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1. A polygenic risk score for alcohol-associated cirrhosis among heavy drinkers with European ancestry.

Author

Schwantes-An, Tae-Hwi, Whitfield, John, Aithal, Guruprasad, Atkinson, Stephen, Bataller, Ramon, Botwin, Greg, Chalasani, Naga, Cordell, Heather, Daly, Ann, Darlay, Rebecca, Day, Christopher, Eyer, Florian, Foroud, Tatiana, Gawrieh, Samer, Gleeson, Dermot, Goldman, David, Haber, Paul, Jacquet, Jean-Marc, Lammert, Craig, Liang, Tiebing, Liangpunsakul, Suthat, Masson, Steven, Mathurin, Philippe, Moirand, Romain, McQuillin, Andrew, Moreno, Christophe, Morgan, Marsha, Mueller, Sebastian, Müllhaupt, Beat, Nagy, Laura, Nahon, Pierre, Nalpas, Bertrand, Naveau, Sylvie, Perney, Pascal, Pirmohamed, Munir, Seitz, Helmut, Soyka, Michael, Stickel, Felix, Thompson, Andrew, Thursz, Mark, Trépo, Eric, Morgan, Timothy, and Seth, Devanshi

Subjects
Humans, Polymorphism, Single Nucleotide, Liver Cirrhosis, Alcoholic, Male, Female, Middle Aged, Genome-Wide Association Study, White People, Multifactorial Inheritance, Aged, Risk Assessment, Alcohol Drinking, Adult, Risk Factors, Genetic Predisposition to Disease, United Kingdom, Genetic Risk Score
Abstract

BACKGROUND: Polygenic Risk Scores (PRS) based on results from genome-wide association studies offer the prospect of risk stratification for many common and complex diseases. We developed a PRS for alcohol-associated cirrhosis by comparing single-nucleotide polymorphisms among patients with alcohol-associated cirrhosis (ALC) versus drinkers who did not have evidence of liver fibrosis/cirrhosis. METHODS: Using a data-driven approach, a PRS for ALC was generated using a meta-genome-wide association study of ALC (N=4305) and an independent cohort of heavy drinkers with ALC and without significant liver disease (N=3037). It was validated in 2 additional independent cohorts from the UK Biobank with diagnosed ALC (N=467) and high-risk drinking controls (N=8981) and participants in the Indiana Biobank Liver cohort with alcohol-associated liver disease (N=121) and controls without liver disease (N=3239). RESULTS: A 20-single-nucleotide polymorphisms PRS for ALC (PRSALC) was generated that stratified risk for ALC comparing the top and bottom deciles of PRS in the 2 validation cohorts (ORs: 2.83 [95% CI: 1.82 -4.39] in UK Biobank; 4.40 [1.56 -12.44] in Indiana Biobank Liver cohort). Furthermore, PRSALC improved the prediction of ALC risk when added to the models of clinically known predictors of ALC risk. It also stratified the risk for metabolic dysfunction -associated steatotic liver disease -cirrhosis (3.94 [2.23 -6.95]) in the Indiana Biobank Liver cohort -based exploratory analysis. CONCLUSIONS: PRSALC incorporates 20 single-nucleotide polymorphisms, predicts increased risk for ALC, and improves risk stratification for ALC compared with the models that only include clinical risk factors. This new score has the potential for early detection of heavy drinking patients who are at high risk for ALC.

Published
2024

2. Multi-ancestry genome-wide association study of major depression aids locus discovery, fine mapping, gene prioritization and causal inference.

