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1. A large meta-analysis identifies genes associated with anterior uveitis

Author: Sahar Gelfman, Arden Moscati, Santiago Mendez Huergo, Rujin Wang, Veera Rajagopal, Neelroop Parikshak, Vijay Kumar Pounraja, Esteban Chen, Michelle Leblanc, Ralph Hazlewood, Jan Freudenberg, Blerta Cooper, Ann J. Ligocki, Charles G. Miller, Tavé Van Zyl, Jonathan Weyne, Carmelo Romano, Botir Sagdullaev, Olle Melander, Aris Baras, Regeneron Genetics Center, Eli A. Stahl, and Giovanni Coppola
Subjects: Science
Abstract: Abstract Anterior Uveitis (AU) is the inflammation of the anterior part of the eye, the iris and ciliary body and is strongly associated with HLA-B*27. We report AU exome sequencing results from eight independent cohorts consisting of 3,850 cases and 916,549 controls. We identify common genome-wide significant loci in HLA-B (OR = 3.37, p = 1.03e-196) and ERAP1 (OR = 0.86, p = 1.1e-08), and find IPMK (OR = 9.4, p = 4.42e-09) and IDO2 (OR = 3.61, p = 6.16e-08) as genome-wide significant genes based on the burden of rare coding variants. Dividing the cohort into HLA-B*27 positive and negative individuals, we find ERAP1 haplotype is strongly protective only for B*27-positive AU (OR = 0.73, p = 5.2e-10). Investigation of B*27-negative AU identifies a common signal near HLA-DPB1 (rs3117230, OR = 1.26, p = 2.7e-08), risk genes IPMK and IDO2, and several additional candidate risk genes, including ADGFR5, STXBP2, and ACHE. Taken together, we decipher the genetics underlying B*27-positive and -negative AU and identify rare and common genetic signals for both subtypes of disease.
Published: 2023
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2. Population-scale analysis of common and rare genetic variation associated with hearing loss in adults

Author: Kavita Praveen, Lee Dobbyn, Lauren Gurski, Ariane H. Ayer, Jeffrey Staples, Shawn Mishra, Yu Bai, Alexandra Kaufman, Arden Moscati, Christian Benner, Esteban Chen, Siying Chen, Alexander Popov, Janell Smith, GHS-REGN DiscovEHR collaboration, Regeneron Genetics Center, Decibel-REGN collaboration, Olle Melander, Marcus B. Jones, Jonathan Marchini, Suganthi Balasubramanian, Brian Zambrowicz, Meghan C. Drummond, Aris Baras, Goncalo R. Abecasis, Manuel A. Ferreira, Eli A. Stahl, and Giovanni Coppola
Subjects: Biology (General), QH301-705.5
Abstract: A GWAS and exome-wide association study meta-analysis identifies 53 loci affecting hearing loss risk from over half a million individuals across five cohorts. Rare variants in Mendelian hearing loss genes contribute to hearing loss risk in adults.
Published: 2022
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3. Using brain cell-type-specific protein interactomes to interpret neurodevelopmental genetic signals in schizophrenia

Author: Yu-Han H. Hsu, Greta Pintacuda, Ruize Liu, Eugeniu Nacu, April Kim, Kalliopi Tsafou, Natalie Petrossian, William Crotty, Jung Min Suh, Jackson Riseman, Jacqueline M. Martin, Julia C. Biagini, Daya Mena, Joshua K.T. Ching, Edyta Malolepsza, Taibo Li, Tarjinder Singh, Tian Ge, Shawn B. Egri, Benjamin Tanenbaum, Caroline R. Stanclift, Annie M. Apffel, Steven A. Carr, Monica Schenone, Jake Jaffe, Nadine Fornelos, Hailiang Huang, Kevin C. Eggan, Kasper Lage, 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, Tune H. Pers, Ingrid Agartz, Esben Agerbo, Margot Albus, Madeline Alexander, Farooq Amin, Silviu A. Bacanu, Martin Begemann, Richard A. Belliveau, Jr., 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. Chan, Eric Y.H. Chen, Wei Cheng, Eric FC. 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 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, 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, Jordan W. Smoller, 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, Naomi R. Wray, 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. 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, Shengying Qin, Akira Sawa, Rene Kahn, Kyung Sue Hong, Wenzhao Shi, Ming Tsuang, Masanari Itokawa, Gang Feng, Stephen J. Glatt, Xiancang Ma, Jinsong Tang, Yunfeng Ruan, Feng Zhu, Yasue Horiuchi, Byung Dae Lee, Eun-Jeong Joo, Woojae Myung, Kyooseob Ha, Hong-Hee Won, Ji Hyung Baek, Young Chul Chung, Sung-Wan Kim, Agung Kusumawardhani, Wei J. Chen, Hai-Gwo Hwu, Akitoyo Hishimoto, Ikuo Otsuka, Ichiro Sora, Tomoko Toyota, Takeo Yoshikawa, Hiroshi Kunugi, Kotaro Hattori, Sayuri Ishiwata, Shusuke Numata, Tetsuro Ohmori, Makoto Arai, Yuji Ozeki, Kumiko Fujii, Se Joo Kim, Heon-Jeong Lee, Yong Min Ahn, Se Hyun Kim, Kazufumi Akiyama, Kazutaka Shimoda, and Makoto Kinoshita
Subjects: Molecular interaction, Developmental neuroscience, Cellular neuroscience, Proteomics, Science
Abstract: Summary: Genetics have nominated many schizophrenia risk genes and identified convergent signals between schizophrenia and neurodevelopmental disorders. However, functional interpretation of the nominated genes in the relevant brain cell types is often lacking. We executed interaction proteomics for six schizophrenia risk genes that have also been implicated in neurodevelopment in human induced cortical neurons. The resulting protein network is enriched for common variant risk of schizophrenia in Europeans and East Asians, is down-regulated in layer 5/6 cortical neurons of individuals affected by schizophrenia, and can complement fine-mapping and eQTL data to prioritize additional genes in GWAS loci. A sub-network centered on HCN1 is enriched for common variant risk and contains proteins (HCN4 and AKAP11) enriched for rare protein-truncating mutations in individuals with schizophrenia and bipolar disorder. Our findings showcase brain cell-type-specific interactomes as an organizing framework to facilitate interpretation of genetic and transcriptomic data in schizophrenia and its related disorders.
Published: 2023
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4. mTADA is a framework for identifying risk genes from de novo mutations in multiple traits

Author: Tan-Hoang Nguyen, Amanda Dobbyn, Ruth C. Brown, Brien P. Riley, Joseph D. Buxbaum, Dalila Pinto, Shaun M. Purcell, Patrick F. Sullivan, Xin He, and Eli A. Stahl
Subjects: Science
Abstract: Joint analysis of multiple traits can increase power and provide insights into shared genetic architecture. Here, Nguyen et al. develop multi-trait TADA (mTADA), an extension of TADA (transmission and de novo association test) that jointly analyses de novo mutations of traits for improved risk-gene identification power.
Published: 2020
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5. Analysis of Genetically Regulated Gene Expression Identifies a Prefrontal PTSD Gene, SNRNP35, Specific to Military Cohorts

Author: Laura M. Huckins, Chris Chatzinakos, Michael S. Breen, Jakob Hartmann, Torsten Klengel, Ana C. da Silva Almeida, Amanda Dobbyn, Kiran Girdhar, Gabriel E. Hoffman, Claudia Klengel, Mark W. Logue, Adriana Lori, Adam X. Maihofer, Filomene G. Morrison, Hoang T. Nguyen, Yongjin Park, Douglas Ruderfer, Laura G. Sloofman, Sanne J.H. van Rooij, Dewleen G. Baker, Chia-Yen Chen, Nancy Cox, Laramie E. Duncan, Mark A. Geyer, Stephen J. Glatt, Hae Kyung Im, Victoria B. Risbrough, Jordan W. Smoller, Dan J. Stein, Rachel Yehuda, Israel Liberzon, Karestan C. Koenen, Tanja Jovanovic, Manolis Kellis, Mark W. Miller, Silviu-Alin Bacanu, Caroline M. Nievergelt, Joseph D. Buxbaum, Pamela Sklar, Kerry J. Ressler, Eli A. Stahl, and Nikolaos P. Daskalakis
Subjects: transcriptomic imputation, GWAS, PTSD, glucocorticoid, splicing, military, Biology (General), QH301-705.5
Abstract: Summary: To reveal post-traumatic stress disorder (PTSD) genetic risk influences on tissue-specific gene expression, we use brain and non-brain transcriptomic imputation. We impute genetically regulated gene expression (GReX) in 29,539 PTSD cases and 166,145 controls from 70 ancestry-specific cohorts and identify 18 significant GReX-PTSD associations corresponding to specific tissue-gene pairs. The results suggest substantial genetic heterogeneity based on ancestry, cohort type (military versus civilian), and sex. Two study-wide significant PTSD associations are identified in European and military European cohorts; ZNF140 is predicted to be upregulated in whole blood, and SNRNP35 is predicted to be downregulated in dorsolateral prefrontal cortex, respectively. In peripheral leukocytes from 175 marines, the observed PTSD differential gene expression correlates with the predicted differences for these individuals, and deployment stress produces glucocorticoid-regulated expression changes that include downregulation of both ZNF140 and SNRNP35. SNRNP35 knockdown in cells validates its functional role in U12-intron splicing. Finally, exogenous glucocorticoids in mice downregulate prefrontal Snrnp35 expression.
Published: 2020
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6. Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics

Author: Alvaro N. Barbeira, Scott P. Dickinson, Rodrigo Bonazzola, Jiamao Zheng, Heather E. Wheeler, Jason M. Torres, Eric S. Torstenson, Kaanan P. Shah, Tzintzuni Garcia, Todd L. Edwards, Eli A. Stahl, Laura M. Huckins, GTEx Consortium, Dan L. Nicolae, Nancy J. Cox, and Hae Kyung Im
Subjects: Science
Abstract: Phenotypic variation and diseases are influenced by factors such as genetic variants and gene expression. Here, Barbeira et al. develop S-PrediXcan to compute PrediXcan results using summary data, and investigate the effects of gene expression variation on human phenotypes in 44 GTEx tissues and >100 phenotypes.
Published: 2018
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7. Improving genetic prediction by leveraging genetic correlations among human diseases and traits

Author: Robert M. Maier, Zhihong Zhu, Sang Hong Lee, Maciej Trzaskowski, Douglas M. Ruderfer, Eli A. Stahl, Stephan Ripke, Naomi R. Wray, Jian Yang, Peter M. Visscher, and Matthew R. Robinson
Subjects: Science
Abstract: Genetic prediction of complex traits so far has limited accuracy because of insufficient understanding of the genetic risk. Here, Maier et al. develop an improved method for trait prediction that makes use of genetic correlations between traits and apply it to summary statistics of psychiatric diseases.
Published: 2018
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8. Transcriptional signatures of schizophrenia in hiPSC-derived NPCs and neurons are concordant with post-mortem adult brains

Author: Gabriel E. Hoffman, Brigham J. Hartley, Erin Flaherty, Ian Ladran, Peter Gochman, Douglas M. Ruderfer, Eli A. Stahl, Judith Rapoport, Pamela Sklar, and Kristen J. Brennand
Subjects: Science
Abstract: Induced pluripotent stem cell (hiPSC)-based models have inherent variations in their cellular and molecular output and readouts. Here, Hoffman and colleagues devise a method to account for gene expression variations in hiPSC-derived neurons from patients with childhood-onset schizophrenia.
Published: 2017
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9. Integrated Bayesian analysis of rare exonic variants to identify risk genes for schizophrenia and neurodevelopmental disorders

Author: Hoang T. Nguyen, Julien Bryois, April Kim, Amanda Dobbyn, Laura M. Huckins, Ana B. Munoz-Manchado, Douglas M. Ruderfer, Giulio Genovese, Menachem Fromer, Xinyi Xu, Dalila Pinto, Sten Linnarsson, Matthijs Verhage, August B. Smit, Jens Hjerling-Leffler, Joseph D. Buxbaum, Christina Hultman, Pamela Sklar, Shaun M. Purcell, Kasper Lage, Xin He, Patrick F. Sullivan, and Eli A. Stahl
Subjects: De novo mutations, Rare variants, Schizophrenia, Autism, Developmental disorders, Intellectual disability, Medicine, Genetics, QH426-470
Abstract: Abstract Background Integrating rare variation from trio family and case–control studies has successfully implicated specific genes contributing to risk of neurodevelopmental disorders (NDDs) including autism spectrum disorders (ASD), intellectual disability (ID), developmental disorders (DDs), and epilepsy (EPI). For schizophrenia (SCZ), however, while sets of genes have been implicated through the study of rare variation, only two risk genes have been identified. Methods We used hierarchical Bayesian modeling of rare-variant genetic architecture to estimate mean effect sizes and risk-gene proportions, analyzing the largest available collection of whole exome sequence data for SCZ (1,077 trios, 6,699 cases, and 13,028 controls), and data for four NDDs (ASD, ID, DD, and EPI; total 10,792 trios, and 4,058 cases and controls). Results For SCZ, we estimate there are 1,551 risk genes. There are more risk genes and they have weaker effects than for NDDs. We provide power analyses to predict the number of risk-gene discoveries as more data become available. We confirm and augment prior risk gene and gene set enrichment results for SCZ and NDDs. In particular, we detected 98 new DD risk genes at FDR < 0.05. Correlations of risk-gene posterior probabilities are high across four NDDs (ρ>0.55), but low between SCZ and the NDDs (ρ
Published: 2017
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10. A Role for Noncoding Variation in Schizophrenia

Author: Panos Roussos, Amanda C. Mitchell, Georgios Voloudakis, John F. Fullard, Venu M. Pothula, Jonathan Tsang, Eli A. Stahl, Anastasios Georgakopoulos, Douglas M. Ruderfer, Alexander Charney, Yukinori Okada, Katherine A. Siminovitch, Jane Worthington, Leonid Padyukov, Lars Klareskog, Peter K. Gregersen, Robert M. Plenge, Soumya Raychaudhuri, Menachem Fromer, Shaun M. Purcell, Kristen J. Brennand, Nikolaos K. Robakis, Eric E. Schadt, Schahram Akbarian, and Pamela Sklar
Subjects: Biology (General), QH301-705.5
Abstract: A large portion of common variant loci associated with genetic risk for schizophrenia reside within noncoding sequence of unknown function. Here, we demonstrate promoter and enhancer enrichment in schizophrenia variants associated with expression quantitative trait loci (eQTL). The enrichment is greater when functional annotations derived from the human brain are used relative to peripheral tissues. Regulatory trait concordance analysis ranked genes within schizophrenia genome-wide significant loci for a potential functional role, based on colocalization of a risk SNP, eQTL, and regulatory element sequence. We identified potential physical interactions of noncontiguous proximal and distal regulatory elements. This was verified in prefrontal cortex and -induced pluripotent stem cell–derived neurons for the L-type calcium channel (CACNA1C) risk locus. Our findings point to a functional link between schizophrenia-associated noncoding SNPs and 3D genome architecture associated with chromosomal loopings and transcriptional regulation in the brain.
Published: 2014
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11. Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia

Author: Duncan S. Palmer, Daniel P. Howrigan, Sinéad B. Chapman, Rolf Adolfsson, Nick Bass, Douglas Blackwood, Marco P. M. Boks, Chia-Yen Chen, Claire Churchhouse, Aiden P. Corvin, Nicholas Craddock, David Curtis, Arianna Di Florio, Faith Dickerson, Nelson B. Freimer, Fernando S. Goes, Xiaoming Jia, Ian Jones, Lisa Jones, Lina Jonsson, Rene S. Kahn, Mikael Landén, Adam E. Locke, Andrew M. McIntosh, Andrew McQuillin, Derek W. Morris, Michael C. O’Donovan, Roel A. Ophoff, Michael J. Owen, Nancy L. Pedersen, Danielle Posthuma, Andreas Reif, Neil Risch, Catherine Schaefer, Laura Scott, Tarjinder Singh, Jordan W. Smoller, Matthew Solomonson, David St. Clair, Eli A. Stahl, Annabel Vreeker, James T. R. Walters, Weiqing Wang, Nicholas A. Watts, Robert Yolken, Peter P. Zandi, Benjamin M. Neale, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Psychiatry, Child and Adolescent Psychiatry / Psychology, Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, and Amsterdam Reproduction & Development (AR&D)
Subjects: Bipolar Disorder, Human Genome, A Kinase Anchor Proteins, Biological Sciences, Serious Mental Illness, Medical and Health Sciences, Article, Brain Disorders, Mental Health, SDG 3 - Good Health and Well-being, Clinical Research, Exome Sequencing, Schizophrenia, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Exome, Aetiology, Genome-Wide Association Study, Biotechnology, Developmental Biology
Abstract: We report results from the Bipolar Exome (BipEx) collaboration analysis of whole-exome sequencing of 13,933 patients with bipolar disorder (BD) matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in patients with BD among genes under strong evolutionary constraint in both major BD subtypes. We find enrichment of ultra-rare PTVs within genes implicated from a recent schizophrenia exome meta-analysis (SCHEMA; 24,248 cases and 97,322 controls) and among binding targets of CHD8. Genes implicated from genome-wide association studies (GWASs) of BD, however, are not significantly enriched for ultra-rare PTVs. Combining gene-level results with SCHEMA, AKAP11 emerges as a definitive risk gene (odds ratio (OR) = 7.06, P = 2.83 × 10−9). At the protein level, AKAP-11 interacts with GSK3B, the hypothesized target of lithium, a primary treatment for BD. Our results lend support to BD’s polygenicity, demonstrating a role for rare coding variation as a significant risk factor in BD etiology.
Published: 2022

12. Predicted gene expression in ancestrally diverse populations leads to discovery of susceptibility loci for lifestyle and cardiometabolic traits

Author: Heather M. Highland, Genevieve L. Wojcik, Mariaelisa Graff, Katherine K. Nishimura, Chani J. Hodonsky, Antoine R. Baldassari, Alanna C. Cote, Iona Cheng, Christopher R. Gignoux, Ran Tao, Yuqing Li, Eric Boerwinkle, Myriam Fornage, Jeffrey Haessler, Lucia A. Hindorff, Yao Hu, Anne E. Justice, Bridget M. Lin, Danyu Lin, Daniel O. Stram, Christopher A. Haiman, Charles Kooperberg, Loic Le Marchand, Tara C. Matise, Eimear E. Kenny, Christopher S. Carlson, Eli A. Stahl, Christy L. Avery, Kari E. North, Jose Luis Ambite, Steven Buyske, Ruth J. Loos, Ulrike Peters, Kristin L. Young, Stephanie A. Bien, and Laura M. Huckins
Subjects: Cardiovascular Diseases, Genetics, Humans, Genetic Predisposition to Disease, Transcriptome, Life Style, Polymorphism, Single Nucleotide, Article, Genetics (clinical), Genome-Wide Association Study
Abstract: One mechanism by which genetic factors influence complex traits and diseases is altering gene expression. Direct measurement of gene expression in relevant tissues is rarely tenable; however, genetically regulated gene expression (GReX) can be estimated using prediction models derived from large multi-omic datasets. These approaches have led to the discovery of many gene-trait associations, but whether models derived from predominantly European ancestry (EA) reference panels can map novel associations in ancestrally diverse populations remains unclear. We applied PrediXcan to impute GReX in 51,520 ancestrally diverse Population Architecture using Genomics and Epidemiology (PAGE) participants (35% African American, 45% Hispanic/Latino, 10% Asian, and 7% Hawaiian) across 25 key cardiometabolic traits and relevant tissues to identify 102 novel associations. We then compared associations in PAGE to those in a random subset of 50,000 White British participants from UK Biobank (UKBB(50k)) for height and body mass index (BMI). We identified 517 associations across 47 tissues in PAGE but not UKBB(50k), demonstrating the importance of diverse samples in identifying trait-associated GReX. We observed that variants used in PrediXcan models were either more or less differentiated across continental-level populations than matched-control variants depending on the specific population reflecting sampling bias. Additionally, variants from identified genes specific to either PAGE or UKBB(50k) analyses were more ancestrally differentiated than those in genes detected in both analyses, underlining the value of population-specific discoveries. This suggests that while EA-derived transcriptome imputation models can identify new associations in non-EA populations, models derived from closely matched reference panels may yield further insights. Our findings call for more diversity in reference datasets of tissue-specific gene expression.
Published: 2022

13. Rare protein‐coding variants implicate genes involved in risk of suicide death

Author: Emily DiBlasi, Douglas Gray, Andrey A. Shabalin, Qingqin S. Li, W. Brandon Callor, Anne V. Kirby, Nicola J. Camp, Ken R. Smith, Elliott Ferris, Anna R. Docherty, Michael Klein, Eoin Gaj, Eric T. Monson, Hilary Coon, Eli A. Stahl, Brooks R. Keeshin, Nancy William, Amanda V. Bakian, Zhe Yu, Leslie Jerominski, Danli Chen, Alison Fraser, and Erik Christensen
Subjects: 0301 basic medicine, Genomics, Single-nucleotide polymorphism, 030105 genetics & heredity, Biology, Polymorphism, Single Nucleotide, Receptors, G-Protein-Coupled, 03 medical and health sciences, Cellular and Molecular Neuroscience, Genetic variation, medicine, Humans, Genetic Predisposition to Disease, Telomeric Repeat Binding Protein 1, Bipolar disorder, Genotyping, Genetics (clinical), Genetic association, Genetics, Nuclear Proteins, Period Circadian Proteins, medicine.disease, Minor allele frequency, Suicide, Psychiatry and Mental health, 030104 developmental biology, Schizophrenia, Genome-Wide Association Study, Transcription Factors
Abstract: Identification of genetic factors leading to increased risk of suicide death is critical to combat rising suicide rates, however, only a fraction of the genetic variation influencing risk has been accounted for. To address this limitation, we conducted the first comprehensive analysis of rare genetic variation in suicide death leveraging the largest suicide death biobank, the Utah Suicide Genetic Risk Study (USGRS). We conducted a single-variant association analysis of rare (minor allele frequency
Published: 2021

