, Bradley T. Webb, Mark Weiser, Dieter B. Wildenauer, Nigel M. Williams, Stephanie Williams, Stephanie H. Witt, Aaron R. Wolen, Emily H.M. Wong, Brandon K. Wormley, Hualin Simon Xi, Clement C. Zai, Xuebin Zheng, Fritz Zimprich, Kari Stefansson, Wellcome Trust Case-Control Consortium, Rolf Adolfsson, Ole A. Andreassen, Douglas H.R. Blackwood, Elvira Bramon, Joseph D. Buxbaum, Anders D. Børglum, Sven Cichon, Ariel Darvasi, Enrico Domenici, Hannelore Ehrenreich, Tõnu Esko, Pablo V. Gejman, Michael Gill, Hugh Gurling, Christina M. Hultman, Nakao Iwata, Assen V. Jablensky, Erik G. Jönsson, Kenneth S. Kendler, George Kirov, Jo Knight, Todd Lencz, Douglas F. Levinson, Qingqin S. Li, Jianjun Liu, Anil K. Malhotra, Steven A. McCarroll, Andrew McQuillin, Jennifer L. Moran, Preben B. Mortensen, Bryan J. Mowry, Markus M. Nöthen, Roel A. Ophoff, Michael J. Owen, Aarno Palotie, Carlos N. Pato, Tracey L. Petryshen, Danielle Posthuma, Marcella Rietschel, Brien P. Riley, Dan Rujescu, Pak C. Sham, Pamela Sklar, David St Clair, Daniel R. Weinberger, Jens R. Wendland, Thomas Werge, Mark J. Daly, Patrick F. Sullivan, Michael C. O’Donovan, Maciej Trzaskowski, Enda M. Byrne, Abdel Abdellaoui, Mark J. Adams, Tracy M. Air, Till F.M. Andlauer, Silviu-Alin Bacanu, Marie Bækvad-Hansen, Aartjan T.F. Beekman, Elisabeth B. Binder, Julien Bryois, Henriette N. Buttenschøn, Jonas Bybjerg-Grauholm, Na Cai, Enrique Castelao, Jane Hvarregaard Christensen, Toni-Kim Clarke, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Gregory E. Crawford, Gail Davies, Ian J. Deary, Eske M. Derks, Nese Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Jerome C. Foo, Andreas J. Forstner, Héléna A. Gaspar, Fernando S. Goes, Scott D. Gordon, Jakob Grove, Lynsey S. Hall, Christine Søholm Hansen, Thomas F. Hansen, Ian B. Hickie, Georg Homuth, Carsten Horn, Jouke-Jan Hottenga, David M. Howard, Marcus Ising, Rick Jansen, Ian Jones, Lisa A. Jones, Eric Jorgenson, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Zoltán Kutalik, Yihan Li, Penelope A. Lind, Donald J. MacIntyre, Dean F. MacKinnon, Robert M. Maier, Jonathan Marchini, Hamdi Mbarek, Patrick McGrath, Peter McGuffin, Sarah E. Medland, Divya Mehta, Christel M. Middeldorp, Evelin Mihailov, Yuri Milaneschi, Francis M. Mondimore, Grant W. Montgomery, Sara Mostafavi, Niamh Mullins, Matthias Nauck, Bernard Ng, Michel G. Nivard, Paul F. O’Reilly, Hogni Oskarsson, Jodie N. Painter, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Roseann E. Peterson, Wouter J. Peyrot, Giorgio Pistis, Jorge A. Quiroz, Per Qvist, John P. Rice, Margarita Rivera, Saira Saeed Mirza, Robert Schoevers, Eva C. Schulte, Ling Shen, Stanley I. Shyn, Grant C.B. Sinnamon, Johannes H. Smit, Daniel J. Smith, Fabian Streit, Katherine E. Tansey, Henning Teismann, Alexander Teumer, Wesley Thompson, Pippa A. Thomson, Thorgeir E. Thorgeirsson, Matthew Traylor, Jens Treutlein, Vassily Trubetskoy, André G. Uitterlinden, Daniel Umbricht, Sandra Van der Auwera, Albert M. van Hemert, Alexander Viktorin, Yunpeng Wang, Shantel Marie Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Yang Wu, Hualin S. Xi, Futao Zhang, Volker Arolt, Bernhard T. Baune, Klaus Berger, Dorret I. Boomsma, Udo Dannlowski, E.J.C. de Geus, J. Raymond DePaulo, Katharina Domschke, Hans J. Grabe, Steven P. Hamilton, Caroline Hayward, Andrew C. Heath, Stefan Kloiber, Glyn Lewis, Susanne Lucae, Pamela A.F. Madden, Patrik K. Magnusson, Nicholas G. Martin, Preben Bo Mortensen, Merete Nordentoft, Sara A. Paciga, Nancy L. Pedersen, Adult Psychiatry, APH - Mental Health, ANS - Complex Trait Genetics, ANS - Mood, Anxiety, Psychosis, Stress & Sleep, Ni, Guiyan, Zeng, Jian, Revez, Joana A., Wang, Ying, Zhili, Zheng, Ge, Tian, Restuadi, Restuadi, Kiewa, Jacqueline, Nyholt, Dale R, Coleman, Jonathan RI, Smoller, Jordan W, Lee, S Hong, APH - Methodology, Biological Psychology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Econometrics, Psychiatry, Department of Technology and Operations Management, Child and Adolescent Psychiatry / Psychology, Epidemiology, Erasmus MC other, Urology, Internal Medicine, Medical Informatics, Immunology, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), and Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep
Subjects: 0301 basic medicine, Multifactorial Inheritance, medicine.medical_specialty, LDpred2, BF, Genomics, Disease, Major depressive disorder, risk prediction, 03 medical and health sciences, 0302 clinical medicine, MegaPRS, SDG 3 - Good Health and Well-being, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Genetic risk, Psychiatry, Biological Psychiatry, Genetic association, Depressive Disorder, Major, business.industry, Mental Disorders, medicine.disease, Genetic architecture, Polygenic scores, Risk prediction, polygenic scores, PRS-CS, psychiatric disorders, 030104 developmental biology, SBayesR, Schizophrenia, Cohort, Lassosum, RC0321, business, Psychiatric disorders, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: BACKGROUND: Polygenic scores (PGSs), which assess the genetic risk of individuals for a disease, are calculated as a weighted count of risk alleles identified in genome-wide association studies. PGS methods differ in which DNA variants are included and the weights assigned to them; some require an independent tuning sample to help inform these choices. PGSs are evaluated in independent target cohorts with known disease status. Variability between target cohorts is observed in applications to real data sets, which could reflect a number of factors, e.g., phenotype definition or technical factors.METHODS: The Psychiatric Genomics Consortium Working Groups for schizophrenia and major depressive disorder bring together many independently collected case-control cohorts. We used these resources (31,328 schizophrenia cases, 41,191 controls; 248,750 major depressive disorder cases, 563,184 controls) in repeated application of leave-one-cohort-out meta-analyses, each used to calculate and evaluate PGS in the left-out (target) cohort. Ten PGS methods (the baseline PC+T method and 9 methods that model genetic architecture more formally: SBLUP, LDpred2-Inf, LDpred-funct, LDpred2, Lassosum, PRS-CS, PRS-CS-auto, SBayesR, MegaPRS) were compared.RESULTS: Compared with PC+T, the other 9 methods gave higher prediction statistics, MegaPRS, LDPred2, and SBayesR significantly so, explaining up to 9.2% variance in liability for schizophrenia across 30 target cohorts, an increase of 44%. For major depressive disorder across 26 target cohorts, these statistics were 3.5% and 59%, respectively.CONCLUSIONS: Although the methods that more formally model genetic architecture have similar performance, MegaPRS, LDpred2, and SBayesR rank highest in most comparisons and are recommended in applications to psychiatric disorders.
Published: 2021

7. Significant out-of-sample classification from methylation profile scoring for amyotrophic lateral sclerosis

Author: Anna A. E. Vinkhuyzen, Frederik J. Steyn, Beben Benyamin, Dominic B. Rowe, Tian Lin, Jan H. Veldink, Kelly L. Williams, Ian P. Blair, Merrilee Needham, Roger Pamphlett, Shyuan T. Ngo, Paul J. Hop, Anna Freydenzon, Allan F. McRae, Anjali K. Henders, Marta F. Nabais, Perminder S. Sachdev, Robert D. Henderson, Eilis Hannon, Futao Zhang, Naomi R. Wray, Pamela A. McCombe, Restuadi Restuadi, Matthew A. Brown, Fleur C. Garton, Nigel G. Laing, Peter M. Visscher, Jonathan Mill, Leanne Wallace, Matthew R. Robinson, Jacob Gratten, Garth A. Nicholson, Jian Yang, Susan Mathers, Karen A. Mather, Ramona A. J. Zwamborn, Costanza L. Vallerga, Nabais, Marta F, Lin, Tian, Benyamin, Beben, Williams, Kelly L, and Wray, Naomi R
Subjects: 0301 basic medicine, amyotrophic lateral sclerosis, medicine.medical_specialty, lcsh:QH426-470, lcsh:Medicine, Predictive markers, Gastroenterology, Article, 03 medical and health sciences, 0302 clinical medicine, single nucleotide polymorphism, Internal medicine, Genetics, Medicine, Amyotrophic lateral sclerosis, Molecular Biology, Genetics (clinical), DNA methylation, business.industry, lcsh:R, Confounding, Area under the curve, Methylation, cohort analysis, medicine.disease, lcsh:Genetics, 030104 developmental biology, Out of sample, Cohort, business, 030217 neurology & neurosurgery
Abstract: We conducted DNA methylation association analyses using Illumina 450K data from whole blood for an Australian amyotrophic lateral sclerosis (ALS) case–control cohort (782 cases and 613 controls). Analyses used mixed linear models as implemented in the OSCA software. We found a significantly higher proportion of neutrophils in cases compared to controls which replicated in an independent cohort from the Netherlands (1159 cases and 637 controls). The OSCA MOMENT linear mixed model has been shown in simulations to best account for confounders. When combined in a methylation profile score, the 25 most-associated probes identified by MOMENT significantly classified case–control status in the Netherlands sample (area under the curve, AUC = 0.65, CI95% = [0.62–0.68], p = 8.3 × 10−22). The maximum AUC achieved was 0.69 (CI95% = [0.66–0.71], p = 4.3 × 10−34) when cell-type proportion was included in the predictor.
Published: 2020

8. Imprint of assortative mating on the human genome

Author: Maciej Trzaskowski, Michael E. Goddard, Jian Yang, Matthew R. Robinson, Peter M. Visscher, Patrick Turley, Kathryn E. Kemper, Daniel J. Benjamin, David Cesarini, Loic Yengo, Yuanhao Yang, Matthew C. Keller, Jacob Gratten, and Naomi R. Wray
Subjects: Male, 0301 basic medicine, Social Psychology, Experimental and Cognitive Psychology, Single-nucleotide polymorphism, Biology, Population stratification, Polymorphism, Single Nucleotide, Genome, White People, Article, 03 medical and health sciences, Behavioral Neuroscience, Quantitative Trait, Heritable, Humans, Marriage, Alleles, reproductive and urinary physiology, Genome, Human, Assortative mating, Genomic signature, Body Height, 030104 developmental biology, Mate choice, Evolutionary biology, behavior and behavior mechanisms, Trait, Educational Status, Female, Human genome
Abstract: Preference for mates with similar phenotypes; that is, assortative mating, is widely observed in humans1–5 and has evolutionary consequences6–8. Under Fisher's classical theory6, assortative mating is predicted to induce a signature in the genome at trait-associated loci that can be detected and quantified. Here, we develop and apply a method to quantify assortative mating on a specific trait by estimating the correlation (θ) between genetic predictors of the trait from single nucleotide polymorphisms on odd- versus even-numbered chromosomes. We show by theory and simulation that the effect of assortative mating can be quantified in the presence of population stratification. We applied this approach to 32 complex traits and diseases using single nucleotide polymorphism data from ~400,000 unrelated individuals of European ancestry. We found significant evidence of assortative mating for height (θ = 3.2%) and educational attainment (θ = 2.7%), both of which were consistent with theoretical predictions. Overall, our results imply that assortative mating involves multiple traits and affects the genomic architecture of loci that are associated with these traits, and that the consequence of mate choice can be detected from a random sample of genomes. A century after being predicted by theory, the authors detect and quantify the genomic signature of assortative mating in ~400,000 contemporary human genomes, and report new genetic evidence for assortative mating on height and educational attainment.
Published: 2018

9. Trans-eQTLs identified in whole blood have limited influence on complex disease biology

Author: Alexander Holloway, Joseph E. Powell, Naomi R. Wray, Peter Smartt, Luke R. Lloyd-Jones, Jacob Gratten, and Chloe X. Yap
Subjects: 0301 basic medicine, Genetics, Blood Cells, Quantitative Trait Loci, Gene regulatory network, Single-nucleotide polymorphism, Genome-wide association study, Disease, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, Phenotype, Article, 03 medical and health sciences, 030104 developmental biology, Polymorphism (computer science), Expression quantitative trait loci, Humans, Genetic Predisposition to Disease, Biomarkers, Genetics (clinical), Genome-Wide Association Study
Abstract: Trans-eQTLs have been implicated in complex traits and common diseases, but many were initially identified on the basis of having an effect in cis, and there has been no assessment of the significance of the overlap in relation to chance expectations. Here, we investigated whether trans-expression quantitative trait loci (eQTL) associations identified in whole blood contribute to variance in complex traits by determining (1) whether genome-wide significant (GWS) single-nucleotide polymorphisms (SNPs) were enriched for trans-eQTL (including trans-only eQTL), and (2) whether the genomic regions surrounding associated trans-genes were enriched for statistical associations in the relevant GWAS. On average for a given phenotype, we identify 4.8% of GWS SNPs overlapping with trans-eQTL present in blood, and show that for the majority of these phenotypes, this observation does not exceed that expected by chance. Likewise, we observe no enrichment for genetic associations with the GWAS phenotype in the regions surrounding the linked trans-genes, with the exception of rheumatoid arthritis. Interestingly, the GWS SNPs for each phenotype were consistently more enriched for unique trans-eQTL SNPs than trans-eQTL SNP-probe pairs (p = 4 × 10−7), with schizophrenia the only exception. This relative enrichment for trans-eQTL SNPs over trans-eQTL SNP-probe pairs implies that trait-associated trans-eQTL SNPs in whole blood are less likely to be 'master regulators' than random trans-eQTL SNPs. Taken together, these results suggest little evidence for the role of blood-based trans-eQTL in complex traits and disease, although this may reflect the finite size of currently available data sets and our findings may not hold for trans-eQTLs in more trait-relevant tissues. All software is publically available at https://github.com/IMB-Computational-Genomics-Lab/eqtlOverlapper .
Published: 2018