Author

Meng, Xiangrui, Navoly, Georgina, Giannakopoulou, Olga, Levey, Daniel, Koller, Dora, Pathak, Gita, Koen, Nastassja, Lin, Kuang, Adams, Mark, Rentería, Miguel, Feng, Yanzhe, Gaziano, J, Stein, Dan, Zar, Heather, Campbell, Megan, van Heel, David, Trivedi, Bhavi, Finer, Sarah, McQuillin, Andrew, Bass, Nick, Chundru, V, Martin, Hilary, Huang, Qin, Valkovskaya, Maria, Chu, Chia-Yi, Kanjira, Susan, Kuo, Po-Hsiu, Chen, Hsi-Chung, Tsai, Shih-Jen, Liu, Yu-Li, Kendler, Kenneth, Peterson, Roseann, Cai, Na, Fang, Yu, Sen, Srijan, Scott, Laura, Burmeister, Margit, Loos, Ruth, Preuss, Michael, Actkins, KyEra, Davis, Lea, Uddin, Monica, Wani, Agaz, Wildman, Derek, Aiello, Allison, Ursano, Robert, Kessler, Ronald, Kanai, Masahiro, Okada, Yukinori, Sakaue, Saori, Rabinowitz, Jill, Maher, Brion, Uhl, George, Eaton, William, Cruz-Fuentes, Carlos, Martinez-Levy, Gabriela, Campos, Adrian, Millwood, Iona, Chen, Zhengming, Li, Liming, Wassertheil-Smoller, Sylvia, Jiang, Yunxuan, Tian, Chao, Martin, Nicholas, Mitchell, Brittany, Byrne, Enda, Awasthi, Swapnil, Coleman, Jonathan, Ripke, Stephan, Sofer, Tamar, Walters, Robin, McIntosh, Andrew, Polimanti, Renato, Dunn, Erin, Stein, Murray, Gelernter, Joel, Lewis, Cathryn, and Kuchenbaecker, Karoline

Subjects
Humans, Genome-Wide Association Study, Genetic Predisposition to Disease, Depressive Disorder, Major, Depression, Chromosome Mapping, Polymorphism, Single Nucleotide
Abstract

Most genome-wide association studies (GWAS) of major depression (MD) have been conducted in samples of European ancestry. Here we report a multi-ancestry GWAS of MD, adding data from 21 cohorts with 88,316 MD cases and 902,757 controls to previously reported data. This analysis used a range of measures to define MD and included samples of African (36% of effective sample size), East Asian (26%) and South Asian (6%) ancestry and Hispanic/Latin American participants (32%). The multi-ancestry GWAS identified 53 significantly associated novel loci. For loci from GWAS in European ancestry samples, fewer than expected were transferable to other ancestry groups. Fine mapping benefited from additional sample diversity. A transcriptome-wide association study identified 205 significantly associated novel genes. These findings suggest that, for MD, increasing ancestral and global diversity in genetic studies may be particularly important to ensure discovery of core genes and inform about transferability of findings.

Published
2024

3. Genome-wide association studies and cross-population meta-analyses investigating short and long sleep duration.

Author

Austin-Zimmerman, Isabelle, Levey, Daniel, Giannakopoulou, Olga, Deak, Joseph, Galimberti, Marco, Adhikari, Keyrun, Zhou, Hang, Denaxas, Spiros, Irizar, Haritz, Kuchenbaecker, Karoline, McQuillin, Andrew, Concato, John, Buysse, Daniel, Gaziano, J, Gottlieb, Daniel, Polimanti, Renato, Stein, Murray, Bramon, Elvira, and Gelernter, Joel

Subjects
Adult, Humans, Sleep Duration, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Sleep, Phenotype, Mendelian Randomization Analysis
Abstract

Sleep duration has been linked to a wide range of negative health outcomes and to reduced life expectancy. We present genome-wide association studies of short ( ≤ 5 h) and long ( ≥ 10 h) sleep duration in adults of European (N = 445,966), African (N = 27,785), East Asian (N = 3141), and admixed-American (N = 16,250) ancestry from UK Biobank and the Million Veteran Programme. In a cross-population meta-analysis, we identify 84 independent loci for short sleep and 1 for long sleep. We estimate SNP-based heritability for both sleep traits in each ancestry based on population derived linkage disequilibrium (LD) scores using cov-LDSC. We identify positive genetic correlation between short and long sleep traits (rg = 0.16 ± 0.04; p = 0.0002), as well as similar patterns of genetic correlation with other psychiatric and cardiometabolic phenotypes. Mendelian randomisation reveals a directional causal relationship between short sleep and depression, and a bidirectional causal relationship between long sleep and depression.

Published
2023

5. Meta-analysis of epigenetic aging in schizophrenia reveals multifaceted relationships with age, sex, illness duration, and polygenic risk

Author

Anil P. S. Ori, Loes M. Olde Loohuis, Jerry Guintivano, Eilis Hannon, Emma Dempster, David St. Clair, Nick J. Bass, Andrew McQuillin, Jonathan Mill, Patrick F. Sullivan, Rene S. Kahn, Steve Horvath, and Roel A. Ophoff

Subjects
Schizophrenia, DNA methylation, Aging, Epigenetic clocks, Biological aging, Accelerated aging, Medicine, Genetics, QH426-470
Abstract

Abstract Background The study of biological age acceleration may help identify at-risk individuals and reduce the rising global burden of age-related diseases. Using DNA methylation (DNAm) clocks, we investigated biological aging in schizophrenia (SCZ), a mental illness that is associated with an increased prevalence of age-related disabilities and morbidities. In a whole blood DNAm sample of 1090 SCZ cases and 1206 controls across four European cohorts, we performed a meta-analysis of differential aging using three DNAm clocks (i.e., Hannum, Horvath, and Levine). To dissect how DNAm aging contributes to SCZ, we integrated information on duration of illness and SCZ polygenic risk, as well as stratified our analyses by chronological age and biological sex. Results We found that blood-based DNAm aging is significantly altered in SCZ independent from duration of the illness since onset. We observed sex-specific and nonlinear age effects that differed between clocks and point to possible distinct age windows of altered aging in SCZ. Most notably, intrinsic cellular age (Horvath clock) is decelerated in SCZ cases in young adulthood, while phenotypic age (Levine clock) is accelerated in later adulthood compared to controls. Accelerated phenotypic aging was most pronounced in women with SCZ carrying a high polygenic burden with an age acceleration of + 3.82 years (CI 2.02–5.61, P = 1.1E−03). Phenotypic aging and SCZ polygenic risk contributed additively to the illness and together explained up to 14.38% of the variance in disease status. Conclusions Our study contributes to the growing body of evidence of altered DNAm aging in SCZ and points to intrinsic age deceleration in younger adulthood and phenotypic age acceleration in later adulthood in SCZ. Since increased phenotypic age is associated with increased risk of all-cause mortality, our findings indicate that specific and identifiable patient groups are at increased mortality risk as measured by the Levine clock. Our study did not find that DNAm aging could be explained by the duration of illness of patients, but we did observe age- and sex-specific effects that warrant further investigation. Finally, our results show that combining genetic and epigenetic predictors can improve predictions of disease outcomes and may help with disease management in schizophrenia.

Published
2024
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7. Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia

Author

Palmer, Duncan S, Howrigan, Daniel P, Chapman, Sinéad B, Adolfsson, Rolf, Bass, Nick, Blackwood, Douglas, Boks, Marco PM, Chen, Chia-Yen, Churchhouse, Claire, Corvin, Aiden P, Craddock, Nicholas, Curtis, David, Di Florio, Arianna, Dickerson, Faith, Freimer, Nelson B, Goes, Fernando S, Jia, Xiaoming, Jones, Ian, Jones, Lisa, Jonsson, Lina, Kahn, Rene S, Landén, Mikael, Locke, Adam E, McIntosh, Andrew M, McQuillin, Andrew, Morris, Derek W, O’Donovan, Michael C, Ophoff, Roel A, Owen, Michael J, Pedersen, Nancy L, Posthuma, Danielle, Reif, Andreas, Risch, Neil, Schaefer, Catherine, Scott, Laura, Singh, Tarjinder, Smoller, Jordan W, Solomonson, Matthew, Clair, David St, Stahl, Eli A, Vreeker, Annabel, Walters, James TR, Wang, Weiqing, Watts, Nicholas A, Yolken, Robert, Zandi, Peter P, and Neale, Benjamin M

Subjects
Biotechnology, Human Genome, Clinical Research, Serious Mental Illness, Schizophrenia, Brain Disorders, Bipolar Disorder, Mental Health, Genetics, 2.1 Biological and endogenous factors, Aetiology, Mental health, A Kinase Anchor Proteins, Exome, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Exome Sequencing, Biological Sciences, Medical and Health Sciences, 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

8. 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

9. Genome-wide association studies and cross-population meta-analyses investigating short and long sleep duration

Author

Isabelle Austin-Zimmerman, Daniel F. Levey, Olga Giannakopoulou, Joseph D. Deak, Marco Galimberti, Keyrun Adhikari, Hang Zhou, Spiros Denaxas, Haritz Irizar, Karoline Kuchenbaecker, Andrew McQuillin, the Million Veteran Program, John Concato, Daniel J. Buysse, J. Michael Gaziano, Daniel J. Gottlieb, Renato Polimanti, Murray B. Stein, Elvira Bramon, and Joel Gelernter

Subjects
Science
Abstract

Abstract Sleep duration has been linked to a wide range of negative health outcomes and to reduced life expectancy. We present genome-wide association studies of short ( ≤ 5 h) and long ( ≥ 10 h) sleep duration in adults of European (N = 445,966), African (N = 27,785), East Asian (N = 3141), and admixed-American (N = 16,250) ancestry from UK Biobank and the Million Veteran Programme. In a cross-population meta-analysis, we identify 84 independent loci for short sleep and 1 for long sleep. We estimate SNP-based heritability for both sleep traits in each ancestry based on population derived linkage disequilibrium (LD) scores using cov-LDSC. We identify positive genetic correlation between short and long sleep traits (rg = 0.16 ± 0.04; p = 0.0002), as well as similar patterns of genetic correlation with other psychiatric and cardiometabolic phenotypes. Mendelian randomisation reveals a directional causal relationship between short sleep and depression, and a bidirectional causal relationship between long sleep and depression.

Published
2023
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10. A genetic risk score and diabetes predict development of alcohol-related cirrhosis in drinkers

Author

Whitfield, John B, Schwantes-An, Tae-Hwi, Darlay, Rebecca, Aithal, Guruprasad P, Atkinson, Stephen R, Bataller, Ramon, Botwin, Greg, Chalasani, Naga P, Cordell, Heather J, Daly, Ann K, Day, Christopher P, Eyer, Florian, Foroud, Tatiana, Gleeson, Dermot, Goldman, David, Haber, Paul S, Jacquet, Jean-Marc, Liang, Tiebing, Liangpunsakul, Suthat, Masson, Steven, Mathurin, Philippe, Moirand, Romain, McQuillin, Andrew, Moreno, Christophe, Morgan, Marsha Y, Mueller, Sebastian, Müllhaupt, Beat, Nagy, Laura E, Nahon, Pierre, Nalpas, Bertrand, Naveau, Sylvie, Perney, Pascal, Pirmohamed, Munir, Seitz, Helmut K, Soyka, Michael, Stickel, Felix, Thompson, Andrew, Thursz, Mark R, Trépo, Eric, Morgan, Timothy R, Seth, Devanshi, and Consortium, GenomALC

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Rare Diseases, Liver Cancer, Genetics, Liver Disease, Clinical Research, Substance Misuse, Genetic Testing, Cancer, Alcoholism, Alcohol Use and Health, Digestive Diseases, Chronic Liver Disease and Cirrhosis, Metabolic and endocrine, Oral and gastrointestinal, Good Health and Well Being, Adult, Alcohol Drinking, Case-Control Studies, Cohort Studies, Diabetes Mellitus, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Liver Cirrhosis, Alcoholic, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk Assessment, Hepatocellular carcinoma, risk stratification, chronic alcohol use, genome-wide association, single nucleotide polymorphism, coffee, GenomALC Consortium, Public Health and Health Services, Gastroenterology & Hepatology, Clinical sciences
Abstract

Background & aimsOnly a minority of excess alcohol drinkers develop cirrhosis. We developed and evaluated risk stratification scores to identify those at highest risk.MethodsThree cohorts (GenomALC-1: n = 1,690, GenomALC-2: n = 3,037, UK Biobank: relevant n = 6,898) with a history of heavy alcohol consumption (≥80 g/day (men), ≥50 g/day (women), for ≥10 years) were included. Cases were participants with alcohol-related cirrhosis. Controls had a history of similar alcohol consumption but no evidence of liver disease. Risk scores were computed from up to 8 genetic loci identified previously as associated with alcohol-related cirrhosis and 3 clinical risk factors. Score performance for the stratification of alcohol-related cirrhosis risk was assessed and compared across the alcohol-related liver disease spectrum, including hepatocellular carcinoma (HCC).ResultsA combination of 3 single nucleotide polymorphisms (SNPs) (PNPLA3:rs738409, SUGP1-TM6SF2:rs10401969, HSD17B13:rs6834314) and diabetes status best discriminated cirrhosis risk. The odds ratios (ORs) and (95% CIs) between the lowest (Q1) and highest (Q5) score quintiles of the 3-SNP score, based on independent allelic effect size estimates, were 5.99 (4.18-8.60) (GenomALC-1), 2.81 (2.03-3.89) (GenomALC-2), and 3.10 (2.32-4.14) (UK Biobank). Patients with diabetes and high risk scores had ORs of 14.7 (7.69-28.1) (GenomALC-1) and 17.1 (11.3-25.7) (UK Biobank) compared to those without diabetes and with low risk scores. Patients with cirrhosis and HCC had significantly higher mean risk scores than patients with cirrhosis alone (0.76 ± 0.06 vs. 0.61 ± 0.02, p = 0.007). Score performance was not significantly enhanced by information on additional genetic risk variants, body mass index or coffee consumption.ConclusionsA risk score based on 3 genetic risk variants and diabetes status enables the stratification of heavy drinkers based on their risk of cirrhosis, allowing for the provision of earlier preventative interventions.Lay summaryExcessive chronic drinking leads to cirrhosis in some people, but so far there is no way to identify those at high risk of developing this debilitating disease. We developed a genetic risk score that can identify patients at high risk. The risk of cirrhosis is increased >10-fold with just two risk factors - diabetes and a high genetic risk score. Risk assessment using this test could enable the early and personalised management of this disease in high-risk patients.

Published
2022

11. 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

12. Characterisation of age and polarity at onset in bipolar disorder.

Author

Kalman, Janos L, Olde Loohuis, Loes M, Vreeker, Annabel, McQuillin, Andrew, Stahl, Eli A, Ruderfer, Douglas, Grigoroiu-Serbanescu, Maria, Panagiotaropoulou, Georgia, Ripke, Stephan, Bigdeli, Tim B, Stein, Frederike, Meller, Tina, Meinert, Susanne, Pelin, Helena, Streit, Fabian, Papiol, Sergi, Adams, Mark J, Adolfsson, Rolf, Adorjan, Kristina, Agartz, Ingrid, Aminoff, Sofie R, Anderson-Schmidt, Heike, Andreassen, Ole A, Ardau, Raffaella, Aubry, Jean-Michel, Balaban, Ceylan, Bass, Nicholas, Baune, Bernhard T, Bellivier, Frank, Benabarre, Antoni, Bengesser, Susanne, Berrettini, Wade H, Boks, Marco P, Bromet, Evelyn J, Brosch, Katharina, Budde, Monika, Byerley, William, Cervantes, Pablo, Chillotti, Catina, Cichon, Sven, Clark, Scott R, Comes, Ashley L, Corvin, Aiden, Coryell, William, Craddock, Nick, Craig, David W, Croarkin, Paul E, Cruceanu, Cristiana, Czerski, Piotr M, Dalkner, Nina, Dannlowski, Udo, Degenhardt, Franziska, Del Zompo, Maria, DePaulo, J Raymond, Djurovic, Srdjan, Edenberg, Howard J, Eissa, Mariam Al, Elvsåshagen, Torbjørn, Etain, Bruno, Fanous, Ayman H, Fellendorf, Frederike, Fiorentino, Alessia, Forstner, Andreas J, Frye, Mark A, Fullerton, Janice M, Gade, Katrin, Garnham, Julie, Gershon, Elliot, Gill, Michael, Goes, Fernando S, Gordon-Smith, Katherine, Grof, Paul, Guzman-Parra, Jose, Hahn, Tim, Hasler, Roland, Heilbronner, Maria, Heilbronner, Urs, Jamain, Stephane, Jimenez, Esther, Jones, Ian, Jones, Lisa, Jonsson, Lina, Kahn, Rene S, Kelsoe, John R, Kennedy, James L, Kircher, Tilo, Kirov, George, Kittel-Schneider, Sarah, Klöhn-Saghatolislam, Farah, Knowles, James A, Kranz, Thorsten M, Lagerberg, Trine Vik, Landen, Mikael, Lawson, William B, Leboyer, Marion, Li, Qingqin S, Maj, Mario, Malaspina, Dolores, Manchia, Mirko, and Mayoral, Fermin

Subjects
Psychiatric Genomics Consortium (PGC) Bipolar Disorder Working Group, International Consortium on Lithium Genetics, Colombia-US Cross Disorder Collaboration in Psychiatric Genetics, Humans, Bipolar Disorder, Depressive Disorder, Major, Age of Onset, Multifactorial Inheritance, Genome-Wide Association Study, Autism Spectrum Disorder, Bipolar disorder, GWAS, age at onset, polarity at onset, polygenic score, Genetics, Mental Health, Prevention, Brain Disorders, Serious Mental Illness, 2.1 Biological and endogenous factors, Aetiology, Mental health, Good Health and Well Being, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

BackgroundStudying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder 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 bipolar disorder disease characteristics.MethodGenome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 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 a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = -0.34 years, s.e. = 0.08), major depression (β = -0.34 years, s.e. = 0.08), schizophrenia (β = -0.39 years, s.e. = 0.08), and educational attainment (β = -0.31 years, s.e. = 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 bipolar disorder 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.

Published
2021

13. Genetic copy number variants, cognition and psychosis: a meta-analysis and a family study

Author

Thygesen, Johan H, Presman, Amelia, Harju-Seppänen, Jasmine, Irizar, Haritz, Jones, Rebecca, Kuchenbaecker, Karoline, Lin, Kuang, Alizadeh, Behrooz Z, Austin-Zimmerman, Isabelle, Bartels-Velthuis, Agna, Bhat, Anjali, Bruggeman, Richard, Cahn, Wiepke, Calafato, Stella, Crespo-Facorro, Benedicto, de Haan, Liewe, de Zwarte, Sonja MC, Di Forti, Marta, Díez-Revuelta, Álvaro, Hall, Jeremy, Hall, Mei-Hua, Iyegbe, Conrad, Jablensky, Assen, Kahn, Rene, Kalaydjieva, Luba, Kravariti, Eugenia, Lawrie, Stephen, Luykx, Jurjen J, Mata, Igancio, McDonald, Colm, McIntosh, Andrew M, McQuillin, Andrew, Muir, Rebecca, Ophoff, Roel, Picchioni, Marco, Prata, Diana P, Ranlund, Siri, Rujescu, Dan, Rutten, Bart PF, Schulze, Katja, Shaikh, Madiha, Schirmbeck, Frederike, Simons, Claudia JP, Toulopoulou, Timothea, van Amelsvoort, Therese, van Haren, Neeltje, van Os, Jim, van Winkel, Ruud, Vassos, Evangelos, Walshe, Muriel, Weisbrod, Matthias, Zartaloudi, Eirini, Bell, Vaughan, Powell, John, Lewis, Cathryn M, Murray, Robin M, and Bramon, Elvira

Subjects
Biological Psychology, Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Psychology, Human Genome, Clinical Research, Brain Disorders, Serious Mental Illness, Schizophrenia, Neurosciences, Genetics, Prevention, Mental Health, 2.1 Biological and endogenous factors, 2.3 Psychological, social and economic factors, Aetiology, Mental health, Cognition, DNA Copy Number Variations, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Psychotic Disorders, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Biological psychology, Clinical and health psychology
Abstract

The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVs increase the risk of developing schizophrenia. Several cognitive measures are purported schizophrenia endophenotypes and may represent an intermediate point between genetics and the illness. This paper investigates the influence of CNVs on cognition. We conducted a systematic review and meta-analysis of the literature exploring the effect of CNV burden on general intelligence. We included ten primary studies with a total of 18,847 participants and found no evidence of association. In a new psychosis family study, we investigated the effects of CNVs on specific cognitive abilities. We examined the burden of large and rare CNVs (>200 kb,

Published
2021

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

Author

Jia, Xiaoming, Goes, Fernando S, Locke, Adam E, Palmer, Duncan, Wang, Weiqing, Cohen-Woods, Sarah, Genovese, Giulio, Jackson, Anne U, Jiang, Chen, Kvale, Mark, Mullins, Niamh, Nguyen, Hoang, Pirooznia, Mehdi, Rivera, Margarita, Ruderfer, Douglas M, Shen, Ling, Thai, Khanh, Zawistowski, Matthew, Zhuang, Yongwen, Abecasis, Gonçalo, Akil, Huda, Bergen, Sarah, Burmeister, Margit, Chapman, Sinéad, DelaBastide, Melissa, Juréus, Anders, Kang, Hyun Min, Kwok, Pui-Yan, Li, Jun Z, Levy, Shawn E, Monson, Eric T, Moran, Jennifer, Sobell, Janet, Watson, Stanley, Willour, Virginia, Zöllner, Sebastian, Adolfsson, Rolf, Blackwood, Douglas, Boehnke, Michael, Breen, Gerome, Corvin, Aiden, Craddock, Nick, DiFlorio, Arianna, Hultman, Christina M, Landen, Mikael, Lewis, Cathryn, McCarroll, Steven A, Richard McCombie, W, McGuffin, Peter, McIntosh, Andrew, McQuillin, Andrew, Morris, Derek, Myers, Richard M, O'Donovan, Michael, Ophoff, Roel, Boks, Marco, Kahn, Rene, Ouwehand, Willem, Owen, Michael, Pato, Carlos, Pato, Michele, Posthuma, Danielle, Potash, James B, Reif, Andreas, Sklar, Pamela, Smoller, Jordan, Sullivan, Patrick F, Vincent, John, Walters, James, Neale, Benjamin, Purcell, Shaun, Risch, Neil, Schaefer, Catherine, Stahl, Eli A, Zandi, Peter P, and Scott, Laura J

Subjects
Humans, Genetic Predisposition to Disease, Bipolar Disorder, Schizophrenia, Polymorphism, Single Nucleotide, Genetic Variation, Genome-Wide Association Study, Exome, Brain Disorders, Prevention, Clinical Research, Human Genome, Serious Mental Illness, Genetics, Mental Health, 2.1 Biological and endogenous factors, Mental health, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
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.

Published
2021

15. Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

Author

Marshall, Christian R., Merico, Daniele, Thiruvahindrapuram, Bhooma, Wang, Zhouzhi, Scherer, Stephen W., Howrigan, Daniel P, Ripke, Stephan, Bulik-Sullivan, Brendan, Farh, Kai-How, Fromer, Menachem, Goldstein, Jacqueline I., Huang, Hailiang, Lee, Phil, Daly, Mark J., Neale, Benjamin M., Belliveau, Richard A., Jr., Bergen, Sarah E., Bevilacqua, Elizabeth, Chambert, Kimberley D., O'Dushlaine, Colm, Scolnick, Edward M., Smoller, Jordan W., Moran, Jennifer L., Palotie, Aarno, Petryshen, Tracey L., Wu, Wenting, Greer, Douglas S., Antaki, Danny, Shetty, Aniket, Gujral, Madhusudan, Brandler, William M., Malhotra, Dheeraj, Fuentes Fajarado, Karin V., Maile, Michelle S., Holmans, Peter A., Carrera, Noa, Craddock, Nick, Escott-Price, Valentina, Georgieva, Lyudmila, Hamshere, Marian L., Kavanagh, David, Legge, Sophie E., Pocklington, Andrew J., Richards, Alexander L., Ruderfer, Douglas M., Williams, Nigel M., Kirov, George, Owen, Michael J., Pinto, Dalila, Cai, Guiqing, Davis, Kenneth L., Drapeau, Elodie, Friedman, Joseph I, Haroutunian, Vahram, Parkhomenko, Elena, Reichenberg, Abraham, Silverman, Jeremy M., Buxbaum, Joseph D., Domenici, Enrico, Agartz, Ingrid, Djurovic, Srdjan, Mattingsdal, Morten, Melle, Ingrid, Andreassen, Ole A., Jönsson, Erik G., Söderman, Erik, Albus, Margot, Alexander, Madeline, Laurent, Claudine, Levinson, Douglas F., Amin, Farooq, Atkins, Joshua, Cairns, Murray J., Scott, Rodney J., Tooney, Paul A., Wu, Jing Qin, Bacanu, Silviu A., Bigdeli, Tim B., Reimers, Mark A., Webb, Bradley T., Wolen, Aaron R., Wormley, Brandon K., Kendler, Kenneth S., Riley, Brien P., Kähler, Anna K., Magnusson, Patrik K.E., Hultman, Christina M., Bertalan, Marcelo, Hansen, Thomas, Olsen, Line, Rasmussen, Henrik B., Werge, Thomas, Mattheisen, Manuel, Black, Donald W., Bruggeman, Richard, Buccola, Nancy G., Buckner, Randy L., Roffman, Joshua L., Byerley, William, Cahn, Wiepke, Kahn, René S, Strengman, Eric, Ophoff, Roel A., Carr, Vaughan J., Catts, Stanley V., Henskens, Frans A., Loughland, Carmel M., Michie, Patricia T., Pantelis, Christos, Schall, Ulrich, Jablensky, Assen V., Kelly, Brian J., Campion, Dominique, Cantor, Rita M., Cheng, Wei, Cloninger, C. Robert, Svrakic, Dragan M, Cohen, David, Cormican, Paul, Donohoe, Gary, Morris, Derek W., Corvin, Aiden, Gill, Michael, Crespo-Facorro, Benedicto, Crowley, James J., Farrell, Martilias S., Giusti-Rodríguez, Paola, Kim, Yunjung, Szatkiewicz, Jin P., Williams, Stephanie, Curtis, David, Pimm, Jonathan, Gurling, Hugh, McQuillin, Andrew, Davidson, Michael, Weiser, Mark, Degenhardt, Franziska, Forstner, Andreas J., Herms, Stefan, Hoffmann, Per, Hofman, Andrea, Cichon, Sven, Nöthen, Markus M., Del Favero, Jurgen, DeLisi, Lynn E., McCarley, Robert W., Levy, Deborah L., Mesholam-Gately, Raquelle I., Seidman, Larry J., Dikeos, Dimitris, Papadimitriou, George N., Dinan, Timothy, Duan, Jubao, Sanders, Alan R., Gejman, Pablo V., Gershon, Elliot S., Dudbridge, Frank, Eichhammer, Peter, Eriksson, Johan, Salomaa, Veikko, Essioux, Laurent, Fanous, Ayman H., Knowles, James A., Pato, Michele T., Pato, Carlos N., Frank, Josef, Meier, Sandra, Schulze, Thomas G., Strohmaier, Jana, Witt, Stephanie H., Rietschel, Marcella, Franke, Lude, Karjalainen, Juha, Freedman, Robert, Olincy, Ann, Freimer, Nelson B., Purcell, Shaun M., Roussos, Panos, Stahl, Eli A., Sklar, Pamela, Giegling, Ina, Hartmann, Annette M., Konte, Bettina, Rujescu, Dan, Godard, Stephanie, Hirschhorn, Joel N., Pers, Tune H., Price, Alkes, Esko, Tõnu, Gratten, Jacob, Lee, S. Hong, Visscher, Peter M., Wray, Naomi R., Mowry, Bryan J., de Haan, Lieuwe, Meijer, Carin J., Hansen, Mark, Ikeda, Masashi, Iwata, Nakao, Joa, Inge, Kalaydjieva, Luba, Keller, Matthew C., Kennedy, James L., Zai, Clement C., Knight, Jo, Lerer, Bernard, Liang, Kung-Yee, Lieberman, Jeffrey, Stroup, T. Scott, Lönnqvist, Jouko, Suvisaari, Jaana, Maher, Brion S., Maier, Wolfgang, Mallet, Jacques, McDonald, Colm, McIntosh, Andrew M., Blackwood, Douglas H.R., Metspalu, Andres, Milani, Lili, Milanova, Vihra, Mokrab, Younes, Collier, David A., Müller-Myhsok, Bertram, Murphy, Kieran C., Murray, Robin M., Powell, John, Myin-Germeys, Inez, Van Os, Jim, Nenadic, Igor, Nertney, Deborah A., Nestadt, Gerald, Pulver, Ann E., Nicodemus, Kristin K., Nisenbaum, Laura, Nordin, Annelie, Adolfsson, Rolf, O'Callaghan, Eadbhard, Oh, Sang-Yun, O'Neill, F. Anthony, Paunio, Tiina, Pietiläinen, Olli, Perkins, Diana O., Quested, Digby, Savitz, Adam, Li, Qingqin S., Schwab, Sibylle G., Shi, Jianxin, Spencer, Chris C.A., Thirumalai, Srinivas, Veijola, Juha, Waddington, John, Walsh, Dermot, Wildenauer, Dieter B., Bramon, Elvira, Darvasi, Ariel, Posthuma, Danielle, St. Clair, David, Shanta, Omar, Klein, Marieke, Park, Peter J., Weinberger, Daniel, Moran, John V., Gage, Fred H., Vaccarino, Flora M., Gleeson, Joseph, Mathern, Gary, Courchesne, Eric, