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

Author

Blokland, Gabriëlla AM, Grove, Jakob, Chen, Chia-Yen, Cotsapas, Chris, Tobet, Stuart, Handa, Robert, Schizophrenia Working Group of the Psychiatric Genomics Consortium, St Clair, David, Lencz, Todd, Mowry, Bryan J, Periyasamy, Sathish, Cairns, Murray J, Tooney, Paul A, Wu, Jing Qin, Kelly, Brian, Kirov, George, Sullivan, Patrick F, Corvin, Aiden, Riley, Brien P, Esko, Tõnu, Milani, Lili, Jönsson, Erik G, Palotie, Aarno, Ehrenreich, Hannelore, Begemann, Martin, Steixner-Kumar, Agnes, Sham, Pak C, Iwata, Nakao, Weinberger, Daniel R, Gejman, Pablo V, Sanders, Alan R, Buxbaum, Joseph D, Rujescu, Dan, Giegling, Ina, Konte, Bettina, Hartmann, Annette M, Bramon, Elvira, Murray, Robin M, Pato, Michele T, Lee, Jimmy, Melle, Ingrid, Molden, Espen, Ophoff, Roel A, McQuillin, Andrew, Bass, Nicholas J, Adolfsson, Rolf, Malhotra, Anil K, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Martin, Nicholas G, Fullerton, Janice M, Mitchell, Philip B, Schofield, Peter R, Forstner, Andreas J, Degenhardt, Franziska, Schaupp, Sabrina, Comes, Ashley L, Kogevinas, Manolis, Guzman-Parra, José, Reif, Andreas, Streit, Fabian, Sirignano, Lea, Cichon, Sven, Grigoroiu-Serbanescu, Maria, Hauser, Joanna, Lissowska, Jolanta, Mayoral, Fermin, Müller-Myhsok, Bertram, Świątkowska, Beata, Schulze, Thomas G, Nöthen, Markus M, Rietschel, Marcella, Kelsoe, John, Leboyer, Marion, Jamain, Stéphane, Etain, Bruno, Bellivier, Frank, Vincent, John B, Alda, Martin, O'Donovan, Claire, Cervantes, Pablo, Biernacka, Joanna M, Frye, Mark, McElroy, Susan L, Scott, Laura J, Stahl, Eli A, Landén, Mikael, Hamshere, Marian L, Smeland, Olav B, Djurovic, Srdjan, Vaaler, Arne E, Andreassen, Ole A, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Baune, Bernhard T, Air, Tracy, Preisig, Martin, Uher, Rudolf, Levinson, Douglas F, Weissman, Myrna M, Potash, James B, and Shi, Jianxin

Subjects
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, Endothelial Cells, Humans, Genetic Predisposition to Disease, Receptors, Vascular Endothelial Growth Factor, Sulfurtransferases, Bipolar Disorder, Depressive Disorder, Major, Psychotic Disorders, Schizophrenia, Sex Characteristics, Polymorphism, Single Nucleotide, Female, Male, Genome-Wide Association Study, Bipolar disorder, Genome-wide association study, Genotype-by-sex interaction, Major depressive disorder, Sex differences, Serious Mental Illness, Biotechnology, Mental Health, Genetics, Human Genome, Neurosciences, Brain Disorders, 2.1 Biological and endogenous factors, Aetiology, Mental health, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
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 (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.ResultsAcross 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).ConclusionsIn 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

2. GWAS of Suicide Attempt in Psychiatric Disorders and Association With Major Depression Polygenic Risk Scores

Author

Mullins, Niamh, Bigdeli, Tim B, Børglum, Anders D, Coleman, Jonathan RI, Demontis, Ditte, Mehta, Divya, Power, Robert A, Ripke, Stephan, Stahl, Eli A, Starnawska, Anna, Anjorin, Adebayo, Corvin, Aiden, Sanders, Alan R, Forstner, Andreas J, Reif, Andreas, Koller, Anna C, Świątkowska, Beata, Baune, Bernhard T, Müller-Myhsok, Bertram, Penninx, Brenda WJH, Pato, Carlos, Zai, Clement, Rujescu, Dan, Hougaard, David M, Quested, Digby, Levinson, Douglas F, Binder, Elisabeth B, Byrne, Enda M, Agerbo, Esben, Streit, Fabian, Mayoral, Fermin, Bellivier, Frank, Degenhardt, Franziska, Breen, Gerome, Morken, Gunnar, Turecki, Gustavo, Rouleau, Guy A, Grabe, Hans J, Völzke, Henry, Jones, Ian, Giegling, Ina, Agartz, Ingrid, Melle, Ingrid, Lawrence, Jacob, Walters, James TR, Strohmaier, Jana, Shi, Jianxin, Hauser, Joanna, Biernacka, Joanna M, Vincent, John B, Kelsoe, John, Strauss, John S, Lissowska, Jolanta, Pimm, Jonathan, Smoller, Jordan W, Guzman-Parra, José, Berger, Klaus, Scott, Laura J, Jones, Lisa A, Azevedo, M Helena, Trzaskowski, Maciej, Kogevinas, Manolis, Rietschel, Marcella, Boks, Marco, Ising, Marcus, Grigoroiu-Serbanescu, Maria, Hamshere, Marian L, Leboyer, Marion, Frye, Mark, Nöthen, Markus M, Alda, Martin, Preisig, Martin, Nordentoft, Merete, Boehnke, Michael, O’Donovan, Michael C, Owen, Michael J, Pato, Michele T, Renteria, Miguel E, Budde, Monika, Weissman, Myrna M, Wray, Naomi R, Bass, Nicholas, Craddock, Nicholas, Smeland, Olav B, Andreassen, Ole A, Mors, Ole, Gejman, Pablo V, Sklar, Pamela, McGrath, Patrick, Hoffmann, Per, McGuffin, Peter, Lee, Phil H, Mortensen, Preben Bo, Kahn, René S, Ophoff, Roel A, Adolfsson, Rolf, Van der Auwera, Sandra, Djurovic, Srdjan, Kloiber, Stefan, and Heilmann-Heimbach, Stefanie