10. Gene networks associated with non-syndromic intellectual disability

Author: Stephen Rudd, Soohyun Lee, Paul A. Dawson, Peter M. Visscher, Jacob Gratten, and Johannes B. Prins
Subjects: 0301 basic medicine, Genetics, Candidate gene, Genetic heterogeneity, Gene regulatory network, Biology, medicine.disease, Phenotype, Genetic architecture, 03 medical and health sciences, Cellular and Molecular Neuroscience, 030104 developmental biology, 0302 clinical medicine, Schizophrenia, Intellectual Disability, Intellectual disability, medicine, Humans, Gene Regulatory Networks, Gene, 030217 neurology & neurosurgery
Abstract: Non-syndromic intellectual disability (NS-ID) is a genetically heterogeneous disorder, with more than 200 candidate genes to date. Despite the increasing number of novel mutations detected, a relatively low number of recurrently mutated genes have been identified, highlighting the complex genetic architecture of the disorder. A systematic search of PubMed and Medline identified 245 genes harbouring non-synonymous variants, insertions or deletions, which were identified as candidate NS-ID genes from case reports or from linkage or pedigree analyses. From this list, 33 genes are common to syndromic intellectual disability (S-ID) and 58 genes are common to certain neurological and neuropsychiatric disorders that often include intellectual disability as a clinical feature. We examined the evolutionary constraint and brain expression of these gene sets, and we performed gene network and protein-protein interaction analyses using GeneGO MetaCoreTM and DAPPLE, respectively. The 245 NS-ID candidate genes were over-represented in axon guidance, synaptogenesis, cell adhesion and neurotransmission pathways, all of which are key neurodevelopmental processes for the establishment of mature neuronal circuitry in the brain. These 245 genes exhibit significantly elevated expression in human brain and are evolutionarily constrained, consistent with expectations for a brain disorder such as NS-ID that is associated with reduced fecundity. In addition, we report enrichment of dopaminergic and glutamatergic pathways for those candidate NS-ID genes that are common to S-ID and/or neurological and neuropsychiatric disorders that exhibit intellectual disability. Collectively, this study provides an overview and analysis of gene networks associated with NS-ID and suggests modulation of neurotransmission, particularly dopaminergic and glutamatergic systems as key contributors to synaptic dysfunction in NS-ID.
Published: 2017

11. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

Author: Patricia T. Michie, Franziska Degenhardt, Brandon Wormley, Paola Giusti-Rodríguez, Mark J. Daly, Raquelle I. Mesholam-Gately, Ingrid Melle, Sibylle G. Schwab, Andrew McQuillin, Benjamin M. Neale, Joshua L. Roffman, Abraham Reichenberg, Pamela Sklar, Diana O. Perkins, Jennifer L. Moran, Donald W. Black, Per Hoffmann, A. Hofman, Hailiang Huang, John L. Waddington, Giulio Genovese, Aaron R. Wolen, Deborah L. Levy, David Curtis, Digby Quested, Carlos N. Pato, Nicholas John Craddock, Stephanie Williams, Kung Yee Liang, Zhouzhi Wang, Tracey L. Petryshen, Ann E. Pulver, Randy L. Buckner, Stephan Ripke, Roel A. Ophoff, Danielle Posthuma, Lili Milani, Jacques Mallet, Menachem Fromer, Christian R. Marshall, Jaana Suvisaari, Jana Strohmaier, Richard Bruggeman, Marcella Rietschel, Ayman H. Fanous, Andrew M. McIntosh, James T.R. Walters, Dimitris Dikeos, Panos Roussos, Veikko Salomaa, Aiden Corvin, Carin J. Meijer, Tiina Paunio, Assen Jablensky, Sarah E. Bergen, Nancy G. Buccola, Annelie Nordin, Wolfgang Maier, Srdjan Djurovic, Naomi R. Wray, Aniket Shetty, Joel Eriksson, Dan Rujescu, Jouko Lönnqvist, Brian Kelly, Wenting Wu, Alexander Richards, Frans Henskens, Rich Belliveau, Bryan J. Mowry, Elodie Drapeau, Andreas J. Forstner, Silviu Alin Bacanu, Jubao Duan, Tõnu Esko, Bernard Lerer, Carmel M. Loughland, Olli Pietiläinen, Michael Conlon O'Donovan, Shaun M. Purcell, Michael Gill, Thomas G. Schulze, Douglas S. Greer, Stephen W. Scherer, Eli A. Stahl, Markus M. Nöthen, Guiqing Cai, William M. Brandler, Kristin K. Nicodemus, Dominique Campion, David A. Collier, Farooq Amin, Joel N. Hirschhorn, Robin M. Murray, Timothy G. Dinan, Mark Reimers, Murray J. Cairns, Rodney J. Scott, Aarno Palotie, Robert Freedman, Nelson B. Freimer, Joshua R. Atkins, Gary Donohoe, Ann Olincy, Jonathan Sebat, Colm McDonald, Srinivas Thirumalai, John Powell, Jo Knight, Vahram Haroutunian, Dieter B. Wildenauer, Tim B. Bigdeli, Lieuwe de Haan, Peter Eichhammer, James J. Crowley, Lynn E. DeLisi, Ulrich Schall, Rolf Adolfsson, Marcelo Bertalan, Thomas Hansen, Eric Strengman, Michael Davidson, Dheeraj Malhotra, Manuel Mattheisen, Jeffrey A. Lieberman, Benedicto Crespo-Facorro, Stephanie Godard, Edward M. Scolnick, Jonathan Pimm, Bertram Müller-Myhsok, Qingqin Li, Michele T. Pato, Wiepke Cahn, Christos Pantelis, Ingrid Agartz, Brendan Bulik-Sullivan, Madhusudan Gujral, Martilias S. Farrell, Brady J. Maher, Laurent Essioux, Karin V Fuentes Fajarado, Andres Metspalu, Stephanie H. Witt, Patrick F. Sullivan, Mark Weiser, Younes Mokrab, Kai How Farh, Line Olsen, Dermot Walsh, Peter Holmans, Hugh Gurling, Joseph I. Friedman, Andrew Pocklington, Daniel P. Howrigan, Lude Franke, Tune H. Pers, Larry J. Seidman, Pablo V. Gejman, Dalila Pinto, Michael John Owen, Inez Myin-Germeys, Steven A. McCarroll, Wei Cheng, Jackie Goldstein, C. Robert Cloninger, Elliot S. Gershon, Deborah A. Nertney, Thomas Werge, Noa Carrera, Kieran C. Murphy, Rita M. Cantor, Ariel Darvasi, Mark Hansen, Annette M. Hartmann, Ole A. Andreassen, Bradley T. Webb, Henrik B. Rasmussen, David Cohen, Elvira Bramon, Erik G. Jönsson, Vaughan J. Carr, Pui Y. Lee, Masashi Ikeda, Daniele Merico, Danny Antaki, Brien P. Riley, Stefan Herms, Igor Nenadic, Bettina Konte, Kimberley D. Chambert, Jurgen Del Favero, George Kirov, Matthew C. Keller, Jacob Gratten, Douglas F. Levinson, Luba Kalaydjieva, Bhooma Thiruvahindrapuram, Alan R. Sanders, Sang-Yun Oh, Alkes L. Price, Vihra Milanova, Juha Veijola, Erik Söderman, Dragan M. Svrakic, David H. Kavanagh, Patrik K. E. Magnusson, Douglas Blackwood, Nakao Iwata, Jim van Os, Jeremy M. Silverman, Elena Parkhomenko, Kenneth L. Davis, Jing Qin Wu, Eadbhard O'Callaghan, Chris C. A. Spencer, Juha Karjalainen, Anna K. Kähler, Clement C. Zai, Nigel Williams, Joseph D. Buxbaum, Jin P. Szatkiewicz, Laura Nisenbaum, Sang Hong Lee, Yunjung Kim, Colm O'Dushlaine, René S. Kahn, Morten Mattingsdal, Inge Joa, Marian L. Hamshere, Frank Dudbridge, Ina Giegling, Sandra Meier, Derek W. Morris, Robert W. McCarley, Douglas M. Ruderfer, Paul Cormican, Lyudmila Georgieva, Sven Cichon, Josef Frank, Jianxin Shi, George N. Papadimitriou, Kenneth S. Kendler, Margot Albus, Enrico Domenici, Claudine Laurent, Francis A. O'Neill, Adam Savitz, Jordan W. Smoller, James L. Kennedy, Peter M. Visscher, Valentina Escott-Price, Christina M. Hultman, T. Scott Stroup, Elizabeth Bevilacqua, James A. Knowles, William Byerley, Paul A. Tooney, Madeline Alexander, Stanley V. Catts, David St Clair, Sophie E. Legge, Gerald Nestadt, Michelle S. Maile, Perceptual and Cognitive Neuroscience (PCN), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Stem Cell Aging Leukemia and Lymphoma (SALL), Psychiatrie & Neuropsychologie, RS: MHeNs - R2 - Mental Health, MUMC+: Hersen en Zenuw Centrum (3), MUMC+: MA Psychiatrie (3), Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, APH - Mental Health, ANS - Complex Trait Genetics, Adult Psychiatry, Other departments, Marshall, Christian R, Howrigan, Daniel P, Merico, Daniele, Thiruvahindrapuram, Bhooma, Lee, S Hong, Sebat, Jonathan, Psychosis Endophenotypes International Consortium, CNV and Schizophrenia Working Groups of the Psychiatric Genomics Consortium, CNV, Schizophrenia Working Grp, Psychosis Endophenotypes, Rehabilitation Medicine, and Child and Adolescent Psychiatry / Psychology
Subjects: 0301 basic medicine, Male, 16P11.2, Duplication, Autism, Rearrangement, Genome-wide association study, Copy number variant, Gene, Medical and Health Sciences, 0302 clinical medicine, DUPLICATIONS, Risk Factors, Gene duplication, Genotype, Disorder, Copy-number variation, Genetics, Genetics & Heredity, RISK, copy number variation, REARRANGEMENTS, Biological Sciences, 16p11.2, 3. Good health, Phenotype, Female, Risk, CNVS, Genetic Markers, genetic etiology, CNV and Schizophrenia Working Groups of the Psychiatric Genomics Consortium, DNA Copy Number Variations, DISORDERS, CNV, Non-allelic homologous recombination, PHENOTYPES, Biology, 03 medical and health sciences, SDG 3 - Good Health and Well-being, genomics, Journal Article, Humans, Comparative Study, Genetic Predisposition to Disease, AUTISM, Psychosis Endophenotypes International Consortium, MUTATIONS, Case-control study, Odds ratio, R1, GENE, 030104 developmental biology, genetics research, Genetic marker, Genetic Loci, Case-Control Studies, Mutation, Schizophrenia, Human medicine, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study
Abstract: Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 x 10(-15)), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 x 10(-6)). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 x 10(-11)) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 x 10(-5)). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination. Refereed/Peer-reviewed
Published: 2017

12. Sizing up whole-genome sequencing studies of common diseases

Author: Naomi R. Wray and Jacob Gratten
Subjects: 0301 basic medicine, Whole genome sequencing, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Genetics, Genome-wide association study, Computational biology, Biology, Genome, 030217 neurology & neurosurgery, De novo mutations, Exome sequencing
Abstract: The triplet code underpins analyses of rare and de novo mutations in exome sequencing data, but analysis of the noncoding genome is much more challenging. A new analytical framework for common, complex diseases highlights the need for very large samples to overcome the unavoidable multiple-testing burden and hence provides preemptive warnings against underpowered studies.
Published: 2018