14. Rare coding variants in ten genes confer substantial risk for schizophrenia

Author: Tarjinder Singh, Timothy Poterba, David Curtis, Huda Akil, Mariam Al Eissa, Jack D. Barchas, Nicholas Bass, Tim B. Bigdeli, Gerome Breen, Evelyn J. Bromet, Peter F. Buckley, William E. Bunney, Jonas Bybjerg-Grauholm, William F. Byerley, Sinéad B. Chapman, Wei J. Chen, Claire Churchhouse, Nicholas Craddock, Caroline M. Cusick, Lynn DeLisi, Sheila Dodge, Michael A. Escamilla, Saana Eskelinen, Ayman H. Fanous, Stephen V. Faraone, Alessia Fiorentino, Laurent Francioli, Stacey B. Gabriel, Diane Gage, Sarah A. Gagliano Taliun, Andrea Ganna, Giulio Genovese, David C. Glahn, Jakob Grove, Mei-Hua Hall, Eija Hämäläinen, Henrike O. Heyne, Matti Holi, David M. Hougaard, Daniel P. Howrigan, Hailiang Huang, Hai-Gwo Hwu, René S. Kahn, Hyun Min Kang, Konrad J. Karczewski, George Kirov, James A. Knowles, Francis S. Lee, Douglas S. Lehrer, Francesco Lescai, Dolores Malaspina, Stephen R. Marder, Steven A. McCarroll, Andrew M. McIntosh, Helena Medeiros, Lili Milani, Christopher P. Morley, Derek W. Morris, Preben Bo Mortensen, Richard M. Myers, Merete Nordentoft, Niamh L. O’Brien, Ana Maria Olivares, Dost Ongur, Willem H. Ouwehand, Duncan S. Palmer, Tiina Paunio, Digby Quested, Mark H. Rapaport, Elliott Rees, Brandi Rollins, F. Kyle Satterstrom, Alan Schatzberg, Edward Scolnick, Laura J. Scott, Sally I. Sharp, Pamela Sklar, Jordan W. Smoller, Janet L. Sobell, Matthew Solomonson, Eli A. Stahl, Christine R. Stevens, Jaana Suvisaari, Grace Tiao, Stanley J. Watson, Nicholas A. Watts, Douglas H. Blackwood, Anders D. Børglum, Bruce M. Cohen, Aiden P. Corvin, Tõnu Esko, Nelson B. Freimer, Stephen J. Glatt, Christina M. Hultman, Andrew McQuillin, Aarno Palotie, Carlos N. Pato, Michele T. Pato, Ann E. Pulver, David St. Clair, Ming T. Tsuang, Marquis P. Vawter, James T. Walters, Thomas M. Werge, Roel A. Ophoff, Patrick F. Sullivan, Michael J. Owen, Michael Boehnke, Michael C. O’Donovan, Benjamin M. Neale, Mark J. Daly, Psychiatry, HUS Psychiatry, Clinicum, University of Helsinki, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Department of Psychiatry, Centre of Excellence in Complex Disease Genetics, Research Programs Unit, and Aarno Palotie / Principal Investigator
Subjects: Multidisciplinary, Schizophrenia/genetics, MUTATIONS, Receptors, N-Methyl-D-Aspartate/genetics, Genetic Predisposition to Disease/genetics, 3112 Neurosciences, ASSOCIATION, Neurodevelopmental Disorders/genetics, Receptors, N-Methyl-D-Aspartate, INDIVIDUALS, Neurodevelopmental Disorders, Case-Control Studies, Mutation, Schizophrenia, Humans, Genetic Predisposition to Disease, Exome, 3111 Biomedicine, BURDEN
Abstract: Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3–50, P < 2.14 × 10−6) and 32 genes at a false discovery rate of 1, epilepsy and severe neurodevelopmental disorders2, although different mutation types are implicated in some shared genes. Most genes described here, however, are not implicated in neurodevelopment. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk3, suggesting that common and rare genetic risk factors converge at least partially on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, which indicates that more risk genes await discovery using this approach.
Published: 2022

15. Dissecting clinical heterogeneity of bipolar disorder using multiple polygenic risk scores

Author: Brandon J. Coombes, Joanna M. Biernacka, J. John Mann, Colin L. Colby, Mark A. Frye, Matej Markota, Myrna M. Weissman, Jyotishman Pathak, Susan L. McElroy, Eli A. Stahl, and Ardesheer Talati
Subjects: Male, Multifactorial Inheritance, medicine.medical_specialty, Psychosis, Bipolar Disorder, media_common.quotation_subject, Suicide, Attempted, Article, lcsh:RC321-571, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Risk Factors, Internal medicine, medicine, Humans, Personality, Bipolar disorder, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biological Psychiatry, 030304 developmental biology, Genetic association, media_common, 0303 health sciences, Suicide attempt, Genetic heterogeneity, business.industry, Comparative genomics, Anhedonia, medicine.disease, 3. Good health, Psychiatry and Mental health, Psychotic Disorders, Female, Polygenic risk score, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: Bipolar disorder (BD) has high clinical heterogeneity, frequent psychiatric comorbidities, and elevated suicide risk. To determine genetic differences between common clinical sub-phenotypes of BD, we performed a systematic polygenic risk score (PRS) analysis using multiple PRSs from a range of psychiatric, personality, and lifestyle traits to dissect differences in BD sub-phenotypes in two BD cohorts: the Mayo Clinic BD Biobank (N = 968) and Genetic Association Information Network (N = 1001). Participants were assessed for history of psychosis, early-onset BD, rapid cycling (defined as four or more episodes in a year), and suicide attempts using questionnaires and the Structured Clinical Interview for DSM-IV. In a combined sample of 1969 bipolar cases (45.5% male), those with psychosis had higher PRS for SCZ (OR = 1.3 per S.D.; p = 3e-5) but lower PRSs for anhedonia (OR = 0.87; p = 0.003) and BMI (OR = 0.87; p = 0.003). Rapid cycling cases had higher PRS for ADHD (OR = 1.23; p = 7e-5) and MDD (OR = 1.23; p = 4e-5) and lower BD PRS (OR = 0.8; p = 0.004). Cases with a suicide attempt had higher PRS for MDD (OR = 1.26; p = 1e-6) and anhedonia (OR = 1.22; p = 2e-5) as well as lower PRS for educational attainment (OR = 0.87; p = 0.003). The observed novel PRS associations with sub-phenotypes align with clinical observations such as rapid cycling BD patients having a greater lifetime prevalence of ADHD. Our findings confirm that genetic heterogeneity contributes to clinical heterogeneity of BD and consideration of genetic contribution to psychopathologic components of psychiatric disorders may improve genetic prediction of complex psychiatric disorders.
Published: 2020

16. 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

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

Author: Andreas J. Forstner, Martin Alda, Manolis Kogevinas, Pak C. Sham, Patrick F. Sullivan, Michele T. Pato, John R. Kelsoe, Paul A. Tooney, Steven P. Hamilton, Dorret I. Boomsma, Gerome Breen, Tracy Air, Hannelore Ehrenreich, Nakao Iwata, Jill M. Goldstein, Olav B. Smeland, Daniel R. Weinberger, Andrew McQuillin, Stuart A. Tobet, Elvira Bramon, Gabriëlla A.M. Blokland, Jing Qin Wu, Erik G. Jönsson, Peter R. Schofield, Fabian Streit, Nicholas Bass, Aarno Palotie, Brian Kelly, Cathryn M. Lewis, Srdjan Djurovic, Thomas Damm Als, Chia-Yen Chen, Bettina Konte, Joanna Hauser, Claire O'Donovan, Laura J. Scott, Hans J. Grabe, Murray J. Cairns, Rudolf Uher, Pablo Cervantes, Nicholas G. Martin, James A. Knowles, Aiden Corvin, Espen Molden, Lili Milani, Andreas Reif, Maria Grigoroiu-Serbanescu, George Kirov, Yuri Milaneschi, David St Clair, Eco J. C. de Geus, Robert Handa, Tõnu Esko, Alexander Teumer, Anders D. Børglum, Divya Mehta, Roel A. Ophoff, Susanne Lucae, Henning Tiemeier, Marion Leboyer, Ina Giegling, Alan R. Sanders, Jouke-Jan Hottenga, Pablo V. Gejman, Bernhard T. Baune, Brenda W.J.H. Penninx, Chris Cotsapas, Martin Preisig, Thomas Werge, Jakob Grove, Ingrid Melle, Jordan W. Smoller, Marcella Rietschel, Myrna M. Weissman, Preben Bo Mortensen, Philip B. Mitchell, Jolanta Lissowska, Andrew M. McIntosh, Annette M. Hartmann, Ole A. Andreassen, Lea Sirignano, John B. Vincent, Niamh Mullins, Jimmy Lee, Gonneke Willemsen, Marian L. Hamshere, Rolf Adolfsson, Mark A. Frye, Markus M. Nöthen, Jianxin Shi, Ashley L. Comes, Robin M. Murray, Patrik K. E. Magnusson, Frank Bellivier, Stéphane Jamain, Ole Mors, Sven Cichon, Uwe Völker, Fermín Mayoral, Bryan J. Mowry, Bruno Etain, James B. Potash, Beata Świątkowska, Bertram Müller-Myhsok, Mikael Landén, Tracey L. Petryshen, Franziska Degenhardt, Mark Adams, Dan Rujescu, Jose Guzman-Parra, Thomas G. Schulze, Merete Nordentoft, Joseph D. Buxbaum, Janice M. Fullerton, Brien P. Riley, Roy H. Perlis, Arne E. Vaaler, David M. Hougaard, Eli A. Stahl, Susan L. McElroy, Sabrina K. Schaupp, Martin Begemann, Sandra Van der Auwera, Todd Lencz, Joanna M. Biernacka, Agnes A. Steixner-Kumar, Douglas F. Levinson, Sathish Periyasamy, Alexander Viktorin, and Anil K. Malhotra
Subjects: Genetics, 0303 health sciences, Medizin, Locus (genetics), Genomics, Biology, medicine.disease, Genetic architecture, 03 medical and health sciences, 0302 clinical medicine, Mood, medicine, Major depressive disorder, Bipolar disorder, Gene, NKAIN2 Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: BACKGROUNDSex 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.METHODSWe conducted the largest to date genome-wide genotype–by–sex (GxS) interaction of risk for these disorders, using 85,735 cases (33,403 SCZ, 19,924 BIP, 32,408 MDD) and 109,946 controls from the Psychiatric Genomics Consortium (PGC) and iPSYCH.RESULTSAcross disorders, genome-wide significant SNP-by-sex interaction was detected for a locus encompassingNKAIN2(rs117780815;p=3.2×10−8), that interacts with sodium/potassium-transporting ATPase enzymes implicating neuronal excitability. Three additional loci showed evidence (p−6) for cross-disorder GxS 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 GxS interaction across disorders (p=8.97×10−7) with transcriptional inhibitorSLTM. Most significant in SCZ was aMOCOSgene 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 containingIDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant GxS of genes regulating vascular endothelial growth factor (VEGF) receptor signaling in MDD (pFDRCONCLUSIONSIn the largest genome-wide GxS 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, immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway enrichment levels.
Published: 2022

18. Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Author: Niamh Mullins, JooEun Kang, Adrian I. Campos, Jonathan R.I. Coleman, Alexis C. Edwards, Hanga Galfalvy, Daniel F. Levey, Adriana Lori, Andrey Shabalin, Anna Starnawska, Mei-Hsin Su, Hunna J. Watson, Mark Adams, Swapnil Awasthi, Michael Gandal, Jonathan D. Hafferty, Akitoyo Hishimoto, Minsoo Kim, Satoshi Okazaki, Ikuo Otsuka, Stephan Ripke, Erin B. Ware, Andrew W. Bergen, Wade H. Berrettini, Martin Bohus, Harry Brandt, Xiao Chang, Wei J. Chen, Hsi-Chung Chen, Steven Crawford, Scott Crow, Emily DiBlasi, Philibert Duriez, Fernando Fernández-Aranda, Manfred M. Fichter, Steven Gallinger, Stephen J. Glatt, Philip Gorwood, Yiran Guo, Hakon Hakonarson, Katherine A. Halmi, Hai-Gwo Hwu, Sonia Jain, Stéphane Jamain, Susana Jiménez-Murcia, Craig Johnson, Allan S. Kaplan, Walter H. Kaye, Pamela K. Keel, James L. Kennedy, Kelly L. Klump, Dong Li, Shih-Cheng Liao, Klaus Lieb, Lisa Lilenfeld, Chih-Min Liu, Pierre J. Magistretti, Christian R. Marshall, James E. Mitchell, Eric T. Monson, Richard M. Myers, Dalila Pinto, Abigail Powers, Nicolas Ramoz, Stefan Roepke, Vsevolod Rozanov, Stephen W. Scherer, Christian Schmahl, Marcus Sokolowski, Michael Strober, Laura M. Thornton, Janet Treasure, Ming T. Tsuang, Stephanie H. Witt, D. Blake Woodside, Zeynep Yilmaz, Lea Zillich, Rolf Adolfsson, Ingrid Agartz, Tracy M. Air, Martin Alda, Lars Alfredsson, Ole A. Andreassen, Adebayo Anjorin, Vivek Appadurai, María Soler Artigas, Sandra Van der Auwera, M. Helena Azevedo, Nicholas Bass, Claiton H.D. Bau, Bernhard T. Baune, Frank Bellivier, Klaus Berger, Joanna M. Biernacka, Tim B. Bigdeli, Elisabeth B. Binder, Michael Boehnke, Marco P. Boks, Rosa Bosch, David L. Braff, Richard Bryant, Monika Budde, Enda M. Byrne, Wiepke Cahn, Miguel Casas, Enrique Castelao, Jorge A. Cervilla, Boris Chaumette, Sven Cichon, Aiden Corvin, Nicholas Craddock, David Craig, Franziska Degenhardt, Srdjan Djurovic, Howard J. Edenberg, Ayman H. Fanous, Jerome C. Foo, Andreas J. Forstner, Mark Frye, Janice M. Fullerton, Justine M. Gatt, Pablo V. Gejman, Ina Giegling, Hans J. Grabe, Melissa J. Green, Eugenio H. Grevet, Maria Grigoroiu-Serbanescu, Blanca Gutierrez, Jose Guzman-Parra, Steven P. Hamilton, Marian L. Hamshere, Annette Hartmann, Joanna Hauser, Stefanie Heilmann-Heimbach, Per Hoffmann, Marcus Ising, Ian Jones, Lisa A. Jones, Lina Jonsson, René S. Kahn, John R. Kelsoe, Kenneth S. Kendler, Stefan Kloiber, Karestan C. Koenen, Manolis Kogevinas, Bettina Konte, Marie-Odile Krebs, Mikael Landén, Jacob Lawrence, Marion Leboyer, Phil H. Lee, Douglas F. Levinson, Calwing Liao, Jolanta Lissowska, Susanne Lucae, Fermin Mayoral, Susan L. McElroy, Patrick McGrath, Peter McGuffin, Andrew McQuillin, Sarah E. Medland, Divya Mehta, Ingrid Melle, Yuri Milaneschi, Philip B. Mitchell, Esther Molina, Gunnar Morken, Preben Bo Mortensen, Bertram Müller-Myhsok, Caroline Nievergelt, Vishwajit Nimgaonkar, Markus M. Nöthen, Michael C. O’Donovan, Roel A. Ophoff, Michael J. Owen, Carlos Pato, Michele T. Pato, Brenda W.J.H. Penninx, Jonathan Pimm, Giorgio Pistis, James B. Potash, Robert A. Power, Martin Preisig, Digby Quested, Josep Antoni Ramos-Quiroga, Andreas Reif, Marta Ribasés, Vanesa Richarte, Marcella Rietschel, Margarita Rivera, Andrea Roberts, Gloria Roberts, Guy A. Rouleau, Diego L. Rovaris, Dan Rujescu, Cristina Sánchez-Mora, Alan R. Sanders, Peter R. Schofield, Thomas G. Schulze, Laura J. Scott, Alessandro Serretti, Jianxin Shi, Stanley I. Shyn, Lea Sirignano, Pamela Sklar, Olav B. Smeland, Jordan W. Smoller, Edmund J.S. Sonuga-Barke, Gianfranco Spalletta, John S. Strauss, Beata Świątkowska, Maciej Trzaskowski, Gustavo Turecki, Laura Vilar-Ribó, John B. Vincent, Henry Völzke, James T.R. Walters, Cynthia Shannon Weickert, Thomas W. Weickert, Myrna M. Weissman, Leanne M. Williams, Naomi R. Wray, Clement C. Zai, Allison E. Ashley-Koch, Jean C. Beckham, Elizabeth R. Hauser, Michael A. Hauser, Nathan A. Kimbrel, Jennifer H. Lindquist, Benjamin McMahon, David W. Oslin, Xuejun Qin, Esben Agerbo, Anders D. Børglum, Gerome Breen, Annette Erlangsen, Tõnu Esko, Joel Gelernter, David M. Hougaard, Ronald C. Kessler, Henry R. Kranzler, Qingqin S. Li, Nicholas G. Martin, Andrew M. McIntosh, Ole Mors, Merete Nordentoft, Catherine M. Olsen, David Porteous, Robert J. Ursano, Danuta Wasserman, Thomas Werge, David C. Whiteman, Cynthia M. Bulik, Hilary Coon, Ditte Demontis, Anna R. Docherty, Po-Hsiu Kuo, Cathryn M. Lewis, J. John Mann, Miguel E. Rentería, Daniel J. Smith, Eli A. Stahl, Murray B. Stein, Fabian Streit, Virginia Willour, Douglas M. Ruderfer, Manuel Mattheisen, Abdel Abdellaoui, Mark J. Adams, Till F.M. Andlauer, Silviu-Alin Bacanu, Marie Bækvad-Hansen, Aartjan T.F. Beekman, Julien Bryois, Henriette N. Buttenschøn, Jonas Bybjerg-Grauholm, Na Cai, Jane Hvarregaard Christensen, Toni-Kim Clarke, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Nick Craddock, Gregory E. Crawford, Gail Davies, Eske M. Derks, Nese Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Valentina Escott-Price, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Josef Frank, Héléna A. Gaspar, Michael Gill, Fernando S. Goes, Scott D. Gordon, Shantel Marie Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Yang Wu, Hualin S. Xi, Jian Yang, Futao Zhang, Volker Arolt, Dorret I. Boomsma, Udo Dannlowski, E.J.C. de Geus, J. Raymond Depaulo, Enrico Domenici, Katharina Domschke, Jakob Grove, Lynsey S. Hall, Christine Søholm Hansen, Thomas F. Hansen, Stefan Herms, Ian B. Hickie, Georg Homuth, Carsten Horn, Jouke-Jan Hottenga, David M. Howard, Rick Jansen, Eric Jorgenson, James A. Knowles, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Zoltán Kutalik, Yihan Li, Penelope A. Lind, Donald J. MacIntyre, Dean F. MacKinnon, Robert M. Maier, Wolfgang Maier, Jonathan Marchini, Hamdi Mbarek, Christel M. Middeldorp, Evelin Mihailov, Lili Milani, Francis M. Mondimore, Grant W. Montgomery, Sara Mostafavi, Matthias Nauck, Bernard Ng, Michel G. Nivard, Dale R. Nyholt, Paul F. O’Reilly, Hogni Oskarsson, Caroline Hayward, Andrew C. Heath, Glyn Lewis, Pamela A.F. Madden, Patrik K. Magnusson, Andres Metspalu, Sara A. Paciga, Nancy L. Pedersen, Jodie N. Painter, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Roseann E. Peterson, Wouter J. Peyrot, Danielle Posthuma, Jorge A. Quiroz, Per Qvist, John P. Rice, Brien P. Riley, Saira Saeed Mirza, Robert Schoevers, Eva C. Schulte, Ling Shen, Engilbert Sigurdsson, Grant C.B. Sinnamon, Johannes H. Smit, Hreinn Stefansson, Stacy Steinberg, Jana Strohmaier, 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, Albert M. van Hemert, Alexander Viktorin, Peter M. Visscher, Yunpeng Wang, Bradley T. Webb, Roy H. Perlis, David J. Porteous, Catherine Schaefer, Kari Stefansson, Henning Tiemeier, Rudolf Uher, Patrick F. Sullivan, Kevin S. O’Connell, Brandon Coombes, Zhen Qiao, Thomas D. Als, Sigrid Børte, Alexander W. Charney, Ole Kristian Drange, Michael J. Gandal, Saskia P. Hagenaars, Masashi Ikeda, Nolan Kamitaki, Kristi Krebs, Georgia Panagiotaropoulou, Brian M. Schilder, Laura G. Sloofman, Bendik S. Winsvold, Hong-Hee Won, Liliya Abramova, Kristina Adorjan, Mariam Al Eissa, Diego Albani, Ney Alliey-Rodriguez, Verneri Antilla, Anastasia Antoniou, Ji Hyun Baek, Michael Bauer, Eva C. Beins, Sarah E. Bergen, Armin Birner, Erlend Bøen, Murielle Brum, Ben M. Brumpton, Nathalie Brunkhorst-Kanaan, William Byerley, Murray Cairns, Miquel Casas, Pablo Cervantes, Cristiana Cruceanu, Alfredo Cuellar-Barboza, Julie Cunningham, David Curtis, Piotr M. Czerski, Anders M. Dale, Nina Dalkner, Friederike S. David, Amanda L. Dobbyn, Athanassios Douzenis, Torbjørn Elvsåshagen, I. Nicol Ferrier, Alessia Fiorentino, Tatiana M. Foroud, Liz Forty, Oleksandr Frei, Nelson B. Freimer, Louise Frisén, Katrin Gade, Julie Garnham, Ian R. Gizer, Katherine Gordon-Smith, Tiffany A. Greenwood, José Guzman-Parra, Kyooseob Ha, Magnus Haraldsson, Martin Hautzinger, Urs Heilbronner, Dennis Hellgren, Peter A. Holmans, Laura Huckins, Jessica S. Johnson, Janos L. Kalman, Yoichiro Kamatani, Sarah Kittel-Schneider, Maria Koromina, Thorsten M. Kranz, Michiaki Kubo, Ralph Kupka, Steven A. Kushner, Catharina Lavebratt, Markus Leber, Heon-Jeong Lee, Shawn E. Levy, Catrin Lewis, Martin Lundberg, Sigurdur H. Magnusson, Adam Maihofer, Dolores Malaspina, Eirini Maratou, Lina Martinsson, Nathaniel W. McGregor, James D. McKay, Helena Medeiros, Vincent Millischer, Jennifer L. Moran, Derek W. Morris, Thomas W. Mühleisen, Niamh O’Brien, Claire O’Donovan, Loes M. Olde Loohuis, Lilijana Oruc, Sergi Papiol, Antonio F. Pardiñas, Amy Perry, Andrea Pfennig, Evgenia Porichi, Towfique Raj, Mark H. Rapaport, J. Raymond DePaulo, Eline J. Regeer, Fabio Rivas, Julian Roth, Panos Roussos, Fanny Senner, Sally Sharp, Paul D. Shilling, Claire Slaney, Janet L. Sobell, Maria Soler Artigas, Anne T. Spijker, Dan J. Stein, Chikashi Terao, Claudio Toma, Paul Tooney, Evangelia-Eirini Tsermpini, Marquis P. Vawter, Helmut Vedder, Simon Xi, Wei Xu, Jessica Mei Kay Yang, Allan H. Young, Hannah Young, Peter P. Zandi, Hang Zhou, null HUNT All-In Psychiatry, Gulja Babadjanova, Lena Backlund, Susanne Bengesser, Douglas H.R. Blackwood, Vaughan J. Carr, Stanley Catts, Dimitris Dikeos, Bruno Etain, Panagiotis Ferentinos, Micha Gawlik, Elliot S. Gershon, Frans Henskens, Jan Hillert, Kyung Sue Hong, Christina M. Hultman, Kristian Hveem, Nakao Iwata, Assen V. Jablensky, George Kirov, Christine Lochner, Carmel Loughland, Carol A. Mathews, Francis J. McMahon, Patricia Michie, Bryan Mowry, Benjamin M. Neale, Caroline M. Nievergelt, Ketil J. Oedegaard, Tomas Olsson, Chris Pantelis, George P. Patrinos, Eva Z. Reininghaus, Takeo Saito, Ulrich Schall, Martin Schalling, Rodney J. Scott, Eystein Stordal, Arne E. Vaaler, Eduard Vieta, Irwin D. Waldman, John-Anker Zwart, John I. Nurnberger, Arianna Di Florio, Roger A.H. Adan, Tetsuya Ando, Harald Aschauer, Jessica H. Baker, Vladimir Bencko, Andreas Birgegård, Joseph M. Boden, Ilka Boehm, Claudette Boni, Vesna Boraska Perica, Katharina Buehren, Roland Burghardt, Laura Carlberg, Matteo Cassina, Maurizio Clementi, Roger D. Cone, Philippe Courtet, James J. Crowley, Unna N. Danner, Oliver S.P. Davis, Martina de Zwaan, George Dedoussis, Daniela Degortes, Janiece E. DeSocio, Danielle M. Dick, Christian Dina, Monika Dmitrzak-Weglarz, Elisa Docampo Martinez, Laramie E. Duncan, Karin Egberts, Morten Mattingsdal, Sara McDevitt, Ingrid Meulenbelt, Nadia Micali, James Mitchell, Karen Mitchell, Palmiero Monteleone, Alessio Maria Monteleone, Melissa A. Munn-Chernoff, Benedetta Nacmias, Marie Navratilova, Ioanna Ntalla, Julie K. O’Toole, Leonid Padyukov, Aarno Palotie, Jacques Pantel, Hana Papezova, Richard Parker, John F. Pearson, Stefan Ehrlich, Geòrgia Escaramís, Thomas Espeseth, Xavier Estivill, Anne Farmer, Angela Favaro, Krista Fischer, James A.B. Floyd, Manuel Föcker, Lenka Foretova, Monica Forzan, Christopher S. Franklin, Giovanni Gambaro, Johanna Giuranna, Paola Giusti-Rodríquez, Fragiskos Gonidakis, Scott Gordon, Monica Gratacos Mayora, Sébastien Guillaume, Ken B. Hanscombe, Konstantinos Hatzikotoulas, Johannes Hebebrand, Sietske G. Helder, Anjali K. Henders, Beate Herpertz-Dahlmann, Wolfgang Herzog, Anke Hinney, L. John Horwood, Christopher Hübel, Liselotte V. Petersen, Kirstin L. Purves, Anu Raevuori, Ted Reichborn-Kjennerud, Valdo Ricca, Samuli Ripatti, Franziska Ritschel, Marion Roberts, Filip Rybakowski, Paolo Santonastaso, André Scherag, Ulrike Schmidt, Nicholas J. Schork, Alexandra Schosser, Jochen Seitz, Lenka Slachtova, P. Eline Slagboom, Margarita C.T. Slof-Op ‘t Landt, Agnieszka Slopien, Nicole Soranzo, Sandro Sorbi, Lorraine Southam, Vidar W. Steen, Laura M. Huckins, James I. Hudson, Hartmut Imgart, Hidetoshi Inoko, Vladimir Janout, Jennifer Jordan, Antonio Julià, Gursharan Kalsi, Deborah Kaminská, Jaakko Kaprio, Leila Karhunen, Andreas Karwautz, Martien J.H. Kas, Martin A. Kennedy, Anna Keski-Rahkonen, Kirsty Kiezebrink, Youl-Ri Kim, Katherine M. Kirk, Lars Klareskog, Gun Peggy S. Knudsen, Janne T. Larsen, Stephanie Le Hellard, Virpi M. Leppä, Paul Lichtenstein, Bochao Danae Lin, Astri Lundervold, Jurjen Luykx, Mario Maj, Katrin Mannik, Sara Marsal, Garret D. Stuber, Jin P. Szatkiewicz, Ioanna Tachmazidou, Elena Tenconi, Alfonso Tortorella, Federica Tozzi, Artemis Tsitsika, Marta Tyszkiewicz-Nwafor, Konstantinos Tziouvas, Annemarie A. van Elburg, Eric F. van Furth, Tracey D. Wade, Gudrun Wagner, Esther Walton, H. Erich Wichmann, Elisabeth Widen, Shuyang Yao, Eleftheria Zeggini, Stephanie Zerwas, Stephan Zipfel, Martin Jungkunz, Lydie Dietl, Cornelia E. Schwarze, Norbert Dahmen, Björn H. Schott, Arian Mobascher, Silvia Crivelli, Michelle F. Dennis, Phillip D. Harvey, Bruce W. Carter, Jennifer E. Huffman, Daniel Jacobson, Ravi Madduri, Maren K. Olsen, John Pestian, J. Michael Gaziano, Sumitra Muralidhar, Rachel Ramoni, Jean Beckham, Kyong-Mi Chang, Christopher J. O’Donnell, Philip S. Tsao, James Breeling, Grant Huang, J.P. Casas Romero, Jennifer Moser, Stacey B. Whitbourne, Jessica V. Brewer, Mihaela Aslan, Todd Connor, Dean P. Argyres, Brady Stephens, Mary T. Brophy, Donald E. Humphries, Luis E. Selva, Nhan Do, Shahpoor Shayan, Kelly Cho, Saiju Pyarajan, Elizabeth Hauser, Yan Sun, Hongyu Zhao, Peter Wilson, Rachel McArdle, Louis Dellitalia, Kristin Mattocks, John Harley, Clement J. Zablocki, Jeffrey Whittle, Frank Jacono, Salvador Gutierrez, Gretchen Gibson, Kimberly Hammer, Laurence Kaminsky, Gerardo Villareal, Scott Kinlay, Junzhe Xu, Mark Hamner, Roy Mathew, Sujata Bhushan, Pran Iruvanti, Michael Godschalk, Zuhair Ballas, Douglas Ivins, Stephen Mastorides, Jonathan Moorman, Saib Gappy, Jon Klein, Nora Ratcliffe, Hermes Florez, Olaoluwa Okusaga, Maureen Murdoch, Peruvemba Sriram, Shing Shing Yeh, Neeraj Tandon, Darshana Jhala, Samuel Aguayo, David Cohen, Satish Sharma, Suthat Liangpunsakul, Kris Ann Oursler, Mary Whooley, Sunil Ahuja, Joseph Constans, Paul Meyer, Jennifer Greco, Michael Rauchman, Richard Servatius, Melinda Gaddy, Agnes Wallbom, Timothy Morgan, Todd Stapley, Scott Sherman, George Ross, Philip Tsao, Patrick Strollo, Edward Boyko, Laurence Meyer, Samir Gupta, Mostaqul Huq, Joseph Fayad, Adriana Hung, Jack Lichy, Robin Hurley, Brooks Robey, Robert Striker, Dietl, Lydie, Schwarze, Cornelia E., Dahmen, Norbert, Schott, Björn H., Nöthen, Markus M., Ripke, Stephan, Mobascher, Arian, Rujescu, Dan, Lieb, Klaus, Roepke, Stefan, Schmahl, Christian, Bohus, Martin, Rietschel, Marcella, Crivelli, Silvia, Dennis, Michelle F., Harvey, Phillip D., Carter, Bruce W., Huffman, Jennifer E., Jacobson, Daniel, Madduri, Ravi, Olsen, Maren K., Pestian, John, Gaziano, J. Michael, Muralidhar, Sumitra, Ramoni, Rachel, Beckham, Jean, Chang, Kyong-Mi, O'Donnell, Christopher J., Tsao, Philip S., Breeling, James, Huang, Grant, Romero, J. P. Casas, Moser, Jennifer, Whitbourne, Stacey B., Brewer, Jessica V., Aslan, Mihaela, Connor, Todd, Argyres, Dean P., Stephens, Brady, Brophy, Mary T., Humphries, Donald E., Selva, Luis E., Do, Nhan, Shayan, Shahpoor, Cho, Kelly, Pyarajan, Saiju, Hauser, Elizabeth, Sun, Yan, Zhao, Hongyu, Wilson, Peter, McArdle, Rachel, Dellitalia, Louis, Mattocks, Kristin, Harley, John, Zablocki, Clement J., Whittle, Jeffrey, Jacono, Frank, Gutierrez, Salvador, Gibson, Gretchen, Hammer, Kimberly, Kaminsky, Laurence, Villareal, Gerardo, Kinlay, Scott, Xu, Junzhe, Hamner, Mark, Mathew, Roy, Bhushan, Sujata, Iruvanti, Pran, Godschalk, Michael, Ballas, Zuhair, Ivins, Douglas, Mastorides, Stephen, Moorman, Jonathan, Gappy, Saib, Klein, Jon, Ratcliffe, Nora, Florez, Hermes, Okusaga, Olaoluwa, Murdoch, Maureen, Sriram, Peruvemba, Yeh, Shing Shing, Tandon, Neeraj, Jhala, Darshana, Aguayo, Samuel, Cohen, David, Sharma, Satish, Liangpunsakul, Suthat, Oursler, Kris Ann, Whooley, Mary, Ahuja, Sunil, Constans, Joseph, Meyer, Paul, Greco, Jennifer, Rauchman, Michael, Servatius, Richard, Gaddy, Melinda, Wallbom, Agnes, Morgan, Timothy, Stapley, Todd, Sherman, Scott, Ross, George, Tsao, Philip, Strollo, Patrick, Boyko, Edward, Meyer, Laurence, Gupta, Samir, Huq, Mostaqul, Fayad, Joseph, Hung, Adriana, Lichy, Jack, Hurley, Robin, Robey, Brooks, Striker, Robert, Wray, Naomi R., Mattheisen, Manuel, Trzaskowski, Maciej, Byrne, Enda M., Abdellaoui, Abdel, Adams, Mark J., Agerbo, Esben, Air, Tracy M., Andlauer, Till F. M., Bacanu, Silviu-Alin, Bækvad-Hansen, Marie, Beekman, Aartjan T. F., Bigdeli, Tim B., Binder, Elisabeth B., Bryois, Julien, Buttenschøn, Henriette N., Bybjerg-Grauholm, Jonas, Cai, Na, Castelao, Enrique, Christensen, Jane Hvarregaard, Clarke, Toni-Kim, Coleman, Jonathan R. I., Colodro-Conde, Lucía, Couvy-Duchesne, Baptiste, Craddock, Nick, Crawford, Gregory E., Davies, Gail, Degenhardt, Franziska, Derks, Eske M., Direk, Nese, Dolan, Conor V., Dunn, Erin C., Eley, Thalia C., Escott-Price, Valentina, Hassan Kiadeh, Farnush Farhadi, Finucane, Hilary K., Foo, Jerome C., Forstner, Andreas J., Frank, Josef, Gaspar, Héléna A., Gill, Michael, Goes, Fernando S., Gordon, Scott D., Weinsheimer, Shantel Marie, Wellmann, Jürgen, Willemsen, Gonneke, Witt, Stephanie H., Wu, Yang, Xi, Hualin S., Yang, Jian, Zhang, Futao, Arolt, Volker, Baune, Bernhard T., Berger, Klaus, Boomsma, Dorret I., Cichon, Sven, Dannlowski, Udo, de Geus, E. J. C., DePaulo, J. Raymond, Domenici, Enrico, Domschke, Katharina, Esko, Tõnu, Grabe, Hans J., Hamilton, Steven P., Grove, Jakob, Hall, Lynsey S., Hansen, Christine Søholm, Hansen, Thomas F., Herms, Stefan, Hickie, Ian B., Hoffmann, Per, Homuth, Georg, Horn, Carsten, Hottenga, Jouke-Jan, Hougaard, David M., Howard, David M., Ising, Marcus, Jansen, Rick, Jones, Ian, Jones, Lisa A., Jorgenson, Eric, Knowles, James A., Kohane, Isaac S., Kraft, Julia, Kretzschmar, Warren W., Kutalik, Zoltán, Li, Yihan, Lind, Penelope A., MacIntyre, Donald J., MacKinnon, Dean F., Maier, Robert M., Maier, Wolfgang, Marchini, Jonathan, Mbarek, Hamdi, McGrath, Patrick, McGuffin, Peter, Medland, Sarah E., Mehta, Divya, Middeldorp, Christel M., Mihailov, Evelin, Milaneschi, Yuri, Milani, Lili, Mondimore, Francis M., Montgomery, Grant W., Mostafavi, Sara, Mullins, Niamh, Nauck, Matthias, Ng, Bernard, Nivard, Michel G., Nyholt, Dale R., O'Reilly, Paul F., Oskarsson, Hogni, Hayward, Caroline, Heath, Andrew C., Kendler, Kenneth S., Kloiber, Stefan, Lewis, Glyn, Li, Qingqin S., Lucae, Susanne, Madden, Pamela A. 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W., O'Brien, N., O'Donovan, C., Olde Loohuis, L. M., Oruc, L., Papiol, S., Pardinas, A. F., Perry, A., Pfennig, A., Porichi, E., Raj, T., Rapaport, M. H., Regeer, E. J., Rivas, F., Roth, J., Roussos, P., Ruderfer, D. M., Senner, F., Sharp, S., Shilling, P. D., Slaney, C., Sobell, J. L., Artigas, M. S., Spijker, A. T., Stein, D. J., Terao, C., Toma, C., Tooney, P., Tsermpini, E. -E., Vawter, M. P., Vedder, H., Xi, S., Xu, W., Kay Yang, J. M., Young, A. H., Young, H., Zandi, P. P., Zhou, H., HUNT All-In, Psychiatry, Babadjanova, G., Backlund, L., Bengesser, S., Blackwood, D. H. R., Carr, V. J., Catts, S., Dikeos, D., Etain, B., Ferentinos, P., Gawlik, M., Gershon, E. S., Henskens, F., Hillert, J., Hong, K. S., Hultman, C. M., Hveem, K., Iwata, N., Jablensky, A. V., Kirov, G., Lochner, C., Loughland, C., Mathews, C. A., Mcmahon, F. J., Michie, P., Mowry, B., Neale, B. M., Nievergelt, C. M., Oedegaard, K. J., Olsson, T., Pantelis, C., Patrinos, G. P., Reininghaus, E. Z., Saito, T., Schall, U., Schalling, M., Scott, R. J., Weickert, C. S., Stordal, E., Vaaler, A. E., Vieta, E., Waldman, I. D., Zwart, J. -A., Nurnberger, J. I., Stahl, E. A., Di Florio, A., Adan, R. A. H., Ando, T., Aschauer, H., Baker, J. H., Bencko, V., Birgegard, A., Boden, J. M., Boehm, I., Boni, C., Perica, V. B., Buehren, K., Bulik, C. M., Burghardt, R., Carlberg, L., Cassina, M., Clementi, M., Cone, R. D., Courtet, P., Crowley, J. J., Danner, U. N., Davis, O. S. P., de Zwaan, M., Dedoussis, G., Degortes, D., Desocio, J. E., Dick, D. M., Dina, C., Dmitrzak-Weglarz, M., Martinez, E. D., Duncan, L. E., Egberts, K., Mattingsdal, M., Mcdevitt, S., Meulenbelt, I., Micali, N., Mitchell, J., Mitchell, K., Monteleone, P., Monteleone, A. M., Munn-Chernoff, M. A., Nacmias, B., Navratilova, M., Ntalla, I., Olsen, C. M., O'Toole, J. K., Padyukov, L., Palotie, A., Pantel, J., Papezova, H., Parker, R., Pearson, J. 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Subjects: LD SCORE REGRESSION, Genome-wide association study, Suicide, Attempted, 3124 Neurology and psychiatry, 0302 clinical medicine, Risk Factors, Insomnia, Suicide attempt, GWAS, Suïcidi, Depression (differential diagnoses), Cause of death, Psychiatry, 0303 health sciences, Factors de risc en les malalties, Mental Disorders, Genetic Correlation, Genome-wide Association Study, Pleiotropy, Polygenicity, Suicide, Suicide Attempt, DEPRESSION, 3. Good health, Genetic correlation, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Depressive Disorder, Major, Mental illness, Cohort, SEX, medicine.symptom, Human, medicine.medical_specialty, Risk factors in diseases, BF, Locus (genetics), BEHAVIORS, Psykiatri, EVENTS, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, ddc:610, GENOME-WIDE ASSOCIATION, IDEATION, Socioeconomic status, METAANALYSIS, Biological Psychiatry, 030304 developmental biology, business.industry, Risk Factor, Genetic architecture, THOUGHTS, RC0321, business, Malalties mentals, 030217 neurology & neurosurgery
Abstract: Statistical analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu), which is supported by the Office of Research Infrastructure of the National Institutes of Health (Grant Nos. S10OD018522 and S10OD026880). This work was conducted in part using the resources of the Advanced Computing Center for Research and Education at Vanderbilt University, Nashville, TN. This work was funded by the National Institutes of Health (Grant Nos. R01MH116269 and R01MH121455 [to DMR]), NIGMS of the National Institutes of Health (Grant No. T32GM007347 [to JK]), and the Brain & Behavior Research Foundation (NARSAD Young Investigator Award No. 29551 [to NM])., BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders., Office of Research Infrastructure of the National Institutes of Health S10OD018522 S10OD026880, United States Department of Health & Human Services, National Institutes of Health (NIH) - USA R01MH116269 R01MH121455, NIH National Institute of General Medical Sciences (NIGMS) T32GM007347 NARSAD 29551
Published: 2022

19. ERAP1, ERAP2, and Two Copies of HLA-Aw19 Alleles Increase the Risk for Birdshot Chorioretinopathy in HLA-A29 Carriers

Author: Xiaodong Bai, Dominique Monnet, Thierry Tabary, Carmelo Romano, Jack A. Kosmicki, Sahar Gelfman, Antoine P. Brézin, Eli A. Stahl, Manuel A. R. Ferreira, Jonathan Weyne, Aris Baras, Giovanni Coppola, Arden Moscati, Jacques H. M. Cohen, Blerta Cooper, Sarah Wolf, Ann J. Ligocki, Jan Freudenberg, and John D. Overton
Subjects: Heterozygote, Genotyping Techniques, HLA-A33, Human leukocyte antigen, Biology, ERAP1, Aminopeptidases, Polymorphism, Single Nucleotide, ERAP2, Minor Histocompatibility Antigens, Gene Frequency, Risk Factors, Genotype, medicine, Odds Ratio, Genetics, Humans, Genetic Predisposition to Disease, Allele, Allele frequency, Alleles, HLA-A Antigens, Haplotype, Birdshot Chorioretinopathy, Odds ratio, medicine.disease, Birdshot chorioretinopathy, birdshot, Haplotypes, HLA-Aw19, Cohort, Immunology, Expression quantitative trait loci, Multiplex Polymerase Chain Reaction, Genome-Wide Association Study
Abstract: PurposeBirdshot Chorioretinopathy (BSCR) is strongly associated with HLA-A29. This study was designed to elucidate the genetic modifiers of BSCR in HLA-A29 carriers.MethodsWe sequenced the largest BSCR cohort to date, including 286 cases and 108 HLA-A29 positive controls to perform genome wide common and rare variant associations. We further typed the HLA alleles of cases and 45,386 HLA-A29 controls of European ancestry to identify HLA alleles that associate with BSCR risk.ResultsCarrying a second allele that belongs to the HLA-Aw19 broad antigen family (including HLA-A29, A30, A31, and A33) increases the risk for BSCR (OR=4.44, p=2.2e-03). This result was validated by comparing allele frequencies to large HLA-A29-controlled cohorts (n=45,386, OR>2.5, pConclusionsThe genetic factors increasing BSCR risk demonstrate a pattern of increased processing, as well as increased presentation of ERAP2 specific peptides. This suggests a mechanism in which exceeding a peptide presentation threshold activates the immune response in choroids of A29 carriers.
Published: 2021

20. Population-scale analysis of common and rare genetic variation associated with hearing loss in adults

Author: Shawn Mishra, Siying Chen, Manuel A. R. Ferreira, Brian Zambrowicz, Jeffrey Staples, Alexander Popov, Yu Bai, Arden Moscati, Alexandra Kaufman, Ariane H. Ayer, Meghan Drummond, Jonathan Marchini, Aris Baras, Janell Smith, Lauren Gurski, Kavita Praveen, Lee Dobbyn, Esteban Chen, Christian Benner, Olle Melander, Gonçalo R. Abecasis, Suganthi Balasubramanian, Marcus Herbert Jones, Giovanni Coppola, and Eli A. Stahl
Subjects: Genetics, education.field_of_study, Hearing loss, Serine Endopeptidases, Population, Genetic Variation, Membrane Proteins, Odds ratio, Biology, Genetic architecture, Neoplasm Proteins, symbols.namesake, Exome Sequencing, Genetic variation, Mendelian inheritance, symbols, Etiology, medicine, Humans, Exome, medicine.symptom, Hearing Loss, education, Exome sequencing, Genome-Wide Association Study
Abstract: Understanding the genetic underpinnings of disabling hearing loss, which affects ∼466 million people worldwide, can provide avenues for new therapeutic target development. We performed a genome-wide association meta-analysis of hearing loss with 125,749 cases and 469,497 controls across five cohorts, including UK Biobank, Geisinger DiscovEHR, the Malmö Diet and Cancer Study, Mount Sinai’s BioMe Personalized Medicine Cohort, and FinnGen. We identified 53 loci affecting hearing loss risk, 15 of which are novel, including common coding variants in COL9A3 and TMPRSS3. Through exome-sequencing of 108,415 cases and 329,581 controls from the same cohorts, we identified hearing loss associations with burden of rare coding variants in FSCN2 (odds ratio [OR] = 1.14, P = 1.9 × 10−15) and burden of predicted loss-of-function variants in KLHDC7B (OR = 2.14, P = 5.2 × 10−30). We also observed single-variant and gene-burden associations with 11 genes known to cause Mendelian forms of hearing loss, including an increased risk in heterozygous carriers of mutations in the autosomal recessive hearing loss genes GJB2 (Gly12fs; OR = 1.21, P = 4.2 × 10−11) and SLC26A5 (gene burden; OR = 1.96, P = 2.8 × 10−17). Our results suggest that loss of KLHDC7B function increases risk for hearing loss, and show that Mendelian hearing loss genes contribute to the burden of hearing loss in the adult population, suggesting a shared etiology between common and rare forms of hearing loss. This work illustrates the potential of large-scale exome sequencing to elucidate the genetic architecture of common traits in which risk is modulated by both common and rare variation.
Published: 2021

21. Genetic and Functional Characterization of ANGPTL7 as a Therapeutic Target for Glaucoma

Author: Scott Waldron, Alexander H. Li, Joan O'Brien, Katia Karalis, Stefanie Lefebvre, Gaurang Patel, Silvio Alessandro Di Gioia, Kristi Krebs, Hua Yang, Dadong Li, Ariane Ayer, Wen Fury, Ying Hu, Eric Jorgenson, James McIninch, Olle Melander, Giusy Della Gatta, Trikaladarshi Persaud, Ben Michael Brumpton, Claudia Schurmann, Stefan Stender, Eli A. Stahl, Michael N. Cantor, Venkata Gudiseva, Aris Baras, Marcus B. Jones, Dylan Sun, Jonathan Weyne, Manuel A. R. Ferreira, Tavé van Zyl, Lauren Gurski, Rebecca Salowe, Esteban Chen, Sarah Hyde, Gonçalo R. Abecasis, Kavita Praveen, Anne Tybjærg-Hansen, Giovanni Coppola, Matthew Still, Venkata Chavali, Tanya M. Teslovich, Lili Milani, Aris N. Economides, Sabrina Walley, Sarthak Zaveri, Kristian Hveem, Jeremey Rabinowitz, Carmelo Romano, Lawrence Miloscio, Bjørn Olav Åsvold, Brijeshkumar Patel, Cristen J. Willer, Anne-Sofie Seidelin, and George D. Yancopoulos
Subjects: genetic structures, business.industry, medicine, Glaucoma, sense organs, Computational biology, medicine.disease, business, eye diseases
Abstract: Glaucoma is a leading cause of blindness. Current glaucoma medications work by lowering intraocular pressure (IOP), a risk factor for glaucoma, but most treatments do not directly target the pathological changes leading to increased IOP, which can manifest as medication resistance as disease progresses. To identify physiological modulators of IOP, we performed genome- and exome-wide association analysis in >129,000 individuals with IOP measurements and extended these findings to an analysis of glaucoma risk. We report the identification and functional characterization of rare coding variants (including loss-of-function variants) in ANGPTL7 associated with reduction in IOP and glaucoma protection. We validated the human genetics findings in mice by establishing that Angptl7 knockout mice have lower (~2 mmHg) basal IOP compared to wild-type, with a trend towards lower IOP also in heterozygotes. Conversely, increasing mAngptl7 levels via injection into mouse eyes increases the IOP. We also show that acute gene silencing via siRNA knockdown of Angptl7 in adult mice lowers the IOP (~2-4 mmHg), reproducing the observations in knockout mice. Collectively, our data suggest that ANGPTL7 is important for IOP homeostasis and is amenable to therapeutic modulation to help maintain a healthy IOP that can prevent onset or slow the progression of glaucoma.
Published: 2021

22. Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder

Author: Arianna DiFlorio, Patrick F. Sullivan, Sebastian Zöllner, Margarita Rivera, Richard M. Myers, Stanley J. Watson, Jun Li, Anders Juréus, Sarah E. Bergen, Gonçalo R. Abecasis, Jordan W. Smoller, Michael Conlon O'Donovan, Neil Risch, Hoang T. Nguyen, Chen Jiang, Xiaoming Jia, Mehdi Pirooznia, Danielle Posthuma, Adam E. Locke, Peter P. Zandi, John B. Vincent, Niamh Mullins, Duncan Palmer, Shaun Purcell, Gerome Breen, Christina M. Hultman, Andreas Reif, Khanh K. Thai, Virginia L. Willour, Pui-Yan Kwok, Laura J. Scott, Anne U. Jackson, Michael John Owen, Fernando S. Goes, Steven A. McCarroll, James B. Potash, Mikael Landén, Jennifer L. Moran, Michele T. Pato, Hyun Min Kang, Marco P. Boks, Sinéad B. Chapman, W. Richard McCombie, Janet L. Sobell, Matthew Zawistowski, Rolf Adolfsson, Yongwen Zhuang, Michael Boehnke, René S. Kahn, Huda Akil, James T.R. Walters, Margit Burmeister, Douglas Blackwood, Cathryn M. Lewis, Eli A. Stahl, Mark N. Kvale, Melissa DelaBastide, Catherine Schaefer, Benjamin M. Neale, Giulio Genovese, Carlos N. Pato, Nicholas John Craddock, Andrew McQuillin, Shawn Levy, Aiden Corvin, Pamela Sklar, Weiqing Wang, Andrew M. McIntosh, Ling Shen, Eric T. Monson, Derek W. Morris, Douglas M. Ruderfer, Roel A. Ophoff, Peter McGuffin, Sarah Cohen-Woods, Willem H. Ouwehand, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Goes, Fernando S [0000-0001-6262-8264], Locke, Adam E [0000-0001-6227-198X], Palmer, Duncan [0000-0002-0824-0047], Wang, Weiqing [0000-0003-1565-0148], Genovese, Giulio [0000-0003-3066-5575], Jackson, Anne U [0000-0002-9672-2547], Nguyen, Hoang [0000-0001-6910-7269], Pirooznia, Mehdi [0000-0002-4210-6458], Zawistowski, Matthew [0000-0002-3005-083X], Abecasis, Gonçalo [0000-0003-1509-1825], Bergen, Sarah [0000-0002-5888-0034], Burmeister, Margit [0000-0002-1914-2434], Kwok, Pui-Yan [0000-0002-5087-3059], Li, Jun Z [0000-0001-6727-0812], Levy, Shawn E [0000-0002-1369-5740], Watson, Stanley [0000-0003-4980-5523], Blackwood, Douglas [0000-0002-4076-9346], Boehnke, Michael [0000-0002-6442-7754], Breen, Gerome [0000-0003-2053-1792], Landen, Mikael [0000-0002-4496-6451], Lewis, Cathryn [0000-0002-8249-8476], McCarroll, Steven A [0000-0002-6954-8184], McIntosh, Andrew [0000-0002-0198-4588], McQuillin, Andrew [0000-0003-1567-2240], Morris, Derek [0000-0002-3413-570X], O'Donovan, Michael [0000-0001-7073-2379], Boks, Marco [0000-0001-6163-7484], Kahn, Rene [0000-0001-5909-8004], Ouwehand, Willem [0000-0002-7744-1790], Owen, Michael [0000-0003-4798-0862], Potash, James B [0000-0002-5802-8079], Reif, Andreas [0000-0002-0992-634X], Vincent, John [0000-0003-0692-2519], Neale, Benjamin [0000-0003-1513-6077], Purcell, Shaun [0000-0002-7402-5812], Schaefer, Catherine [0000-0003-2644-055X], Stahl, Eli A [0000-0002-1192-0561], Zandi, Peter P [0000-0001-8423-2623], Scott, Laura J [0000-0002-4886-5084], Apollo - University of Cambridge Repository, Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and APH - Digital Health
Subjects: Bipolar Disorder, Genome-wide association study, Biology, Medical and Health Sciences, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Clinical Research, Genetic variation, medicine, Genetics, 2.1 Biological and endogenous factors, Humans, Exome, Genetic Predisposition to Disease, Bipolar disorder, Polymorphism, Molecular Biology, Gene, 030304 developmental biology, Medicinsk genetik, Psychiatry, 0303 health sciences, Prevention, Human Genome, Psychology and Cognitive Sciences, Genetic Variation, Single Nucleotide, Heritability, Biological Sciences, medicine.disease, Serious Mental Illness, Phenotype, 3. Good health, Brain Disorders, Psychiatry and Mental health, Mental Health, Schizophrenia, Medical Genetics, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3–2.8, one-sided p = 6.0 × 10−4), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ., International Bipolar Sequencing Consortium (NIMH) R01 MH 110437, Whole Genome Sequencing for Schizophrenia and Biopolar Disorder in the GPS (NIMH) UO1 MH105653, Whole Genome and Exome Sequencing for Bipolar Disorder (NIMH) R01 MH 094145, Multi-ethnic GWAS of Bipolar I Disorder (NIH) R01 MH 085543, Genetic Epidemiology Research in Adult Health and Aging (GERA) RC2 AG036607, Kaiser Permanente Research Program on Genes, Environment, and Health, Rare Bipolar Loci Identification Through Synaptome Sequencing (NIMH) R01 MH 087979 MH 087992, 2/2 Large Scale Genetic Studies of Schizophrenia in Sweden R01MH095034, 1/3 Genetic Analysis of the International Cohort Collection for Bipolar Disorder R01MH106531, 1/2 Large Scale Genetic Studies of Schizophrenia in Sweden R01MH077139, 2/3 Genetic Analysis of the International Cohort Collection for Bipolar Disorder R01MH106527, Dalio Foundation
Published: 2021

23. Contributions of common genetic variants to risk of schizophrenia among individuals of African and Latino ancestry

Author: António Macedo, Patrick F. Sullivan, Pamela Sklar, Diana O. Perkins, David L. Braff, Eric D. Achtyes, Roman Kotov, Eli A. Stahl, Maria Helena Pinto de Azevedo, Colm O'Dushlaine, Elizabeth Bevilacqua, Célia Barreto Carvalho, Marquis P. Vawter, James Nemesh, Edward M. Scolnick, Jacquelyn L. Meyers, Jorge Valderrama, Shaun Purcell, Becky Kinkead, Douglas S. Lehrer, Peter F. Buckley, William Byerley, Humberto Nicolini, Fabio Macciardi, James L. Kennedy, Michael Escamilla, Ruben C. Gur, Dolores Malaspina, Ashley Dumont, Giulio Genovese, Helena Medeiros, Penelope Georgakopoulos, Colony Abbott, Diane Gage, Carlos N. Pato, Brooke M. Sklar, Roseann E. Peterson, Jordan W. Smoller, Steven A. McCarroll, Raquel E. Gur, Ayman H. Fanous, Laura J. Fochtmann, Stephen R. Marder, Sinéad B. Chapman, Mark Hyman Rapaport, James A. Knowles, Michele T. Pato, Janet L. Sobell, Evelyn J. Bromet, Conrad Iyegbe, Lynn E DeLisi, Jeffrey J. Rakofsky, Oleg V. Evgrafov, Jennifer L. Moran, Christopher P. Morley, Tim B. Bigdeli, Richard A. Belliveau, and Mantosh J. Dewan
Subjects: Male, 0301 basic medicine, Linkage disequilibrium, Population, Black People, Genomics, Biology, Polymorphism, Single Nucleotide, Article, European descent, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Genetics, Humans, Genetic Predisposition to Disease, education, Molecular Biology, Genetic association, education.field_of_study, Genetic variants, Hispanic or Latino, Heritability, Psychiatry and Mental health, 030104 developmental biology, Genetic Loci, Schizophrenia, Etiology, Female, 030217 neurology & neurosurgery, Genome-Wide Association Study, Demography
Abstract: Schizophrenia is a common, chronic and debilitating neuropsychiatric syndrome affecting tens of millions of individuals worldwide. While rare genetic variants play a role in the etiology of schizophrenia, most of the currently explained liability is within common variation, suggesting that variation predating the human diaspora out of Africa harbors a large fraction of the common variant attributable heritability. However, common variant association studies in schizophrenia have concentrated mainly on cohorts of European descent. We describe genome-wide association studies of 6152 cases and 3918 controls of admixed African ancestry, and of 1234 cases and 3090 controls of Latino ancestry, representing the largest such study in these populations to date. Combining results from the samples with African ancestry with summary statistics from the Psychiatric Genomics Consortium (PGC) study of schizophrenia yielded seven newly genome-wide significant loci, and we identified an additional eight loci by incorporating the results from samples with Latino ancestry. Leveraging population differences in patterns of linkage disequilibrium, we achieve improved fine-mapping resolution at 22 previously reported and 4 newly significant loci. Polygenic risk score profiling revealed improved prediction based on trans-ancestry meta-analysis results for admixed African (Nagelkerke’s R2 = 0.032; liability R2 = 0.017; P −52), Latino (Nagelkerke’s R2 = 0.089; liability R2 = 0.021; P −58), and European individuals (Nagelkerke’s R2 = 0.089; liability R2 = 0.037; P −113), further highlighting the advantages of incorporating data from diverse human populations.
Published: 2019

24. Genome-wide Association Studies in Ancestrally Diverse Populations: Opportunities, Methods, Pitfalls, and Recommendations

Author: Jacquelyn L. Meyers, Laramie E. Duncan, Leslie A. Brick, Roseann E. Peterson, Jinni Su, Max Lam, Eli A. Stahl, Howard J. Edenberg, Sathish Periyasamy, Caitlin E. Carey, Chia-Yen Chen, Raymond K. Walters, Emanuel Schwarz, Tim B. Bigdeli, Conrad Iyegbe, Miguel L. Prieto, Nastassja Koen, Alfredo B. Cuellar-Barboza, Allan Kalungi, Patrick F. Sullivan, Alice B. Popejoy, Rona J. Strawbridge, Evangelos Vassos, Alicia R. Martin, Lerato Majara, Bryan J. Mowry, Hailiang Huang, Jordan W. Smoller, Junfang Chen, Karoline Kuchenbaecker, and Alexis C. Edwards
Subjects: Genotyping Techniques, media_common.quotation_subject, Population genetics, Genome-wide association study, Biology, Article, General Biochemistry, Genetics and Molecular Biology, European descent, 03 medical and health sciences, 0302 clinical medicine, Humans, 030304 developmental biology, Genetic association, media_common, 0303 health sciences, Genetic Variation, Genetic data, Human Genetics, Data science, Toolbox, Genetic architecture, Data Accuracy, Pedigree, Genetics, Population, human activities, 030217 neurology & neurosurgery, Genome-Wide Association Study, Diversity (politics)
Abstract: Genome-wide association studies (GWASs) have focused primarily on populations of European descent, but it is essential that diverse populations become better represented. Increasing diversity among study participants will advance our understanding of genetic architecture in all populations and ensure that genetic research is broadly applicable. To facilitate and promote research in multi-ancestry and admixed cohorts, we outline key methodological considerations and highlight opportunities, challenges, solutions, and areas in need of development. Despite the perception that analyzing genetic data from diverse populations is difficult, it is scientifically and ethically imperative, and there is an expanding analytical toolbox to do it well.
Published: 2019

25. Synergistic effects of common schizophrenia risk variants

Author: Esther Cheng, Erin Flaherty, Gabriel E. Hoffman, Marliette R. Matos, Amanda Dobbyn, Vineeta Singh, Deeptha Girish, Eli A. Stahl, Hirofumi Morishita, Laura M. Huckins, Seok-Man Ho, Emily Hoelzli, Sonya Abadali, Robert E. McCullumsmith, Pamela Sklar, Kazuhiko Yamamuro, Aaron Topol, Hemali Phatnani, Khaled Alganem, P J Michael Deans, Nadine Schrode, Bruce J. Aronow, James Gardner Gregory, Natalie Barretto, and Kristen J. Brennand
Subjects: Male, Induced Pluripotent Stem Cells, Quantitative Trait Loci, Genome-wide association study, Computational biology, Quantitative trait locus, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Genome editing, Chloride Channels, Gene expression, Genetics, Humans, Genetic Predisposition to Disease, Furin, Gene, 030304 developmental biology, Regulation of gene expression, Gene Editing, 0303 health sciences, Binding Sites, biology, Gene Expression Regulation, Monomeric Clathrin Assembly Proteins, Expression quantitative trait loci, biology.protein, Schizophrenia, Female, CRISPR-Cas Systems, SNARE Proteins, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: The mechanisms by which common risk variants of small effect interact to contribute to complex genetic disorders remain unclear. Here, we apply a genetic approach, using isogenic human induced pluripotent stem cells (hiPSCs), to evaluate the effects of schizophrenia-associated common variants predicted to function as brain expression quantitative trait loci (SZ-eQTLs). By integrating CRISPR-mediated gene editing, activation and repression technologies to study one putative SZ-eQTL (FURIN rs4702) and four top-ranked SZ-eQTL genes (FURIN, SNAP91, TSNARE1, CLCN3), our platform resolves pre- and post-synaptic neuronal deficits, recapitulates genotype-dependent gene expression differences, and identifies convergence downstream of SZ-eQTL gene perturbations. Our observations highlight the cell-type-specific effects of common variants and demonstrate a synergistic effect between SZ-eQTL genes that converges on synaptic function. We propose that the links between rare and common variants implicated in psychiatric disease risk constitute a potentially generalizable phenomenon occurring more widely in complex genetic disorders.
Published: 2019

26. Characterization of Age and Polarity at Onset in Bipolar Disorder

Author: Aiden Corvin, Maria Grigoroiu-Serbanescu, Mark Hyman Rapaport, Frederike T. Fellendorf, Urs Heilbronner, Mariam M. Al Eissa, John J Nurnberger, Claire O'Donovan, Claire Slaney, Mark A. Frye, Niamh L. O'Brien, Roland Hasler, Michael John Owen, Michael Conlon O'Donovan, Farah Klöhn-Saghatolislam, Markus M. Nöthen, Scott R. Clark, Mikael Landén, Lina Jonsson, Peter Falkai, Qingqin S. Li, Alessio Squassina, Simon Schmitt, Gustavo Turecki, Heike Anderson-Schmidt, Jonathan Repple, Sofie R. Aminoff, Eduard Vieta, Katherine Gordon-Smith, Stéphane Jamain, William Byerley, Hélène Richard-Lepouriel, Fermín Mayoral, Francis J. McMahon, Marin Veldic, Ingrid Melle, Andrew McQuillin, Nicholas Bass, Gloria Roberts, Douglas M. Ruderfer, John B. Vincent, Nelson B. Freimer, Kirov George, Wei Xu, Susan L. McElroy, Ceylan Balaban, Marco P. Boks, Franziska Degenhardt, Paul E. Croarkin, Wade H. Berrettini, Piotr M. Czerski, Fernando S. Goes, Peter P. Zandi, Sabrina K. Schaupp, Barbara W. Schweizer, Andrew M. McIntosh, Marcella Rietschel, Helena Pelin, Evelyn J. Bromet, Marion Leboyer, Ole A. Andreassen, Georgia Panagiotaropoulou, Alessia Fiorentino, Sally I. Sharp, Torbjørn Elvsåshagen, Kristina Adorjan, Monika Budde, Lisa Jones, Thomas G. Schulze, Vihra Milanova, Janos Kalman, Tim B. Bigdeli, Esther Jiménez, Abigail Ortiz, Dolores Malaspina, Kevin S. O’Connell, Sergi Papiol, Mario Maj, Tim Hahn, Frederike Stein, Jordan W. Smoller, Tomas Novak, Katrin Gade, J. Raymond DePaulo, Sarah Kittel-Schneider, Julia-Katharina Pfarr, Martin Alda, James A. Knowles, Sven Cichon, David Craig, Eli A. Stahl, William A. Scheftner, Bruno Etain, Annabel Vreeker, Guy A. Rouleau, Stephan Ripke, Clement C. Zai, Frank Bellivier, Giovanni Severino, Palmiero Monteleone, Ian Jones, Bertram Müller-Myhsok, Mark Adams, John Strauss, Philip B. Mitchell, Andreas Reif, Fabian Streit, Roel A. Ophoff, James L. Kennedy, Nils Opel, Raffaella Ardau, Paul Grof, Peter R. Schofield, Susanne Bengesser, Maria Hake, Loes M. Olde Loohuis, Joanna Pawlak, Daniela Reich-Erkelenz, Ingrid Agartz, Maria Del Zompo, Antonio Benabarre, Bernhard T. Baune, Arianna Di Florio, Ashley L. Comes, Michael Gill, Cristiana Cruceanu, Susanne Meinert, William Coryell, Alessio Maria Monteleone, Fanny Senner, Trine Vik Lagerberg, Jose Guzman-Parra, Erik Pålsson, Elliot S. Gershon, Melvin G. McInnis, Pavla Stopkova, Nikolaos Koutsouleris, René S. Kahn, Janice M. Fullerton, Howard J. Edenberg, Tilo Kircher, Nina Dalkner, Udo Dannlowski, Rolf Adolfsson, Alfonso Tortorella, Jean-Michel Aubry, James B. Potash, Catina Chillotti, Eva Z. Reininghaus, Janet L. Sobell, Thorsten M. Kranz, Tina Meller, Ayman H. Fanous, Kai Ringwald, K Oliver Schubert, Andreas J. Forstner, Till F. M. Andlauer, Helena Medeiros, Mirko Manchia, Joanna M. Biernacka, Katharina Brosch, Julie Garnham, Olav B. Smeland, Eva C. Schulte, Carlos N. Pato, Nicholas John Craddock, Srdjan Djurovic, Pablo Cervantes, Michele T. Pato, John R. Kelsoe, Claudia Pisanu, Joanna Twarowska-Hauser, and William Lawson
Subjects: 0303 health sciences, medicine.medical_specialty, business.industry, Genome-wide association study, Disease, Heritability, medicine.disease, Genetic architecture, 03 medical and health sciences, 0302 clinical medicine, Autism spectrum disorder, Schizophrenia, Internal medicine, medicine, Bipolar disorder, business, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract: BackgroundStudying the phenotypic and genetic characteristics of age and polarity at onset (AAO, PAO) in bipolar disorder (BD) can provide new insights into disease pathology and facilitate the development of screening tools.AimsTo examine the genetic architecture of AAO and PAO and their association with BD disease characteristics.MethodsGenome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (N=12977) and PAO (N=6773) were conducted in BD patients of 34 cohorts and a replication sample (N=2237). The association of onset with disease characteristics was investigated in two of these cohorts.ResultsEarlier AAO was associated with an increased risk of psychotic symptoms, suicidality, and fewer episodes. A depressive onset correlated with lifetime suicidality and a manic onset with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in SNV-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased polygenic scores for autism spectrum disorder (β=-0.34 years, SE=0.08), major depression (β=-0.34 years, SE=0.08), schizophrenia (β=-0.39 years, SE=0.08), and educational attainment (β=-0.31 years, SE=0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.ConclusionsAAO and PAO are associated with indicators of BD severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents, and phenotype definitions introduce significant heterogeneity, affecting analyses.RELEVANCE STATEMENTIn the largest study to systematically characterize age at onset (N=12977) and polarity at onset (N=6773) in bipolar disorder, we describe an association between illness onset characteristics and indicators of severity, confirming their clinical relevance. Our study shows that that early illness onset is associated with genetic liability for a broad range of psychiatric disorders. However, we also highlight systematic differences in age at onset across cohorts, continents, and phenotype definitions. This heterogeneity results in reduced heritability and affects genetic analyses, underscoring the need for the development of standardized phenotype definitions.
Published: 2021

27. Exome sequencing in bipolar disorder reveals shared risk geneAKAP11with schizophrenia

Author: Matthew Solomonson, Michael Conlon O'Donovan, Nancy L. Pedersen, Faith Dickerson, Eli A. Stahl, Neil Risch, Catherine Schaefer, Laura J. Scott, René S. Kahn, Duncan S. Palmer, Derek W. Morris, Claire Churchhouse, Xiaoming Jia, James T.R. Walters, Andrew M. McIntosh, Chia-Yen Chen, Michael John Owen, Arianna Di Florio, Lina Jonsson, Benjamin M. Neale, Roel A. Ophoff, Annabel Vreeker, Tarjinder Singh, Douglas Blackwood, Nicholas John Craddock, Jordan W. Smoller, Ian Jones, Weiqing Wang, Peter P. Zandi, Marco P. Boks, Fernando S. Goes, Lisa Jones, Robert H. Yolken, Mikael Landén, David Curtis, Danielle Posthuma, Andreas Reif, David St Clair, Sinéad B. Chapman, Nicholas A. Watts, Rolf Adolfsson, Adam E. Locke, Aiden Corvin, Nick Bass, Daniel P. Howrigan, and Andrew McQuillin
Subjects: Genetics, business.industry, Schizophrenia, Medicine, Risk gene, Genome-wide association study, Bipolar disorder, business, medicine.disease, Exome, Gene, GSK3B, Exome sequencing
Abstract: Here we report results from the Bipolar Exome (BipEx) collaboration analysis of whole exome sequencing of 13,933 individuals diagnosed with bipolar disorder (BD), matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in BD patients among genes under strong evolutionary constraint, a signal evident in both major BD subtypes, bipolar 1 disorder (BD1) and bipolar 2 disorder (BD2). We also find an excess of ultra-rare PTVs within genes implicated from a recent schizophrenia exome meta-analysis (SCHEMA; 24,248 SCZ cases and 97,322 controls) and among binding targets of CHD8. Genes implicated from GWAS of BD, however, are not significantly enriched for ultra-rare PTVs. Combining BD gene-level results with SCHEMA,AKAP11emerges as a definitive risk gene (ultra-rare PTVs seen in 33 cases and 13 controls, OR = 7.06,P= 2.83 × 10−9). At the protein level, AKAP-11 is known to interact with GSK3B, the hypothesized mechanism of action for lithium, one of the few treatments for BD. Overall, our results lend further support to the polygenic basis of BD and demonstrate a role for rare coding variation as a significant risk factor in BD onset.
Published: 2021

28. 50. IDENTIFICATION OF MOLECULAR RELATIONSHIPS BETWEEN LIVING AND POST-MORTEM BRAIN TISSUE

Author: Eli A. Stahl, Brian H. Kopell, Julie Park, Pamela Sklar, Eric E. Schadt, Jaroslav Bendl, Claudia Feng, Alexander W. Charney, Gabriel E. Hoffman, Lora Liharska, Noam D. Beckmann, and Panos Roussos
Subjects: Pharmacology, Psychiatry and Mental health, Pathology, medicine.medical_specialty, Neurology, business.industry, Medicine, Pharmacology (medical), Identification (biology), Neurology (clinical), business, Post mortem brain, Biological Psychiatry
Published: 2021

29. 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

30. Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology

Author: James McKay, Frank Bellivier, Mark A. Frye, Bertram Müller-Myhsok, Fermín Mayoral, I. Nicol Ferrier, Marion Leboyer, Fabian Streit, Dan J. Stein, James L. Kennedy, Christine Søholm Hansen, Scott D. Gordon, Beata Świątkowska, Valentina Escott-Price, Michael Bauer, Lina Martinsson, Donald J. MacIntyre, Oleksandr Frei, Daniel J. Smith, Sara A. Paciga, Takeo Saito, Jennifer L. Moran, Verneri Antilla, C Pantelis, Tomas Olsson, Swapnil Awasthi, Lena Backlund, Eirini Maratou, Martin Schalling, John B. Vincent, Niamh Mullins, Sarah E. Bergen, Niamh L. O'Brien, Marco P. Boks, Carsten Bøcker Pedersen, Mikael Landén, Franziska Degenhardt, Hang Zhou, Margarita Rivera, Andrew M. McIntosh, Manuel Mattheisen, Shawn Levy, Roy H. Perlis, John P. Rice, Sigurdur H. Magnusson, Amanda Dobbyn, Michael Conlon O'Donovan, Julien Bryois, Wolfgang Maier, John-Anker Zwart, J. Raymond DePaulo, Martin Alda, Laura G. Sloofman, Friederike Sophie David, James A. Knowles, Aiden Corvin, Thomas G. Schulze, Markus M. Nöthen, Nolan Kamitaki, Nina Dalkner, Brandon J. Coombes, Gustavo Turecki, Allan H. Young, Caroline M. Nievergelt, Patricia T. Michie, Ingrid Agartz, Towfique Raj, Diego Albani, Maria Grigoroiu-Serbanescu, Bernhard T. Baune, Kyooseob Ha, Vincent Millischer, Engilbert Sigurdsson, Eva C. Beins, Nicholas G. Martin, Gulja Babadjanova, Josef Frank, Eva Z. Reininghaus, Patrick F. Sullivan, Ian R. Gizer, Guy A. Rouleau, Carmel M. Loughland, Christine Lochner, Thorsten M. Kranz, Amy Perry, Arne E. Vaaler, Mariam M. Al Eissa, Simon Xi, Claire O'Donovan, Josep Antoni Ramos-Quiroga, Ketil J. Oedegaard, Helmut Vedder, Carol A. Mathews, Panagiotis Ferentinos, Tim B. Bigdeli, Derek W. Morris, Per Hoffmann, Mark Hyman Rapaport, Peter P. Zandi, Michael John Owen, Douglas M. Ruderfer, Anders D. Børglum, Catharina Lavebratt, Thorgeir E. Thorgeirsson, Paul A. Tooney, Michiaki Kubo, Steven A. Kushner, Jan Hillert, Loes M. Olde Loohuis, Anastasia Antoniou, Murielle Brum, Chikashi Terao, Nathaniel W. McGregor, Fabio Rivas, James B. Potash, Kevin S. O’Connell, Susanne Lucae, Brian M. Schilder, Katrin Gade, Stephan Ripke, Kristina Adorjan, Kari Stefansson, Tiffany A. Greenwood, Panos Roussos, Sarah Kittel-Schneider, Steven A. McCarroll, Sergi Papiol, Heon Jeong Lee, Assen Jablensky, Liliya Abramova, Dennis Hellgren, Jonas Bybjerg-Grauholm, Martin Lundberg, Hong-Hee Won, William Byerley, Lars Alfredsson, Joel Gelernter, Andrew McQuillin, Claire Slaney, Marta Ribasés, Stephanie H. Witt, Yoichiro Kamatani, Kyung Sue Hong, Marie Bækvad-Hansen, María Soler Artigas, Julie M. Cunningham, Fanny Senner, Stacy Steinberg, Paul D. Shilling, Nakao Iwata, Eystein Stordal, Armin Birner, Sarah E. Medland, Miquel Casas, Ben Michael Brumpton, Erlend Bøen, Bryan J. Mowry, Jolanta Lissowska, Francis J. McMahon, Howard J. Edenberg, Grant W. Montgomery, John I. Nurnberger, Stéphane Jamain, Claudio Toma, Ney Alliey-Rodriguez, Ole Mors, Micha Gawlik, David Curtis, Catrin Lewis, Evangelia-Eirini Tsermpini, Georgia Panagiotaropoulou, Marcella Rietschel, Jessica Yang, Ian Jones, Eduard Vieta, Ole A. Andreassen, Richard M. Myers, Dimitris Dikeos, Melissa J. Green, Janet L. Sobell, Maria Koromina, Piotr M. Czerski, Lilijana Oruc, Sven Cichon, Udo Dannlowski, Bruno Etain, Monika Budde, Alessia Fiorentino, Naomi R. Wray, Qingqin S. Li, Murray J. Cairns, Jonathan R. I. Coleman, Jose Guzman-Parra, Andreas J. Forstner, Hannah Young, Alfredo B. Cuellar-Barboza, Julian Roth, Torbjørn Elvsåshagen, Zhen Qiao, Thomas Werge, Athanassios Douzenis, Cristiana Cruceanu, Rolf Adolfsson, Peter Holmans, Vaughan J. Carr, Thomas W. Weickert, Masashi Ikeda, Joanna M. Biernacka, Lea Sirignano, Adam X. Maihofer, Ralph W. Kupka, John Strauss, Anders M. Dale, Elliot S. Gershon, Jakob Grove, Arianna Di Florio, Helena Medeiros, Ingrid Melle, Preben Bo Mortensen, Kristi Krebs, Saskia P. Hagenaars, Liz Forty, Stanley V. Catts, David M. Hougaard, Marianne Giørtz Pedersen, Andreas Reif, Toni-Kim Clarke, Anne T. Spijker, Danielle Posthuma, Manolis Kogevinas, Michael Boehnke, Rosa Bosch, Gerome Breen, Benjamin M. Neale, Jessica S. Johnson, Katherine Gordon-Smith, Cristina Sánchez-Mora, Alexander W. Charney, Henry R. Kranzler, Digby Quested, René S. Kahn, Lili Milani, Merete Nordentoft, Nathalie Brunkhorst-Kanaan, Laura M. Huckins, James T.R. Walters, Sigrid Børte, Antonio F. Pardiñas, Kristian Hveem, Julie Garnham, Jacob Lawrence, Vassily Trubetskoy, Rodney J. Scott, Nicholas Bass, Carlos N. Pato, Andrea Pfennig, Wei Xu, Calwing Liao, Nicholas John Craddock, Thomas Damm Als, Christina M. Hultman, Fernando S. Goes, Adebayo Anjorin, Evgenia Porichi, Frans Henskens, Nelson B. Freimer, Janice M. Fullerton, Cathryn M. Lewis, Srdjan Djurovic, Roel A. Ophoff, Phil Lee, Peter McGuffin, Gunnar Morken, George P. Patrinos, Alessandro Serretti, Cynthia Shannon Weickert, Pablo Cervantes, Bendik S. Winsvold, Tatiana Foroud, Tõnu Esko, Ulrich Schall, Michele T. Pato, Ji Hyun Baek, John R. Kelsoe, Olav B. Smeland, Janos Kalman, Eva C. Schulte, Joanna Hauser, Urs Heilbronner, Magnús Haraldsson, Martin Hautzinger, Lea Zillich, Eline J. Regeer, Douglas Blackwood, Laura J. Scott, Jordan W. Smoller, Michael J. Gandal, Marquis P. Vawter, Philip B. Mitchell, Ole Kristian Drange, Peter R. Schofield, Susanne Bengesser, Stefan Herms, George Kirov, Markus Leber, Louise Frisén, Thomas W. Mühleisen, Susan L. McElroy, Irwin D. Waldman, Wade H. Berrettini, Sally I. Sharp, Minsoo Kim, Lisa Jones, Eli A. Stahl, Hreinn Stefansson, Esben Agerbo, Dolores Malaspina, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), APH - Digital Health, Mullins N., Forstner A.J., O'Connell K.S., Coombes B., Coleman J.R.I., Qiao Z., Als T.D., Bigdeli T.B., Borte S., Bryois J., Charney A.W., Drange O.K., Gandal M.J., Hagenaars S.P., Ikeda M., Kamitaki N., Kim M., Krebs K., Panagiotaropoulou G., Schilder B.M., Sloofman L.G., Steinberg S., Trubetskoy V., Winsvold B.S., Won H.-H., Abramova L., Adorjan K., Agerbo E., Al Eissa M., Albani D., Alliey-Rodriguez N., Anjorin A., Antilla V., Antoniou A., Awasthi S., Baek J.H., Baekvad-Hansen M., Bass N., Bauer M., Beins E.C., Bergen S.E., Birner A., Bocker Pedersen C., Boen E., Boks M.P., Bosch R., Brum M., Brumpton B.M., Brunkhorst-Kanaan N., Budde M., Bybjerg-Grauholm J., Byerley W., Cairns M., Casas M., Cervantes P., Clarke T.-K., Cruceanu C., Cuellar-Barboza A., Cunningham J., Curtis D., Czerski P.M., Dale A.M., Dalkner N., David F.S., Degenhardt F., Djurovic S., Dobbyn A.L., Douzenis A., Elvsashagen T., Escott-Price V., Ferrier I.N., Fiorentino A., Foroud T.M., Forty L., Frank J., Frei O., Freimer N.B., Frisen L., Gade K., Garnham J., Gelernter J., Giortz Pedersen M., Gizer I.R., Gordon S.D., Gordon-Smith K., Greenwood T.A., Grove J., Guzman-Parra J., Ha K., Haraldsson M., Hautzinger M., Heilbronner U., Hellgren D., Herms S., Hoffmann P., Holmans P.A., Huckins L., Jamain S., Johnson J.S., Kalman J.L., Kamatani Y., Kennedy J.L., Kittel-Schneider S., Knowles J.A., Kogevinas M., Koromina M., Kranz T.M., Kranzler H.R., Kubo M., Kupka R., Kushner S.A., Lavebratt C., Lawrence J., Leber M., Lee H.-J., Lee P.H., Levy S.E., Lewis C., Liao C., Lucae S., Lundberg M., MacIntyre D.J., Magnusson S.H., Maier W., Maihofer A., Malaspina D., Maratou E., Martinsson L., Mattheisen M., McCarroll S.A., McGregor N.W., McGuffin P., McKay J.D., Medeiros H., Medland S.E., Millischer V., Montgomery G.W., Moran J.L., Morris D.W., Muhleisen T.W., O'Brien N., O'Donovan C., Olde Loohuis L.M., Oruc L., Papiol S., Pardinas A.F., Perry A., Pfennig A., Porichi E., Potash J.B., Quested D., Raj T., Rapaport M.H., DePaulo J.R., Regeer E.J., Rice J.P., Rivas F., Rivera M., Roth J., Roussos P., Ruderfer D.M., Sanchez-Mora C., Schulte E.C., Senner F., Sharp S., Shilling P.D., Sigurdsson E., Sirignano L., Slaney C., Smeland O.B., Smith D.J., Sobell J.L., Soholm Hansen C., Soler Artigas M., Spijker A.T., Stein D.J., Strauss J.S., Swiatkowska B., Terao C., Thorgeirsson T.E., Toma C., Tooney P., Tsermpini E.-E., Vawter M.P., Vedder H., Walters J.T.R., Witt S.H., Xi S., Xu W., Yang J.M.K., Young A.H., Young H., Zandi P.P., Zhou H., Zillich L., Adolfsson R., Agartz I., Alda M., Alfredsson L., Babadjanova G., Backlund L., Baune B.T., Bellivier F., Bengesser S., Berrettini W.H., Blackwood D.H.R., Boehnke M., Borglum A.D., Breen G., Carr V.J., Catts S., Corvin A., Craddock N., Dannlowski U., Dikeos D., Esko T., Etain B., Ferentinos P., Frye M., Fullerton J.M., Gawlik M., Gershon E.S., Goes F.S., Green M.J., Grigoroiu-Serbanescu M., Hauser J., Henskens F., Hillert J., Hong K.S., Hougaard D.M., Hultman C.M., Hveem K., Iwata N., Jablensky A.V., Jones I., Jones L.A., Kahn R.S., Kelsoe J.R., Kirov G., Landen M., Leboyer M., Lewis C.M., Li Q.S., Lissowska J., Lochner C., Loughland C., Martin N.G., Mathews C.A., Mayoral F., McElroy S.L., McIntosh A.M., McMahon F.J., Melle I., Michie P., Milani L., Mitchell P.B., Morken G., Mors O., Mortensen P.B., Mowry B., Muller-Myhsok B., Myers R.M., Neale B.M., Nievergelt C.M., Nordentoft M., Nothen M.M., O'Donovan M.C., Oedegaard K.J., Olsson T., Owen M.J., Paciga S.A., Pantelis C., Pato C., Pato M.T., Patrinos G.P., Perlis R.H., Posthuma D., Ramos-Quiroga J.A., Reif A., Reininghaus E.Z., Ribases M., Rietschel M., Ripke S., Rouleau G.A., Saito T., Schall U., Schalling M., Schofield P.R., Schulze T.G., Scott L.J., Scott R.J., Serretti A., Shannon Weickert C., Smoller J.W., Stefansson H., Stefansson K., Stordal E., Streit F., Sullivan P.F., Turecki G., Vaaler A.E., Vieta E., Vincent J.B., Waldman I.D., Weickert T.W., Werge T., Wray N.R., Zwart J.-A., Biernacka J.M., Nurnberger J.I., Cichon S., Edenberg H.J., Stahl E.A., McQuillin A., Di Florio A., Ophoff R.A., Andreassen O.A., IMRB - 'Neuropsychiatrie translationnelle' [Créteil] (U955 Inserm - UPEC), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Etain, Bruno
Subjects: Multifactorial Inheritance, Bipolar Disorder, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Medizin, Genome-wide association study, Major Histocompatibility Complex/genetics, Major Histocompatibility Complex, 0302 clinical medicine, Risk Factors, MESH: Risk Factors, MESH: Bipolar Disorder, Chromosomes, Human, Spectrum disorder, Genetics, 0303 health sciences, Bipolar Disorder/genetics, MESH: Genetic Predisposition to Disease, MESH: Case-Control Studies, Phenotype, Schizophrenia, Synaptic signaling, Case-Control Studie, Human, Quantitative Trait Loci, Biology, MESH: Phenotype, MESH: Chromosomes, Human, Article, 03 medical and health sciences, MESH: Major Histocompatibility Complex, SDG 3 - Good Health and Well-being, ddc:570, medicine, Humans, Genetic Predisposition to Disease, Bipolar disorder, Multifactorial Inheritance/genetics, MESH: Genome, Human, 030304 developmental biology, MESH: Humans, Genome, Human, Risk Factor, Chromosomes, Human/genetics, Mental illness, medicine.disease, MESH: Quantitative Trait Loci, Human genetics, Psychologie, Case-Control Studies, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, MESH: Genome-Wide Association Study, Expression quantitative trait loci, MESH: Multifactorial Inheritance, Quantitative Trait Loci/genetics, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: International audience; Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
Published: 2021

31. Genome-wide analysis in 756,646 individuals provides first genetic evidence that ACE2 expression influences COVID-19 risk and yields genetic risk scores predictive of severe disease

Author: Marie V. Coignet, Dylan Sun, Lukas Habegger, Evan Maxwell, Daniel J. Rader, David J. Carey, Katherine A. Siminovitch, Giorgio Sirugo, Anne E. Justice, Joelle Mbatchou, Eli A. Stahl, Gonçalo R. Abecasis, Alexander H. Li, David A. Turissini, Adam E. Locke, Kristin A. Rand, Aris Baras, Joseph B. Leader, Genevieve H.L. Roberts, Ahna R. Girshick, Deepika Sharma, Nilanjana Banerjee, Fabricio S. P. Kury, John D. Overton, Shane McCarthy, Jonathan Marchini, Xiaodong Bai, Eurie L. Hong, Rouel Lanche, Amy Damask, Ashish Yadav, Raghavendran Partha, Shannon R. McCurdy, Miao Zhang, Suganthi Balasubramanian, Hyun Min Kang, Anurag Verma, Marcus B. Jones, Marylyn D. Ritchie, Colm O'Dushlaine, Manuel A. R. Ferreira, Adam J. Mansfield, Anthony Marcketta, Joshua D. Backman, Alan R. Shuldiner, Michael N. Cantor, Tooraj Mirshahi, Lee Dobbyn, Spencer C. Knight, William J Salerno, Harenda Guturu, Jeffrey G. Reid, Julie E. Horowitz, Lauren Gurski, Danny S. Park, Kyoko Watanabe, Catherine A. Ball, Asher K. Haug Baltzell, and Jack A. Kosmicki
Subjects: 2019-20 coronavirus outbreak, Increased risk, Coronavirus disease 2019 (COVID-19), business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Genetic variants, MEDLINE, Severe disease, Medicine, Bioinformatics, business
Abstract: SARS-CoV-2 enters host cells by binding angiotensin-converting enzyme 2 (ACE2). Through a genome-wide association study, we show that a rare variant (MAF = 0.3%, odds ratio 0.60, P=4.5x10-13) that down-regulates ACE2 expression reduces risk of COVID-19 disease, providing human genetics support for the hypothesis that ACE2 levels influence COVID-19 risk. Further, we show that common genetic variants define a risk score that predicts severe disease among COVID-19 cases.
Published: 2020

32. Genome-wide association study of over 40,000 bipolar disorder cases provides new insights into the underlying biology

Author: Niamh Mullins, Andreas J. Forstner, Kevin S. O’Connell, Brandon Coombes, Jonathan R. I. Coleman, Zhen Qiao, Thomas D. Als, Tim B. Bigdeli, Sigrid Børte, Julien Bryois, Alexander W. Charney, Ole Kristian Drange, Michael J. Gandal, Saskia P. Hagenaars, Masashi Ikeda, Nolan Kamitaki, Minsoo Kim, Kristi Krebs, Georgia Panagiotaropoulou, Brian M. Schilder, Laura G. Sloofman, Stacy Steinberg, Vassily Trubetskoy, Bendik S. Winsvold, Hong-Hee Won, Liliya Abramova, Kristina Adorjan, Esben Agerbo, Mariam Al Eissa, Diego Albani, Ney Alliey-Rodriguez, Adebayo Anjorin, Verneri Antilla, Anastasia Antoniou, Swapnil Awasthi, Ji Hyun Baek, Marie Bækvad-Hansen, Nicholas Bass, Michael Bauer, Eva C. Beins, Sarah E. Bergen, Armin Birner, Carsten Bøcker Pedersen, Erlend Bøen, Marco P. Boks, Rosa Bosch, Murielle Brum, Ben M. Brumpton, Nathalie Brunkhorst-Kanaan, Monika Budde, Jonas Bybjerg-Grauholm, William Byerley, Murray Cairns, Miquel Casas, Pablo Cervantes, Toni-Kim Clarke, Cristiana Cruceanu, Alfredo Cuellar-Barboza, Julie Cunningham, David Curtis, Piotr M. Czerski, Anders M. Dale, Nina Dalkner, Friederike S. David, Franziska Degenhardt, Srdjan Djurovic, Amanda L. Dobbyn, Athanassios Douzenis, Torbjørn Elvsåshagen, Valentina Escott-Price, I. Nicol Ferrier, Alessia Fiorentino, Tatiana M. Foroud, Liz Forty, Josef Frank, Oleksandr Frei, Nelson B. Freimer, Louise Frisén, Katrin Gade, Julie Garnham, Joel Gelernter, Marianne Giørtz Pedersen, Ian R. Gizer, Scott D. Gordon, Katherine Gordon-Smith, Tiffany A. Greenwood, Jakob Grove, José Guzman-Parra, Kyooseob Ha, Magnus Haraldsson, Martin Hautzinger, Urs Heilbronner, Dennis Hellgren, Stefan Herms, Per Hoffmann, Peter A. Holmans, Laura Huckins, Stéphane Jamain, Jessica S. Johnson, Janos L. Kalman, Yoichiro Kamatani, James L. Kennedy, Sarah Kittel-Schneider, James A. Knowles, Manolis Kogevinas, Maria Koromina, Thorsten M. Kranz, Henry R. Kranzler, Michiaki Kubo, Ralph Kupka, Steven A. Kushner, Catharina Lavebratt, Jacob Lawrence, Markus Leber, Heon-Jeong Lee, Phil H. Lee, Shawn E. Levy, Catrin Lewis, Calwing Liao, Susanne Lucae, Martin Lundberg, Donald J. MacIntyre, Sigurdur H. Magnusson, Wolfgang Maier, Adam Maihofer, Dolores Malaspina, Eirini Maratou, Lina Martinsson, Manuel Mattheisen, Steven A. McCarroll, Nathaniel W. McGregor, Peter McGuffin, James D. McKay, Helena Medeiros, Sarah E. Medland, Vincent Millischer, Grant W. Montgomery, Jennifer L. Moran, Derek W. Morris, Thomas W. Mühleisen, Niamh O’Brien, Claire O’Donovan, Loes M. Olde Loohuis, Lilijana Oruc, Sergi Papiol, Antonio F. Pardiñas, Amy Perry, Andrea Pfennig, Evgenia Porichi, James B. Potash, Digby Quested, Towfique Raj, Mark H. Rapaport, J. Raymond DePaulo, Eline J. Regeer, John P. Rice, Fabio Rivas, Margarita Rivera, Julian Roth, Panos Roussos, Douglas M. Ruderfer, Cristina Sánchez-Mora, Eva C. Schulte, Fanny Senner, Sally Sharp, Paul D. Shilling, Engilbert Sigurdsson, Lea Sirignano, Claire Slaney, Olav B. Smeland, Daniel J. Smith, Janet L. Sobell, Christine Søholm Hansen, Maria Soler Artigas, Anne T. Spijker, Dan J. Stein, John S. Strauss, Beata Świątkowska, Chikashi Terao, Thorgeir E. Thorgeirsson, Claudio Toma, Paul Tooney, Evangelia-Eirini Tsermpini, Marquis P. Vawter, Helmut Vedder, James T. R. Walters, Stephanie H. Witt, Simon Xi, Wei Xu, Jessica Mei Kay Yang, Allan H. Young, Hannah Young, Peter P. Zandi, Hang Zhou, Lea Zillich, HUNT All-In Psychiatry, Rolf Adolfsson, Ingrid Agartz, Martin Alda, Lars Alfredsson, Gulja Babadjanova, Lena Backlund, Bernhard T. Baune, Frank Bellivier, Susanne Bengesser, Wade H. Berrettini, Douglas H. R. Blackwood, Michael Boehnke, Anders D. Børglum, Gerome Breen, Vaughan J. Carr, Stanley Catts, Aiden Corvin, Nicholas Craddock, Udo Dannlowski, Dimitris Dikeos, Tõnu Esko, Bruno Etain, Panagiotis Ferentinos, Mark Frye, Janice M. Fullerton, Micha Gawlik, Elliot S. Gershon, Fernando S. Goes, Melissa J. Green, Maria Grigoroiu-Serbanescu, Joanna Hauser, Frans Henskens, Jan Hillert, Kyung Sue Hong, David M. Hougaard, Christina M. Hultman, Kristian Hveem, Nakao Iwata, Assen V. Jablensky, Ian Jones, Lisa A. Jones, René S. Kahn, John R. Kelsoe, George Kirov, Mikael Landén, Marion Leboyer, Cathryn M. Lewis, Qingqin S. Li, Jolanta Lissowska, Christine Lochner, Carmel Loughland, Nicholas G. Martin, Carol A. Mathews, Fermin Mayoral, Susan L. McElroy, Andrew M. McIntosh, Francis J. McMahon, Ingrid Melle, Patricia Michie, Lili Milani, Philip B. Mitchell, Gunnar Morken, Ole Mors, Preben Bo Mortensen, Bryan Mowry, Bertram Müller-Myhsok, Richard M. Myers, Benjamin M. Neale, Caroline M. Nievergelt, Merete Nordentoft, Markus M. Nöthen, Michael C. O’Donovan, Ketil J. Oedegaard, Tomas Olsson, Michael J. Owen, Sara A. Paciga, Chris Pantelis, Carlos Pato, Michele T. Pato, George P. Patrinos, Roy H. Perlis, Danielle Posthuma, Josep Antoni Ramos-Quiroga, Andreas Reif, Eva Z. Reininghaus, Marta Ribasés, Marcella Rietschel, Stephan Ripke, Guy A. Rouleau, Takeo Saito, Ulrich Schall, Martin Schalling, Peter R. Schofield, Thomas G. Schulze, Laura J. Scott, Rodney J. Scott, Alessandro Serretti, Cynthia Shannon Weickert, Jordan W. Smoller, Hreinn Stefansson, Kari Stefansson, Eystein Stordal, Fabian Streit, Patrick F. Sullivan, Gustavo Turecki, Arne E. Vaaler, Eduard Vieta, John B. Vincent, Irwin D. Waldman, Thomas W. Weickert, Thomas Werge, Naomi R. Wray, John-Anker Zwart, Joanna M. Biernacka, John I. Nurnberger, Sven Cichon, Howard J. Edenberg, Eli A. Stahl, Andrew McQuillin, Arianna Di Florio, Roel A. Ophoff, and Ole A. Andreassen
Subjects: Genetics, 0303 health sciences, Druggability, Genome-wide association study, Biology, medicine.disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Gene expression, Expression quantitative trait loci, medicine, Bipolar disorder, Synaptic signaling, Prefrontal cortex, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Bipolar disorder (BD) is a heritable mental illness with complex etiology. We performed a genome-wide association study (GWAS) of 41,917 BD cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. BD risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating eQTL data implicated 15 genes robustly linked to BD via gene expression, including druggable genes such as HTR6, MCHR1, DCLK3 and FURIN. This GWAS provides the best-powered BD polygenic scores to date, when applied in both European and diverse ancestry samples. Analyses of BD subtypes indicated high but imperfect genetic correlation between BD type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of BD, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
Published: 2020

33. Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology

Author: Niamh, Mullins, Andreas J, Forstner, Kevin S, O'Connell, Brandon, Coombes, Jonathan R I, Coleman, Zhen, Qiao, Thomas D, Als, Tim B, Bigdeli, Sigrid, Børte, Julien, Bryois, Alexander W, Charney, Ole Kristian, Drange, Michael J, Gandal, Saskia P, Hagenaars, Masashi, Ikeda, Nolan, Kamitaki, Minsoo, Kim, Kristi, Krebs, Georgia, Panagiotaropoulou, Brian M, Schilder, Laura G, Sloofman, Stacy, Steinberg, Vassily, Trubetskoy, Bendik S, Winsvold, Hong-Hee, Won, Liliya, Abramova, Kristina, Adorjan, Esben, Agerbo, Mariam, Al Eissa, Diego, Albani, Ney, Alliey-Rodriguez, Adebayo, Anjorin, Verneri, Antilla, Anastasia, Antoniou, Swapnil, Awasthi, Ji Hyun, Baek, Marie, Bækvad-Hansen, Nicholas, Bass, Michael, Bauer, Eva C, Beins, Sarah E, Bergen, Armin, Birner, Carsten, Bøcker Pedersen, Erlend, Bøen, Marco P, Boks, Rosa, Bosch, Murielle, Brum, Ben M, Brumpton, Nathalie, Brunkhorst-Kanaan, Monika, Budde, Jonas, Bybjerg-Grauholm, William, Byerley, Murray, Cairns, Miquel, Casas, Pablo, Cervantes, Toni-Kim, Clarke, Cristiana, Cruceanu, Alfredo, Cuellar-Barboza, Julie, Cunningham, David, Curtis, Piotr M, Czerski, Anders M, Dale, Nina, Dalkner, Friederike S, David, Franziska, Degenhardt, Srdjan, Djurovic, Amanda L, Dobbyn, Athanassios, Douzenis, Torbjørn, Elvsåshagen, Valentina, Escott-Price, I Nicol, Ferrier, Alessia, Fiorentino, Tatiana M, Foroud, Liz, Forty, Josef, Frank, Oleksandr, Frei, Nelson B, Freimer, Louise, Frisén, Katrin, Gade, Julie, Garnham, Joel, Gelernter, Marianne, Giørtz Pedersen, Ian R, Gizer, Scott D, Gordon, Katherine, Gordon-Smith, Tiffany A, Greenwood, Jakob, Grove, José, Guzman-Parra, Kyooseob, Ha, Magnus, Haraldsson, Martin, Hautzinger, Urs, Heilbronner, Dennis, Hellgren, Stefan, Herms, Per, Hoffmann, Peter A, Holmans, Laura, Huckins, Stéphane, Jamain, Jessica S, Johnson, Janos L, Kalman, Yoichiro, Kamatani, James L, Kennedy, Sarah, Kittel-Schneider, James A, Knowles, Manolis, Kogevinas, Maria, Koromina, Thorsten M, Kranz, Henry R, Kranzler, Michiaki, Kubo, Ralph, Kupka, Steven A, Kushner, Catharina, Lavebratt, Jacob, Lawrence, Markus, Leber, Heon-Jeong, Lee, Phil H, Lee, Shawn E, Levy, Catrin, Lewis, Calwing, Liao, Susanne, Lucae, Martin, Lundberg, Donald J, MacIntyre, Sigurdur H, Magnusson, Wolfgang, Maier, Adam, Maihofer, Dolores, Malaspina, Eirini, Maratou, Lina, Martinsson, Manuel, Mattheisen, Steven A, McCarroll, Nathaniel W, McGregor, Peter, McGuffin, James D, McKay, Helena, Medeiros, Sarah E, Medland, Vincent, Millischer, Grant W, Montgomery, Jennifer L, Moran, Derek W, Morris, Thomas W, Mühleisen, Niamh, O'Brien, Claire, O'Donovan, Loes M, Olde Loohuis, Lilijana, Oruc, Sergi, Papiol, Antonio F, Pardiñas, Amy, Perry, Andrea, Pfennig, Evgenia, Porichi, James B, Potash, Digby, Quested, Towfique, Raj, Mark H, Rapaport, J Raymond, DePaulo, Eline J, Regeer, John P, Rice, Fabio, Rivas, Margarita, Rivera, Julian, Roth, Panos, Roussos, Douglas M, Ruderfer, Cristina, Sánchez-Mora, Eva C, Schulte, Fanny, Senner, Sally, Sharp, Paul D, Shilling, Engilbert, Sigurdsson, Lea, Sirignano, Claire, Slaney, Olav B, Smeland, Daniel J, Smith, Janet L, Sobell, Christine, Søholm Hansen, Maria, Soler Artigas, Anne T, Spijker, Dan J, Stein, John S, Strauss, Beata, Świątkowska, Chikashi, Terao, Thorgeir E, Thorgeirsson, Claudio, Toma, Paul, Tooney, Evangelia-Eirini, Tsermpini, Marquis P, Vawter, Helmut, Vedder, James T R, Walters, Stephanie H, Witt, Simon, Xi, Wei, Xu, Jessica Mei Kay, Yang, Allan H, Young, Hannah, Young, Peter P, Zandi, Hang, Zhou, Lea, Zillich, Rolf, Adolfsson, Ingrid, Agartz, Martin, Alda, Lars, Alfredsson, Gulja, Babadjanova, Lena, Backlund, Bernhard T, Baune, Frank, Bellivier, Susanne, Bengesser, Wade H, Berrettini, Douglas H R, Blackwood, Michael, Boehnke, Anders D, Børglum, Gerome, Breen, Vaughan J, Carr, Stanley, Catts, Aiden, Corvin, Nicholas, Craddock, Udo, Dannlowski, Dimitris, Dikeos, Tõnu, Esko, Bruno, Etain, Panagiotis, Ferentinos, Mark, Frye, Janice M, Fullerton, Micha, Gawlik, Elliot S, Gershon, Fernando S, Goes, Melissa J, Green, Maria, Grigoroiu-Serbanescu, Joanna, Hauser, Frans, Henskens, Jan, Hillert, Kyung Sue, Hong, David M, Hougaard, Christina M, Hultman, Kristian, Hveem, Nakao, Iwata, Assen V, Jablensky, Ian, Jones, Lisa A, Jones, René S, Kahn, John R, Kelsoe, George, Kirov, Mikael, Landén, Marion, Leboyer, Cathryn M, Lewis, Qingqin S, Li, Jolanta, Lissowska, Christine, Lochner, Carmel, Loughland, Nicholas G, Martin, Carol A, Mathews, Fermin, Mayoral, Susan L, McElroy, Andrew M, McIntosh, Francis J, McMahon, Ingrid, Melle, Patricia, Michie, Lili, Milani, Philip B, Mitchell, Gunnar, Morken, Ole, Mors, Preben Bo, Mortensen, Bryan, Mowry, Bertram, Müller-Myhsok, Richard M, Myers, Benjamin M, Neale, Caroline M, Nievergelt, Merete, Nordentoft, Markus M, Nöthen, Michael C, O'Donovan, Ketil J, Oedegaard, Tomas, Olsson, Michael J, Owen, Sara A, Paciga, Chris, Pantelis, Carlos, Pato, Michele T, Pato, George P, Patrinos, Roy H, Perlis, Danielle, Posthuma, Josep Antoni, Ramos-Quiroga, Andreas, Reif, Eva Z, Reininghaus, Marta, Ribasés, Marcella, Rietschel, Stephan, Ripke, Guy A, Rouleau, Takeo, Saito, Ulrich, Schall, Martin, Schalling, Peter R, Schofield, Thomas G, Schulze, Laura J, Scott, Rodney J, Scott, Alessandro, Serretti, Cynthia, Shannon Weickert, Jordan W, Smoller, Hreinn, Stefansson, Kari, Stefansson, Eystein, Stordal, Fabian, Streit, Patrick F, Sullivan, Gustavo, Turecki, Arne E, Vaaler, Eduard, Vieta, John B, Vincent, Irwin D, Waldman, Thomas W, Weickert, Thomas, Werge, Naomi R, Wray, John-Anker, Zwart, Joanna M, Biernacka, John I, Nurnberger, Sven, Cichon, Howard J, Edenberg, Eli A, Stahl, Andrew, McQuillin, Arianna, Di Florio, Roel A, Ophoff, and Ole A, Andreassen
Subjects: Major Histocompatibility Complex, Multifactorial Inheritance, Bipolar Disorder, Phenotype, Genome, Human, Risk Factors, Case-Control Studies, Quantitative Trait Loci, Chromosomes, Human, Humans, Genetic Predisposition to Disease, Genome-Wide Association Study
Abstract: Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
Published: 2020

34. The Genetics of the Mood Disorder Spectrum: Genome-wide Association Analyses of More Than 185,000 Cases and 439,000 Controls

Author: Jonathan R.I. Coleman, Héléna A. Gaspar, Julien Bryois, Gerome Breen, Enda M. Byrne, Andreas J. Forstner, Peter A. Holmans, Christiaan A. de Leeuw, Manuel Mattheisen, Andrew McQuillin, Jennifer M. Whitehead Pavlides, Tune H. Pers, Stephan Ripke, Eli A. Stahl, Stacy Steinberg, Vassily Trubetskoy, Maciej Trzaskowski, Yunpeng Wang, Liam Abbott, Abdel Abdellaoui, Mark J. Adams, Annelie Nordin Adolfsson, Esben Agerbo, Huda Akil, Diego Albani, Ney Alliey-Rodriguez, Thomas D. Als, Till F.M. Andlauer, Adebayo Anjorin, Verneri Antilla, Sandra Van der Auwera, Swapnil Awasthi, Silviu-Alin Bacanu, Judith A. Badner, Marie Bækvad-Hansen, Jack D. Barchas, Nicholas Bass, Michael Bauer, Aartjan T.F. Beekman, Richard Belliveau, Sarah E. Bergen, Tim B. Bigdeli, Elisabeth B. Binder, Erlend Bøen, Marco Boks, James Boocock, Monika Budde, William Bunney, Margit Burmeister, Henriette N. Buttenschøn, Jonas Bybjerg-Grauholm, William Byerley, Na Cai, Miquel Casas, Enrique Castelao, Felecia Cerrato, Pablo Cervantes, Kimberly Chambert, Alexander W. Charney, Danfeng Chen, Jane Hvarregaard Christensen, Claire Churchhouse, David St Clair, Toni-Kim Clarke, Lucía Colodro-Conde, William Coryell, Baptiste Couvy-Duchesne, David W. Craig, Gregory E. Crawford, Cristiana Cruceanu, Piotr M. Czerski, Anders M. Dale, Gail Davies, Ian J. Deary, Franziska Degenhardt, Jurgen Del-Favero, J Raymond DePaulo, Eske M. Derks, Nese Direk, Srdjan Djurovic, Amanda L. Dobbyn, Conor V. Dolan, Ashley Dumont, Erin C. Dunn, Thalia C. Eley, Torbjørn Elvsåshagen, Valentina Escott-Price, Chun Chieh Fan, Hilary K. Finucane, Sascha B. Fischer, Matthew Flickinger, Jerome C. Foo, Tatiana M. Foroud, Liz Forty, Josef Frank, Christine Fraser, Nelson B. Freimer, Louise Frisén, Katrin Gade, Diane Gage, Julie Garnham, Claudia Giambartolomei, Fernando S. Goes, Jaqueline Goldstein, Scott D. Gordon, Katherine Gordon-Smith, Elaine K. Green, Melissa J. Green, Tiffany A. Greenwood, Jakob Grove, Weihua Guan, Lynsey S. Hall, Marian L. Hamshere, Christine Søholm Hansen, Thomas F. Hansen, Martin Hautzinger, Urs Heilbronner, Albert M. van Hemert, Stefan Herms, Ian B. Hickie, Maria Hipolito, Per Hoffmann, Dominic Holland, Georg Homuth, Carsten Horn, Jouke-Jan Hottenga, Laura Huckins, Marcus Ising, Stéphane Jamain, Rick Jansen, Jessica S. Johnson, Simone de Jong, Eric Jorgenson, Anders Juréus, Radhika Kandaswamy, Robert Karlsson, James L. Kennedy, Farnush Farhadi Hassan Kiadeh, Sarah Kittel-Schneider, James A. Knowles, Manolis Kogevinas, Isaac S. Kohane, Anna C. Koller, Julia Kraft, Warren W. Kretzschmar, Jesper Krogh, Ralph Kupka, Zoltán Kutalik, Catharina Lavebratt, Jacob Lawrence, William B. Lawson, Markus Leber, Phil H. Lee, Shawn E. Levy, Jun Z. Li, Yihan Li, Penelope A. Lind, Chunyu Liu, Loes M. Olde Loohuis, Anna Maaser, Donald J. MacIntyre, Dean F. MacKinnon, Pamela B. Mahon, Wolfgang Maier, Robert M. Maier, Jonathan Marchini, Lina Martinsson, Hamdi Mbarek, Steve McCarroll, Patrick McGrath, Peter McGuffin, Melvin G. McInnis, James D. McKay, Helena Medeiros, Sarah E. Medland, Divya Mehta, Fan Meng, Christel M. Middeldorp, Evelin Mihailov, Yuri Milaneschi, Lili Milani, Saira Saeed Mirza, Francis M. Mondimore, Grant W. Montgomery, Derek W. Morris, Sara Mostafavi, Thomas W. Mühleisen, Niamh Mullins, Matthias Nauck, Bernard Ng, Hoang Nguyen, Caroline M. Nievergelt, Michel G. Nivard, Evaristus A. Nwulia, Dale R. Nyholt, Claire O'Donovan, Paul F. O'Reilly, Anil P.S. Ori, Lilijana Oruc, Urban Ösby, Hogni Oskarsson, Jodie N. Painter, José Guzman Parra, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Amy Perry, Roseann E. Peterson, Erik Pettersson, Wouter J. Peyrot, Andrea Pfennig, Giorgio Pistis, Shaun M. Purcell, Jorge A. Quiroz, Per Qvist, Eline J. Regeer, Andreas Reif, Céline S. Reinbold, John P. Rice, Brien P. Riley, Fabio Rivas, Margarita Rivera, Panos Roussos, Douglas M. Ruderfer, Euijung Ryu, Cristina Sánchez-Mora, Alan F. Schatzberg, William A. Scheftner, Robert Schoevers, Nicholas J. Schork, Eva C. Schulte, Tatyana Shehktman, Ling Shen, Jianxin Shi, Paul D. Shilling, Stanley I. Shyn, Engilbert Sigurdsson, Claire Slaney, Olav B. Smeland, Johannes H. Smit, Daniel J. Smith, Janet L. Sobell, Anne T. Spijker, Michael Steffens, John S. Strauss, Fabian Streit, Jana Strohmaier, Szabolcs Szelinger, Katherine E. Tansey, Henning Teismann, Alexander Teumer, Robert C. Thompson, Wesley Thompson, Pippa A. Thomson, Thorgeir E. Thorgeirsson, Matthew Traylor, Jens Treutlein, André G. Uitterlinden, Daniel Umbricht, Helmut Vedder, Alexander Viktorin, Peter M. Visscher, Weiqing Wang, Stanley J. Watson, Bradley T. Webb, Cynthia Shannon Weickert, Thomas W. Weickert, Shantel Marie Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Stephanie H. Witt, Yang Wu, Hualin S. Xi, Wei Xu, Jian Yang, Allan H. Young, Peter Zandi, Peng Zhang, Futao Zhang, Sebastian Zollner, Rolf Adolfsson, Ingrid Agartz, Martin Alda, Volker Arolt, Lena Backlund, Bernhard T. Baune, Frank Bellivier, Klaus Berger, Wade H. Berrettini, Joanna M. Biernacka, Douglas H.R. Blackwood, Michael Boehnke, Dorret I. Boomsma, Aiden Corvin, Nicholas Craddock, Mark J. Daly, Udo Dannlowski, Enrico Domenici, Katharina Domschke, Tõnu Esko, Bruno Etain, Mark Frye, Janice M. Fullerton, Elliot S. Gershon, E.J.C. de Geus, Michael Gill, Fernando Goes, Hans J. Grabe, Maria Grigoroiu-Serbanescu, Steven P. Hamilton, Joanna Hauser, Caroline Hayward, Andrew C. Heath, David M. Hougaard, Christina M. Hultman, Ian Jones, Lisa A. Jones, René S. Kahn, Kenneth S. Kendler, George Kirov, Stefan Kloiber, Mikael Landén, Marion Leboyer, Glyn Lewis, Qingqin S. Li, Jolanta Lissowska, Susanne Lucae, Pamela A.F. Madden, Patrik K. Magnusson, Nicholas G. Martin, Fermin Mayoral, Susan L. McElroy, Andrew M. McIntosh, Francis J. McMahon, Ingrid Melle, Andres Metspalu, Philip B. Mitchell, Gunnar Morken, Ole Mors, Preben Bo Mortensen, Bertram Müller-Myhsok, Richard M. Myers, Benjamin M. Neale, Vishwajit Nimgaonkar, Merete Nordentoft, Markus M. Nöthen, Michael C. O'Donovan, Ketil J. Oedegaard, Michael J. Owen, Sara A. Paciga, Carlos Pato, Michele T. Pato, Nancy L. Pedersen, Brenda W.J. H. Penninx, Roy H. Perlis, David J. Porteous, Danielle Posthuma, James B. Potash, Martin Preisig, Josep Antoni Ramos-Quiroga, Marta Ribasés, Marcella Rietschel, Guy A. Rouleau, Catherine Schaefer, Martin Schalling, Peter R. Schofield, Thomas G. Schulze, Alessandro Serretti, Jordan W. Smoller, Hreinn Stefansson, Kari Stefansson, Eystein Stordal, Henning Tiemeier, Gustavo Turecki, Rudolf Uher, Arne E. Vaaler, Eduard Vieta, John B. Vincent, Henry Völzke, Myrna M. Weissman, Thomas Werge, Ole A. Andreassen, Anders D. Børglum, Sven Cichon, Howard J. Edenberg, Arianna Di Florio, John Kelsoe, Douglas F. Levinson, Cathryn M. Lewis, John I. Nurnberger, Roel A. Ophoff, Laura J. Scott, Pamela Sklar, Patrick F. Sullivan, Naomi R. Wray, APH - Methodology, Biological Psychology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, Amsterdam Neuroscience - Complex Trait Genetics, Complex Trait Genetics, Epidemiology, Erasmus MC other, Urology, Psychiatry, Internal Medicine, Medical Informatics, Immunology, Child and Adolescent Psychiatry / Psychology, Adult Psychiatry, Coleman J.R.I., Gaspar H.A., Bryois J., Byrne E.M., Forstner A.J., Holmans P.A., de Leeuw C.A., Mattheisen M., McQuillin A., Whitehead Pavlides J.M., Pers T.H., Ripke S., Stahl E.A., Steinberg S., Trubetskoy V., Trzaskowski M., Wang Y., Abbott L., Abdellaoui A., Adams M.J., Adolfsson A.N., Agerbo E., Akil H., Albani D., Alliey-Rodriguez N., Als T.D., Andlauer T.F.M., Anjorin A., Antilla V., Van der Auwera S., Awasthi S., Bacanu S.-A., Badner J.A., Baekvad-Hansen M., Barchas J.D., Bass N., Bauer M., Beekman A.T.F., Belliveau R., Bergen S.E., Bigdeli T.B., Binder E.B., Boen E., Boks M., Boocock J., Budde M., Bunney W., Burmeister M., Buttenschon H.N., Bybjerg-Grauholm J., Byerley W., Cai N., Casas M., Castelao E., Cerrato F., Cervantes P., Chambert K., Charney A.W., Chen D., Christensen J.H., Churchhouse C., St Clair D., Clarke T.-K., Colodro-Conde L., Coryell W., Couvy-Duchesne B., Craig D.W., Crawford G.E., Cruceanu C., Czerski P.M., Dale A.M., Davies G., Deary I.J., Degenhardt F., Del-Favero J., DePaulo J.R., Derks E.M., Direk N., Djurovic S., Dobbyn A.L., Dolan C.V., Dumont A., Dunn E.C., Eley T.C., Elvsashagen T., Escott-Price V., Fan C.C., Finucane H.K., Fischer S.B., Flickinger M., Foo J.C., Foroud T.M., Forty L., Frank J., Fraser C., Freimer N.B., Frisen L., Gade K., Gage D., Garnham J., Giambartolomei C., Goes F.S., Goldstein J., Gordon S.D., Gordon-Smith K., Green E.K., Green M.J., Greenwood T.A., Grove J., Guan W., Hall L.S., Hamshere M.L., Hansen C.S., Hansen T.F., Hautzinger M., Heilbronner U., van Hemert A.M., Herms S., Hickie I.B., Hipolito M., Hoffmann P., Holland D., Homuth G., Horn C., Hottenga J.-J., Huckins L., Ising M., Jamain S., Jansen R., Johnson J.S., de Jong S., Jorgenson E., Jureus A., Kandaswamy R., Karlsson R., Kennedy J.L., Hassan Kiadeh F.F., Kittel-Schneider S., Knowles J.A., Kogevinas M., Kohane I.S., Koller A.C., Kraft J., Kretzschmar W.W., Krogh J., Kupka R., Kutalik Z., Lavebratt C., Lawrence J., Lawson W.B., Leber M., Lee P.H., Levy S.E., Li J.Z., Li Y., Lind P.A., Liu C., Olde Loohuis L.M., Maaser A., MacIntyre D.J., MacKinnon D.F., Mahon P.B., Maier W., Maier R.M., Marchini J., Martinsson L., Mbarek H., McCarroll S., McGrath P., McGuffin P., McInnis M.G., McKay J.D., Medeiros H., Medland S.E., Mehta D., Meng F., Middeldorp C.M., Mihailov E., Milaneschi Y., Milani L., Mirza S.S., Mondimore F.M., Montgomery G.W., Morris D.W., Mostafavi S., Muhleisen T.W., Mullins N., Nauck M., Ng B., Nguyen H., Nievergelt C.M., Nivard M.G., Nwulia E.A., Nyholt D.R., O'Donovan C., O'Reilly P.F., Ori A.P.S., Oruc L., Osby U., Oskarsson H., Painter J.N., Parra J.G., Pedersen C.B., Pedersen M.G., Perry A., Peterson R.E., Pettersson E., Peyrot W.J., Pfennig A., Pistis G., Purcell S.M., Quiroz J.A., Qvist P., Regeer E.J., Reif A., Reinbold C.S., Rice J.P., Riley B.P., Rivas F., Rivera M., Roussos P., Ruderfer D.M., Ryu E., Sanchez-Mora C., Schatzberg A.F., Scheftner W.A., Schoevers R., Schork N.J., Schulte E.C., Shehktman T., Shen L., Shi J., Shilling P.D., Shyn S.I., Sigurdsson E., Slaney C., Smeland O.B., Smit J.H., Smith D.J., Sobell J.L., Spijker A.T., Steffens M., Strauss J.S., Streit F., Strohmaier J., Szelinger S., Tansey K.E., Teismann H., Teumer A., Thompson R.C., Thompson W., Thomson P.A., Thorgeirsson T.E., Traylor M., Treutlein J., Uitterlinden A.G., Umbricht D., Vedder H., Viktorin A., Visscher P.M., Wang W., Watson S.J., Webb B.T., Weickert C.S., Weickert T.W., Weinsheimer S.M., Wellmann J., Willemsen G., Witt S.H., Wu Y., Xi H.S., Xu W., Yang J., Young A.H., Zandi P., Zhang P., Zhang F., Zollner S., Adolfsson R., Agartz I., Alda M., Arolt V., Backlund L., Baune B.T., Bellivier F., Berger K., Berrettini W.H., Biernacka J.M., Blackwood D.H.R., Boehnke M., Boomsma D.I., Corvin A., Craddock N., Daly M.J., Dannlowski U., Domenici E., Domschke K., Esko T., Etain B., Frye M., Fullerton J.M., Gershon E.S., de Geus E.J.C., Gill M., Goes F., Grabe H.J., Grigoroiu-Serbanescu M., Hamilton S.P., Hauser J., Hayward C., Heath A.C., Hougaard D.M., Hultman C.M., Jones I., Jones L.A., Kahn R.S., Kendler K.S., Kirov G., Kloiber S., Landen M., Leboyer M., Lewis G., Li Q.S., Lissowska J., Lucae S., Madden P.A.F., Magnusson P.K., Martin N.G., Mayoral F., McElroy S.L., McIntosh A.M., McMahon F.J., Melle I., Metspalu A., Mitchell P.B., Morken G., Mors O., Mortensen P.B., Muller-Myhsok B., Myers R.M., Neale B.M., Nimgaonkar V., Nordentoft M., Nothen M.M., O'Donovan M.C., Oedegaard K.J., Owen M.J., Paciga S.A., Pato C., Pato M.T., Pedersen N.L., Penninx B.W.J.H., Perlis R.H., Porteous D.J., Posthuma D., Potash J.B., Preisig M., Ramos-Quiroga J.A., Ribases M., Rietschel M., Rouleau G.A., Schaefer C., Schalling M., Schofield P.R., Schulze T.G., Serretti A., Smoller J.W., Stefansson H., Stefansson K., Stordal E., Tiemeier H., Turecki G., Uher R., Vaaler A.E., Vieta E., Vincent J.B., Volzke H., Weissman M.M., Werge T., Andreassen O.A., Borglum A.D., Cichon S., Edenberg H.J., Di Florio A., Kelsoe J., Levinson D.F., Lewis C.M., Nurnberger J.I., Ophoff R.A., Scott L.J., Sklar P., Sullivan P.F., Wray N.R., and Breen G.
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), Genetic correlation, Genome-wide association study, Mood Disorder, Bipolar disorder, Population, BF, Genomics, Major depressive disorder, Affective disorder, Article, Mice, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, mental disorders, medicine, Animals, ddc:610, education, Depression (differential diagnoses), Biological Psychiatry, 030304 developmental biology, Genetic association, Genetics, Depressive Disorder, Major, 0303 health sciences, education.field_of_study, Animal, business.industry, Risk Factor, medicine.disease, 3. Good health, Affective disorders, 030104 developmental biology, Mood, Mood disorders, RC0321, Biological psychiatry, business, 030217 neurology & neurosurgery, Clinical psychology
Abstract: BackgroundMood disorders (including major depressive disorder and bipolar disorder) affect 10-20% of the population. They range from brief, mild episodes to severe, incapacitating conditions that markedly impact lives. Despite their diagnostic distinction, multiple approaches have shown considerable sharing of risk factors across the mood disorders.MethodsTo clarify their shared molecular genetic basis, and to highlight disorder-specific associations, we meta-analysed data from the latest Psychiatric Genomics Consortium (PGC) genome-wide association studies of major depression (including data from 23andMe) and bipolar disorder, and an additional major depressive disorder cohort from UK Biobank (total: 185,285 cases, 439,741 controls; non-overlapping N = 609,424).ResultsSeventy-three loci reached genome-wide significance in the meta-analysis, including 15 that are novel for mood disorders. More genome-wide significant loci from the PGC analysis of major depression than bipolar disorder reached genome-wide significance. Genetic correlations revealed that type 2 bipolar disorder correlates strongly with recurrent and single episode major depressive disorder. Systems biology analyses highlight both similarities and differences between the mood disorders, particularly in the mouse brain cell types implicated by the expression patterns of associated genes. The mood disorders also differ in their genetic correlation with educational attainment – positive in bipolar disorder but negative in major depressive disorder.ConclusionsThe mood disorders share several genetic associations, and can be combined effectively to increase variant discovery. However, we demonstrate several differences between these disorders. Analysing subtypes of major depressive disorder and bipolar disorder provides evidence for a genetic mood disorders spectrum.
Published: 2020

35. mTADA is a framework for identifying risk genes from de novo mutations in multiple traits

Author: Eli A. Stahl, Amanda Dobbyn, Shaun Purcell, Tan-Hoang Nguyen, Xin He, Patrick F. Sullivan, Ruth C. Brown, Joseph D. Buxbaum, Brien P. Riley, and Dalila Pinto
Subjects: 0301 basic medicine, Science, Systems biology, General Physics and Astronomy, Computational biology, Biology, Genome informatics, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Intellectual Disability, Exome Sequencing, Intellectual disability, medicine, Humans, Genetic Predisposition to Disease, lcsh:Science, Gene, De novo mutations, Genetic association study, Multidisciplinary, Neurodevelopmental disorders, Cardiovascular genetics, General Chemistry, medicine.disease, Genetic architecture, 030104 developmental biology, Schizophrenia, Mutation, Trait, lcsh:Q, Identification (biology), 030217 neurology & neurosurgery
Abstract: Joint analysis of multiple traits can result in the identification of associations not found through the analysis of each trait in isolation. Studies of neuropsychiatric disorders and congenital heart disease (CHD) which use de novo mutations (DNMs) from parent-offspring trios have reported multiple putatively causal genes. However, a joint analysis method designed to integrate DNMs from multiple studies has yet to be implemented. We here introduce multiple-trait TADA (mTADA) which jointly analyzes two traits using DNMs from non-overlapping family samples. We first demonstrate that mTADA is able to leverage genetic overlaps to increase the statistical power of risk-gene identification. We then apply mTADA to large datasets of >13,000 trios for five neuropsychiatric disorders and CHD. We report additional risk genes for schizophrenia, epileptic encephalopathies and CHD. We outline some shared and specific biological information of intellectual disability and CHD by conducting systems biology analyses of genes prioritized by mTADA., Joint analysis of multiple traits can increase power and provide insights into shared genetic architecture. Here, Nguyen et al. develop multi-trait TADA (mTADA), an extension of TADA (transmission and de novo association test) that jointly analyses de novo mutations of traits for improved risk-gene identification power.
Published: 2020

36. Genome-wide non-HLA donor-recipient genetic differences influence renal allograft survival via early allograft fibrosis

Author: Zhongyang Zhang, Chengguo Wei, Ajay K. Israni, Eli A. Stahl, Weiqing Huang, Madhav C. Menon, Khadija Banu, Bao-Li Loza, Zeguo Sun, Ivy A. Rosales, Brendan J. Keating, Qisheng Lin, Barbara Murphy, Felipe Garzon, Weijia Zhang, Zhengzi Yi, Robert B. Colvin, and Ke Hao
Subjects: 0301 basic medicine, Graft Rejection, medicine.medical_treatment, 030232 urology & nephrology, Single-nucleotide polymorphism, Human leukocyte antigen, Kidney, Article, 03 medical and health sciences, 0302 clinical medicine, Fibrosis, HLA Antigens, Medicine, Humans, Kidney transplantation, Subclinical infection, business.industry, Proportional hazards model, Alloimmunity, Graft Survival, Immunosuppression, medicine.disease, Allografts, Kidney Transplantation, 030104 developmental biology, Nephrology, Immunology, business
Abstract: Donor-recipient (D-R) differences at human leukocyte antigen (HLA) loci are currently incorporated into organ sharing, allocation and immunosuppression decisions. However, while acute rejection episodes have substantially diminished, progressive histologic damage occurs in allografts and improved long-term survival remains an unrealized goal among kidney recipients. Here we tested the hypothesis that non-HLA dependent, genome-wide D-R genetic differences could contribute to unchecked alloimmunity with histologic and functional consequences, culminating in long-term allograft failure. Genome-wide single nucleotide polymorphism (SNP) array data, excluding the HLA region, was utilized from 385 transplants to study the role of D-R differences upon serial histology and allograft survival. ADMIXTURE analysis was performed to quantitatively estimate ancestry in each D-R pair and PLINK was used to estimate the proportion of genome-shared identity-by-descent (pIBD) between D-R pairs. Subsequently, quantitative measures of recipient ancestry based on non-HLA SNPs was associated with death-censored allograft survival in adjusted Cox models. In D-R pairs of similar ancestry, pIBD was significantly associated with allograft survival independent of HLA mismatches in 224 transplants. Surprisingly, pIBD and recipient ancestry were not associated with clinical or subclinical rejection at any time post-transplant. Significantly, in multivariable analysis, pIBD inversely correlated with vascular intimal fibrosis in 160 biopsies obtained less than one year which in turn was significantly associated with allograft survival. Thus, our novel data show that non-HLA D-R differences associate with early vascular intimal fibrosis and allograft survival.
Published: 2020

37. Rare protein coding variants implicate genes involved in risk of suicide death

Author: Emily DiBlasi, Nicola J. Camp, Andrey A. Shabalin, Anna R. Docherty, Zhe Yu, Ken R. Smith, W. Brandon Callor, Amanda V. Bakian, Eoin Gaj, Brooks R. Keeshin, Erik Christensen, Douglas Gray, Qingqin S. Li, Eric T. Monson, Leslie Jerominski, Anne V. Kirby, Eli A. Stahl, Nancy William, Hilary Coon, Danli Chen, Alison Fraser, Elliott Ferris, and Michael Klein
Subjects: Genetics, Protein coding, 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, Biology, Genetic risk, Gene, 030217 neurology & neurosurgery, 3. Good health, 030304 developmental biology, Suicide death
Abstract: Suicide death is a worldwide health crisis, claiming close to 800,000 lives per year. Recent evidence suggests that prediction and prevention challenges may be aided by discoveries of genetic risk factors. Here we focus on the role of rare (MAF SNAPC1, rs75418419; TNKS1BP1, rs143883793; ADGRF5, rs149197213; PER1, rs145053802; and ESS2, rs62223875). Both PER1 and SNAPC1 have other supporting gene-level evidence of suicide risk, and an association with bipolar disorder has been reported for PER1 and with schizophrenia for PER1, TNKS1BP1, and ESS2. Three genes (PER1, TNKS1BP1, and ADGRF5), with additional genes implicated by GWAS studies on suicidal behavior, showed significant enrichment in immune system, homeostatic and signal transduction processes. Pain, depression, and accidental trauma were the most prevalent phenotypes in electronic medical record data for the categories assessed. These findings suggest an important role for rare variants in suicide risk and provide new insights into the genetic architecture of suicide death. Furthermore, we demonstrate the added utility of careful assessment of genotyping arrays in rare variant discovery.
Published: 2020
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38. The genetic architecture of bipolar disorder: Entering the road of discoveries

Author: Andreas J. Forstner, Olav B. Smeland, Alexander W. Charney, Eli A. Stahl, and Ole A. Andreassen
Subjects: medicine.medical_specialty, business.industry, Disease, medicine.disease, Genetic architecture, Mood, Genetic epidemiology, medicine, Personalized medicine, Bipolar disorder, medicine.symptom, Psychiatry, business, Mania, Depression (differential diagnoses)
Abstract: Bipolar disorder is a severe mental disorder characterized by episodes of abnormal mood, including both mania and depression. Accumulation of bipolar disorder in families has been observed for centuries, and genetic epidemiology studies have demonstrated a high degree of heritability. However, it is only in recent years that many disease risk genes have been identified, leveraging genome-wide genotyping technology and large samples from international collaborations, particularly the Psychiatric Genomics Consortium. It is likely that bipolar disorder patients inherit a number of gene variants that increase vulnerability to disease, and are exposed to stress conditions that trigger the disease and cause relapses. The genetic risk loci identified so far explain too little variance to be used for clinical diagnostics or for individual prediction of disease risk. Further, the specific molecular genetic mechanisms underlying susceptibility to bipolar disorder are still poorly understood. However, through large-scale international efforts, we are expecting a series of genetic discoveries in bipolar disorders in the coming years, providing a better understanding of disease mechanisms. This new knowledge will form a basis for developing better pharmacological agents and inform new diagnostic tools, with great potential for personalized medicine approaches in bipolar disorders. In line with the recently improved insight into the genetic architecture of bipolar disorders, it is important to communicate the stress-vulnerability model to patients and relatives, which can promote better acceptance and involvement from patients and the community, leading to better treatment adherence and outcome.
Published: 2020

39. Landscape of Conditional eQTL in Dorsolateral Prefrontal Cortex and Co-localization with Schizophrenia GWAS

Author: Amanda Dobbyn, Laura M. Huckins, James Boocock, Laura G. Sloofman, Benjamin S. Glicksberg, Claudia Giambartolomei, Gabriel E. Hoffman, Thanneer M. Perumal, Kiran Girdhar, Yan Jiang, Towfique Raj, Douglas M. Ruderfer, Robin S. Kramer, Dalila Pinto, Schahram Akbarian, Panos Roussos, Enrico Domenici, Bernie Devlin, Pamela Sklar, Eli A. Stahl, Solveig K. Sieberts, Joseph Buxbaum, David Lewis, Raquel Gur, Chang-Gyu Hahn, Keisuke Hirai, Hiroyoshi Toyoshiba, Laurent Essioux, Lara Mangravite, Mette Peters, Thomas Lehner, Barbara Lipska, A. Ercument Cicek, Cong Lu, Kathryn Roeder, Lu Xie, Konrad Talbot, Scott E. Hemby, Andrew Browne, Andrew Chess, Aaron Topol, Alexander Charney, Ben Readhead, Bin Zhang, David A. Bennett, David H. Kavanagh, Eric E. Schadt, Hardik R. Shah, Jun Zhu, Jessica S. Johnson, John F. Fullard, Joel T. Dudley, Kristen J. Brennand, Menachem Fromer, Milind C. Mahajan, Shaun M. Purcell, Tymor Hamamsy, Vahram Haroutunian, Ying-Chih Wang, Zeynep H. Gümüş, Geetha Senthil, Robin Kramer, Benjamin A. Logsdon, Jonathan M.J. Derry, Kristen K. Dang, Roberto Visintainer, Leslie A. Shinobu, Patrick F. Sullivan, and Lambertus L. Klei
Subjects: GWAS co-localization, 0301 basic medicine, Cells, Quantitative Trait Loci, conditional eQTL, Posterior probability, Prefrontal Cortex, Genome-wide association study, Genomics, Computational biology, Biology, Genome, Article, Epigenesis, Genetic, 03 medical and health sciences, Genetic, Genetics, Humans, Gene, Cells, Cultured, Genetics (clinical), Regulation of gene expression, Cultured, risk gene, Genome, Human, expression quantitative trait loci, eQTLs, neuropsychiatric disorder, gene expression regulation, schizophrenia, 030104 developmental biology, complex trait, Conditional independence, fine mapping, Expression quantitative trait loci, Schizophrenia, Genome-Wide Association Study, Epigenesis, Human
Abstract: Causal genes and variants within genome-wide association study (GWAS) loci can be identified by integrating GWAS statistics with expression quantitative trait loci (eQTL) and determining which variants underlie both GWAS and eQTL signals. Most analyses, however, consider only the marginal eQTL signal, rather than dissect this signal into multiple conditionally independent signals for each gene. Here we show that analyzing conditional eQTL signatures, which could be important under specific cellular or temporal contexts, leads to improved fine mapping of GWAS associations. Using genotypes and gene expression levels from post-mortem human brain samples (n = 467) reported by the CommonMind Consortium (CMC), we find that conditional eQTL are widespread; 63% of genes with primary eQTL also have conditional eQTL. In addition, genomic features associated with conditional eQTL are consistent with context-specific (e.g., tissue-, cell type-, or developmental time point-specific) regulation of gene expression. Integrating the 2014 Psychiatric Genomics Consortium schizophrenia (SCZ) GWAS and CMC primary and conditional eQTL data reveals 40 loci with strong evidence for co-localization (posterior probability > 0.8), including six loci with co-localization of conditional eQTL. Our co-localization analyses support previously reported genes, identify novel genes associated with schizophrenia risk, and provide specific hypotheses for their functional follow-up.
Published: 2018

40. Genetic validation of bipolar disorder identified by automated phenotyping using electronic health records

Author: Douglas M. Ruderfer, Eli A. Stahl, Carlos N. Pato, Phil H. Lee, Jordan W. Smoller, Ian Jones, Jessica Minnier, Chia-Yen Chen, Tianxi Cai, Victor M. Castro, Pamela Sklar, Shawn N. Murphy, Vivian S. Gainer, Michele T. Pato, Alexander W. Charney, Mikael Landén, and Roy H. Perlis
Subjects: 0301 basic medicine, medicine.medical_specialty, Bipolar Disorder, Medical Records Systems, Computerized, Genome-wide association study, Biology, Bioinformatics, Polymorphism, Single Nucleotide, Genetic correlation, White People, Article, lcsh:RC321-571, Cohort Studies, Cellular and Molecular Neuroscience, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Genotype, medicine, Electronic Health Records, Humans, SNP, Genetic Predisposition to Disease, Bipolar disorder, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biological Psychiatry, 030304 developmental biology, Genetics, 0303 health sciences, business.industry, Heritability, medicine.disease, 3. Good health, Psychiatry and Mental health, Phenotype, 030104 developmental biology, Sample size determination, medicine.symptom, business, Mania, Algorithms, 030217 neurology & neurosurgery
Abstract: Bipolar disorder (BD) is a heritable mood disorder characterized by episodes of mania and depression. Although genomewide association studies (GWAS) have successfully identified genetic loci contributing to BD risk, sample size has become a rate-limiting obstacle to genetic discovery. Electronic health records (EHRs) represent a vast but relatively untapped resource for high-throughput phenotyping. As part of the International Cohort Collection for Bipolar Disorder (ICCBD), we previously validated automated EHR-based phenotyping algorithms for BD against in-person diagnostic interviews (Castro et al. Am J Psychiatry 172:363–372, 2015). Here, we establish the genetic validity of these phenotypes by determining their genetic correlation with traditionally ascertained samples. Case and control algorithms were derived from structured and narrative text in the Partners Healthcare system comprising more than 4.6 million patients over 20 years. Genomewide genotype data for 3330 BD cases and 3952 controls of European ancestry were used to estimate SNP-based heritability (h2g) and genetic correlation (rg) between EHR-based phenotype definitions and traditionally ascertained BD cases in GWAS by the ICCBD and Psychiatric Genomics Consortium (PGC) using LD score regression. We evaluated BD cases identified using 4 EHR-based algorithms: an NLP-based algorithm (95-NLP) and three rule-based algorithms using codified EHR with decreasing levels of stringency—“coded-strict”, “coded-broad”, and “coded-broad based on a single clinical encounter” (coded-broad-SV). The analytic sample comprised 862 95-NLP, 1968 coded-strict, 2581 coded-broad, 408 coded-broad-SV BD cases, and 3 952 controls. The estimated h2g were 0.24 (p = 0.015), 0.09 (p = 0.064), 0.13 (p = 0.003), 0.00 (p = 0.591) for 95-NLP, coded-strict, coded-broad and coded-broad-SV BD, respectively. The h2g for all EHR-based cases combined except coded-broad-SV (excluded due to 0 h2g) was 0.12 (p = 0.004). These h2g were lower or similar to the h2g observed by the ICCBD + PGCBD (0.23, p = 3.17E−80, total N = 33,181). However, the rg between ICCBD + PGCBD and the EHR-based cases were high for 95-NLP (0.66, p = 3.69 × 10–5), coded-strict (1.00, p = 2.40 × 10−4), and coded-broad (0.74, p = 8.11 × 10–7). The rg between EHR-based BD definitions ranged from 0.90 to 0.98. These results provide the first genetic validation of automated EHR-based phenotyping for BD and suggest that this approach identifies cases that are highly genetically correlated with those ascertained through conventional methods. High throughput phenotyping using the large data resources available in EHRs represents a viable method for accelerating psychiatric genetic research.
Published: 2018

41. Mitochondrial genetic variation and gout in Māori and Pacific people living in Aotearoa New Zealand

Author: Lisa K. Stamp, Tony R. Merriman, Nicola Dalbeth, Eli A. Stahl, Anna L. Gosling, James Boocock, Jennie Harré Hindmarsh, Elizabeth Matisoo-Smith, and Hyon K. Choi
Subjects: Adult, Male, 0301 basic medicine, Mitochondrial DNA, Native Hawaiian or Other Pacific Islander, DNA Copy Number Variations, Gout, Inflammasomes, Immunology, Copy number analysis, Genome, Polynesia, General Biochemistry, Genetics and Molecular Biology, Haplogroup, 03 medical and health sciences, Rheumatology, NLR Family, Pyrin Domain-Containing 3 Protein, Genetic variation, Ethnicity, Humans, Immunology and Allergy, Medicine, Copy-number variation, Genetics, Whole Genome Sequencing, business.industry, Middle Aged, Heteroplasmy, Mitochondria, Hypervariable region, CARD Signaling Adaptor Proteins, 030104 developmental biology, Case-Control Studies, Female, business, New Zealand
Abstract: ObjectiveMitochondria have an important role in the induction of the NLRP3 inflammasome response central in gout. The objective was to test whether mitochondrial genetic variation and copy number in New Zealand Māori and Pacific (Polynesian) people in Aotearoa New Zealand associate with susceptibility to gout.Methods437 whole mitochondrial genomes from Māori and Pacific people (predominantly men) from Aotearoa New Zealand (327 people with gout, 110 without gout) were sequenced. Mitochondrial DNA copy number variation was determined by assessing relative read depth using data produced from whole genome sequencing (32 cases, 43 controls) and targeted resequencing of urate loci (151 cases, 222 controls). Quantitative PCR was undertaken for replication of copy number findings in an extended sample set of 1159 Māori and Pacific men and women (612 cases, 547 controls).ResultsThere was relatively little mitochondrial genetic diversity, with around 96% of those sequenced in this study belonging to the B4a1a and derived sublineages. A B haplogroup heteroplasmy in hypervariable region I was found to associate with a higher risk of gout among the mitochondrial sequenced sample set (position 16181: OR=1.57, P=0.001). Increased copies of mitochondrial DNA were found to protect against gout risk with the effect being consistent when using hyperuricaemic controls across each of the three independent sample sets (OR=0.89, P=0.007; OR=0.90, P=0.002; OR=0.76, P=0.03). Paradoxically, an increase of mitochondrial DNA also associated with an increase in gout flare frequency in people with gout in the two larger sample sets used for the copy number analysis (β=0.003, P=7.1×10–7; β=0.08, P=1.2×10–4).ConclusionAssociation of reduced copy number with gout in hyperuricaemia was replicated over three Polynesian sample sets. Our data are consistent with emerging research showing that mitochondria are important for the colocalisation of the NLRP3 and ASC inflammasome subunits, a process essential for the generation of interleukin-1β in gout.
Published: 2017

42. The Genetic Architecture of Depression in Individuals of East Asian Ancestry

Author: Murray B. Stein, Xiangrui Meng, Yiping Chen, Ming-Chyi Huang, Po-Hsiu Kuo, Niamh Mullins, Robin G. Walters, Arden Moscati, Andrew M. McIntosh, Mei-Hsin Su, Stephan Ripke, Olga Giannakopoulou, Nick Bass, Hsi-Chung Chen, Cathryn M. Lewis, Mong Liang Lu, Chao Tian, Jess Tyrrell, Eli A. Stahl, Robert J. Ursano, Iona Y Millwood, Roseann E. Peterson, Kenneth S. Kendler, Ruth J. F. Loos, Karoline Kuchenbaecker, Ronald C. Kessler, Laura J. Scott, Yu Fang, Kuang Lin, Erin C. Dunn, Margit Burmeister, Swapnil Awasthi, Yunxuan Jiang, Zhengming Chen, Srijan Sen, Jonathan R. I. Coleman, Chun-Hsin Chen, Oral Implantology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Biological Psychology, Amsterdam Neuroscience - Complex Trait Genetics, Complex Trait Genetics, APH - Mental Health, APH - Methodology, AMS - Sports, AMS - Ageing & Vitality, and Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics
Subjects: Adult, Male, DISORDER, SYMPTOMS, LOCI, Genome-wide association study, ASSESS RISK, VARIANTS, BIOBANK, Logistic regression, White People, CHINA, Asian People, DESIGN, Asians/ethnology, SCORE, Online First, Humans, Medicine, Depression (differential diagnoses), Original Investigation, Genetic association, Depressive Disorder, Depressive Disorder/ethnology, Depression, Asia, Eastern, business.industry, Research, Far East/ethnology, Middle Aged, RESILIENCE, Depression/ethnology, Genetic architecture, Psychiatry and Mental health, East Asian Studies, Cohort, Female, business, Body mass index, Comments, Genome-Wide Association Study, Whites/genetics, Demography
Abstract: Key Points Question Are the genetic risk factors for depression the same in individuals of East Asian and European descent? Findings In this genome-wide association meta-analysis of depression in 194 548 individuals with East Asian ancestry, 2 novel genetic associations were identified, one of which is specific to individuals of East Asian descent living in East Asian countries. There was limited evidence for transferability with only 11% of depression loci previously identified in individuals of European descent reaching nominal significance levels in the individuals of East Asian descent. Meaning Caution is advised against generalizing findings about genetic risk factors for depression beyond the studied population., This genetic association study investigates the genetics of depression across multiple data sets of individuals of East Asian and European descent living in different countries and within different nongenetic cultural contexts., Importance Most previous genome-wide association studies (GWAS) of depression have used data from individuals of European descent. This limits the understanding of the underlying biology of depression and raises questions about the transferability of findings between populations. Objective To investigate the genetics of depression among individuals of East Asian and European descent living in different geographic locations, and with different outcome definitions for depression. Design, Setting, and Participants Genome-wide association analyses followed by meta-analysis, which included data from 9 cohort and case-control data sets comprising individuals with depression and control individuals of East Asian descent. This study was conducted between January 2019 and May 2021. Exposures Associations of genetic variants with depression risk were assessed using generalized linear mixed models and logistic regression. The results were combined across studies using fixed-effects meta-analyses. These were subsequently also meta-analyzed with the largest published GWAS for depression among individuals of European descent. Additional meta-analyses were carried out separately by outcome definition (clinical depression vs symptom-based depression) and region (East Asian countries vs Western countries) for East Asian ancestry cohorts. Main Outcomes and Measures Depression status was defined based on health records and self-report questionnaires. Results There were a total of 194 548 study participants (approximate mean age, 51.3 years; 62.8% women). Participants included 15 771 individuals with depression and 178 777 control individuals of East Asian descent. Five novel associations were identified, including 1 in the meta-analysis for broad depression among those of East Asian descent: rs4656484 (β = −0.018, SE = 0.003, P = 4.43x10−8) at 1q24.1. Another locus at 7p21.2 was associated in a meta-analysis restricted to geographically East Asian studies (β = 0.028, SE = 0.005, P = 6.48x10−9 for rs10240457). The lead variants of these 2 novel loci were not associated with depression risk in European ancestry cohorts (β = −0.003, SE = 0.005, P = .53 for rs4656484 and β = −0.005, SE = 0.004, P = .28 for rs10240457). Only 11% of depression loci previously identified in individuals of European descent reached nominal significance levels in the individuals of East Asian descent. The transancestry genetic correlation between cohorts of East Asian and European descent for clinical depression was r = 0.413 (SE = 0.159). Clinical depression risk was negatively genetically correlated with body mass index in individuals of East Asian descent (r = −0.212, SE = 0.084), contrary to findings for individuals of European descent. Conclusions and Relevance These results support caution against generalizing findings about depression risk factors across populations and highlight the need to increase the ancestral and geographic diversity of samples with consistent phenotyping.
Published: 2021

43. 24. WHOLE EXOME SEQUENCING META-ANALYSIS OF DEPRESSION SUGGESTS SUBTLE ROLE FOR FUNCTIONAL VARIANTS IN KNOWN GENETIC ASSOCIATION LOCI

Author: Eli A. Stahl, Arden Moscati, Silvio Alessandro Di Gioia, Lee Dobbyn, Giovanni Coppola, and Veera M. Rajagopal
Subjects: Pharmacology, Genetics, Psychiatry and Mental health, Neurology, Meta-analysis, Pharmacology (medical), Neurology (clinical), Biology, Biological Psychiatry, Depression (differential diagnoses), Exome sequencing, Genetic association
Published: 2021

44. EXOME SEQUENCING IN BIPOLAR DISORDER REVEALS SHARED RISK GENE AKAP11 WITH SCHIZOPHRENIA

Author: Di Florio A, Peter P. Zandi, St. Clair D, Annabel Vreeker, Mikael Landén, Daniel P. Howrigan, Laura J. Scott, Michael Conlon O'Donovan, Benjamin M. Neale, I. Jones, Weiqing Wang, N. Craddock, Fernando S. Goes, Faith Dickerson, Robert H. Yolken, Eli A. Stahl, Nicholas A. Watts, Nancy L. Pedersen, Duncan Palmer, James T.R. Walters, Neil Risch, Aiden Corvin, Lina Jonsson, Chia-Yen Chen, Adam E. Locke, D. H. R. Blackwood, Marco P. Boks, Catherine Schaefer, Tarjinder Singh, Matthew Solomonson, Derrek Morris, L. A. Jones, Andrew McQuillin, Roel A. Ophoff, Rolf Adolfsson, Danielle Posthuma, Andrew M. McIntosh, R.S. Kahn, Sinéad B. Chapman, M J Owen, Claire Churchhouse, N Bass, Xiaoming Jia, Andreas Reif, and Jordan W. Smoller
Subjects: Pharmacology, business.industry, Schizophrenia (object-oriented programming), Risk gene, Computational biology, medicine.disease, Psychiatry and Mental health, Text mining, Neurology, medicine, Pharmacology (medical), Neurology (clinical), Bipolar disorder, business, Biological Psychiatry, Exome sequencing
Published: 2021

45. Population-Specific Resequencing Associates the ATP-Binding Cassette Subfamily C Member 4 Gene With Gout in New Zealand Māori and Pacific Men

Author: Murray Cadzow, Amanda Dobbyn, James Boocock, Ruth Topless, David B. Mount, Hyon K. Choi, Callum Tanner, Nicola Dalbeth, Asim K. Mandal, Amanda Phipps-Green, Jennie Harré Hindmarsh, Lisa K. Stamp, Tony R. Merriman, and Eli A. Stahl
Subjects: 0301 basic medicine, Genetics, education.field_of_study, Immunology, Population, Odds ratio, Biology, medicine.disease, Gout, Excretion, 03 medical and health sciences, chemistry.chemical_compound, 030104 developmental biology, Rheumatology, chemistry, medicine, Immunology and Allergy, Uric acid, Hyperuricemia, Allele, education, Genetic association
Abstract: OBJECTIVE There is no evidence for a genetic association between organic anion transporters 1-3 (SLC22A6, SLC22A7, and SLC22A8) and multidrug resistance protein 4 (MRP4; encoded by ABCC4) with the levels of serum urate or gout. The Māori and Pacific (Polynesian) population of New Zealand has the highest prevalence of gout worldwide. The aim of this study was to determine whether any Polynesian population-specific genetic variants in SLC22A6-8 and ABCC4 are associated with gout. METHODS All participants had ≥3 self-reported Māori and/or Pacific grandparents. Among the total sample set of 1,808 participants, 191 hyperuricemic and 202 normouricemic individuals were resequenced over the 4 genes, and the remaining 1,415 individuals were used for replication. Regression analyses were performed, adjusting for age, sex, and Polynesian ancestry. To study the functional effect of nonsynonymous variants of ABCC4, transport assays were performed in Xenopus laevis oocytes. RESULTS A total of 39 common variants were detected, with an ABCC4 variant (rs4148500) significantly associated with hyperuricemia and gout. This variant was monomorphic for the urate-lowering allele in Europeans. There was evidence for an association of rs4148500 with gout in the resequenced samples (odds ratio [OR] 1.62 [P = 0.012]) that was replicated (OR 1.25 [P = 0.033]) and restricted to men (OR 1.43 [P = 0.001] versus OR 0.98 [P = 0.89] in women). The gout risk allele was associated with fractional excretion of uric acid in male individuals (β = -0.570 [P = 0.01]). A rare population-specific allele (P1036L) with predicted strong functional consequence reduced the uric acid transport activity of ABCC4 by 30%. CONCLUSION An association between ABCC4 and gout and fractional excretion of uric acid is consistent with the established role of MRP4 as a unidirectional renal uric acid efflux pump.
Published: 2017

46. Brief Report: The Role of Rare Protein‐Coding Variants in Anti–Tumor Necrosis Factor Treatment Response in Rheumatoid Arthritis

Author: João Eurico Fonseca, Michelle O'Laughlin, Catrina Fronick, Yukinori Okada, Robert S. Fulton, Soumya Raychaudhuri, Tom W J Huizinga, Eli A. Stahl, Dimitrios A. Pappas, Robert M. Plenge, Peter K. Gregersen, Gertjan Wolbink, Joel M. Kremer, Jeff Greenberg, Corinne Miceli-Richard, David E. Larson, Niek de Vries, Dorothée Diogo, Tracie L. Deluca, Michael T. Nurmohamed, Paul P. Tak, Lucinda Fulton, Anne Barton, Fina A S Kurreeman, Elizabeth W. Karlson, Annette Lee, Helena Canhão, Marieke J H Coenen, Elaine R. Mardis, Xavier Mariette, Irene E. van der Horst-Bruinsma, Jing Cui, J. Bart A. Crusius, Clinical Immunology and Rheumatology, AII - Inflammatory diseases, Amsterdam institute for Infection and Immunity, and Experimental Immunology
Subjects: Male, 0301 basic medicine, Necrosis, Immunology, Alpha (ethology), Bioinformatics, Article, Arthritis, Rheumatoid, Open Reading Frames, 03 medical and health sciences, Text mining, Rheumatology, medicine, Humans, Immunology and Allergy, Coding region, Gene, Tumor Necrosis Factor-alpha, business.industry, Genetic Variation, Middle Aged, medicine.disease, Phenotype, Treatment Outcome, 030104 developmental biology, Rheumatoid arthritis, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], Female, Tumor necrosis factor alpha, medicine.symptom, business
Abstract: Item does not contain fulltext OBJECTIVE: In many rheumatoid arthritis (RA) patients, disease is controlled with anti-tumor necrosis factor (anti-TNF) biologic therapies. However, in a significant number of patients, the disease fails to respond to anti-TNF therapy. We undertook the present study to examine the hypothesis that rare and low-frequency genetic variants might influence response to anti-TNF treatment. METHODS: We sequenced the coding region of 750 genes in 1,094 RA patients of European ancestry who were treated with anti-TNF. After quality control, 690 genes were included in the analysis. We applied single-variant association and gene-based association tests to identify variants associated with anti-TNF treatment response. In addition, given the key mechanistic role of TNF, we performed gene set analyses of 27 TNF pathway genes. RESULTS: We identified 14,420 functional variants, of which 6,934 were predicted as nonsynonymous 2,136 of which were further predicted to be "damaging." Despite the fact that the study was well powered, no single variant or gene showed study-wide significant association with change in the outcome measures disease activity or European League Against Rheumatism response. Intriguingly, we observed 3 genes, of 27 with nominal signals of association (P < 0.05), that were involved in the TNF signaling pathway. However, when we performed a rigorous gene set enrichment analysis based on association P value ranking, we observed no evidence of enrichment of association at genes involved in the TNF pathway (Penrichment = 0.15, based on phenotype permutations). CONCLUSION: Our findings suggest that rare and low-frequency protein-coding variants in TNF signaling pathway genes or other genes do not contribute substantially to anti-TNF treatment response in patients with RA.
Published: 2017

47. 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

48. Characterization of single gene copy number variants in schizophrenia

Author: Jessica S. Johnson, Peter Holmans, Patrick F. Sullivan, Elliott Rees, Menachem Fromer, Sarah E. Bergen, NaEshia Ancalade, Michael Conlon O'Donovan, Jin P. Szatkiewicz, Douglas M. Ruderfer, Michael J. Owen, Eli A. Stahl, James J. Crowley, George Kirov, Christina M. Hultman, Shaun Purcell, Randal J. Nonneman, and Pamela Sklar
Subjects: 0301 basic medicine, endocrine system diseases, DNA Copy Number Variations, Schizophrenia (object-oriented programming), Gene Dosage, Single gene, Biology, Article, 03 medical and health sciences, 0302 clinical medicine, mental disorders, medicine, Humans, Genetic Predisposition to Disease, Copy-number variation, Gene, Genotyping, Biological Psychiatry, Exome sequencing, 030304 developmental biology, Genetics, Sweden, 0303 health sciences, Gene sets, Limiting, Exons, medicine.disease, 030104 developmental biology, Schizophrenia, 030217 neurology & neurosurgery
Abstract: Genetic studies of schizophrenia (SCZ) have now implicated numerous genomic loci that contribute to risk including several copy number variants (CNV) of large effect and hundreds of associated loci of small effect. However, in only a few cases has a specific gene been clearly identified. Rare CNV that affect only a single gene offer a potential avenue to discovering specific SCZ risk genes. Here, we use CNV generated from exome-sequencing of 4,913 SCZ cases and 6,188 controls in a homogenous Swedish cohort to assess the contribution of single-gene deletions and duplications to SCZ risk. As previously seen, we found an excess of rare deletions (p = 0.0004) and duplications (p = 0.0006) in SCZ cases compared to controls. When limiting to only single-gene CNV we identified nominally significant excess of deletions (p = 0.04) and duplications (p = 0.03). In an effort to increase the number of single-gene CNV, we reduced strict filtering criteria but required support from two independent CNV calling methods to create an expanded set that showed a significant burden of deletions in 11 out of 22 gene sets previously implicated in SCZ and in the combined set of genes across those sets (p = 0.008). Finally, for the significantly enriched set of voltage-gated calcium channels, we performed an extensive validation of all deletions generated from exome-sequencing as well as any deletion with evidence from previously analyzed genotyping arrays. In total, 4 exonic, single-gene deletions validated in cases and none in controls (p = 0.039), of which all were identified by exome-sequencing. Broadly, these results point to the potential contribution of single-gene CNV to SCZ and the added value of a deeper dive into CNV calls from exome-sequencing.
Published: 2019

49. Penetrance and pleiotropy of polygenic risk scores for schizophrenia in 106,160 patients across four health care systems

Author: Peter Straub, Christopher F. Chabris, Douglas M. Ruderfer, Laura M. Huckins, Jordan W. Smoller, Chia-Yen Chen, H. Lester Kirchner, Jessica Dennis, Lea K. Davis, Arden Moscati, Tian Ge, Richard Karlsson Linnér, Eli A. Stahl, Amanda B Zheutlin, Victor M. Castro, Alexander W. Charney, Nicole Restrepo, Economics, and Amsterdam Neuroscience - Complex Trait Genetics
Subjects: Male, Multifactorial Inheritance, Schizophrenia (object-oriented programming), Penetrance, Cognitive neuroscience, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Risk Factors, Intervention (counseling), Health care, mental disorders, Medicine, Humans, Genetic Predisposition to Disease, business.industry, Genetic Pleiotropy, Middle Aged, 030227 psychiatry, Psychiatry and Mental health, Pleiotropy (drugs), Risk stratification, Schizophrenia, Polygenic risk score, Female, business, Delivery of Health Care, 030217 neurology & neurosurgery, Clinical psychology
Abstract: Objective: Individuals at high risk for schizophrenia may benefit from early intervention, but few validated risk predictors are available. Genetic profiling is one approach to risk stratification that has been extensively validated in research cohorts. The authors sought to test the utility of this approach in clinical settings and to evaluate the broader health consequences of high genetic risk for schizophrenia. Methods: The authors used electronic health records for 106,160 patients from four health care systems to evaluate the penetrance and pleiotropy of genetic risk for schizophrenia. Polygenic risk scores (PRSs) for schizophrenia were calculated from summary statistics and tested for association with 1,359 disease categories, including schizophrenia and psychosis, in phenome-wide association studies. Effects were combined through meta-analysis across sites. Results: PRSs were robustly associated with schizophrenia (odds ratio per standard deviation increase in PRS, 1.55; 95% CI=1.4, 1.7), and patients in the highest risk decile of the PRS distribution had up to 4.6-fold higher odds of schizophrenia compared with those in the bottom decile (95% CI=2.9, 7.3). PRSs were also positively associated with other phenotypes, including anxiety, mood, substance use, neurological, and personality disorders, as well as suicidal behavior, memory loss, and urinary syndromes; they were inversely related to obesity. Conclusions: The study demonstrates that an available measure of genetic risk for schizophrenia is robustly associated with schizophrenia in health care settings and has pleiotropic effects on related psychiatric disorders as well as other medical syndromes. The results provide an initial indication of the opportunities and limitations that may arise with the future application of PRS testing in health care systems.
Published: 2019

50. Analysis of Genetically Regulated Gene Expression Identifies a Prefrontal PTSD Gene, SNRNP35, Specific to Military Cohorts

Author: Michael S. Breen, Mark W. Logue, Dan J. Stein, Victoria B. Risbrough, Chia-Yen Chen, Stephen J. Glatt, Pamela Sklar, Douglas M. Ruderfer, Nikolaos P. Daskalakis, Torsten Klengel, Chris Chatzinakos, Adriana Lori, Amanda Dobbyn, Silviu-Alin Bacanu, Claudia Klengel, Filomene G. Morrison, Laura G. Sloofman, Dewleen G. Baker, Laramie E. Duncan, Eli A. Stahl, Laura M. Huckins, Manolis Kellis, Israel Liberzon, Caroline M. Nievergelt, Ana C da Silva Almeida, Mark W. Miller, Joseph D. Buxbaum, Gabriel E. Hoffman, Karestan C. Koenen, Kiran Girdhar, Mark A. Geyer, Jordan W. Smoller, Adam X. Maihofer, Tanja Jovanovic, Sanne J.H. van Rooij, Hae Kyung Im, Jakob Hartmann, Kerry J. Ressler, Nancy J. Cox, Hoang T. Nguyen, Rachel Yehuda, Yongjin Park, and Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory
Subjects: Male, 0301 basic medicine, Medical Physiology, Genome-wide association study, Inbred C57BL, Dexamethasone, Stress Disorders, Post-Traumatic, Cohort Studies, Transcriptome, Mice, 0302 clinical medicine, Gene expression, Leukocytes, GWAS, Gene Regulatory Networks, RNA, Small Interfering, Prefrontal cortex, lcsh:QH301-705.5, military, Stress Disorders, Genetics, Gene knockdown, PTSD, Ribonucleoproteins, Small Nuclear, Post-Traumatic Stress Disorder (PTSD), Military Personnel, Mental Health, trauma, medicine.anatomical_structure, Ribonucleoproteins, Neurological, RNA Interference, civilian, 1.1 Normal biological development and functioning, Prefrontal Cortex, Down-Regulation, Biology, Small Interfering, Article, General Biochemistry, Genetics and Molecular Biology, Transcriptomic Imputation, 03 medical and health sciences, splicing, Small Nuclear, blood, Underpinning research, medicine, Animals, Humans, sex, Genetic Predisposition to Disease, Gene, Genetic heterogeneity, Neurosciences, transcriptomic imputation, Brain Disorders, Mice, Inbred C57BL, Repressor Proteins, Dorsolateral prefrontal cortex, 030104 developmental biology, Gene Expression Regulation, lcsh:Biology (General), Case-Control Studies, Post-Traumatic, RNA, glucocorticoid, Biochemistry and Cell Biology, PTSD Working Group of Psychiatric Genomics Consortium, 030217 neurology & neurosurgery
Abstract: Summary: To reveal post-traumatic stress disorder (PTSD) genetic risk influences on tissue-specific gene expression, we use brain and non-brain transcriptomic imputation. We impute genetically regulated gene expression (GReX) in 29,539 PTSD cases and 166,145 controls from 70 ancestry-specific cohorts and identify 18 significant GReX-PTSD associations corresponding to specific tissue-gene pairs. The results suggest substantial genetic heterogeneity based on ancestry, cohort type (military versus civilian), and sex. Two study-wide significant PTSD associations are identified in European and military European cohorts; ZNF140 is predicted to be upregulated in whole blood, and SNRNP35 is predicted to be downregulated in dorsolateral prefrontal cortex, respectively. In peripheral leukocytes from 175 marines, the observed PTSD differential gene expression correlates with the predicted differences for these individuals, and deployment stress produces glucocorticoid-regulated expression changes that include downregulation of both ZNF140 and SNRNP35. SNRNP35 knockdown in cells validates its functional role in U12-intron splicing. Finally, exogenous glucocorticoids in mice downregulate prefrontal Snrnp35 expression.
Published: 2019

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