Subjects
Prevention, Suicide, Serious Mental Illness, Schizophrenia, Human Genome, Depression, Mental Health, Genetics, Brain Disorders, Aetiology, 2.3 Psychological, social and economic factors, 2.1 Biological and endogenous factors, Mental health, Good Health and Well Being, Bipolar Disorder, Case-Control Studies, Depressive Disorder, Major, Female, Genome-Wide Association Study, Humans, Male, Multifactorial Inheritance, Risk Factors, Suicide, Attempted, M.R.C.Psych, Dr.Med.Sc, Dipl.-Psych, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Mood Disorders, Polygenic Risk Scoring, Psychiatric Genomics Consortium, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

ObjectiveMore than 90% of people who attempt suicide have a psychiatric diagnosis; however, twin and family studies suggest that the genetic etiology of suicide attempt is partially distinct from that of the psychiatric disorders themselves. The authors present the largest genome-wide association study (GWAS) on suicide attempt, using cohorts of individuals with major depressive disorder, bipolar disorder, and schizophrenia from the Psychiatric Genomics Consortium.MethodsThe samples comprised 1,622 suicide attempters and 8,786 nonattempters with major depressive disorder; 3,264 attempters and 5,500 nonattempters with bipolar disorder; and 1,683 attempters and 2,946 nonattempters with schizophrenia. A GWAS on suicide attempt was performed by comparing attempters to nonattempters with each disorder, followed by a meta-analysis across disorders. Polygenic risk scoring was used to investigate the genetic relationship between suicide attempt and the psychiatric disorders.ResultsThree genome-wide significant loci for suicide attempt were found: one associated with suicide attempt in major depressive disorder, one associated with suicide attempt in bipolar disorder, and one in the meta-analysis of suicide attempt in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with suicide attempt in major depressive disorder (R2=0.25%), bipolar disorder (R2=0.24%), and schizophrenia (R2=0.40%).ConclusionsThis study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size may help to robustly identify genetic associations and provide biological insights into the etiology of suicide attempt.

Published
2019

3. 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

4. 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, GERAD1 Consortium, CRESTAR Consortium, Collier, David A, Rujescu, Dan, Kirov, George, Owen, Michael J, O'Donovan, Michael C, and Walters, James TR

Subjects
GERAD1 Consortium, CRESTAR Consortium, Medical and Health Sciences, Biological 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

5. Genome-wide association study identifies 30 loci associated with bipolar disorder

Author

Stahl, Eli A, Breen, Gerome, Forstner, Andreas J, McQuillin, Andrew, Ripke, Stephan, Trubetskoy, Vassily, Mattheisen, Manuel, Wang, Yunpeng, Coleman, Jonathan RI, Gaspar, Héléna A, de Leeuw, Christiaan A, Steinberg, Stacy, Pavlides, Jennifer M Whitehead, Trzaskowski, Maciej, Byrne, Enda M, Pers, Tune H, Holmans, Peter A, Richards, Alexander L, Abbott, Liam, Agerbo, Esben, Akil, Huda, Albani, Diego, Alliey-Rodriguez, Ney, Als, Thomas D, Anjorin, Adebayo, Antilla, Verneri, Awasthi, Swapnil, Badner, Judith A, Bækvad-Hansen, Marie, Barchas, Jack D, Bass, Nicholas, Bauer, Michael, Belliveau, Richard, Bergen, Sarah E, Pedersen, Carsten Bøcker, Bøen, Erlend, Boks, Marco P, Boocock, James, Budde, Monika, Bunney, William, Burmeister, Margit, Bybjerg-Grauholm, Jonas, Byerley, William, Casas, Miquel, Cerrato, Felecia, Cervantes, Pablo, Chambert, Kimberly, Charney, Alexander W, Chen, Danfeng, Churchhouse, Claire, Clarke, Toni-Kim, Coryell, William, Craig, David W, Cruceanu, Cristiana, Curtis, David, Czerski, Piotr M, Dale, Anders M, de Jong, Simone, Degenhardt, Franziska, Del-Favero, Jurgen, DePaulo, J Raymond, Djurovic, Srdjan, Dobbyn, Amanda L, Dumont, Ashley, Elvsåshagen, Torbjørn, Escott-Price, Valentina, Fan, Chun Chieh, Fischer, Sascha B, Flickinger, Matthew, Foroud, Tatiana M, Forty, Liz, Frank, Josef, Fraser, Christine, Freimer, Nelson B, Frisén, Louise, Gade, Katrin, Gage, Diane, Garnham, Julie, Giambartolomei, Claudia, Pedersen, Marianne Giørtz, Goldstein, Jaqueline, Gordon, Scott D, Gordon-Smith, Katherine, Green, Elaine K, Green, Melissa J, Greenwood, Tiffany A, Grove, Jakob, Guan, Weihua, Guzman-Parra, José, Hamshere, Marian L, Hautzinger, Martin, Heilbronner, Urs, Herms, Stefan, Hipolito, Maria, Hoffmann, Per, Holland, Dominic, Huckins, Laura, Jamain, Stéphane, Johnson, Jessica S, and Juréus, Anders