13. Evidence for Genetic Overlap Between Schizophrenia and Age at First Birth in Women

Author: Elodie Drapeau, Robert W. McCarley, Jim van Os, Svetlana A. Limborska, Elvira Bramon, Milan Macek, Divya Mehta, Lieuwe de Haan, Christos Pantelis, Inge Joa, Daniel R. Weinberger, Andrew McQuillin, Lynn E. DeLisi, Ulrich Schall, Tõnu Esko, Digby Quested, Jacob Gratten, Gary Donohoe, Kenneth S. Kendler, Derek W. Morris, Ole A. Andreassen, Peter M. Visscher, Valentina Escott-Price, Lyudmila Georgieva, John L. Waddington, Sara Marsal, Naomi R. Wray, Danielle Posthuma, Benedicto Crespo-Facorro, Rita M. Cantor, Ariel Darvasi, Béla Melegh, Jing Qin Wu, Zhihong Zhu, Kieran C. Murphy, Felix C. Tropf, Inez Myin-Germeys, Antonio Julià, Paul A. Tooney, Frans Henskens, C. Robert Cloninger, Bryan J. Mowry, Larry J. Seidman, Bernard Lerer, Andres Metspalu, Carmel M. Loughland, Mark Weiser, Gibran Hemani, Ann Olincy, Joseph D. Buxbaum, Silviu-Alin Bacanu, Srdjan Djurovic, Andrew M. McIntosh, Jian Yang, Patricia T. Michie, Harold Snieder, Richard Bruggeman, John J. McGrath, Nicola Barban, Rodney J. Scott, Nelson B. Freimer, Timothy G. Dinan, Melinda Mills, S. Hong Lee, David Cohen, Andrey Khrunin, Andrew Bakshi, Murray J. Cairns, Patrik K. E. Magnusson, Draga Toncheva, Universidad de Cantabria, Mehta, Divya, Tropf, Felix C, Gratten, Jacob, Bakshi, Andrew, Zhu, Zhihong, Bacanu, Silviu-Alin, Hemani, Gibran, Magnusson, Patrik KE, Barban, Nicola, Esko, Tonu, Metspalu, Andres, Snieder, Harold, Mowry, Bryan J, Kendler, Kenneth S, Yang, Jian, Visscher, Peter M, McGrath, John J, Mills, Melinda C, Wray, Naomi R, Lee, S Hong, Schizophrenia Working Group of the Psychiatric Genomics Consortium, LifeLines Cohort Study, TwinsUK, RS: MHeNs - R2 - Mental Health, MUMC+: MA Psychiatrie (3), MUMC+: Hersen en Zenuw Centrum (3), Psychiatrie & Neuropsychologie, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Adult Psychiatry, Sociology/ICS, Life Course Epidemiology (LCE), Mehta Divya, Tropf Felix C., Gratten Jacob, Bakshi Andrew, Zhu Zhihong, Bacanu Silviu-Alin, Hemani Gibran, Magnusson Patrik K. E., BARBAN N, Esko Tonu, Metspalu Andre, Snieder Harold, Mowry Bryan J., Kendler Kenneth S., Yang Jian, Visscher Peter M., McGrath John J., Mills Melinda C., Wray Naomi R., and Lee S. Hong
Subjects: 0301 basic medicine, Denmark, Genome-wide association study, genetic risk, Cohort Studies, 0302 clinical medicine, Pregnancy, GWAS, genetics, Psychiatry, RISK, PSYCHIATRIC-DISORDERS, BIPOLAR DISORDER, 3. Good health, Psychiatry and Mental health, Birth order, Phenotype, PATERNAL AGE, Schizophrenia, Female, Maternal Age, Cohort study, Adult, medicine.medical_specialty, Offspring, Article, 03 medical and health sciences, PSYCHOSIS, medicine, Humans, Genetic Predisposition to Disease, Bipolar disorder, Alleles, Genetic association, genome-wide association study, business.industry, medicine.disease, de novo mutation, schizophrenia, 030104 developmental biology, maternal age, DE-NOVO MUTATIONS, Birth Order, business, 030217 neurology & neurosurgery, Genome-Wide Association Study, Demography, first birth
Abstract: IMPORTANCE: A recently published study of national data by McGrath et al in 2014 showed increased risk of schizophrenia (SCZ) in offspring associated with both early and delayed parental age, consistent with a U-shaped relationship. However, it remains unclear if the risk to the child is due to psychosocial factors associated with parental age or if those at higher risk for SCZ tend to have children at an earlier or later age. OBJECTIVE: To determine if there is a genetic association between SCZ and age at first birth (AFB) using genetically informative but independently ascertained data sets. DESIGN, SETTING, AND PARTICIPANTS: This investigation used multiple independent genome-wide association study data sets. The SCZ sample comprised 18?957 SCZ cases and 22?673 controls in a genome-wide association study from the second phase of the Psychiatric Genomics Consortium, and the AFB sample comprised 12?247 genotyped women measured for AFB from the following 4 community cohorts: Estonia (Estonian Genome Center Biobank, University of Tartu), the Netherlands (LifeLines Cohort Study), Sweden (Swedish Twin Registry), and the United Kingdom (TwinsUK). Schizophrenia genetic risk for each woman in the AFB community sample was estimated using genetic effects inferred from the SCZ genome-wide association study. MAIN OUTCOMES AND MEASURES: We tested if SCZ genetic risk was a significant predictor of response variables based on published polynomial functions that described the relationship between maternal age and SCZ risk in offspring in Denmark. We substituted AFB for maternal age in these functions, one of which was corrected for the age of the father, and found that the fit was superior for the model without adjustment for the father's age. RESULTS: We observed a U-shaped relationship between SCZ risk and AFB in the community cohorts, consistent with the previously reported relationship between SCZ risk in offspring and maternal age when not adjusted for the age of the father. We confirmed that SCZ risk profile scores significantly predicted the response variables (coefficient of determination R2?=?1.1E-03, P?=?4.1E-04), reflecting the published relationship between maternal age and SCZ risk in offspring by McGrath et al in 2014. CONCLUSIONS AND RELEVANCE: This study provides evidence for a significant overlap between genetic factors associated with risk of SCZ and genetic factors associated with AFB. It has been reported that SCZ risk associated with increased maternal age is explained by the age of the father and that de novo mutations that occur more frequently in the germline of older men are the underlying causal mechanism. This explanation may need to be revised if, as suggested herein and if replicated in future studies, there is also increased genetic risk of SCZ in older mothers. This research is supported by grants 613602, 1047956, 1078901, 1080157, 1087889, and 1067795 from the Australian National Health and Medical Research Council and by grants DE130100614 and DP160102126 from the Australian Research Council. Primary analyses of the SchizophreniaWorking Group of the Psychiatric Genomics Consortium data were conducted on the Genetic Cluster Computer (http://www .geneticcluster.org) hosted by SURFsara and supported by grant NOW480-05-003 from the Netherlands Scientific Organization, along with a supplement from the Dutch Brain Foundation and the Vrije Universitiet Amsterdam. TwinsUK was funded by theWellcome Trust, by grant FP7/2007-2013 from the European Community’s Seventh Framework Programme, and by support from the National Institute for Health Research–funded BioResource, Clinical Research Facility, and Biomedical Research Centre based at Guy’s and St Thomas’ National Health Service Foundation Trust in partnership with King’s College London, and single-nucleotide polymorphism genotyping was performed by theWellcome Trust Sanger Institute and National Eye Institute via the National Institute for Health/Center for Inherited Disease Research. Estonian Genome Center Biobank, University of Tartu, received targeted financing by grant IUT20-60 from the Estonian Research Council, Center of Excellence in Genomics, and University of Tartu, and data analyses were carried out in part in the High Performance Computing Center of the University of Tartu. The Swedish Twin Registry is supported by Karolinska Institutet. Mr Tropf received funding from sciencestarter.de for a research visit to The University of Queensland. The research leading to these results received funding from the European Research Council via an ERC Consolidator Grant SOCIOGENOME (grant 615603 awarded to Dr Mills [http://www.sociogenome.com]).
Published: 2016

14. Mapping and differential expression analysis from short-read RNA-Seq data in model organisms

Author: Qiongyi Zhao, Xuan Li, Restuadi Restuadi, and Jacob Gratten
Subjects: 0301 basic medicine, Genetics, Differential expression analysis, ved/biology, Applied Mathematics, genetic processes, ved/biology.organism_classification_rank.species, RNA, RNA-Seq, Computational biology, Biology, Short read, Biochemistry, Genetics and Molecular Biology (miscellaneous), Computer Science Applications, Transcriptome, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Modeling and Simulation, natural sciences, Differential expression, Model organism, 030217 neurology & neurosurgery, Reference genome
Abstract: Recent advances in next-generation sequencing technology allow high-throughput RNA sequencing (RNA-Seq) to be widely applied in transcriptomic studies. For model organisms with a reference genome, the first step in analysis of RNA-Seq data involves mapping of short-read sequences to the reference genome. Reference-guided transcriptome assembly is an optional step, which is recommended if the aim is to identify novel transcripts. Following read mapping, the primary interest of biologists in many RNA-Seq studies is the investigation of differential expression between experimental groups. In this review, we discuss recent developments in RNA-Seq data analysis applied to model organisms, including methods and algorithms for direct mapping, reference-guided transcriptome assembly and differential expression analysis, and provide insights for the future direction of RNA-Seq.
Published: 2016

15. Rare variants are common in schizophrenia

Author: Jacob Gratten
Subjects: 0301 basic medicine, Genetics, General Neuroscience, Schizophrenia (object-oriented programming), Biology, Polymorphism, Single Nucleotide, Article, DNA sequencing, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Schizophrenia, Humans, Genetic Predisposition to Disease, Gene, 030217 neurology & neurosurgery
Abstract: By analyzing the exomes of 12,332 unrelated Swedish individuals – including 4,877 affected with schizophrenia – in ways informed by exome sequences from 45,376 other individuals, we identified 244,246 coding-sequence and splice-site ultra-rare variants (URVs) that were unique to individual Swedes. We found that gene-disruptive and putatively protein-damaging URVs (but not synonymous URVs) were more abundant in schizophrenia cases than controls (P = 1.3 × 10−10). This elevation of protein-compromising URVs was several times larger than an analogously elevated rate for de novo mutations, suggesting that most rare-variant effects on schizophrenia risk are inherited. Among individuals with schizophrenia, the elevated frequency of protein-compromising URVs was concentrated in brain-expressed genes, particularly in neuronally expressed genes; most of this genetic signal arose from large sets of genes whose RNAs have been found to interact with synaptically localized proteins. Our results suggest that synaptic dysfunction may mediate a large fraction of strong, individually rare genetic influences on schizophrenia risk.
Published: 2016

16. Whole-exome sequencing in amyotrophic lateral sclerosis suggests NEK1 is a risk gene in Chinese

Author: Zhongshan Li, Xiang-Ding Chen, Xiaolu Liu, Yingying Han, Robyn H. Wallace, Paul Leo, Zong Hong Zhang, Dongsheng Fan, Qiongyi Zhao, Li-Jun Tan, Matthew A. Brown, Ji He, Naomi R. Wray, Janette Edson, Zi-Bing Jin, Perry F. Bartlett, Sharon Song, Jian Yang, Lawrie Wheeler, Bryan J. Mowry, Jacob Gratten, Fleur C. Garton, Lu Chen, Mhairi Marshall, Huji Xu, Shu Ran, Yong Lin, Lu Tang, Peter M. Visscher, Hong-Weng Deng, Jessica Harris, Lisa Anderson, Anjali K. Henders, David C. Reutens, Jinyu Wu, Marie Mangelsdorf, Katie Cremin, Beben Benyamin, Gratten, Jacob, Zhao, Qiongyi, Benyamin, Beben, Garton, Fleur, and Fan, Dongsheng
Subjects: Risk, 0301 basic medicine, Oncology, amyotrophic lateral sclerosis, medicine.medical_specialty, lcsh:QH426-470, SOD1, lcsh:Medicine, Disease, Biology, whole exome sequencing, 03 medical and health sciences, Asian People, Internal medicine, Exome Sequencing, Genetics, medicine, Humans, Genetic Predisposition to Disease, Amyotrophic lateral sclerosis, Molecular Biology, Allele frequency, Gene, Genetics (clinical), Exome sequencing, Chinese, Research, Amyotrophic Lateral Sclerosis, lcsh:R, medicine.disease, Human genetics, 3. Good health, lcsh:Genetics, NIMA-Related Kinase 1, 030104 developmental biology, Etiology, Molecular Medicine
Abstract: Background Amyotrophic lateral sclerosis (ALS) is a progressive neurological disease characterised by the degeneration of motor neurons, which are responsible for voluntary movement. There remains limited understanding of disease aetiology, with median survival of ALS of three years and no effective treatment. Identifying genes that contribute to ALS susceptibility is an important step towards understanding aetiology. The vast majority of published human genetic studies, including for ALS, have used samples of European ancestry. The importance of trans-ethnic studies in human genetic studies is widely recognised, yet a dearth of studies of non-European ancestries remains. Here, we report analyses of novel whole-exome sequencing (WES) data from Chinese ALS and control individuals. Methods WES data were generated for 610 ALS cases and 460 controls drawn from Chinese populations. We assessed evidence for an excess of rare damaging mutations at the gene level and the gene set level, considering only singleton variants filtered to have allele frequency less than 5 × 10–5 in reference databases. To meta-analyse our results with a published study of European ancestry, we used a Cochran–Mantel–Haenszel test to compare gene-level variant counts in cases vs controls. Results No gene passed the genome-wide significance threshold with ALS in Chinese samples alone. Combining rare variant counts in Chinese with those from the largest WES study of European ancestry resulted in three genes surpassing genome-wide significance: TBK1 (p = 8.3 × 10–12), SOD1 (p = 8.9 × 10–9) and NEK1 (p = 1.1 × 10–9). In the Chinese data alone, SOD1 and NEK1 were nominally significantly associated with ALS (p = 0.04 and p = 7 × 10–3, respectively) and the case/control frequencies of rare coding variants in these genes were similar in Chinese and Europeans (SOD1: 1.5%/0.2% vs 0.9%/0.1%, NEK1 1.8%/0.4% vs 1.9%/0.8%). This was also true for TBK1 (1.2%/0.2% vs 1.4%/0.4%), but the association with ALS in Chinese was not significant (p = 0.14). Conclusions While SOD1 is already recognised as an ALS-associated gene in Chinese, we provide novel evidence for association of NEK1 with ALS in Chinese, reporting variants in these genes not previously found in Europeans. Electronic supplementary material The online version of this article (doi:10.1186/s13073-017-0487-0) contains supplementary material, which is available to authorized users.
Published: 2017

17. Estimation of Genetic Correlation via Linkage Disequilibrium Score Regression and Genomic Restricted Maximum Likelihood

Author: Guiyan Ni, Gerhard Moser, Naomi R. Wray, S. Hong Lee, Stephan Ripke, Benjamin M. Neale, Aiden Corvin, James T.R. Walters, Kai-How Farh, Peter A. Holmans, Phil Lee, Brendan Bulik-Sullivan, David A. Collier, Hailiang Huang, Tune H. Pers, Ingrid Agartz, Esben Agerbo, Margot Albus, Madeline Alexander, Farooq Amin, Silviu A. Bacanu, Martin Begemann, Richard A. Belliveau, Judit Bene, Sarah E. Bergen, Elizabeth Bevilacqua, Tim B. Bigdeli, Donald W. Black, Richard Bruggeman, Nancy G. Buccola, Randy L. Buckner, William Byerley, Wiepke Cahn, Guiqing Cai, Dominique Campion, Rita M. Cantor, Vaughan J. Carr, Noa Carrera, Stanley V. Catts, Kimberly D. Chambert, Raymond C.K. Chan, Ronald Y.L. Chen, Eric Y.H. Chen, Wei Cheng, Eric F.C. Cheung, Siow Ann Chong, C. Robert Cloninger, David Cohen, Nadine Cohen, Paul Cormican, Nick Craddock, James J. Crowley, David Curtis, Michael Davidson, Kenneth L. Davis, Franziska Degenhardt, Jurgen Del Favero, Ditte Demontis, Dimitris Dikeos, Timothy Dinan, Srdjan Djurovic, Gary Donohoe, Elodie Drapeau, Jubao Duan, Frank Dudbridge, Naser Durmishi, Peter Eichhammer, Johan Eriksson, Valentina Escott-Price, Laurent Essioux, Ayman H. Fanous, Martilias S. Farrell, Josef Frank, Lude Franke, Robert Freedman, Nelson B. Freimer, Marion Friedl, Joseph I. Friedman, Menachem Fromer, Giulio Genovese, Lyudmila Georgieva, Ina Giegling, Paola Giusti-Rodríguez, Stephanie Godard, Jacqueline I. Goldstein, Vera Golimbet, Srihari Gopal, Jacob Gratten, Lieuwe de Haan, Christian Hammer, Marian L. Hamshere, Mark Hansen, Thomas Hansen, Vahram Haroutunian, Annette M. Hartmann, Frans A. Henskens, Stefan Herms, Joel N. Hirschhorn, Per Hoffmann, Andrea Hofman, Mads V. Hollegaard, David M. Hougaard, Masashi Ikeda, Inge Joa, Antonio Juliá, René S. Kahn, Luba Kalaydjieva, Sena Karachanak-Yankova, Juha Karjalainen, David Kavanagh, Matthew C. Keller, James L. Kennedy, Andrey Khrunin, Yunjung Kim, Janis Klovins, James A. Knowles, Bettina Konte, Vaidutis Kucinskas, Zita Ausrele Kucinskiene, Hana Kuzelova-Ptackova, Anna K. Kähler, Claudine Laurent, Jimmy Lee Chee Keong, Sophie E. Legge, Bernard Lerer, Miaoxin Li, Tao Li, Kung-Yee Liang, Jeffrey Lieberman, Svetlana Limborska, Carmel M. Loughland, Jan Lubinski, Jouko Lönnqvist, Milan Macek, Patrik K.E. Magnusson, Brion S. Maher, Wolfgang Maier, Jacques Mallet, Sara Marsal, Manuel Mattheisen, Morten Mattingsda, Robert W. McCarley, Colm McDonald, Andrew M. McIntosh, Sandra Meier, Carin J. Meijer, Bela Melegh, Ingrid Melle, Raquelle I. Mesholam-Gately, Andres Metspalu, Patricia T. Michie, Lili Milani, Vihra Milanova, Younes Mokrab, Derek W. Morris, Ole Mors, Kieran C. Murphy, Robin M. Murray, Inez Myin-Germeys, Bertram Müller-Myhsok, Mari Nelis, Igor Nenadic, Deborah A. Nertney, Gerald Nestadt, Kristin K. Nicodemus, Liene Nikitina-Zake, Laura Nisenbaum, Annelie Nordin, Eadbhard O’Callaghan, Colm O’Dushlaine, F. Anthony O’Neill, Sang-Yun Oh, Ann Olinc, Line Olsen, Jim Van Os, Christos Pantelis, George N. Papadimitriou, Sergi Papio, Elena Parkhomenko, Michele T. Pato, Tiina Paunio, Milica Pejovic-Milovancevic, Diana O. Perkins, Olli Pietiläinenl, Jonathan Pimm, Andrew J. Pocklington, John Powell, Alkes Price, Ann E. Pulver, Shaun M. Purcell, Digby Quested, Henrik B. Rasmussen, Abraham Reichenberg, Mark A. Reimers, Alexander L. Richards, Joshua L. Roffman, Panos Roussos, Douglas M. Ruderfer, Veikko Salomaa, Alan R. Sanders, Ulrich Schall, Christian R. Schubert, Thomas G. Schulze, Sibylle G. Schwab, Edward M. Scolnick, Rodney J. Scott, Larry J. Seidman, Jianxin Shi, Engilbert Sigurdsson, Teimuraz Silagadze, Jeremy M. Silverman, Kang Sim, Petr Slominsky, Jordan W. Smoller, Hon-Cheong So, Chris C.A. Spencer, Eli A. Stah, Hreinn Stefansson, Stacy Steinberg, Elisabeth Stogmann, Richard E. Straub, Eric Strengman, Jana Strohmaier, T. Scott Stroup, Mythily Subramaniam, Jaana Suvisaari, Dragan M. Svrakic, Jin P. Szatkiewicz, Erik Söderman, Srinivas Thirumalai, Draga Toncheva, Sarah Tosato, Juha Veijola, John Waddington, Dermot Walsh, Dai Wang, Qiang Wang, Bradley T. Webb, Mark Weiser, Dieter B. Wildenauer, Nigel M. Williams, Stephanie Williams, Stephanie H. Witt, Aaron R. Wolen, Emily H.M. Wong, Brandon K. Wormley, Hualin Simon Xi, Clement C. Zai, Xuebin Zheng, Fritz Zimprich, Kari Stefansson, Peter M. Visscher, Rolf Adolfsson, Ole A. Andreassen, Douglas H.R. Blackwood, Elvira Bramon, Joseph D. Buxbaum, Anders D. Børglum, Sven Cichon, Ariel Darvasi, Enrico Domenici, Hannelore Ehrenreich, Tõnu Esko, Pablo V. Gejman, Michael Gill, Hugh Gurling, Christina M. Hultman, Nakao Iwata, Assen V. Jablensky, Erik G. Jönsson, Kenneth S. Kendler, George Kirov, Jo Knight, Todd Lencz, Douglas F. Levinson, Qingqin S. Li, Jianjun Liu, Anil K. Malhotra, Steven A. McCarrol, Andrew McQuillin, Jennifer L. Moran, Preben B. Mortensen, Bryan J. Mowry, Markus M. Nöthen, Roel A. Ophoff, Michael J. Owen, Aarno Palotie, Carlos N. Pato, Tracey L. Petryshen, Danielle Posthuma, Marcella Rietsche, Brien P. Riley, Dan Rujescu, Pak C. Sham, Pamela Sklar, David St Clair, Daniel R. Weinberger, Jens R. Wendland, Thomas Werge, Mark J. Daly, Patrick F. Sullivan, Michael C. O’Donovan, APH - Mental Health, ANS - Complex Trait Genetics, Adult Psychiatry, Ni, Guiyan, Moser, Gerhard, Wray, Naomi R, Lee, S Hong, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Amsterdam Neuroscience - Complex Trait Genetics, Complex Trait Genetics, Clinicum, Department of Psychiatry, and HUS Psychiatry
Subjects: 0301 basic medicine, Linkage disequilibrium, Schizophrenia/genetics, INFORMATION, Restricted maximum likelihood, Inheritance Patterns, linkage disequilibrium score regression, Bioinformatics, Medical and Health Sciences, 3124 Neurology and psychiatry, Linkage Disequilibrium, biasedness, 0302 clinical medicine, Statistics, Databases, Genetic, WIDE ASSOCIATION, Genetics(clinical), PARTITIONING HERITABILITY, Genetics (clinical), Genetics & Heredity, education.field_of_study, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Likelihood Functions, Genome, Body Height/genetics, accuracy, Regression analysis, Single Nucleotide, Biological Sciences, Polymorphism, Single Nucleotide/genetics, genetic correlation, Regression, STATISTICS, genomic restricted maximum likelihood, Mental Health, Phenotype, Regression Analysis, COMPLEX HUMAN TRAITS, Single Nucleotide/genetics, Human, Adult, SUSCEPTIBILITY LOCI, Genotype, SNP heritability, body mass index, genome-wide SNPs, height, schizophrenia, Population, Haplotypes/genetics, Biology, Genetic correlation, Polymorphism, Single Nucleotide, 03 medical and health sciences, Databases, Genetic, ddc:570, Report, Genetics, Humans, Linkage Disequilibrium/genetics, Computer Simulation, Polymorphism, education, linkage disequilibrium score regression (LDSC), Genome, Human, Human Genome, genetic architecture, Genetic architecture, Body Height, Brain Disorders, Inheritance Patterns/genetics, BODY-MASS INDEX, 030104 developmental biology, Haplotypes, Sample size determination, Schizophrenia, 3111 Biomedicine, HUMAN HEIGHT, 030217 neurology & neurosurgery
Abstract: J. Lönnqvist on työryhmän Psychiat Genomics Consortium jäsen. Genetic correlation is a key population parameter that describes the shared genetic architecture of complex traits and diseases. It can be estimated by current state-of-art methods, i.e., linkage disequilibrium score regression (LDSC) and genomic restricted maximum likelihood (GREML). The massively reduced computing burden of LDSC compared to GREML makes it an attractive tool, although the accuracy (i.e., magnitude of standard errors) of LDSC estimates has not been thoroughly studied. In simulation, we show that the accuracy of GREML is generally higher than that of LDSC. When there is genetic heterogeneity between the actual sample and reference data from which LD scores are estimated, the accuracy of LDSC decreases further. In real data analyses estimating the genetic correlation between schizophrenia (SCZ) and body mass index, we show that GREML estimates based on similar to 150,000 individuals give a higher accuracy than LDSC estimates based on similar to 400,000 individuals (from combinedmeta-data). A GREML genomic partitioning analysis reveals that the genetic correlation between SCZ and height is significantly negative for regulatory regions, which whole genome or LDSC approach has less power to detect. We conclude that LDSC estimates should be carefully interpreted as there can be uncertainty about homogeneity among combined meta-datasets. We suggest that any interesting findings from massive LDSC analysis for a large number of complex traits should be followed up, where possible, with more detailed analyses with GREML methods, even if sample sizes are lesser.
Published: 2017

18. Age at first birth in women is genetically associated with increased risk of schizophrenia

Author: Fritz Zimprich, Manuel Mattheisen, Edward M. Scolnick, Ayman H. Fanous, Henrik B. Rasmussen, Steven A. McCarroll, Ingrid Agartz, Carmel M. Loughland, Aiden Corvin, Ann Olincy, Anders D. Børglum, F. Anthony O'Neill, T. Scott Stroup, Elizabeth Bevilacqua, Sandra Meier, Ulrich Schall, Jouko Lönnqvist, Jianxin Shi, C. Robert Cloninger, Judit Bene, Veikko Salomaa, George N. Papadimitriou, Milica Pejovic-Milovancevic, Béla Melegh, Kari Stefansson, Brendan Bulik-Sullivan, Janis Klovins, Enrico Domenici, Sibylle G. Schwab, Dai Wang, Assen Jablensky, Mari Nelis, Sang Yun Oh, Peter Holmans, Aaron R. Wolen, Hualin Simon Xi, Eric Strengman, Bryan J. Mowry, Michael Gill, Kung Yee Liang, William Byerley, Rolf Adolfsson, Hugh Gurling, Joseph I. Friedman, Andrew Pocklington, Brien P. Riley, Engilbert Sigurdsson, Benjamin M. Neale, Miaoxin Li, Michael Davidson, Bernard Lerer, Michele T. Pato, Xuebin Zheng, Patrick F. Sullivan, Frans Henskens, Madeline Alexander, Andrew M. McIntosh, Inez Myin-Germeys, Draga Toncheva, Liene Nikitina-Zake, Kenneth S. Kendler, Carin J. Meijer, Robin M. Murray, Richard E. Straub, Ann E. Pulver, Menachem Fromer, Derek W. Morris, Douglas M. Ruderfer, Mythily Subramaniam, Paul Cormican, Lyudmila Georgieva, Giulio Genovese, Brion S. Maher, Stanley V. Catts, David St Clair, Robert W. McCarley, David Cohen, Nancy G. Buccola, Dan Rujescu, Carlos N. Pato, Kristin K. Nicodemus, Josef Frank, Claudine Laurent, Dominique Campion, Guiyan Ni, James L. Kennedy, Sena Karachanak-Yankova, Nicholas John Craddock, Peter M. Visscher, Valentina Escott-Price, Jeffrey A. Lieberman, Deborah A. Nertney, Bertram Müller-Myhsok, Marcella Rietschel, Dimitris Dikeos, Stephanie Godard, Stephanie Williams, Andres Metspalu, John L. Waddington, Sophie E. Legge, Roel A. Ophoff, Jonathan Pimm, Richard Bruggeman, Tim B. Bigdeli, Gerald Nestadt, Mark Weiser, Kieran C. Murphy, Eric F.C. Cheung, Kang Sim, Jordan W. Smoller, David J. Kavanagh, Inge Joa, Jens R. Wendland, Thomas G. Schulze, Richard A. Belliveau, Sarah E. Bergen, Ditte Demontis, David Curtis, Todd Lencz, Danielle Posthuma, René S. Kahn, Lili Milani, Randy L. Buckner, Jianjun Liu, Petr Slominsky, Wiepke Cahn, Hana Kuzelova-Ptackova, Sergi Papiol, Tune H. Pers, Stephan Ripke, Rita M. Cantor, Ariel Darvasi, Christina M. Hultman, Larry J. Seidman, Eli A. Stahl, David A. Collier, Michael Conlon O'Donovan, Svetlana A. Limborska, James T.R. Walters, Farooq Amin, Noa Carrera, Ronald Y.L. Chen, Pablo V. Gejman, Joel N. Hirschhorn, Zita Ausrele Kucinskiene, Michael John Owen, Ina Giegling, Stephanie H. Witt, Timothy G. Dinan, Margot Albus, Wei Cheng, Marian L. Hamshere, Markus M. Nöthen, Thomas Werge, Guiqing Cai, Raquelle I. Mesholam-Gately, Annette M. Hartmann, Ingrid Melle, Ole A. Andreassen, Preben Bo Mortensen, Hannelore Ehrenreich, Tiina Paunio, James A. Knowles, Pak C. Sham, Marion Friedl, Teimuraz Silagadze, Dermot Walsh, Emily H. M. Wong, Igor Nenadic, Matthew C. Keller, John Powell, Naomi R. Wray, Patricia T. Michie, Bradley T. Webb, Lude Franke, Mark Hansen, Masashi Ikeda, Sven Cichon, Elvira Bramon, Frank Dudbridge, Erik G. Jönsson, Annelie Nordin, Wolfgang Maier, Peter Eichhammer, Christian R. Schubert, J. Mallet, Jacob Gratten, Andrey Khrunin, Jacqueline I. Goldstein, Panos Roussos, Pamela Sklar, Diana O. Perkins, Srdjan Djurovic, Phil Lee, Elodie Drapeau, Douglas F. Levinson, Nadine Cohen, Luba Kalaydjieva, Brandon Wormley, Tao Li, Tõnu Esko, Alexander Richards, Srihari Gopal, Jubao Duan, Anil K. Malhotra, Elisabeth Stögmann, Gary Donohoe, Kimberly Chambert, Sara Marsal, Hreinn Stefansson, Jo Knight, Ole Mors, Per Hoffmann, Dieter B. Wildenauer, James J. Crowley, Srinivas Thirumalai, Vahram Haroutunian, A. Hofman, Hailiang Huang, Thomas Hansen, Daniel R. Weinberger, Andrew McQuillin, Vaughan J. Carr, Vaidutis Kučinskas, Jimmy Lee Chee Keong, Digby Quested, Aarno Palotie, Robert Freedman, Hon-Cheong So, Jennifer L. Moran, Donald W. Black, Mark Reimers, Abraham Reichenberg, Jurgen Del Favero, Paola Giusti-Rodríguez, Tracey L. Petryshen, Olli Pietiläinen, Franziska Degenhardt, Laurent Essioux, Esben Agerbo, Qiang Wang, Jana Strohmaier, Siow Ann Chong, Johan G. Eriksson, Martin Begemann, Younes Mokrab, Colm McDonald, Silviu Alin Bacanu, Martilias S. Farrell, Christos Pantelis, Kai How Farh, Line Olsen, Naser Durmishi, Antonio Julià, Stefan Herms, Qingqin S. Li, Bettina Konte, George Kirov, Rodney J. Scott, Nelson B. Freimer, Mads V. Hollegaard, Shaun Purcell, Erik Söderman, Dragan M. Svrakic, Patrik K. E. Magnusson, Douglas Blackwood, Jin P. Szatkiewicz, Sang Hong Lee, Yunjung Kim, Colm O'Dushlaine, Morten Mattingsdal, Jim van Os, Sarah Tosato, Milan Macek, Joshua L. Roffman, Jan Lubinski, Eadbhard O'Callaghan, Juha Karjalainen, Vera Golimbet, Anna K. Kähler, Clement C. Zai, Nigel Williams, Joseph D. Buxbaum, Laura Nisenbaum, Eric Y.H. Chen, David M. Hougaard, Jaana Suvisaari, Chris C. A. Spencer, Alan R. Sanders, Alkes L. Price, Vihra Milanova, Juha Veijola, Christian Hammer, Raymond C.K. Chan, Stacy Steinberg, Nakao Iwata, Jeremy M. Silverman, Mark J. Daly, Elena Parkhomenko, Kenneth L. Davis, Lieuwe de Haan, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), Kučinskas, Vaidutis, Kučinskienė, Zita Aušrelė, Ni, Guiyan, Gratten, Jacob, Wray, Naomi R, Lee, Sang Hong, Germeys, Inez, Complex Trait Genetics, Háskóli Íslands, University of Iceland, Child and Adolescent Psychiatry / Psychology, Research Programs Unit, Diabetes and Obesity Research Program, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, University Management, Department of Psychiatry, Center for Population, Health and Society, Department of Public Health, Centre of Excellence in Complex Disease Genetics, Research Programme of Molecular Medicine, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, and Genomics of Neurological and Neuropsychiatric Disorders
Subjects: 0301 basic medicine, Multifactorial Inheritance, PATERNAL-AGE, 3124 Neurology and psychiatry, COMMON SNPS, fluids and secretions, 0302 clinical medicine, CHILD, Risk Factors, Pregnancy, 2.1 Biological and endogenous factors, Medicine, Aetiology, Pediatric, PROPORTION, Schizophrenia Working Group of the Psychiatric Genomics Consortium, 0303 health sciences, Multidisciplinary, PSYCHIATRIC-DISORDERS, BIPOLAR DISORDER, Biobank, 3. Good health, AFB, Mental Health, Schizophrenia, Female, Erfðarannsóknir, Psychosocial, TRAITS, schizophrenia, age at birth, AFB, Maternal Age, Adult, age at first birth in women, genetic association, Offspring, Science, Genetic correlation, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Geðklofi, Genetics, age at birth, Humans, Genetic Predisposition to Disease, Bipolar disorder, General, Biology, Genetic association study, 030304 developmental biology, Genetic association, business.industry, Genetic heterogeneity, Prevention, average aged parents, Parturition, SCORE REGRESSION, bacterial infections and mycoses, medicine.disease, Mental health, Brain Disorders, respiratory tract diseases, schizophrenia, Good Health and Well Being, 030104 developmental biology, younger and older parents, DE-NOVO MUTATIONS, ddc:000, Human medicine, business, 030217 neurology & neurosurgery, Demography
Abstract: Publisher's version (útgefin grein), Previous studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is −0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health., This research is supported by the Australian National Health and Medical Research Council (1080157, 1087889, 1103418, 1127440), and the Australian Research Council (DP160102126, FT160100229). This research has been conducted using the UK Biobank Resource. UK Biobank (http://www.ukbiobank.ac.uk) Research Ethics Committee (REC) approval number is 11/NW/0382. Our reference number approved by UK Biobank is 14575.
Published: 2017

19. Whole exome sequencing and DNA methylation analysis in a clinical amyotrophic lateral sclerosis cohort

Author: Qiongyi Zhao, Sarah Furlong, Robert D. Henderson, Zong Hong Zhang, Sonia Shah, Pamela A. McCombe, Anjali K. Henders, Perminder S. Sachdev, Zhijun Liu, Kathryn A Thorpe, Beben Benyamin, Fleur C. Garton, Jacob Gratten, Sarah Morgan, Susan Heggie, Matthew R. Robinson, Casey M. M. Pfluger, Janette Edson, Peter M. Visscher, Naomi R. Wray, Allan F. McRae, Karen A. Mather, Marie Mangelsdorf, Garton, FC, Benyamin, B, Zhao, Q, Liu, Z, and McCombe, PA
Subjects: 0301 basic medicine, medicine.medical_specialty, Population, next‐generation sequencing, Biology, TARDBP, whole exome sequencing, 03 medical and health sciences, 0302 clinical medicine, C9orf72, Genetics, medicine, Amyotrophic lateral sclerosis, education, Molecular Biology, Genetics (clinical), Exome sequencing, Genetic testing, education.field_of_study, medicine.diagnostic_test, Original Articles, medicine.disease, 3. Good health, 030104 developmental biology, DNA methylation, motor neuron disease, Medical genetics, next-generation sequencing, Original Article, ALS, 030217 neurology & neurosurgery, clinical genetics
Abstract: Background: Gene discovery has provided remarkable biological insights into amyotrophic lateral sclerosis (ALS). One challenge for clinical application of genetic testing is critical evaluation of the significance of reported variants. Methods: We use whole exome sequencing (WES) to develop a clinically relevant approach to identify a subset of ALS patients harboring likely pathogenic mutations. In parallel, we assess if DNA methylation can be used to screen for pathogenicity of novel variants since a methylation signature has been shown to associate with the pathogenic C9orf72 expansion, but has not been explored for other ALS mutations. Australian patients identified with ALS-relevant variants were cross-checked with population databases and case reports to critically assess whether they were “likely causal,” “uncertain significance,” or “unlikely causal.”. Results: Published ALS variants were identified in >10% of patients; however, in only 3% of patients (4/120) could these be confidently considered pathogenic (in SOD1 and TARDBP). We found no evidence for a differential DNA methylation signature in these mutation carriers. Conclusions: The use of WES in a typical ALS clinic demonstrates a critical approach to variant assessment with the capability to combine cohorts to enhance the largely unknown genetic basis of ALS Refereed/Peer-reviewed
Published: 2017

20. 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

21. Cross-ethnic meta-analysis identifies association of the GPX3-TNIP1 locus with amyotrophic lateral sclerosis

Author: Zong Hong Zhang, Mengmeng Li, Jan H. Veldink, Qiongyi Zhao, Lu Chen, Huji Xu, Jacob Gratten, Wouter van Rheenen, Perry F. Bartlett, Dai Zhang, Ting Li, Roger Pamphlett, Jessica Harris, Anjali K. Henders, Ian P. Blair, Tim J. Butler, Naomi R. Wray, Yong Lin, Matthew S Devine, Kelly L. Williams, Peter G. Noakes, Robert D. Henderson, Peter M. Visscher, Weihua Yue, Ammar Al-Chalabi, Xin Wu, Shu Ran, Zi-Bing Jin, Dongsheng Fan, Matthew A. Brown, Lu Tang, Rosalind L. Jeffree, Mhairi Marshall, Ji He, Xiang Ding Chen, Lawrie Wheeler, Jian Yang, Zhongshan Li, Pamela A. McCombe, Bryan J. Mowry, Sharon Song, Dominic B. Rowe, Janette Edson, Leonard H. van den Berg, Perminder S. Sachdev, Fleur C. Garton, Emily P. McCann, Shyuan T. Ngo, Xiaolu Liu, Sarah Furlong, Paul Leo, Li Jun Tan, Katie Cremin, Jinyu Wu, Marie Mangelsdorf, Robyn H. Wallace, Sonia Shah, Zhijun Liu, Jennifer A. Fifita, Beben Benyamin, David C. Reutens, Hong Weng Deng, Ying Ying Han, Lisa Anderson, Benyamin, Beben, He, Ji, Zhao, Qiongyi, Gratten, Jacob, and Fan, Dongsheng
Subjects: 0301 basic medicine, Linkage disequilibrium, China, amyotrophic lateral sclerosis, Science, SOD1, General Physics and Astronomy, Locus (genetics), Genome-wide association study, Biology, Bioinformatics, General Biochemistry, Genetics and Molecular Biology, White People, Article, 03 medical and health sciences, Asian People, medicine, Journal Article, Humans, Amyotrophic lateral sclerosis, lcsh:Science, Allele frequency, Genetics, Glutathione Peroxidase, Multidisciplinary, Amyotrophic Lateral Sclerosis, Australia, High-Throughput Nucleotide Sequencing, Mendelian Randomization Analysis, General Chemistry, Sequence Analysis, DNA, medicine.disease, Genetic architecture, DNA-Binding Proteins, 030104 developmental biology, genome-wide association studies, lcsh:Q, next-generation sequencing, Genome-Wide Association Study
Abstract: Cross-ethnic genetic studies can leverage power from differences in disease epidemiology and population-specific genetic architecture. In particular, the differences in linkage disequilibrium and allele frequency patterns across ethnic groups may increase gene-mapping resolution. Here we use cross-ethnic genetic data in sporadic amyotrophic lateral sclerosis (ALS), an adult-onset, rapidly progressing neurodegenerative disease. We report analyses of novel genome-wide association study data of 1,234 ALS cases and 2,850 controls. We find a significant association of rs10463311 spanning GPX3-TNIP1 with ALS (p = 1.3 × 10−8), with replication support from two independent Australian samples (combined 576 cases and 683 controls, p = 1.7 × 10−3). Both GPX3 and TNIP1 interact with other known ALS genes (SOD1 and OPTN, respectively). In addition, GGNBP2 was identified using gene-based analysis and summary statistics-based Mendelian randomization analysis, although further replication is needed to confirm this result. Our results increase our understanding of genetic aetiology of ALS., Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease. Here, Wray and colleagues identify association of the GPX3-TNIP1 locus with ALS using cross-ethnic meta-analyses.
Published: 2017

22. Genetic variants linked to education predict longevity

Author: Chris Power, Gail Davies, Ilaria Gandin, Panagiotis Deloukas, Jennifer E. Huffman, Pascal Timshel, Albert V. Smith, A. Kong, Paul Lichtenstein, Joseph K. Pickrell, Philipp Koellinger, P. L. De Jager, Reedik Mägi, G. B. Chen, Neil Pendleton, B. V. Halldórsson, George Dedoussis, Antti-Pekka Sarin, Natalia Pervjakova, Veikko Salomaa, Simona Vaccargiu, Ozren Polasek, K. H. Jöckel, Elisabeth Steinhagen-Thiessen, Y. Milaneschi, Jessica D. Faul, Patricia A. Boyle, Patrik K. E. Magnusson, Igor Rudan, Christopher P. Nelson, Vilmundur Gudnason, John Attia, Jürgen Wellmann, Kristi Läll, Konstantin Strauch, Stuart J. Ritchie, Markus Perola, Nicola Pirastu, Klaus Bønnelykke, Robert Karlsson, R. de Vlaming, Liisa Keltigangas-Jarvinen, Thomas Meitinger, Riccardo E. Marioni, Anu Loukola, Barbera Franke, Reinhold Schmidt, Maël Lebreton, Sven Oskarsson, E. Mihailov, Harm-Jan Westra, David R. Weir, Aldi T. Kraja, Niek Verweij, Peter M. Visscher, Hans-Jörgen Grabe, Johannes H. Brandsma, Mark Adams, R. J. Scott, G. Thorleifsson, Tõnu Esko, Mika Kähönen, Saskia P. Hagenaars, Patrick Turley, Johannes Waage, Peter Lichtner, Dragana Vuckovic, Antonietta Robino, Henry Völzke, Lydia Quaye, C. de Leeuw, Marika Kaakinen, Wei Zhao, Abdel Abdellaoui, Reka Nagy, Pedro Marques-Vidal, Johan G. Eriksson, Alan F. Wright, Andres Metspalu, Lavinia Paternoster, Momoko Horikoshi, Jan A. Staessen, Tarunveer S. Ahluwalia, Tian Liu, Martin Kroh, Aldo Rustichini, Giorgia Girotto, Cristina Venturini, Lili Milani, Jennifer A. Smith, Ginevra Biino, Tessel E. Galesloot, Michael A. Horan, Gerardus A. Meddens, James F. Wilson, Francesco Cucca, Peter Vollenweider, Erika Salvi, P. J. van der Most, Jari Lahti, Campbell A, David Laibson, Andrew Bakshi, Wolfgang Hoffmann, Tomi Mäki-Opas, Andreas J. Forstner, C M van Duijn, Nicholas G. Martin, Jonathan Marten, Ute Bültmann, Olli T. Raitakari, David A. Bennett, A.G. Uitterlinden, J. E. De Neve, Ingrid B. Borecki, WD Hill, Bo Jacobsson, Antti Latvala, Katri Räikkönen, Michael B. Miller, Jonathan P. Beauchamp, S. J. van der Lee, Ilja Demuth, Stavroula Kanoni, Veronique Vitart, Elina Hyppönen, N. Eklund, Francesco P. Cappuccio, Robert F. Krueger, Maria Pina Concas, Jaime Derringer, F. J.A. Van Rooij, Helena Schmidt, Patrick J. F. Groenen, Valur Emilsson, Rico Rueedi, Aysu Okbay, Georg Homuth, Edith Hofer, W. E. R. Ollier, Hannah Campbell, Paolo Gasparini, Mark Alan Fontana, Magnus Johannesson, Seppo Koskinen, Christopher F. Chabris, Jouke-Jan Hottenga, Christine Meisinger, Kari Stefansson, Jun Ding, Tia Sorensen, Brenda W.J.H. Penninx, Michelle N. Meyer, James J. Lee, Diego Vozzi, Gonneke Willemsen, K. Petrovic, Sarah E. Medland, Mary F. Feitosa, Henning Tiemeier, L. J. Launer, William G. Iacono, Massimo Mangino, Tune H. Pers, S. E. Baumeister, Christopher Oldmeadow, Grant W. Montgomery, Marjo-Riitta Järvelin, Jaakko Kaprio, Catharine R. Gale, S.F.W. Meddens, Kevin Thom, Klaus Berger, Pablo V. Gejman, Lude Franke, Gyda Bjornsdottir, Daniel J. Benjamin, Steven F. Lehrer, Krista Fischer, Alan R. Sanders, S. Ulivi, Katharina E. Schraut, Tim D. Spector, Amy Hofman, Matt McGue, Terho Lehtimäki, D. C. Liewald, Hans Bisgaard, L. Eisele, Astanand Jugessur, George Davey Smith, T.B. Harris, A.R. Thurik, Cornelius A. Rietveld, David Schlessinger, Z. Kutalik, David J. Porteous, Lynne J. Hocking, N J Timpson, A. Palotie, Lambertus A. Kiemeney, Ian J. Deary, Sharon L.R. Kardia, Peter K. Joshi, Nilesh J. Samani, Michael A. Province, Börge Schmidt, Richa Gupta, Carmen Amador, Erin B. Ware, Joyce Y. Tung, Ioanna-Panagiota Kalafati, Lars Bertram, Caroline Hayward, P. van der Harst, Penelope A. Lind, Kadri Kaasik, N.A. Furlotte, Sarah E. Harris, B. St Pourcain, Susan M. Ring, Zhihong Zhu, Alexander Teumer, Behrooz Z. Alizadeh, Judith M. Vonk, Blair H. Smith, A Payton, Wouter J. Peyrot, Jacob Gratten, Douglas F. Levinson, C Gieger, Leanne M. Hall, Andrew Heath, Mario Pirastu, Peter Eibich, Nancy L. Pedersen, Ronny Myhre, Antonio Terracciano, David M. Evans, Raymond A. Poot, Uwe Völker, Dorret I. Boomsma, Clemens Baumbach, Unnur Thorsteinsdottir, Ivana Kolcic, Jia-Shu Yang, Dalton Conley, A. A. Vinkhuyzen, Danielle Posthuma, Karl-Oskar Lindgren, Olga Rostapshova, Jonas Bacelis, Daniele Cusi, Yong Qian, Bjarni Gunnarsson, George McMahon, Elizabeth G. Holliday, Pamela A. F. Madden, David A. Hinds, David Cesarini, Jianxin Shi, Najaf Amin, Dale R. Nyholt, Applied Economics, Epidemiology, Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Research Institute for Asthma and COPD (GRIAC), Aletta Jacobs School of Public Health, Public Health Research (PHR), Stem Cell Aging Leukemia and Lymphoma (SALL), Cardiovascular Centre (CVC), Amsterdam Neuroscience - Complex Trait Genetics, Psychiatry, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, EMGO - Mental health, Complex Trait Genetics, Biological Psychology, Marioni, RE, Ritchie, SJ, Joshi, PK, Hagenaars, SP, Hypponen, E, Benjamin, DJ, Social Science Genetic Association Consortium, Marioni, Re, Ritchie, Sj, Joshi, Pk, Hagenaars, Sp, Okbay, A, Fischer, K, Adams, Mj, Hill, Wd, Davies, G, Nagy, R, Amador, C, Läll, K, Metspalu, A, Liewald, Dc, Campbell, A, Wilson, Jf, Hayward, C, Esko, T, Porteous, Dj, Gale, Cr, Deary, Ij, Beauchamp, Jp, Fontana, Ma, Lee, Jj, Pers, Th, Rietveld, Ca, Turley, P, Chen, Gb, Emilsson, V, Meddens, Sf, Oskarsson, S, Pickrell, Jk, Thom, K, Timshel, P, de Vlaming, R, Abdellaoui, A, Ahluwalia, T, Bacelis, J, Baumbach, C, Bjornsdottir, G, Brandsma, Jh, Concas, MARIA PINA, Derringer, J, Furlotte, Na, Galesloot, Te, Girotto, Giorgia, Gupta, R, Hall, Lm, Harris, Se, Hofer, E, Horikoshi, M, Huffman, Je, Kaasik, K, Kalafati, Ip, Karlsson, R, Kong, A, Lahti, J, van der Lee, Sj, de Leeuw, C, Lind, Pa, Lindgren, Ko, Liu, T, Mangino, M, Marten, J, Mihailov, E, Miller, Mb, van der Most, Pj, Oldmeadow, C, Payton, A, Pervjakova, N, Peyrot, Wj, Qian, Y, Raitakari, O, Rueedi, R, Salvi, E, Schmidt, B, Schraut, Ke, Shi, J, Smith, Av, Poot, Ra, St Pourcain, B, Teumer, A, Thorleifsson, G, Verweij, N, Vuckovic, Dragana, Wellmann, J, Westra, Hj, Yang, J, Zhao, W, Zhu, Z, Alizadeh, Bz, Amin, N, Bakshi, A, Baumeister, Se, Biino, G, Bønnelykke, K, Boyle, Pa, Campbell, H, Cappuccio, Fp, De Neve, Je, Deloukas, P, Demuth, I, Ding, J, Eibich, P, Eisele, L, Eklund, N, Evans, Dm, Faul, Jd, Feitosa, Mf, Forstner, Aj, Gandin, Ilaria, Gunnarsson, B, Halldórsson, Bv, Harris, Tb, Heath, Ac, Hocking, Lj, Holliday, Eg, Homuth, G, Horan, Ma, Hottenga, Jj, de Jager, Pl, Jugessur, A, Kaakinen, Ma, Kähönen, M, Kanoni, S, Keltigangas Järvinen, L, Kiemeney, La, Kolcic, I, Koskinen, S, Kraja, At, Kroh, M, Kutalik, Z, Latvala, A, Launer, Lj, Lebreton, Mp, Levinson, Df, Lichtenstein, P, Lichtner, P, Loukola, A, Madden, Pa, Mägi, R, Mäki Opas, T, Marques Vidal, P, Meddens, Ga, Mcmahon, G, Meisinger, C, Meitinger, T, Milaneschi, Y, Milani, L, Montgomery, Gw, Myhre, R, Nelson, Cp, Nyholt, Dr, Ollier, We, Palotie, A, Paternoster, L, Pedersen, Nl, Petrovic, Ke, Räikkönen, K, Ring, Sm, Robino, Antonietta, Rostapshova, O, Rudan, I, Rustichini, A, Salomaa, V, Sanders, Ar, Sarin, Ap, Schmidt, H, Scott, Rj, Smith, Bh, Smith, Ja, Staessen, Ja, Steinhagen Thiessen, E, Strauch, K, Terracciano, A, Tobin, Md, Ulivi, Sheila, Vaccargiu, S, Quaye, L, van Rooij, Fj, Venturini, C, Vinkhuyzen, Aa, Völker, U, Völzke, H, Vonk, Jm, Vozzi, Diego, Waage, J, Ware, Eb, Willemsen, G, Attia, Jr, Bennett, Da, Berger, K, Bertram, L, Bisgaard, H, Boomsma, Di, Borecki, Ib, Bultmann, U, Chabris, Cf, Cucca, F, Cusi, D, Dedoussis, Gv, van Duijn, Cm, Eriksson, Jg, Franke, B, Franke, L, Gasparini, Paolo, Gejman, Pv, Gieger, C, Grabe, Hj, Gratten, J, Groenen, Pj, Gudnason, V, van der Harst, P, Hinds, Da, Hoffmann, W, Iacono, Wg, Jacobsson, B, Järvelin, Mr, Jöckel, Kh, Kaprio, J, Kardia, Sl, Lehtimäki, T, Lehrer, Sf, Magnusson, Pk, Martin, Ng, Mcgue, M, Pendleton, N, Penninx, Bw, Perola, M, Pirastu, Nicola, Pirastu, M, Polasek, O, Posthuma, D, Power, C, Province, Ma, Samani, Nj, Schlessinger, D, Schmidt, R, Sørensen, Ti, Spector, Td, Stefansson, K, Thorsteinsdottir, U, Thurik, Ar, Timpson, Nj, Tiemeier, H, Tung, Jy, Uitterlinden, Ag, Vitart, V, Vollenweider, P, Weir, Dr, Wright, Af, Conley, Dc, Krueger, Rf, Smith, Gd, Hofman, A, Laibson, Di, Medland, Se, Meyer, Mn, Johannesson, M, Visscher, Pm, Koellinger, Pd, Cesarini, D, and Benjamin, Dj
Subjects: Netherlands Twin Register (NTR), 0301 basic medicine, Male, Parents, education: longevity: prediction: polygenic score [genetics], Multifactorial Inheritance, polygenic, Lebenserwartung, Cohort Studies, 0302 clinical medicine, Databases, Genetic, Medicine, genetics, polygenic score, longevity, education, gene, Soziales und Gesundheit, media_common, Aged, 80 and over, education, Multidisciplinary, Longevity, Middle Aged, Biobank, humanities, 3. Good health, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Cohort, Educational Status, Female, Cohort study, Estonia, education, longevity, polygenic, Offspring, media_common.quotation_subject, Kultursektor, Prognose, Lernen, Lower risk, Education, 03 medical and health sciences, longevity, SDG 3 - Good Health and Well-being, Commentaries, Polygenic score, Journal Article, Genetics, Humans, Non-Profit-Sektor, Genetic Association Studies, Aged, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, ta1184, Genetic Variation, prediction, Educational attainment, United Kingdom, Gesundheitsstatistik, 030104 developmental biology, Genetic epidemiology, Scotland, Gesundheitszustand, Genetische Forschung, business, Prediction, Bildung, 030217 neurology & neurosurgery, Demography
Abstract: Educational attainment is associated with many health outcomes, including longevity. It is also known to be substantially heritable. Here, we used data from three large genetic epidemiology cohort studies (Generation Scotland, n = ∼17,000; UK Biobank, n = ∼115,000; and the Estonian Biobank, n = ∼6,000) to test whether education-linked genetic variants can predict lifespan length. We did so by using cohort members' polygenic profile score for education to predict their parents' longevity. Across the three cohorts, meta-analysis showed that a 1 SD higher polygenic education score was associated with ∼2.7% lower mortality risk for both mothers (total n deaths = 79,702) and ∼2.4% lower risk for fathers (total n deaths = 97,630). On average, the parents of offspring in the upper third of the polygenic score distribution lived 0.55 y longer compared with those of offspring in the lower third. Overall, these results indicate that the genetic contributions to educational attainment are useful in the prediction of human longevity. Marioni RE, Ritchie SJ, Joshi PK, Hagenaars SP, Okbay A, Fischer K, Adams MJ, Hill WD, Davies G, Social Science Genetic Association Consortium, Nagy R, Amador C, Läll K, Metspalu A, Liewald DC, Campbell A, Wilson JF, Hayward C, Esko T, Porteous DJ, Proceedings of the National Academy of Sciences of the United States of America, 2016, vol. 113, no. 47, pp. 13366-13371, 2016 Refereed/Peer-reviewed
Published: 2016

23. Genetic pleiotropy in complex traits and diseases: implications for genomic medicine

Author: Peter M. Visscher and Jacob Gratten
Subjects: 0301 basic medicine, Genotype, Quantitative Trait Loci, Genome-wide association study, Biology, Quantitative trait locus, Arthritis, Rheumatoid, 03 medical and health sciences, Quantitative Trait, Heritable, Genome editing, Genetic variation, Rett Syndrome, Genetics, Genetic Pleiotropy, Animals, Humans, Genetics(clinical), Molecular Biology, Genetics (clinical), Genetic association, Models, Genetic, Comment, Genetic Variation, Epistasis, Genetic, Human genetics, 3. Good health, Phenotype, 030104 developmental biology, Psychotic Disorders, Evolutionary biology, Molecular Medicine, Epistasis, Genome-Wide Association Study
Abstract: Editorial summary Several recent papers have used summary results from genome-wide association studies to characterize genetic overlap between human complex traits and common diseases. The emerging evidence is that individual DNA variants frequently influence multiple phenotypes, often in unexpected ways. This has important implications for genomic medicine and for the application of genome editing.
Published: 2016

24. Risk of psychiatric illness from advanced paternal age is not predominantly from de novo mutations

Author: John J. McGrath, Jacob Gratten, Naomi R. Wray, Michael E. Goddard, Wouter J. Peyrot, Peter M. Visscher, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep
Subjects: Genetic Markers, Male, 0301 basic medicine, medicine.medical_specialty, Mutation rate, Offspring, Population, Biology, Paternal Age, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Epidemiology, Genetic model, Genetics, medicine, Humans, Bipolar disorder, Autistic Disorder, Child, education, Psychiatry, education.field_of_study, business.industry, Age Factors, Obstetrics and Gynecology, General Medicine, Heritability, medicine.disease, 030104 developmental biology, Schizophrenia, Mutation, Autism, business, 030217 neurology & neurosurgery
Abstract: The offspring of older fathers have higher risk of psychiatric disorders such as schizophrenia and autism. Paternal-age-related de novo mutations are widely assumed to be the underlying causal mechanism, and, although such mutations must logically make some contribution, there are alternative explanations (for example, elevated liability to psychiatric illness may delay fatherhood). We used population genetic models based on empirical observations of key parameters (for example, mutation rate, prevalence, and heritability) to assess the genetic relationship between paternal age and risk of psychiatric illness. These models suggest that age-related mutations are unlikely to explain much of the increased risk of psychiatric disorders in children of older fathers. Conversely, a model incorporating a weak correlation between age at first child and liability to psychiatric illness matched epidemiological observations. Our results suggest that genetic risk factors shared by older fathers and their offspring are a credible alternative explanation to de novo mutations for risk to children of older fathers.
Published: 2016

25. Small non-coding RNA expression from anterior cingulate cortex in schizophrenia shows sex specific regulation

Author: Zong Hong Zhang, Janette Edson, Jacob Gratten, Bryan J. Mowry, Kalpana Patel, and Chikako Ragan
Subjects: 0301 basic medicine, Adult, Male, Small RNA, RNA-Seq, Biology, Gyrus Cinguli, 03 medical and health sciences, microRNA, Gene expression, Humans, Small nucleolar RNA, Gene, Biological Psychiatry, Aged, Regulation of gene expression, Genetics, Sex Characteristics, urogenital system, Age Factors, Middle Aged, Non-coding RNA, Psychiatry and Mental health, 030104 developmental biology, Gene Expression Regulation, Case-Control Studies, Postmortem Changes, Schizophrenia, RNA, Small Untranslated, Female
Abstract: MicroRNAs (miRNAs) are known to regulate the expression of genes that are important for brain development and function, but the roles of other classes of small non-coding RNAs (sncRNAs) are less well understood. Additionally, although miRNA expression studies have been conducted in post-mortem brain samples from schizophrenia (SCZ) patients, other classes of sncRNAs are yet to be investigated in SCZ. We profiled the expression of miRNAs, piwi-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs) and small nuclear RNAs (snRNAs) in SCZ by applying small RNA sequencing (RNA-Seq) to sncRNA isolated from post-mortem anterior cingulate cortex (ACC) of SCZ-affected individuals (n=22) and matched controls (n=22). We identified about one-third of annotated miRNAs, one-quarter of snoRNAs and a small proportion of piRNAs and snRNAs. No sncRNAs were significantly differentially expressed between SCZ and controls, but there was evidence for an interaction between disease status and sex on the expression level of a number of miRNAs and snoRNAs. Many of these transcripts exhibited differential expression between male and female cases, and/or between female cases and controls, suggesting sex based dysregulation in ACC of SCZ. These findings require replication in an independent sample, but our study provides further insights into the potential involvement of sncRNAs in brain function and SCZ.
Published: 2016

26. Genome-wide association study identifies 74 loci associated with educational attainment

Author: K. Petrovic, Massimo Mangino, Daniele Cusi, Ozren Polasek, Rodney J. Scott, Yong Qian, Aysu Okbay, Jari Lahti, Bjarni Gunnarsson, George McMahon, Elizabeth G. Holliday, Thomas Meitinger, Frank J. A. van Rooij, Mika Kähönen, Martin Kroh, Ian J. Deary, Neil Pendleton, Pamela A. F. Madden, David J. Porteous, Lambertus A. Kiemeney, Sven Oskarsson, Edith Hofer, Robert F. Krueger, Olga Rostapshova, Georg Homuth, Paolo Gasparini, Aldo Rustichini, Sarah E. Medland, Christian Gieger, Veronique Vitart, Nicholas J. Timpson, George Dedoussis, Joseph K. Pickrell, Christopher Oldmeadow, Aldi T. Kraja, Johan G. Eriksson, Lydia Quaye, William G. Iacono, Danielle Posthuma, George Davey Smith, Karl-Oskar Lindgren, David C. Liewald, Pim van der Harst, Börge Schmidt, Christine Power, Francesco P. Cappuccio, Francesco Cucca, Simona Vaccargiu, Joyce Y. Tung, Aarno Palotie, Natalia Pervjakova, Jonas Bacelis, Jouke-Jan Hottenga, Helena Schmidt, Kari Stefansson, Tamara B. Harris, Momoko Horikoshi, Lude Franke, Wolfgang Hoffmann, Ingrid B. Borecki, William E R Ollier, Johannes Waage, Andreas J. Forstner, Caroline Hayward, Penelope A. Lind, Patricia A. Boyle, Kadri Kaasik, Jian Yang, Gerardus A. Meddens, Antti Latvala, John Attia, Pascal Timshel, Vilmundur Gudnason, Maël Lebreton, Valur Emilsson, James F. Wilson, Jonathan Marten, Ute Bültmann, Erika Salvi, Olli T. Raitakari, Peter M. Visscher, Niek Verweij, Elisabeth Steinhagen-Thiessen, Cristina Venturini, Lili Milani, Tessel E. Galesloot, Kevin Thom, Klaus Berger, Paul Lichtenstein, Tian Liu, Philipp Koellinger, Riccardo E. Marioni, Marjo-Riitta Järvelin, Clemens Baumbach, Unnur Thorsteinsdottir, Magnus Johannesson, Susan M. Ring, David A. Bennett, Anu Loukola, Hans-Jörgen Grabe, Jan A. Staessen, Igor Rudan, Ginevra Biino, Nicholas G. Martin, Jingyun Yang, Anna A. E. Vinkhuyzen, Katri Räikkönen, Zhihong Zhu, Gudmar Thorleifsson, Mary F. Feitosa, Ivana Kolcic, Alexander Teumer, Jaakko Kaprio, David Schlessinger, Katharina E. Schraut, Konstantin Strauch, Ilja Demuth, Albert V. Smith, Juergen Wellmann, Jennifer E. Huffman, Panos Deloukas, Mario Pirastu, Reedik Mägi, Maria Pina Concas, Jaime Derringer, Patrick J. F. Groenen, Henry Völzke, Wei Zhao, Abdel Abdellaoui, Andres Metspalu, Nicholas A. Furlotte, Christopher P. Nelson, Barbara Franke, Steven F. Lehrer, Patrick Turley, Tõnu Esko, Jun Ding, Pedro Marques-Vidal, S. Fleur W. Meddens, Zoltán Kutalik, Gonneke Willemsen, Andrew C. Heath, Michelle N. Meyer, James J. Lee, Roy Thurik, Antonietta Robino, Henning Tiemeier, Grant W. Montgomery, C. deLeeuw, Astanand Jugessur, Antti-Pekka Sarin, Veikko Salomaa, Dalton Conley, Tim D. Spector, Sebastian E. Baumeister, Gyda Bjornsdottir, Lavinia Paternoster, Tune H. Pers, Jacob Gratten, Martin D. Tobin, Daniel J. Benjamin, Douglas F. Levinson, Stavroula Kanoni, Elina Hyppönen, David R. Weir, Peter J. van der Most, Terho Lehtimäki, David A. Hinds, Pablo V. Gejman, Uwe Völker, Cornelia M. van Duijn, Karl-Heinz Jöckel, Bjarni V. Halldorsson, Markus Perola, Nicola Pirastu, Klaus Bønnelykke, Robert Karlsson, David Cesarini, Michael A. Province, Jianxin Shi, Najaf Amin, Dale R. Nyholt, Lenore J. Launer, Nilesh J. Samani, Sven J. van der Lee, Dorret I. Boomsma, Harry Campbell, Peter Vollenweider, Liisa Keltigangas-Jarvinen, David Laibson, Ronald de Vlaming, Lynne J. Hocking, Christopher F. Chabris, Blair H. Smith, Gail Davies, Niina Eklund, Ioanna P. Kalafati, Bo Jacobsson, Sheila Ulivi, Alan F. Wright, Sarah E. Harris, Mark Alan Fontana, Diego Vozzi, Tomi Mäki-Opas, Albert Hofman, Hans Bisgaard, Andrew Bakshi, Marika Kaakinen, Johannes H. Brandsma, Christa Meisinger, Ilaria Gandin, Tarunveer S. Ahluwalia, Jennifer A. Smith, Beate St Pourcain, Rico Rueedi, Lewin Eisele, Michael B. Miller, Brenda W.J.H. Penninx, Alan R. Sanders, Thorkild I. A. Sørensen, André G. Uitterlinden, Cornelius A. Rietveld, Peter Lichtner, Dragana Vuckovic, Giorgia Girotto, Behrooz Z. Alizadeh, Reinhold Schmidt, Raymond A. Poot, Judith M. Vonk, Antony Payton, Wouter J. Peyrot, Augustine Kong, Y. Milaneschi, Jessica D. Faul, Patrik K. E. Magnusson, Antonio Terracciano, David M. Evans, Sharon L.R. Kardia, Peter K. Joshi, Michael A. Horan, Matt McGue, Richa Gupta, Jonathan P. Beauchamp, Peter Eibich, Erin B. Ware, Lars Bertram, Philip L. De Jager, Nancy L. Pedersen, Ronny Myhre, Guo-Bo Chen, Harm-Jan Westra, Jan-Emmanuel De Neve, Evelin Mihailov, Leanne M. Hall, Seppo Koskinen, Rush University Medical Center [Chicago], Department of Epidemiology [Rotterdam], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Helmholtz-Zentrum München (HZM), University of Queensland [Brisbane], Erasmus University Rotterdam, Universidad de Navarra [Pamplona] (UNAV), National Institute for Health and Welfare [Helsinki], 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, Consiglio Nazionale delle Ricerche (CNR), Montpellier Research in Management (MRM), Université Paul-Valéry - Montpellier 3 (UPVM)-Université de Perpignan Via Domitia (UPVD)-Groupe Sup de Co Montpellier (GSCM) - Montpellier Business School-Université de Montpellier (UM), University of Bristol [Bristol], Queensland Institute of Medical Research, Massachusetts General Hospital [Boston], Medical University Graz, Institut des Sciences Moléculaires (ISM), Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), King‘s College London, Tampere University Hospital, University of Turku, AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Edinburgh, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Imperial College London, Reykjavík University, Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], Karolinska Institutet [Stockholm], Department of Health Sciences [Leicester], University of Leicester, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Department of Medical Epidemiology and Biostatistics (MEB), Dpt of Pharmacology and Personalised Medicine [Maastricht], Maastricht University [Maastricht], Florida State University [Tallahassee] (FSU), IT University of Copenhagen, University of Helsinki-University of Helsinki, Université Montpellier 1 (UM1)-Groupe Sup de Co Montpellier (GSCM) - Montpellier Business School-Université Paul-Valéry - Montpellier 3 (UPVM)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Perpignan Via Domitia (UPVD), Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Université Sciences et Technologies - Bordeaux 1-Université Montesquieu - Bordeaux 4-Institut de Chimie du CNRS (INC), Faculteit Economie en Bedrijfskunde, Microeconomics (ASE, FEB), LifeLines Cohort Study, Alizadeh, BZ., de Boer, RA., Boezen, HM., Bruinenberg, M., Franke, L., van der Harst, P., Hillege, HL., van der Klauw, MM., Navis, G., Ormel, J., Postma, DS., Rosmalen, JG., Slaets, JP., Snieder, H., Stolk, RP., Wolffenbuttel, BH., Wijmenga, C., Applied Economics, Cell biology, Epidemiology, Erasmus MC other, Econometrics, Child and Adolescent Psychiatry / Psychology, Psychiatry, Internal Medicine, EMGO+ - Mental Health, Complex Trait Genetics, Biological Psychology, Functional Genomics, Economics, Amsterdam Neuroscience - Complex Trait Genetics, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Research Institute for Asthma and COPD (GRIAC), Public Health Research (PHR), Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Stem Cell Aging Leukemia and Lymphoma (SALL), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Okbay, Aysu, Beauchamp, Jonathan P., Fontana, Mark Alan, Lee, James J., Pers, Tune H., Rietveld, Cornelius A., Turley, Patrick, Chen, Guo Bo, Emilsson, Valur, Meddens, S. Fleur W., Oskarsson, Sven, Pickrell, Joseph K., Thom, Kevin, Timshel, Pascal, De Vlaming, Ronald, Abdellaoui, Abdel, Ahluwalia, Tarunveer S., Bacelis, Jona, Baumbach, Clemen, Bjornsdottir, Gyda, Brandsma, Johannes H., Concas, MARIA PINA, Derringer, Jaime, Furlotte, Nicholas A., Galesloot, Tessel E., Girotto, Giorgia, Gupta, Richa, Hall, Leanne M., Harris, Sarah E., Hofer, Edith, Horikoshi, Momoko, Huffman, Jennifer E., Kaasik, Kadri, Kalafati, Ioanna P., Karlsson, Robert, Kong, Augustine, Lahti, Jari, Van Der Lee, Sven J., Deleeuw, Christiaan, Lind, Penelope A., Lindgren, Karl Oskar, Liu, Tian, Mangino, Massimo, Marten, Jonathan, Mihailov, Evelin, Miller, Michael B., Van Der Most, Peter J., Oldmeadow, Christopher, Payton, Antony, Pervjakova, Natalia, Peyrot, Wouter J., Qian, Yong, Raitakari, Olli, Rueedi, Rico, Salvi, Erika, Schmidt, Börge, Schraut, Katharina E., Shi, Jianxin, Smith, Albert V., Poot, Raymond A., St Pourcain, Beate, Teumer, Alexander, Thorleifsson, Gudmar, Verweij, Niek, Vuckovic, Dragana, Wellmann, Juergen, Westra, Harm Jan, Yang, Jingyun, Zhao, Wei, Zhu, Zhihong, Alizadeh, Behrooz Z., Amin, Najaf, Bakshi, Andrew, Baumeister, Sebastian E., Biino, Ginevra, Bønnelykke, Klau, Boyle, Patricia A., Campbell, Harry, Cappuccio, Francesco P., Davies, Gail, De Neve, Jan Emmanuel, Deloukas, Pano, Demuth, Ilja, Ding, Jun, Eibich, Peter, Eisele, Lewin, Eklund, Niina, Evans, David M., Faul, Jessica D., Feitosa, Mary F., Forstner, Andreas J., Gandin, Ilaria, Gunnarsson, Bjarni, Halldórsson, Bjarni V., Harris, Tamara B., Holliday, Elizabeth G., Heath, Andrew C., Hocking, Lynne J., Homuth, Georg, Horan, Michael A., Hottenga, Jouke Jan, De Jager, Philip L., Joshi, Peter K., Jugessur, Astanand, Kaakinen, Marika A., Kähönen, Mika, Kanoni, Stavroula, Keltigangas Järvinen, Liisa, Kiemeney, Lambertus A. L. M., Kolcic, Ivana, Koskinen, Seppo, Kraja, Aldi T., Kroh, Martin, Kutalik, Zoltan, Latvala, Antti, Launer, Lenore J., Lebreton, Maël P., Levinson, Douglas F., Lichtenstein, Paul, Lichtner, Peter, Liewald, David C. M., Loukola, Anu, Madden, Pamela A., Mägi, Reedik, Mäki Opas, Tomi, Marioni, Riccardo E., Marques Vidal, Pedro, Meddens, Gerardus A., Mcmahon, George, Meisinger, Christa, Meitinger, Thoma, Milaneschi, Yusplitri, Milani, Lili, Montgomery, Grant W., Myhre, Ronny, Nelson, Christopher P., Nyholt, Dale R., Ollier, William E. R., Palotie, Aarno, Paternoster, Lavinia, Pedersen, Nancy L., Petrovic, Katja E., Porteous, David J., Raïkkönen, Katri, Ring, Susan M., Robino, Antonietta, Rostapshova, Olga, Rudan, Igor, Rustichini, Aldo, Salomaa, Veikko, Sanders, Alan R., Sarin, Antti Pekka, Schmidt, Helena, Scott, Rodney J., Smith, Blair H., Smith, Jennifer A., Staessen, Jan A., Steinhagen Thiessen, Elisabeth, Strauch, Konstantin, Terracciano, Antonio, Tobin, Martin D., Ulivi, Sheila, Vaccargiu, Simona, Quaye, Lydia, Van Rooij, Frank J. A., Venturini, Cristina, Vinkhuyzen, Anna A. E., Völker, Uwe, Völzke, Henry, Vonk, Judith M., Vozzi, Diego, Waage, Johanne, Ware, Erin B., Willemsen, Gonneke, Attia, John R., Bennett, David A., Berger, Klau, Bertram, Lar, Bisgaard, Han, Boomsma, Dorret I., Borecki, Ingrid B., Bültmann, Ute, Chabris, Christopher F., Cucca, Francesco, Cusi, Daniele, Deary, Ian J., Dedoussis, George V., Van Duijn, Cornelia M., Eriksson, Johan G., Franke, Barbara, Franke, Lude, Gasparini, Paolo, Gejman, Pablo V., Gieger, Christian, Grabe, Hans Jörgen, Gratten, Jacob, Groenen, Patrick J. F., Gudnason, Vilmundur, Van Der Harst, Pim, Hayward, Caroline, Hinds, David A., Hoffmann, Wolfgang, Hyppönen, Elina, Iacono, William G., Jacobsson, Bo, Järvelin, Marjo Riitta, Jöckel, Karl Heinz, Kaprio, Jaakko, Kardia, Sharon L. R., Lehtimäki, Terho, Lehrer, Steven F., Magnusson, Patrik K. E., Martin, Nicholas G., Mcgue, Matt, Metspalu, Andre, Pendleton, Neil, Penninx, Brenda W. J. H., Perola, Marku, Pirastu, Nicola, Pirastu, Mario, Polasek, Ozren, Posthuma, Danielle, Power, Christine, Province, Michael A., Samani, Nilesh J., Schlessinger, David, Schmidt, Reinhold, Sørensen, Thorkild I. A., Spector, Tim D., Stefansson, Kari, Thorsteinsdottir, Unnur, Thurik, A. Roy, Timpson, Nicholas J., Tiemeier, Henning, Tung, Joyce Y., Uitterlinden, André G., Vitart, Veronique, Vollenweider, Peter, Weir, David R., Wilson, James F., Wright, Alan F., Conley, Dalton C., Krueger, Robert F., Davey Smith, George, Hofman, Albert, Laibson, David I., Medland, Sarah E., Meyer, Michelle N., Yang, Jian, Johannesson, Magnu, Visscher, Peter M., Esko, Toñu, Koellinger, Philipp D., Cesarini, David, Benjamin, Daniel J., EMGO - Mental health, IOO, Human genetics, Beauchamp, Jonathan P, Lee, James JJ, Hypponen, Elina, and Benjamin, Daniel J
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), Candidate gene, Bipolar Disorder, Medizin, Genome-wide association study, Genome-wide association studies, 0302 clinical medicine, Cognition, Alzheimer Disease, Brain, Computational Biology, Fetus, Gene Expression Regulation, Gene-Environment Interaction, Great Britain, Humans, Molecular Sequence Annotation, Polymorphism, Single Nucleotide, Schizophrenia, Educational Status, Genome-Wide Association Study, Medicine (all), Multidisciplinary, Fetu, tau, Gene–environment interaction, Soziales und Gesundheit, Genetics, [QFIN]Quantitative Finance [q-fin], HERITABILITY, General Commentary, Alzheimer's disease, Biobank, Phenotype, Multidisciplinary Sciences, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], educational attainment, Behavioural genetics, Science & Technology - Other Topics, Bildungsniveau, TRAITS, Human, General Science & Technology, Kultursektor, SNP, ta3111, Polymorphism, Single Nucleotide, Learning and memory, Alzheimer Disease/genetics, Bipolar Disorder/genetics, Brain/metabolism, Fetus/metabolism, Gene Expression Regulation/genetics, Polymorphism, Single Nucleotide/genetics, Schizophrenia/genetics, 03 medical and health sciences, ACHIEVEMENT, MD Multidisciplinary, Non-Profit-Sektor, QH426, Science & Technology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], tauopathies, Data Science, gene, education, school, Heritability, Educational Statu, Educational attainment, United Kingdom, 030104 developmental biology, IQ, Genetische Forschung, Psychiatric disorders, Bildung, 030217 neurology & neurosurgery, LifeLines Cohort Study, Neuroscience
Abstract: Contains fulltext : 167137.pdf (Publisher’s version ) (Closed access) Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.
Published: 2016
Full Text: View/download PDF

27. Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

Author: Sharon L.R. Kardia, Melinda Mills, Ian J. Deary, Sven Bergmann, Magnus Johannesson, Igor Rudan, Nicholas J. Timpson, Richa Gupta, Hester M. den Ruijter, Rico Rueedi, Lars Bertram, Juliette Harris, Jennifer A. Smith, Eero Kajantie, Jian Yang, David C. Liewald, Ronald de Vlaming, Anu Realo, Jessica D. Faul, Patrik K. E. Magnusson, Jadwiga Buchwald, Philip L. De Jager, Rajesh Rawal, Marisa Koini, K. Petrovic, Unnur Thorsteinsdottir, Pedro Marques-Vidal, Roy Thurik, Evie Stergiakouli, Ivana Kolcic, William G. Iacono, Laura D. Kubzansky, Jaakko Kaprio, Behrooz Z. Alizadeh, Samantha Cherney, Reinhold Schmidt, Vilmundur Gudnason, Nicholas A. Furlotte, Nicholas G. Martin, Delilah Zabaneh, Rebecca T. Emeny, Eco J. C. de Geus, Klaus Berger, Lude Franke, Sven J. van der Lee, S. Fleur W. Meddens, Bart M. L. Baselmans, Dalton Conley, Jouke-Jan Hottenga, David A. Bennett, Saskia Haitjema, Jun Ding, Elina Hyppönen, Kari Stefansson, Henning Tiemeier, Grant W. Montgomery, Michelle N. Meyer, James J. Lee, Aysu Okbay, Lei Yu, Gyda Bjornsdottir, Marie Henrike Geisel, Albertine J. Oldehinkel, Liisa Keltikangas-Järvinen, George Davey Smith, Harold Snieder, Juho Wedenoja, Frits R. Rosendaal, Michel G. Nivard, Simon R. Cox, Christine Power, Dorret I. Boomsma, Börge Schmidt, David A. Hinds, Philipp Koellinger, Harm-Jan Westra, Terho Lehtimäki, Alison Pattie, Jan-Emmanuel De Neve, Torben Hansen, John M. Starr, Albert V. Smith, Antonio Terracciano, Juergen Wellmann, Albert Hofman, Katri Räikkönen, Patrick Turley, Andrew Steptoe, Jimmy Z. Liu, Evelin Mihailov, Jari Lahti, Marika Kaakinen, David R. Weir, Cornelia M. van Duijn, Maciej Trzaskowski, David Cesarini, Najaf Amin, Lydia Quaye, Sara M. Willems, Ghazaleh Fatemifar, Christopher Oldmeadow, Ville Karhunen, Alana Cavadino, Juan R. González, Caroline Hayward, Penelope A. Lind, Tamara B. Harris, Jaime Derringer, Camelia C. Minică, Jacob Gratten, Patrick J. F. Groenen, Ozren Polasek, Anu Loukola, Peter Vollenweider, Christian Gieger, Rodney J. Scott, Lindsay K. Matteson, Meike Bartels, Andrew Bakshi, David Laibson, Andrew C. Heath, Daniel J. Benjamin, Stephen S. Rich, Claire M. A. Haworth, C.A. Hartman, Angelina R. Sutin, Tian Liu, Johan G. Eriksson, Robert Plomin, Francesco Cucca, John Attia, Tarunveer S. Ahluwalia, Andreas J. Forstner, Gudmar Thorleifsson, Rauli Svento, Ute Bültmann, Olli T. Raitakari, Karl-Heinz Jöckel, Mark Alan Fontana, Oliver S. P. Davis, Yong Qian, Anna A. E. Vinkhuyzen, Wei Zhao, Elizabeth G. Holliday, Andres Metspalu, Alexis C. Frazier-Wood, Meena Kumari, Nese Direk, Miriam A. Mosing, Ilja M. Nolte, Sander W. van der Laan, Matt McGue, Tim D. Spector, Marjo-Riitta Järvelin, Peter Eibich, Nancy L. Pedersen, David Schlessinger, Toshiko Tanaka, Dennis O. Mook-Kanamori, Luigi Ferrucci, Gerard Pasterkamp, Jonathan P. Beauchamp, Robert Karlsson, Lenore J. Launer, Helena Schmidt, Renée de Mutsert, Gert G. Wagner, Peter Kraft, Joseph K. Pickrell, Thorkild I. A. Sørensen, André G. Uitterlinden, Patricia A. Boyle, Cornelius A. Rietveld, Robert F. Krueger, Karl-Heinz Ladwig, Michael B. Miller, Sarah E. Medland, Tõnu Esko, Kent D. Taylor, Lavinia Paternoster, Peter J. van der Most, Richard Karlsson Linnér, Laura Pulkki-Råback, Gail Davies, Victoria Garfield, Shun-Chiao Chang, Ruifang Li-Gao, Applied Economics, Pathology, Epidemiology, Public Health, Child and Adolescent Psychiatry / Psychology, Psychiatry, Internal Medicine, Ophthalmology, Social Science Genetic Association Consortium (SSGAC), CHARGE Consortium, Okbay, Aysu, Baselmans, Bart ML, De Neve, Jan-Emmanuel, Turley, Patrick, Hyppönen, Elina, Cesarini, David, EMGO+ - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Complex Trait Genetics, Biological Psychology, Functional Genomics, Economics, Amsterdam Neuroscience - Complex Trait Genetics, Queensland Institute of Medical Research, Massachusetts General Hospital [Boston], University of Queensland [Brisbane], Center for Research in Environmental Epidemiology (CREAL), Universitat Pompeu Fabra [Barcelona] (UPF)-Catalunya ministerio de salud, Universitat Pompeu Fabra [Barcelona] (UPF), CIBER de Epidemiología y Salud Pública (CIBERESP), Institut des Sciences Moléculaires (ISM), Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Université Sciences et Technologies - Bordeaux 1-Université Montesquieu - Bordeaux 4-Institut de Chimie du CNRS (INC), Tampere University Hospital, University of Turku, King‘s College London, University of Helsinki, AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Lausanne (UNIL), Birmingham City University (BCU), Helmholtz-Zentrum München (HZM), Department of Epidemiology and Public Health, University College of London [London] (UCL), Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], University of Edinburgh, Florida State University [Tallahassee] (FSU), Wuhan University [China], Rush University Medical Center [Chicago], Department of Epidemiology [Rotterdam], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Erasmus University Rotterdam, National Institute for Health and Welfare [Helsinki], Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Dpt of Pharmacology and Personalised Medicine [Maastricht], Maastricht University [Maastricht], Montpellier Research in Management (MRM), Université Montpellier 1 (UM1)-Groupe Sup de Co Montpellier (GSCM) - Montpellier Business School-Université Paul-Valéry - Montpellier 3 (UPVM)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Perpignan Via Domitia (UPVD), Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Université Paul-Valéry - Montpellier 3 (UPVM)-Université de Perpignan Via Domitia (UPVD)-Groupe Sup de Co Montpellier (GSCM) - Montpellier Business School-Université de Montpellier (UM), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Public Health Research (PHR), Sociology/ICS, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Stem Cell Aging Leukemia and Lymphoma (SALL), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), and LifeLines Cohort Study
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), Medizin, Genome-wide association study, Disease, Genome-wide association studies, DISEASE, 0302 clinical medicine, well-being, neuroticism, Anxiety Disorders/genetics, Bayes Theorem, Depression/genetics, Genome-Wide Association Study, Humans, Phenotype, Polymorphism, Single Nucleotide, Genetics & Heredity, RISK, Genetics, PERSONALITY, [QFIN]Quantitative Finance [q-fin], Depression, HERITABILITY, COMMON VARIANTS, 11 Medical And Health Sciences, Anxiety Disorders, Neuroticism, depression, Behavioural genetics, Life Sciences & Biomedicine, Biology, personality, genetic, epidemiology, ta3111, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, RESOURCE, Journal Article, Human height, Subjective well-being, behavioural genetics, METAANALYSIS, Genetic association, HAPPINESS, Science & Technology, MAJOR DEPRESSION, 06 Biological Sciences, Heritability, 030104 developmental biology, genome-wide association studies, HUMAN HEIGHT, 030217 neurology & neurosurgery, LifeLines Cohort Study, Developmental Biology, genome-wide analysis
Abstract: Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (vertical bar(p) over cap vertical bar approximate to 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.
Published: 2016

28. Correction: Corrigendum: Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

Author: Nicholas A. Furlotte, S. Fleur W. Meddens, Ronald de Vlaming, Anu Realo, Bart M. L. Baselmans, Patrick Turley, Jacob Gratten, Jan-Emmanuel De Neve, Melinda Mills, Alexis C. Frazier-Wood, Marie Henrike Geisel, Peter J. van der Most, Richard Karlsson Linnér, Saskia Haitjema, Tian Liu, Yong Qian, Juan R. González, Ilja M. Nolte, Sven J. van der Lee, Harm-Jan Westra, Jaime Derringer, Mark Alan Fontana, Behrooz Z. Alizadeh, Jimmy Z. Liu, Meena Kumari, Evelin Mihailov, Tarunveer S. Ahluwalia, Jadwiga Buchwald, Alana Cavadino, Penelope A. Lind, Aysu Okbay, Christopher Oldmeadow, Harold Snieder, Michael B. Miller, Albertine J. Oldehinkel, Sander W. van der Laan, Camelia C. Minică, Michel G. Nivard, Dennis O. Mook-Kanamori, Victoria Garfield, Karl-Heinz Ladwig, Lindsay K. Matteson, James J. Lee, Ute Bültmann, Olli T. Raitakari, Robert Karlsson, Lude Franke, Rajesh Rawal, Cornelius A. Rietveld, and Jari Lahti
Subjects: 0301 basic medicine, medicine.medical_specialty, Public health, Genetic variants, Biology, Neuroticism, Genome, 03 medical and health sciences, 030104 developmental biology, Genetics, medicine, Subjective well-being, Depressive symptoms, Clinical psychology
Abstract: In the version of this article initially published, one of the affiliations listed for author Maciej Trzaskowski, to the Department of Public Health, Faculty of Medicine, University of Split, Split, Croatia, was included in error. The correct affiliation for this author is the Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia. The error has been corrected in the HTML and PDF versions of the article.
Published: 2016

29. Predicting gene targets from integrative analyses of summary data from GWAS and eQTL studies for 28 human complex traits

Author: Allan F. McRae, Jacob Gratten, Jennifer M. Whitehead Pavlides, Zhihong Zhu, Jian Yang, and Naomi R. Wray
Subjects: 0301 basic medicine, Genotype, Autism Spectrum Disorder, Quantitative Trait Loci, Locus (genetics), Genome-wide association study, Coronary Artery Disease, Biology, Quantitative trait locus, Database, 03 medical and health sciences, Expression quantitative trait loci (eQTL), Quantitative Trait, Heritable, Alzheimer Disease, Mendelian randomization, Databases, Genetic, Genetic Pleiotropy, Genetics, Humans, Genetic Predisposition to Disease, Genetics(clinical), Genome-wide association studies (GWAS), Molecular Biology, Genetics (clinical), Genetic association, Models, Statistical, Genome, Human, Gene Expression Profiling, Summary data-based Mendelian randomization (SMR), Complex traits, Inflammatory Bowel Diseases, Human genetics, 3. Good health, 030104 developmental biology, Phenotype, Gene Expression Regulation, Expression quantitative trait loci, Molecular Medicine, Genome-Wide Association Study
Abstract: Genome-wide association studies (GWAS) have identified hundreds of genetic variants associated with complex traits and diseases. However, elucidating the causal genes underlying GWAS hits remains challenging. We applied the summary data-based Mendelian randomization (SMR) method to 28 GWAS summary datasets to identify genes whose expression levels were associated with traits and diseases due to pleiotropy or causality (the expression level of a gene and the trait are affected by the same causal variant at a locus). We identified 71 genes, of which 17 are novel associations (no GWAS hit within 1 Mb distance of the genes). We integrated all the results in an online database (http://www.cnsgenomics/shiny/SMRdb/), providing important resources to prioritize genes for further follow-up, for example in functional studies. Electronic supplementary material The online version of this article (doi:10.1186/s13073-016-0338-4) contains supplementary material, which is available to authorized users.
Full Text: View/download PDF

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources

Refine your results

29 results on '"Jacob Gratten"'

1. Analysis of DNA methylation associates the cystine–glutamate antiporter SLC7A11 with risk of Parkinson’s disease

2. Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders

3. The genetic relationship between female reproductive traits and six psychiatric disorders

4. Improved precision of epigenetic clock estimates across tissues and its implication for biological ageing

5. Parkinson's disease age at onset genome‐wide association study: Defining heritability, genetic loci, and α‐synuclein mechanisms

6. A Comparison of Ten Polygenic Score Methods for Psychiatric Disorders Applied Across Multiple Cohorts

7. Significant out-of-sample classification from methylation profile scoring for amyotrophic lateral sclerosis

8. Imprint of assortative mating on the human genome

9. Trans-eQTLs identified in whole blood have limited influence on complex disease biology

10. Gene networks associated with non-syndromic intellectual disability

11. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

12. Sizing up whole-genome sequencing studies of common diseases

13. Evidence for Genetic Overlap Between Schizophrenia and Age at First Birth in Women

14. Mapping and differential expression analysis from short-read RNA-Seq data in model organisms

15. Rare variants are common in schizophrenia

16. Whole-exome sequencing in amyotrophic lateral sclerosis suggests NEK1 is a risk gene in Chinese

17. Estimation of Genetic Correlation via Linkage Disequilibrium Score Regression and Genomic Restricted Maximum Likelihood

18. Age at first birth in women is genetically associated with increased risk of schizophrenia

19. Whole exome sequencing and DNA methylation analysis in a clinical amyotrophic lateral sclerosis cohort

20. Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

21. Cross-ethnic meta-analysis identifies association of the GPX3-TNIP1 locus with amyotrophic lateral sclerosis

22. Genetic variants linked to education predict longevity

23. Genetic pleiotropy in complex traits and diseases: implications for genomic medicine

24. Risk of psychiatric illness from advanced paternal age is not predominantly from de novo mutations

25. Small non-coding RNA expression from anterior cingulate cortex in schizophrenia shows sex specific regulation

26. Genome-wide association study identifies 74 loci associated with educational attainment

27. Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

28. Correction: Corrigendum: Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

29. Predicting gene targets from integrative analyses of summary data from GWAS and eQTL studies for 28 human complex traits

Catalog

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Topic

Publication Year Range

Language

Journal

Database

Publisher

29 results on '"Jacob Gratten"'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources