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

Author

Singh, Tarjinder, Poterba, Timothy, Curtis, David, Akil, Huda, Al Eissa, Mariam, Barchas, Jack D, Bass, Nicholas, Bigdeli, Tim B, Breen, Gerome, Bromet, Evelyn J, Buckley, Peter F, Bunney, William E, Bybjerg-Grauholm, Jonas, Byerley, William F, Chapman, Sinéad B, Chen, Wei J, Churchhouse, Claire, Craddock, Nicholas, Cusick, Caroline M, DeLisi, Lynn, Dodge, Sheila, Escamilla, Michael A, Eskelinen, Saana, Fanous, Ayman H, Faraone, Stephen V, Fiorentino, Alessia, Francioli, Laurent, Gabriel, Stacey B, Gage, Diane, Gagliano Taliun, Sarah A, Ganna, Andrea, Genovese, Giulio, Glahn, David C, Grove, Jakob, Hall, Mei-Hua, Hämäläinen, Eija, Heyne, Henrike O, Holi, Matti, Hougaard, David M, Howrigan, Daniel P, Huang, Hailiang, Hwu, Hai-Gwo, Kahn, René S, Kang, Hyun Min, Karczewski, Konrad J, Kirov, George, Knowles, James A, Lee, Francis S, Lehrer, Douglas S, Lescai, Francesco, Malaspina, Dolores, Marder, Stephen R, McCarroll, Steven A, McIntosh, Andrew M, Medeiros, Helena, Milani, Lili, Morley, Christopher P, Morris, Derek W, Mortensen, Preben Bo, Myers, Richard M, Nordentoft, Merete, O'Brien, Niamh L, Olivares, Ana Maria, Ongur, Dost, Ouwehand, Willem H, Palmer, Duncan S, Paunio, Tiina, Quested, Digby, Rapaport, Mark H, Rees, Elliott, Rollins, Brandi, Satterstrom, F Kyle, Schatzberg, Alan, Scolnick, Edward, Scott, Laura J, Sharp, Sally I, Sklar, Pamela, Smoller, Jordan W, Sobell, Janet L, Solomonson, Matthew, Stahl, Eli A, Stevens, Christine R, Suvisaari, Jaana, Tiao, Grace, Watson, Stanley J, Watts, Nicholas A, Blackwood, Douglas H, Børglum, Anders D, Cohen, Bruce M, Corvin, Aiden P, Esko, Tõnu, Freimer, Nelson B, Glatt, Stephen J, Hultman, Christina M, McQuillin, Andrew, Palotie, Aarno, Pato, Carlos N, Pato, Michele T, Pulver, Ann E, and St Clair, David

Subjects
Humans, Genetic Predisposition to Disease, Receptors, N-Methyl-D-Aspartate, Case-Control Studies, Schizophrenia, Mutation, Exome, Neurodevelopmental Disorders, Human Genome, Biotechnology, Mental Health, Neurosciences, Brain Disorders, Genetics, Serious Mental Illness, Aetiology, 2.1 Biological and endogenous factors, Mental health, Neurological, General Science & Technology
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

Published
2022

6. Schizophrenia, autism spectrum disorders and developmental disorders share specific disruptive coding mutations.

Author

Rees, Elliott, Creeth, Hugo DJ, Hwu, Hai-Gwo, Chen, Wei J, Tsuang, Ming, Glatt, Stephen J, Rey, Romain, Kirov, George, Walters, James TR, Holmans, Peter, Owen, Michael J, and O'Donovan, Michael C

Subjects
Mental Health, Neurosciences, Genetics, Schizophrenia, Serious Mental Illness, Brain Disorders, Intellectual and Developmental Disabilities (IDD), Pediatric, Autism, 2.1 Biological and endogenous factors, Mental health
Abstract

People with schizophrenia are enriched for rare coding variants in genes associated with neurodevelopmental disorders, particularly autism spectrum disorders and intellectual disability. However, it is unclear if the same changes to gene function that increase risk to neurodevelopmental disorders also do so for schizophrenia. Using data from 3444 schizophrenia trios and 37,488 neurodevelopmental disorder trios, we show that within shared risk genes, de novo variants in schizophrenia and neurodevelopmental disorders are generally of the same functional category, and that specific de novo variants observed in neurodevelopmental disorders are enriched in schizophrenia (P = 5.0 × 10-6). The latter includes variants known to be pathogenic for syndromic disorders, suggesting that schizophrenia be included as a characteristic of those syndromes. Our findings imply that, in part, neurodevelopmental disorders and schizophrenia have shared molecular aetiology, and therefore likely overlapping pathophysiology, and support the hypothesis that at least some forms of schizophrenia lie on a continuum of neurodevelopmental disorders.

Published
2021

9. Genetic and Phenotypic Features of Schizophrenia in the UK Biobank

Author

Legge, Sophie E., primary, Pardiñas, Antonio F., additional, Woolway, Grace, additional, Rees, Elliott, additional, Cardno, Alastair G., additional, Escott-Price, Valentina, additional, Holmans, Peter, additional, Kirov, George, additional, Owen, Michael J., additional, O’Donovan, Michael C., additional, and Walters, James T. R., additional

Published
2024
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10. Transcriptional programs regulating neuronal differentiation are disrupted in DLG2 knockout human embryonic stem cells and enriched for schizophrenia and related disorders risk variants

Author

Sanders, Bret, D’Andrea, Daniel, Collins, Mark O., Rees, Elliott, Steward, Tom G. J., Zhu, Ying, Chapman, Gareth, Legge, Sophie E., Pardiñas, Antonio F., Harwood, Adrian J., Gray, William P., O’Donovan, Michael C., Owen, Michael J., Errington, Adam C., Blake, Derek J., Whitcomb, Daniel J., Pocklington, Andrew J., and Shin, Eunju

Published
2022
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11. Exome sequencing of individuals with Huntington’s disease implicates FAN1 nuclease activity in slowing CAG expansion and disease onset

Author

McAllister, Branduff, Donaldson, Jasmine, Binda, Caroline S., Powell, Sophie, Chughtai, Uroosa, Edwards, Gareth, Stone, Joseph, Lobanov, Sergey, Elliston, Linda, Schuhmacher, Laura-Nadine, Rees, Elliott, Menzies, Georgina, Ciosi, Marc, Maxwell, Alastair, Chao, Michael J., Hong, Eun Pyo, Lucente, Diane, Wheeler, Vanessa, Lee, Jong-Min, MacDonald, Marcy E., Long, Jeffrey D., Aylward, Elizabeth H., Landwehrmeyer, G. Bernhard, Rosser, Anne E., Paulsen, Jane S., Williams, Nigel M., Gusella, James F., Monckton, Darren G., Allen, Nicholas D., Holmans, Peter, Jones, Lesley, and Massey, Thomas H.

Published
2022
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12. Publisher Correction: Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection

Author

Pardiñas, Antonio F, Holmans, Peter, Pocklington, Andrew J, Escott-Price, Valentina, Ripke, Stephan, Carrera, Noa, Legge, Sophie E, Bishop, Sophie, Cameron, Darren, Hamshere, Marian L, Han, Jun, Hubbard, Leon, Lynham, Amy, Mantripragada, Kiran, Rees, Elliott, MacCabe, James H, McCarroll, Steven A, Baune, Bernhard T, Breen, Gerome, Byrne, Enda M, Dannlowski, Udo, Eley, Thalia C, Hayward, Caroline, Martin, Nicholas G, McIntosh, Andrew M, Plomin, Robert, Porteous, David J, Wray, Naomi R, Caballero, Armando, Geschwind, Daniel H, Huckins, Laura M, Ruderfer, Douglas M, Santiago, Enrique, Sklar, Pamela, Stahl, Eli A, Won, Hyejung, Agerbo, Esben, Als, Thomas D, Andreassen, Ole A, Bækvad-Hansen, Marie, Mortensen, Preben Bo, Pedersen, Carsten Bøcker, Børglum, Anders D, Bybjerg-Grauholm, Jonas, Djurovic, Srdjan, Durmishi, Naser, Pedersen, Marianne Giørtz, Golimbet, Vera, Grove, Jakob, Hougaard, David M, Mattheisen, Manuel, Molden, Espen, Mors, Ole, Nordentoft, Merete, Pejovic-Milovancevic, Milica, Sigurdsson, Engilbert, Silagadze, Teimuraz, Hansen, Christine Søholm, Stefansson, Kari, Stefansson, Hreinn, Steinberg, Stacy, Tosato, Sarah, Werge, Thomas, Collier, David A, Rujescu, Dan, Kirov, George, Owen, Michael J, O’Donovan, Michael C, and Walters, James TR

Subjects
GERAD1 Consortium, CRESTAR Consortium, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2019

14. Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection

Author

Pardiñas, Antonio F, Holmans, Peter, Pocklington, Andrew J, Escott-Price, Valentina, Ripke, Stephan, Carrera, Noa, Legge, Sophie E, Bishop, Sophie, Cameron, Darren, Hamshere, Marian L, Han, Jun, Hubbard, Leon, Lynham, Amy, Mantripragada, Kiran, Rees, Elliott, MacCabe, James H, McCarroll, Steven A, Baune, Bernhard T, Breen, Gerome, Byrne, Enda M, Dannlowski, Udo, Eley, Thalia C, Hayward, Caroline, Martin, Nicholas G, McIntosh, Andrew M, Plomin, Robert, Porteous, David J, Wray, Naomi R, Caballero, Armando, Geschwind, Daniel H, Huckins, Laura M, Ruderfer, Douglas M, Santiago, Enrique, Sklar, Pamela, Stahl, Eli A, Won, Hyejung, Agerbo, Esben, Als, Thomas D, Andreassen, Ole A, Bækvad-Hansen, Marie, Mortensen, Preben Bo, Pedersen, Carsten Bøcker, Børglum, Anders D, Bybjerg-Grauholm, Jonas, Djurovic, Srdjan, Durmishi, Naser, Pedersen, Marianne Giørtz, Golimbet, Vera, Grove, Jakob, Hougaard, David M, Mattheisen, Manuel, Molden, Espen, Mors, Ole, Nordentoft, Merete, Pejovic-Milovancevic, Milica, Sigurdsson, Engilbert, Silagadze, Teimuraz, Hansen, Christine Søholm, Stefansson, Kari, Stefansson, Hreinn, Steinberg, Stacy, Tosato, Sarah, Werge, Thomas, GERAD1 Consortium, CRESTAR Consortium, Collier, David A, Rujescu, Dan, Kirov, George, Owen, Michael J, O’Donovan, Michael C, and Walters, James TR

Subjects
Serious Mental Illness, Brain Disorders, Human Genome, Genetics, Mental Health, Biotechnology, Schizophrenia, 2.1 Biological and endogenous factors, Aetiology, Mental health, Good Health and Well Being, Alleles, Case-Control Studies, Gene Frequency, Genes, Lethal, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Inheritance Patterns, Polymorphism, Single Nucleotide, Selection, Genetic, GERAD1 Consortium, CRESTAR Consortium, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide insights. We report a new genome-wide association study of schizophrenia (11,260 cases and 24,542 controls), and through meta-analysis with existing data we identify 50 novel associated loci and 145 loci in total. Through integrating genomic fine-mapping with brain expression and chromosome conformation data, we identify candidate causal genes within 33 loci. We also show for the first time that the common variant association signal is highly enriched among genes that are under strong selective pressures. These findings provide new insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation-intolerant genes and suggest a mechanism by which common risk variants persist in the population.

Published
2018

18. Rare Copy Number Variants in NRXN1 and CNTN6 Increase Risk for Tourette Syndrome.

Author

Huang, Alden Y, Yu, Dongmei, Davis, Lea K, Sul, Jae Hoon, Tsetsos, Fotis, Ramensky, Vasily, Zelaya, Ivette, Ramos, Eliana Marisa, Osiecki, Lisa, Chen, Jason A, McGrath, Lauren M, Illmann, Cornelia, Sandor, Paul, Barr, Cathy L, Grados, Marco, Singer, Harvey S, Nöthen, Markus M, Hebebrand, Johannes, King, Robert A, Dion, Yves, Rouleau, Guy, Budman, Cathy L, Depienne, Christel, Worbe, Yulia, Hartmann, Andreas, Müller-Vahl, Kirsten R, Stuhrmann, Manfred, Aschauer, Harald, Stamenkovic, Mara, Schloegelhofer, Monika, Konstantinidis, Anastasios, Lyon, Gholson J, McMahon, William M, Barta, Csaba, Tarnok, Zsanett, Nagy, Peter, Batterson, James R, Rizzo, Renata, Cath, Danielle C, Wolanczyk, Tomasz, Berlin, Cheston, Malaty, Irene A, Okun, Michael S, Woods, Douglas W, Rees, Elliott, Pato, Carlos N, Pato, Michele T, Knowles, James A, Posthuma, Danielle, Pauls, David L, Cox, Nancy J, Neale, Benjamin M, Freimer, Nelson B, Paschou, Peristera, Mathews, Carol A, Scharf, Jeremiah M, Coppola, Giovanni, Tourette Syndrome Association International Consortium for Genetics (TSAICG), and Gilles de la Tourette Syndrome GWAS Replication Initiative (GGRI)

Subjects
Tourette Syndrome Association International Consortium for Genetics, Gilles de la Tourette Syndrome GWAS Replication Initiative, Humans, Tourette Syndrome, Genetic Predisposition to Disease, Calcium-Binding Proteins, Cell Adhesion Molecules, Neuronal, Neural Cell Adhesion Molecules, Nerve Tissue Proteins, Odds Ratio, Case-Control Studies, Genotype, Adolescent, Adult, Child, Female, Male, Genome-Wide Association Study, Young Adult, DNA Copy Number Variations, Contactins, White People, CNTN6, NRXN1, copy number variation, genetics, neurodevelopmental disorders, structural variation, tic disorders, Prevention, Human Genome, Genetics, Brain Disorders, Neurodegenerative, Neurosciences, Mental Health, 2.1 Biological and endogenous factors, Aetiology, Psychology, Cognitive Sciences, Neurology & Neurosurgery
Abstract

Tourette syndrome (TS) is a model neuropsychiatric disorder thought to arise from abnormal development and/or maintenance of cortico-striato-thalamo-cortical circuits. TS is highly heritable, but its underlying genetic causes are still elusive, and no genome-wide significant loci have been discovered to date. We analyzed a European ancestry sample of 2,434 TS cases and 4,093 ancestry-matched controls for rare (< 1% frequency) copy-number variants (CNVs) using SNP microarray data. We observed an enrichment of global CNV burden that was prominent for large (> 1 Mb), singleton events (OR = 2.28, 95% CI [1.39-3.79], p = 1.2 × 10-3) and known, pathogenic CNVs (OR = 3.03 [1.85-5.07], p = 1.5 × 10-5). We also identified two individual, genome-wide significant loci, each conferring a substantial increase in TS risk (NRXN1 deletions, OR = 20.3, 95% CI [2.6-156.2]; CNTN6 duplications, OR = 10.1, 95% CI [2.3-45.4]). Approximately 1% of TS cases carry one of these CNVs, indicating that rare structural variation contributes significantly to the genetic architecture of TS.

Published
2017

20. Characterization of Single Gene Copy Number Variants in Schizophrenia

Author

Szatkiewicz, Jin P., Fromer, Menachem, Nonneman, Randal J., Ancalade, NaEshia, Johnson, Jessica S., Stahl, Eli A., Rees, Elliott, Bergen, Sarah E., Hultman, Christina M., Kirov, George, O’Donovan, Michael, Owen, Michael, Holmans, Peter, Sklar, Pamela, Sullivan, Patrick F., Purcell, Shaun M., Crowley, James J., and Ruderfer, Douglas M.

Published
2020
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21. Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders

Author

Singh, Tarjinder, Kurki, Mitja I, Curtis, David, Purcell, Shaun M, Crooks, Lucy, McRae, Jeremy, Suvisaari, Jaana, Chheda, Himanshu, Blackwood, Douglas, Breen, Gerome, Pietiläinen, Olli, Gerety, Sebastian S, Ayub, Muhammad, Blyth, Moira, Cole, Trevor, Collier, David, Coomber, Eve L, Craddock, Nick, Daly, Mark J, Danesh, John, DiForti, Marta, Foster, Alison, Freimer, Nelson B, Geschwind, Daniel, Johnstone, Mandy, Joss, Shelagh, Kirov, Georg, Körkkö, Jarmo, Kuismin, Outi, Holmans, Peter, Hultman, Christina M, Iyegbe, Conrad, Lönnqvist, Jouko, Männikkö, Minna, McCarroll, Steve A, McGuffin, Peter, McIntosh, Andrew M, McQuillin, Andrew, Moilanen, Jukka S, Moore, Carmel, Murray, Robin M, Newbury-Ecob, Ruth, Ouwehand, Willem, Paunio, Tiina, Prigmore, Elena, Rees, Elliott, Roberts, David, Sambrook, Jennifer, Sklar, Pamela, Clair, David St, Veijola, Juha, Walters, James TR, Williams, Hywel, Sullivan, Patrick F, Hurles, Matthew E, O'Donovan, Michael C, Palotie, Aarno, Owen, Michael J, and Barrett, Jeffrey C

Subjects
Biological Psychology, Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Psychology, Genetics, Serious Mental Illness, Human Genome, Schizophrenia, Biotechnology, Brain Disorders, Mental Health, 2.1 Biological and endogenous factors, Aetiology, Mental health, Case-Control Studies, Cohort Studies, Female, Finland, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Histone-Lysine N-Methyltransferase, Humans, Male, Neurodevelopmental Disorders, Swedish Schizophrenia Study, INTERVAL Study, DDD Study, UK10 K Consortium, Neurosciences, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

By analyzing the whole-exome sequences of 4,264 schizophrenia cases, 9,343 controls and 1,077 trios, we identified a genome-wide significant association between rare loss-of-function (LoF) variants in SETD1A and risk for schizophrenia (P = 3.3 × 10(-9)). We found only two heterozygous LoF variants in 45,376 exomes from individuals without a neuropsychiatric diagnosis, indicating that SETD1A is substantially depleted of LoF variants in the general population. Seven of the ten individuals with schizophrenia carrying SETD1A LoF variants also had learning difficulties. We further identified four SETD1A LoF carriers among 4,281 children with severe developmental disorders and two more carriers in an independent sample of 5,720 Finnish exomes, both with notable neuropsychiatric phenotypes. Together, our observations indicate that LoF variants in SETD1A cause a range of neurodevelopmental disorders, including schizophrenia. Combining these data with previous common variant evidence, we suggest that epigenetic dysregulation, specifically in the histone H3K4 methylation pathway, is an important mechanism in the pathogenesis of schizophrenia.

Published
2016

26. Targeted Sequencing of 10,198 Samples Confirms Abnormalities in Neuronal Activity and Implicates Voltage-Gated Sodium Channels in Schizophrenia Pathogenesis

Author

Alizadeh, Behrooz Z., van Amelsvoort, Therese, Bartels-Velthuis, Agna A., van Beveren, Nico J., Bruggeman, Richard, Cahn, Wiepke, de Haan, Lieuwe, Delespaul, Philippe, Meijer, Carin J., Myin-Germeys, Inez, Kahn, Rene S., Schirmbeck, Frederike, Simons, Claudia J.P., van Haren, Neeltje E., van Os, Jim, van Winkel, Ruud, Luykx, Jurjen J., Rees, Elliott, Carrera, Noa, Morgan, Joanne, Hambridge, Kirsty, Escott-Price, Valentina, Pocklington, Andrew J., Richards, Alexander L., Pardiñas, Antonio F., McDonald, Colm, Donohoe, Gary, Morris, Derek W., Kenny, Elaine, Kelleher, Eric, Gill, Michael, Corvin, Aiden, Kirov, George, Walters, James T.R., Holmans, Peter, Owen, Michael J., and O’Donovan, Michael C.

Published
2019
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28. List of contributors

Author

Agrawal, Anurag, primary, Agrawal, Megha, additional, AlBanyan, Saleh, additional, Baranwal, Ajay Kumar, additional, Behr, Elijah R., additional, Bhatnagar, Deepak, additional, Bose, D., additional, Busi, María V., additional, Chakraborty, Samarpana, additional, Chitayat, David, additional, Craig, Donald P., additional, Das, Reena, additional, Davies, Dyfud Mark, additional, Doctor, Pezad, additional, Garofalidou, Tatiana, additional, Godbole, Koumudi, additional, Gogtay, N.J., additional, Gomez-Casati, Diego F., additional, Gupta, Anubhuti, additional, Haddad, Luciana Amaral, additional, Hamandi, Khalid, additional, Hegde, Shivaram, additional, Hodgson, Shirley V., additional, Kalhan, Atul, additional, Kirov, George, additional, Kleinendorst, Lotte, additional, Kumar, Dhavendra, additional, Lewis-Smith, David, additional, MacIver, Claire, additional, Mehra, Narinder Kumar, additional, Merchant, Rashid, additional, Morgan, Dafydd, additional, Munroe, Patricia B., additional, Ormerod, Julian O.M., additional, Pathan, Saad, additional, Peall, Kathryn J., additional, Ravi, R., additional, Rees, Elliott, additional, Schofield, Jonathan, additional, Shah, Parin, additional, Sharma, Gaurav, additional, Sharma, Prashant, additional, Sinajon, Pierre, additional, Singh, Indu, additional, Singh, Raghu Inder, additional, Soran, Handrean, additional, Stuart, Alan Graham, additional, Thatte, U.M., additional, Thomas, Naomi J.P., additional, Thomas, Rhys H., additional, Tully, IAN, additional, van Haelst, Mieke M., additional, Varaiya, Ami, additional, Yamada, Yoshiji, additional, and Zaidi, Abbas, additional

Published
2020
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45. Rare coding variants in 10 genes confer substantial risk for schizophrenia

Author

Singh, Tarjinder, Poterba, Timothy, Curtis, David, Akil, Huda, Al Eissa, Mariam, Barchas, Jack D., Bass, Nicholas, Bigdeli, Tim B., Breen, Gerome, Bromet, Evelyn J., Buckley, Peter F., Bunney, William E., Bybjerg-Grauholm, Jonas, Byerley, William F., Chapman, Sinéad B., Chen, Wei J., Churchhouse, Claire, Craddock, Nicholas, Cusick, Caroline M., DeLisi, Lynn, Dodge, Sheila, Escamilla, Michael A., Eskelinen, Saana, Fanous, Ayman H., Faraone, Stephen V., Fiorentino, Alessia, Francioli, Laurent, Gabriel, Stacey B., Gage, Diane, Taliun, Sarah A. Gagliano, Ganna, Andrea, Genovese, Giulio, Glahn, David C., Grove, Jakob, Hall, Mei-Hua, Hämäläinen, Eija, Heyne, Henrike O., Holi, Matti, Hougaard, David M., Howrigan, Daniel P., Huang, Hailiang, Hwu, Hai-Gwo, Kahn, René S., Kang, Hyun Min, Karczewski, Konrad J., Kirov, George, Knowles, James A., Lee, Francis S., Lehrer, Douglas S., Lescai, Francesco, Malaspina, Dolores, Marder, Stephen R., McCarroll, Steven A., McIntosh, Andrew M., Medeiros, Helena, Milani, Lili, Morley, Christopher P., Morris, Derek W., Bo Mortensen, Preben, Myers, Richard M., Nordentoft, Merete, O’Brien, Niamh L., Olivares, Ana Maria, Ongur, Dost, Ouwehand, Willem H., Palmer, Duncan S., Paunio, Tiina, Quested, Digby, Rapaport, Mark H., Rees, Elliott, Rollins, Brandi, Satterstrom, F. Kyle, Schatzberg, Alan, Scolnick, Edward, Scott, Laura J., Sharp, Sally I., Sklar, Pamela, Smoller, Jordan W., Sobell, Janet l., Solomonson, Matthew, Stevens, Christine R., Suvisaari, Jaana, Tiao, Grace, Watson, Stanley J., Watts, Nicholas A., Blackwood, Douglas H., Børglum, Anders D., Cohen, Bruce M., Corvin, Aiden P., Esko, Tõnu, Freimer, Nelson B., Glatt, Stephen J., Hultman, Christina M., McQuillin, Andrew, Palotie, Aarno, Pato, Carlos N., Pato, Michele T., Pulver, Ann E., St. Clair, David, Tsuang, Ming T., Vawter, Marquis P., Walters, James T., Werge, Thomas M., Ophoff, Roel A., Sullivan, Patrick F., Owen, Michael J., Boehnke, Michael, O’Donovan, Michael C., Neale, Benjamin M., and Daly, Mark J.

Subjects
Article
Abstract

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analyzing the whole-exomes of 24,248 cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in ten genes as conferring substantial risk for schizophrenia (odds ratios 3 – 50, P < 2.14 × 10(−6)), and 32 genes at a FDR < 5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure, and function of the synapse. The associations of NMDA receptor subunit GRIN2A and AMPA receptor subunit GRIA3 provide support for the dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk between schizophrenia, autism spectrum disorders (ASD)(1), epilepsy and severe neurodevelopmental disorders (DD/ID)(2), though in some shared genes different mutation types are implicated. Most genes described here however are not implicated in neurodevelopment and we demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk(3), suggesting that common and rare genetic risk factors at least partially converge on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, implying that more risk genes await discovery using this approach.

Published
2022

47. De novo mutations identified by exome sequencing implicate rare missense variants in SLC6A1 in schizophrenia

Author

Rees, Elliott, Han, Jun, Morgan, Joanne, Carrera, Noa, Escott-Price, Valentina, Pocklington, Andrew J., Duffield, Madeleine, Hall, Lynsey S., Legge, Sophie E., Pardinas, Antonio F., Richards, Alexander L., Roth, Julian, Lezheiko, Tatyana, Kondratyev, Nikolay, Kaleda, Vasilii, Golimbet, Vera, Parellada, Mara, Gonzalez-Penas, Javier, Arango, Celso, Alizadeh, Behrooz Z., van Amelsvoort, Therese, Bruggeman, Richard, Cahn, Wiepke, de Haan, Lieuwe, Luykx, Jurjen J., Rutten, Bart P. F., van Os, Jim, van Winkel, Ruud, Gawlik, Micha, Kirov, George, Walters, James T. R., Holmans, Peter, O'Donovan, Michael C., Owen, Michael J., Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), ANS - Complex Trait Genetics, Adult Psychiatry, APH - Mental Health, Psychiatrie & Neuropsychologie, MUMC+: MA Med Staf Spec Psychiatrie (9), RS: MHeNs - R2 - Mental Health, MUMC+: MA Psychiatrie (3), and RS: MHeNs - R3 - Neuroscience

Subjects
0301 basic medicine, Proband, Adult, Male, GABA Plasma Membrane Transport Proteins, DISORDERS, Mutation, Missense, Genome-wide association study, Biology, medicine.disease_cause, Article, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, Exome Sequencing, mental disorders, medicine, Missense mutation, Humans, Genetic Predisposition to Disease, Bipolar disorder, COMMON, Exome sequencing, Genetics, RISK, Mutation, ARCHITECTURE, General Neuroscience, ASSOCIATION, medicine.disease, FRAMEWORK, INDIVIDUALS, INSIGHTS, 030104 developmental biology, Schizophrenia, Female, BURDEN, Neuroscience, 030217 neurology & neurosurgery
Abstract

Schizophrenia is a highly polygenic disorder with important contributions from both common and rare risk alleles. We analyzed exome sequencing data for de novo variants (DNVs) in a new sample of 613 schizophrenia trios and combined this with published data to give a total of 3,444 trios. In this new data, loss-of-function (LoF) DNVs were significantly enriched among 3,471 LoF-intolerant genes, which supports previous findings. In the full dataset, genes associated with neurodevelopmental disorders (n = 159) were significantly enriched for LoF DNVs. Within these neurodevelopmental disorder genes, SLC6A1, which encodes a γ-aminobutyric acid transporter, was associated with missense-damaging DNVs. In 1,122 trios for which genome-wide common variant data were available, schizophrenia and bipolar disorder polygenic risk were significantly overtransmitted to probands. Probands carrying LoF or deletion DNVs in LoF-intolerant or neurodevelopmental disorder genes had significantly less overtransmission of schizophrenia polygenic risk than did non-carriers, which provides a second robust line of evidence that these DNVs increase liability to schizophrenia.

Published
2020

50. Associations Between Schizophrenia Polygenic Liability, Symptom Dimensions, and Cognitive Ability in Schizophrenia

Author

Legge, Sophie E., primary, Cardno, Alastair G., additional, Allardyce, Judith, additional, Dennison, Charlotte, additional, Hubbard, Leon, additional, Pardiñas, Antonio F., additional, Richards, Alexander, additional, Rees, Elliott, additional, Di Florio, Arianna, additional, Escott-Price, Valentina, additional, Zammit, Stanley, additional, Holmans, Peter, additional, Owen, Michael J., additional, O’Donovan, Michael C., additional, and Walters, James T. R., additional

Published
2021
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