Subjects
Biological Sciences, Genetics, Serious Mental Illness, Mental Health, Human Genome, Brain Disorders, Schizophrenia, Aetiology, 2.1 Biological and endogenous factors, Mental health, Bipolar Disorder, Case-Control Studies, Depressive Disorder, Major, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide, Psychotic Disorders, Systems Biology, eQTLGen Consortium, BIOS Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P

Published
2019

6. Genome-wide association study identifies 30 loci associated with bipolar disorder.

Author

Stahl, Eli A, Breen, Gerome, Forstner, Andreas J, McQuillin, Andrew, Ripke, Stephan, Trubetskoy, Vassily, Mattheisen, Manuel, Wang, Yunpeng, Coleman, Jonathan RI, Gaspar, Héléna A, de Leeuw, Christiaan A, Steinberg, Stacy, Pavlides, Jennifer M Whitehead, Trzaskowski, Maciej, Byrne, Enda M, Pers, Tune H, Holmans, Peter A, Richards, Alexander L, Abbott, Liam, Agerbo, Esben, Akil, Huda, Albani, Diego, Alliey-Rodriguez, Ney, Als, Thomas D, Anjorin, Adebayo, Antilla, Verneri, Awasthi, Swapnil, Badner, Judith A, Bækvad-Hansen, Marie, Barchas, Jack D, Bass, Nicholas, Bauer, Michael, Belliveau, Richard, Bergen, Sarah E, Pedersen, Carsten Bøcker, Bøen, Erlend, Boks, Marco P, Boocock, James, Budde, Monika, Bunney, William, Burmeister, Margit, Bybjerg-Grauholm, Jonas, Byerley, William, Casas, Miquel, Cerrato, Felecia, Cervantes, Pablo, Chambert, Kimberly, Charney, Alexander W, Chen, Danfeng, Churchhouse, Claire, Clarke, Toni-Kim, Coryell, William, Craig, David W, Cruceanu, Cristiana, Curtis, David, Czerski, Piotr M, Dale, Anders M, de Jong, Simone, Degenhardt, Franziska, Del-Favero, Jurgen, DePaulo, J Raymond, Djurovic, Srdjan, Dobbyn, Amanda L, Dumont, Ashley, Elvsåshagen, Torbjørn, Escott-Price, Valentina, Fan, Chun Chieh, Fischer, Sascha B, Flickinger, Matthew, Foroud, Tatiana M, Forty, Liz, Frank, Josef, Fraser, Christine, Freimer, Nelson B, Frisén, Louise, Gade, Katrin, Gage, Diane, Garnham, Julie, Giambartolomei, Claudia, Pedersen, Marianne Giørtz, Goldstein, Jaqueline, Gordon, Scott D, Gordon-Smith, Katherine, Green, Elaine K, Green, Melissa J, Greenwood, Tiffany A, Grove, Jakob, Guan, Weihua, Guzman-Parra, José, Hamshere, Marian L, Hautzinger, Martin, Heilbronner, Urs, Herms, Stefan, Hipolito, Maria, Hoffmann, Per, Holland, Dominic, Huckins, Laura, Jamain, Stéphane, Johnson, Jessica S, and Juréus, Anders

Subjects
eQTLGen Consortium, BIOS Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Humans, Genetic Predisposition to Disease, Case-Control Studies, Bipolar Disorder, Depressive Disorder, Major, Psychotic Disorders, Schizophrenia, Systems Biology, Polymorphism, Single Nucleotide, Female, Male, Genome-Wide Association Study, Genetic Loci, Serious Mental Illness, Genetics, Mental Health, Brain Disorders, Human Genome, 2.1 Biological and endogenous factors, Mental health, Developmental Biology, Biological Sciences, Medical and Health Sciences
Abstract

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P

Published
2019

7. 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

8. 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
GERAD1 Consortium, CRESTAR Consortium, Humans, Genetic Predisposition to Disease, Case-Control Studies, Schizophrenia, Gene Frequency, Inheritance Patterns, Polymorphism, Single Nucleotide, Alleles, Genes, Lethal, Genome-Wide Association Study, Selection, Genetic, Genetic Loci, Polymorphism, Single Nucleotide, Genes, Lethal, Selection, Genetic, Medical and Health Sciences, Biological 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

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

Author

Marshall, Christian R, Howrigan, Daniel P, Merico, Daniele, Thiruvahindrapuram, Bhooma, Wu, Wenting, Greer, Douglas S, Antaki, Danny, Shetty, Aniket, Holmans, Peter A, Pinto, Dalila, Gujral, Madhusudan, Brandler, William M, Malhotra, Dheeraj, Wang, Zhouzhi, Fajarado, Karin V Fuentes, Maile, Michelle S, Ripke, Stephan, Agartz, Ingrid, Albus, Margot, Alexander, Madeline, Amin, Farooq, Atkins, Joshua, Bacanu, Silviu A, Belliveau, Richard A, Bergen, Sarah E, Bertalan, Marcelo, Bevilacqua, Elizabeth, Bigdeli, Tim B, Black, Donald W, Bruggeman, Richard, Buccola, Nancy G, Buckner, Randy L, Bulik-Sullivan, Brendan, Byerley, William, Cahn, Wiepke, Cai, Guiqing, Cairns, Murray J, Campion, Dominique, Cantor, Rita M, Carr, Vaughan J, Carrera, Noa, Catts, Stanley V, Chambert, Kimberley D, Cheng, Wei, Cloninger, C Robert, Cohen, David, Cormican, Paul, Craddock, Nick, Crespo-Facorro, Benedicto, Crowley, James J, Curtis, David, Davidson, Michael, Davis, Kenneth L, Degenhardt, Franziska, Del Favero, Jurgen, DeLisi, Lynn E, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Dudbridge, Frank, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Essioux, Laurent, Fanous, Ayman H, Farh, Kai-How, Farrell, Martilias S, Frank, Josef, Franke, Lude, Freedman, Robert, Freimer, Nelson B, Friedman, Joseph I, Forstner, Andreas J, Fromer, Menachem, Genovese, Giulio, Georgieva, Lyudmila, Gershon, Elliot S, Giegling, Ina, Giusti-Rodríguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I, Gratten, Jacob, de Haan, Lieuwe, Hamshere, Marian L, Hansen, Mark, Hansen, Thomas, Haroutunian, Vahram, Hartmann, Annette M, Henskens, Frans A, Herms, Stefan, Hirschhorn, Joel N, Hoffmann, Per, Hofman, Andrea, Huang, Hailiang, Ikeda, Masashi, Joa, Inge, and Kähler, Anna K

Subjects
Serious Mental Illness, Human Genome, Schizophrenia, Genetics, Biotechnology, Prevention, Mental Health, Brain Disorders, 2.1 Biological and endogenous factors, Aetiology, Mental health, Case-Control Studies, DNA Copy Number Variations, Female, Genetic Loci, Genetic Markers, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Risk Factors, Psychosis Endophenotypes International Consortium, CNV and Schizophrenia Working Groups of the Psychiatric Genomics Consortium, Biological Sciences, Medical and Health Sciences, Developmental Biology
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 × 10-15), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 × 10-6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 × 10-11) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 × 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.

Published
2017

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

Author

Marshall, Christian R, Howrigan, Daniel P, Merico, Daniele, Thiruvahindrapuram, Bhooma, Wu, Wenting, Greer, Douglas S, Antaki, Danny, Shetty, Aniket, Holmans, Peter A, Pinto, Dalila, Gujral, Madhusudan, Brandler, William M, Malhotra, Dheeraj, Wang, Zhouzhi, Fajarado, Karin V Fuentes, Maile, Michelle S, Ripke, Stephan, Agartz, Ingrid, Albus, Margot, Alexander, Madeline, Amin, Farooq, Atkins, Joshua, Bacanu, Silviu A, Belliveau, Richard A, Bergen, Sarah E, Bertalan, Marcelo, Bevilacqua, Elizabeth, Bigdeli, Tim B, Black, Donald W, Bruggeman, Richard, Buccola, Nancy G, Buckner, Randy L, Bulik-Sullivan, Brendan, Byerley, William, Cahn, Wiepke, Cai, Guiqing, Cairns, Murray J, Campion, Dominique, Cantor, Rita M, Carr, Vaughan J, Carrera, Noa, Catts, Stanley V, Chambert, Kimberley D, Cheng, Wei, Cloninger, C Robert, Cohen, David, Cormican, Paul, Craddock, Nick, Crespo-Facorro, Benedicto, Crowley, James J, Curtis, David, Davidson, Michael, Davis, Kenneth L, Degenhardt, Franziska, Del Favero, Jurgen, DeLisi, Lynn E, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Dudbridge, Frank, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Essioux, Laurent, Fanous, Ayman H, Farh, Kai-How, Farrell, Martilias S, Frank, Josef, Franke, Lude, Freedman, Robert, Freimer, Nelson B, Friedman, Joseph I, Forstner, Andreas J, Fromer, Menachem, Genovese, Giulio, Georgieva, Lyudmila, Gershon, Elliot S, Giegling, Ina, Giusti-Rodríguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I, Gratten, Jacob, de Haan, Lieuwe, Hamshere, Marian L, Hansen, Mark, Hansen, Thomas, Haroutunian, Vahram, Hartmann, Annette M, Henskens, Frans A, Herms, Stefan, Hirschhorn, Joel N, Hoffmann, Per, Hofman, Andrea, Huang, Hailiang, Ikeda, Masashi, and Joa, Inge

Subjects
Psychosis Endophenotypes International Consortium, CNV and Schizophrenia Working Groups of the Psychiatric Genomics Consortium, Humans, Genetic Predisposition to Disease, Genetic Markers, Risk Factors, Case-Control Studies, Schizophrenia, Genotype, Female, Male, Genome-Wide Association Study, Genetic Loci, DNA Copy Number Variations, Clinical Research, Prevention, Genetics, Human Genome, Mental Health, Brain Disorders, 2.1 Biological and endogenous factors, Developmental Biology, Medical and Health Sciences, Biological Sciences
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 × 10-15), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 × 10-6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 × 10-11) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 × 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.

Published
2017

11. New data and an old puzzle: the negative association between schizophrenia and rheumatoid arthritis

Author

Lee, S Hong, Byrne, Enda M, Hultman, Christina M, Kähler, Anna, Vinkhuyzen, Anna AE, Ripke, Stephan, Andreassen, Ole A, Frisell, Thomas, Gusev, Alexander, Hu, Xinli, Karlsson, Robert, Mantzioris, Vasilis X, McGrath, John J, Mehta, Divya, Stahl, Eli A, Zhao, Qiongyi, Kendler, Kenneth S, Sullivan, Patrick F, Price, Alkes L, O’Donovan, Michael, Okada, Yukinori, Mowry, Bryan J, Raychaudhuri, Soumya, Wray, Naomi R, Byerley, William, Cahn, Wiepke, Cantor, Rita M, Cichon, Sven, Cormican, Paul, Curtis, David, Djurovic, Srdjan, Escott-Price, Valentina, Gejman, Pablo V, Georgieva, Lyudmila, Giegling, Ina, Hansen, Thomas F, Ingason, Andrés, Kim, Yunjung, Konte, Bettina, Lee, Phil H, McIntosh, Andrew, McQuillin, Andrew, Morris, Derek W, Nöthen, Markus M, O’Dushlaine, Colm, Olincy, Ann, Olsen, Line, Pato, Carlos N, Pato, Michele T, Pickard, Benjamin S, Posthuma, Danielle, Rasmussen, Henrik B, Rietschel, Marcella, Rujescu, Dan, Schulze, Thomas G, Silverman, Jeremy M, Thirumalai, Srinivasa, Werge, Thomas, Agartz, Ingrid, Amin, Farooq, Azevedo, Maria H, Bass, Nicholas, Black, Donald W, Blackwood, Douglas HR, Bruggeman, Richard, Buccola, Nancy G, Choudhury, Khalid, Cloninger, Robert C, Corvin, Aiden, Craddock, Nicholas, Daly, Mark J, Datta, Susmita, Donohoe, Gary J, Duan, Jubao, Dudbridge, Frank, Fanous, Ayman, Freedman, Robert, Freimer, Nelson B, Friedl, Marion, Gill, Michael, Gurling, Hugh, De Haan, Lieuwe, Hamshere, Marian L, Hartmann, Annette M, Holmans, Peter A, Kahn, René S, Keller, Matthew C, Kenny, Elaine, Kirov, George K, Krabbendam, Lydia, Krasucki, Robert, Lawrence, Jacob, Lencz, Todd, Levinson, Douglas F, Lieberman, Jeffrey A, Lin, Dan-Yu, Linszen, Don H, Magnusson, Patrik KE, Maier, Wolfgang, and Malhotra, Anil K

Subjects
Epidemiology, Health Sciences, Human Genome, Mental Health, Brain Disorders, Autoimmune Disease, Schizophrenia, Clinical Research, Arthritis, Serious Mental Illness, Genetics, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Mental health, Adolescent, Adult, Arthritis, Rheumatoid, Cohort Studies, Cross-Sectional Studies, Female, Gene-Environment Interaction, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Young Adult, Schizophrenia Working Group of the Psychiatric Genomics Consortium and Rheumatoid Arthritis Consortium International, Schizophrenia Working Group of the Psychiatric Genomics Consortium Authors, Schizophrenia Working Group of the Psychiatric Genomics Consortium Collaborators, Rheumatoid Arthritis Consortium International Authors, Rheumatoid Arthritis Consortium International Collaborators, Statistics, Public Health and Health Services, Public health
Abstract

BackgroundA long-standing epidemiological puzzle is the reduced rate of rheumatoid arthritis (RA) in those with schizophrenia (SZ) and vice versa. Traditional epidemiological approaches to determine if this negative association is underpinned by genetic factors would test for reduced rates of one disorder in relatives of the other, but sufficiently powered data sets are difficult to achieve. The genomics era presents an alternative paradigm for investigating the genetic relationship between two uncommon disorders.MethodsWe use genome-wide common single nucleotide polymorphism (SNP) data from independently collected SZ and RA case-control cohorts to estimate the SNP correlation between the disorders. We test a genotype X environment (GxE) hypothesis for SZ with environment defined as winter- vs summer-born.ResultsWe estimate a small but significant negative SNP-genetic correlation between SZ and RA (-0.046, s.e. 0.026, P = 0.036). The negative correlation was stronger for the SNP set attributed to coding or regulatory regions (-0.174, s.e. 0.071, P = 0.0075). Our analyses led us to hypothesize a gene-environment interaction for SZ in the form of immune challenge. We used month of birth as a proxy for environmental immune challenge and estimated the genetic correlation between winter-born and non-winter born SZ to be significantly less than 1 for coding/regulatory region SNPs (0.56, s.e. 0.14, P = 0.00090).ConclusionsOur results are consistent with epidemiological observations of a negative relationship between SZ and RA reflecting, at least in part, genetic factors. Results of the month of birth analysis are consistent with pleiotropic effects of genetic variants dependent on environmental context.

Published
2015

12. Biological insights from 108 schizophrenia-associated genetic loci

Author

Ripke, Stephan, Neale, Benjamin M, Corvin, Aiden, Walters, James TR, Farh, Kai-How, Holmans, Peter A, Lee, Phil, Bulik-Sullivan, Brendan, Collier, David A, Huang, Hailiang, Pers, Tune H, Agartz, Ingrid, Agerbo, Esben, Albus, Margot, Alexander, Madeline, Amin, Farooq, Bacanu, Silviu A, Begemann, Martin, Belliveau, Richard A Jr, Bene, Judit, Bergen, Sarah E, Bevilacqua, Elizabeth, Bigdeli, Tim B, Black, Donald W, Bruggeman, Richard, Buccola, Nancy G, Buckner, Randy L, Byerley, William, Cahn, Wiepke, Cai, Guiqing, Campion, Dominique, Cantor, Rita M, Carr, Vaughan J, Carrera, Noa, Catts, Stanley V, Chambert, Kimberly D, Chan, Raymond CK, Chen, Ronald YL, Chen, Eric YH, Cheng, Wei, Cheung, Eric FC, Chong, Siow Ann, Cloninger, C Robert, Cohen, David, Cohen, Nadine, Cormican, Paul, Craddock, Nick, Crowley, James J, Curtis, David, Davidson, Michael, Davis, Kenneth L, Degenhardt, Franziska, Del Favero, Jurgen, Demontis, Ditte, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Dudbridge, Frank, Durmishi, Naser, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Essioux, Laurent, Fanous, Ayman H, Farrell, Martilias S, Frank, Josef, Franke, Lude, Freedman, Robert, Freimer, Nelson B, Friedl, Marion, Friedman, Joseph I, Fromer, Menachem, Genovese, Giulio, Georgieva, Lyudmila, Giegling, Ina, Giusti-Rodriguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I, Golimbet, Vera, Gopal, Srihari, Gratten, Jacob, de Haan, Lieuwe, Hammer, Christian, Hamshere, Marian L, Hansen, Mark, Hansen, Thomas, Haroutunian, Vahram, Hartmann, Annette M, Henskens, Frans A, Herms, Stefan, Hirschhorn, Joel N, Hoffmann, Per, Hofman, Andrea, Hollegaard, Mads V, Hougaard, David M, Ikeda, Masashi, and Joa, Inge

Subjects
Human Genome, Brain Disorders, Serious Mental Illness, Prevention, Schizophrenia, Genetics, Neurosciences, Mental Health, 2.1 Biological and endogenous factors, Aetiology, Mental health, Alleles, Brain, Enhancer Elements, Genetic, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Glutamic Acid, Humans, Immunity, Multifactorial Inheritance, Mutation, Odds Ratio, Polymorphism, Single Nucleotide, Synaptic Transmission, Schizophrenia Working Group of the Psychiatric Genomics Consortium, General Science & Technology
Abstract

Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.

Published
2014

13. Genome-wide association analysis identifies 13 new risk loci for schizophrenia.

Author

Ripke, Stephan, O'Dushlaine, Colm, Chambert, Kimberly, Moran, Jennifer L, Kähler, Anna K, Akterin, Susanne, Bergen, Sarah E, Collins, Ann L, Crowley, James J, Fromer, Menachem, Kim, Yunjung, Lee, Sang Hong, Magnusson, Patrik KE, Sanchez, Nick, Stahl, Eli A, Williams, Stephanie, Wray, Naomi R, Xia, Kai, Bettella, Francesco, Borglum, Anders D, Bulik-Sullivan, Brendan K, Cormican, Paul, Craddock, Nick, de Leeuw, Christiaan, Durmishi, Naser, Gill, Michael, Golimbet, Vera, Hamshere, Marian L, Holmans, Peter, Hougaard, David M, Kendler, Kenneth S, Lin, Kuang, Morris, Derek W, Mors, Ole, Mortensen, Preben B, Neale, Benjamin M, O'Neill, Francis A, Owen, Michael J, Milovancevic, Milica Pejovic, Posthuma, Danielle, Powell, John, Richards, Alexander L, Riley, Brien P, Ruderfer, Douglas, Rujescu, Dan, Sigurdsson, Engilbert, Silagadze, Teimuraz, Smit, August B, Stefansson, Hreinn, Steinberg, Stacy, Suvisaari, Jaana, Tosato, Sarah, Verhage, Matthijs, Walters, James T, Multicenter Genetic Studies of Schizophrenia Consortium, Levinson, Douglas F, Gejman, Pablo V, Laurent, Claudine, Mowry, Bryan J, O'Donovan, Michael C, Pulver, Ann E, Schwab, Sibylle G, Wildenauer, Dieter B, Dudbridge, Frank, Shi, Jianxin, Albus, Margot, Alexander, Madeline, Campion, Dominique, Cohen, David, Dikeos, Dimitris, Duan, Jubao, Eichhammer, Peter, Godard, Stephanie, Hansen, Mark, Lerer, F Bernard, Liang, Kung-Yee, Maier, Wolfgang, Mallet, Jacques, Nertney, Deborah A, Nestadt, Gerald, Norton, Nadine, Papadimitriou, George N, Ribble, Robert, Sanders, Alan R, Silverman, Jeremy M, Walsh, Dermot, Williams, Nigel M, Wormley, Brandon, Psychosis Endophenotypes International Consortium, Arranz, Maria J, Bakker, Steven, Bender, Stephan, Bramon, Elvira, and Collier, David

Subjects
Multicenter Genetic Studies of Schizophrenia Consortium, Psychosis Endophenotypes International Consortium, Wellcome Trust Case Control Consortium 2, Humans, Genetic Predisposition to Disease, Case-Control Studies, Schizophrenia, Polymorphism, Single Nucleotide, Sweden, Female, Male, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Developmental Biology, Biological Sciences, Medical and Health Sciences
Abstract

Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder.

Published
2013

14. High Loading of Polygenic Risk for ADHD in Children With Comorbid Aggression

Author

Hamshere, Marian L, Langley, Kate, Martin, Joanna, Agha, Sharifah Shameem, Stergiakouli, Evangelia, Anney, Richard JL, Buitelaar, Jan, Faraone, Stephen V, Lesch, Klaus-Peter, Neale, Benjamin M, Franke, Barbara, Sonuga-Barke, Edmund, Asherson, Philip, Merwood, Andrew, Kuntsi, Jonna, Medland, Sarah E, Ripke, Stephan, Steinhausen, Hans-Christoph, Freitag, Christine, Reif, Andreas, Renner, Tobias J, Romanos, Marcel, Romanos, Jasmin, Warnke, Andreas, Meyer, Jobst, Palmason, Haukur, Vasquez, Alejandro Arias, Lambregts-Rommelse, Nanda, Roeyers, Herbert, Biederman, Joseph, Doyle, Alysa E, Hakonarson, Hakon, Rothenberger, Aribert, Banaschewski, Tobias, Oades, Robert D, McGough, James J, Kent, Lindsey, Williams, Nigel, Owen, Michael J, Holmans, Peter, O’Donovan, Michael C, and Thapar, Anita

Subjects
Prevention, Behavioral and Social Science, Human Genome, Genetics, Mental Health, Attention Deficit Hyperactivity Disorder (ADHD), Clinical Research, Brain Disorders, Pediatric, Aetiology, 2.1 Biological and endogenous factors, Mental health, Aggression, Anxiety Disorders, Attention Deficit Disorder with Hyperactivity, Child, Child, Preschool, Comorbidity, Conduct Disorder, Depressive Disorder, Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Male, Multifactorial Inheritance, United Kingdom, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

OBJECTIVE Although attention deficit hyperactivity disorder (ADHD) is highly heritable, genome-wide association studies (GWAS) have not yet identified any common genetic variants that contribute to risk. There is evidence that aggression or conduct disorder in children with ADHD indexes higher genetic loading and clinical severity. The authors examine whether common genetic variants considered en masse as polygenic scores for ADHD are especially enriched in children with comorbid conduct disorder. METHOD Polygenic scores derived from an ADHD GWAS meta-analysis were calculated in an independent ADHD sample (452 case subjects, 5,081 comparison subjects). Multivariate logistic regression analyses were employed to compare polygenic scores in the ADHD and comparison groups and test for higher scores in ADHD case subjects with comorbid conduct disorder relative to comparison subjects and relative to those without comorbid conduct disorder. Association with symptom scores was tested using linear regression. RESULTS Polygenic risk for ADHD, derived from the meta-analysis, was higher in the independent ADHD group than in the comparison group. Polygenic score was significantly higher in ADHD case subjects with conduct disorder relative to ADHD case subjects without conduct disorder. ADHD polygenic score showed significant association with comorbid conduct disorder symptoms. This relationship was explained by the aggression items. CONCLUSIONS Common genetic variation is relevant to ADHD, especially in individuals with comorbid aggression. The findings suggest that the previously published ADHD GWAS meta-analysis contains weak but true associations with common variants, support for which falls below genome-wide significance levels. The findings also highlight the fact that aggression in ADHD indexes genetic as well as clinical severity.

Published
2013

15. High loading of polygenic risk for ADHD in children with comorbid aggression.

Author

Hamshere, Marian L, Langley, Kate, Martin, Joanna, Agha, Sharifah Shameem, Stergiakouli, Evangelia, Anney, Richard JL, Buitelaar, Jan, Faraone, Stephen V, Lesch, Klaus-Peter, Neale, Benjamin M, Franke, Barbara, Sonuga-Barke, Edmund, Asherson, Philip, Merwood, Andrew, Kuntsi, Jonna, Medland, Sarah E, Ripke, Stephan, Steinhausen, Hans-Christoph, Freitag, Christine, Reif, Andreas, Renner, Tobias J, Romanos, Marcel, Romanos, Jasmin, Warnke, Andreas, Meyer, Jobst, Palmason, Haukur, Vasquez, Alejandro Arias, Lambregts-Rommelse, Nanda, Roeyers, Herbert, Biederman, Joseph, Doyle, Alysa E, Hakonarson, Hakon, Rothenberger, Aribert, Banaschewski, Tobias, Oades, Robert D, McGough, James J, Kent, Lindsey, Williams, Nigel, Owen, Michael J, Holmans, Peter, O'Donovan, Michael C, and Thapar, Anita

Subjects
Humans, Genetic Predisposition to Disease, Aggression, Anxiety Disorders, Attention Deficit Disorder with Hyperactivity, Conduct Disorder, Depressive Disorder, Comorbidity, Multifactorial Inheritance, Child, Child, Preschool, Female, Male, Genetic Variation, United Kingdom, Preschool, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

OBJECTIVE Although attention deficit hyperactivity disorder (ADHD) is highly heritable, genome-wide association studies (GWAS) have not yet identified any common genetic variants that contribute to risk. There is evidence that aggression or conduct disorder in children with ADHD indexes higher genetic loading and clinical severity. The authors examine whether common genetic variants considered en masse as polygenic scores for ADHD are especially enriched in children with comorbid conduct disorder. METHOD Polygenic scores derived from an ADHD GWAS meta-analysis were calculated in an independent ADHD sample (452 case subjects, 5,081 comparison subjects). Multivariate logistic regression analyses were employed to compare polygenic scores in the ADHD and comparison groups and test for higher scores in ADHD case subjects with comorbid conduct disorder relative to comparison subjects and relative to those without comorbid conduct disorder. Association with symptom scores was tested using linear regression. RESULTS Polygenic risk for ADHD, derived from the meta-analysis, was higher in the independent ADHD group than in the comparison group. Polygenic score was significantly higher in ADHD case subjects with conduct disorder relative to ADHD case subjects without conduct disorder. ADHD polygenic score showed significant association with comorbid conduct disorder symptoms. This relationship was explained by the aggression items. CONCLUSIONS Common genetic variation is relevant to ADHD, especially in individuals with comorbid aggression. The findings suggest that the previously published ADHD GWAS meta-analysis contains weak but true associations with common variants, support for which falls below genome-wide significance levels. The findings also highlight the fact that aggression in ADHD indexes genetic as well as clinical severity.

Published
2013

16. Investigating the Contribution of Common Genetic Variants to the Risk and Pathogenesis of ADHD

Author

Stergiakouli, Evangelia, Hamshere, Marian, Holmans, Peter, Langley, Kate, Zaharieva, Irina, Hawi, Ziarah, Kent, Lindsey, Gill, Michael, Williams, Nigel, Owen, Michael J, O'Donovan, Michael, and Thapar, Anita

Subjects
Prevention, Brain Disorders, Mental Health, Biotechnology, Clinical Research, Human Genome, Genetics, Pediatric, Attention Deficit Hyperactivity Disorder (ADHD), 2.1 Biological and endogenous factors, Aetiology, Adolescent, Attention Deficit Disorder with Hyperactivity, Child, Female, Gene Dosage, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Inheritance Patterns, Linkage Disequilibrium, Male, Polymorphism, Single Nucleotide, Receptors, Nicotinic, Risk Assessment, alpha7 Nicotinic Acetylcholine Receptor, deCODE Genetics, Psychiatric GWAS Consortium, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

ObjectiveA major motivation for seeking disease-associated genetic variation is to identify novel risk processes. Although rare copy number variants (CNVs) appear to contribute to attention deficit hyperactivity disorder (ADHD), common risk variants (single-nucleotide polymorphisms [SNPs]) have not yet been detected using genome-wide association studies (GWAS). This raises the concern as to whether future larger-scale, adequately powered GWAS will be worthwhile. The authors undertook a GWAS of ADHD and examined whether associated SNPs, including those below conventional levels of significance, influenced the same biological pathways affected by CNVs.MethodThe authors analyzed genome-wide SNP frequencies in 727 children with ADHD and 5,081 comparison subjects. The gene sets that were enriched in a pathway analysis of the GWAS data (the top 5% of SNPs) were tested for an excess of genes spanned by large, rare CNVs in the children with ADHD.ResultsNo SNP achieved genome-wide significance levels. As previously reported in a subsample of the present study, large, rare CNVs were significantly more common in case subjects than comparison subjects. Thirteen biological pathways enriched for SNP association significantly overlapped with those enriched for rare CNVs. These included cholesterol-related and CNS development pathways. At the level of individual genes, CHRNA7, which encodes a nicotinic receptor subunit previously implicated in neuropsychiatric disorders, was affected by six large duplications in case subjects (none in comparison subjects), and SNPs in the gene had a gene-wide p value of 0.0002 for association in the GWAS.ConclusionsBoth common and rare genetic variants appear to be relevant to ADHD and index-shared biological pathways.

Published
2012

17. Investigating the contribution of common genetic variants to the risk and pathogenesis of ADHD.

Author

Stergiakouli, Evangelia, Hamshere, Marian, Holmans, Peter, Langley, Kate, Zaharieva, Irina, deCODE Genetics, Psychiatric GWAS Consortium, Hawi, Ziarah, Kent, Lindsey, Gill, Michael, Williams, Nigel, Owen, Michael J, O'Donovan, Michael, and Thapar, Anita

Subjects
deCODE Genetics, Psychiatric GWAS Consortium, Humans, Genetic Predisposition to Disease, Receptors, Nicotinic, Risk Assessment, Attention Deficit Disorder with Hyperactivity, Gene Dosage, Inheritance Patterns, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Adolescent, Child, Female, Male, Genome-Wide Association Study, alpha7 Nicotinic Acetylcholine Receptor, Receptors, Nicotinic, Polymorphism, Single Nucleotide, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

ObjectiveA major motivation for seeking disease-associated genetic variation is to identify novel risk processes. Although rare copy number variants (CNVs) appear to contribute to attention deficit hyperactivity disorder (ADHD), common risk variants (single-nucleotide polymorphisms [SNPs]) have not yet been detected using genome-wide association studies (GWAS). This raises the concern as to whether future larger-scale, adequately powered GWAS will be worthwhile. The authors undertook a GWAS of ADHD and examined whether associated SNPs, including those below conventional levels of significance, influenced the same biological pathways affected by CNVs.MethodThe authors analyzed genome-wide SNP frequencies in 727 children with ADHD and 5,081 comparison subjects. The gene sets that were enriched in a pathway analysis of the GWAS data (the top 5% of SNPs) were tested for an excess of genes spanned by large, rare CNVs in the children with ADHD.ResultsNo SNP achieved genome-wide significance levels. As previously reported in a subsample of the present study, large, rare CNVs were significantly more common in case subjects than comparison subjects. Thirteen biological pathways enriched for SNP association significantly overlapped with those enriched for rare CNVs. These included cholesterol-related and CNS development pathways. At the level of individual genes, CHRNA7, which encodes a nicotinic receptor subunit previously implicated in neuropsychiatric disorders, was affected by six large duplications in case subjects (none in comparison subjects), and SNPs in the gene had a gene-wide p value of 0.0002 for association in the GWAS.ConclusionsBoth common and rare genetic variants appear to be relevant to ADHD and index-shared biological pathways.

Published
2012

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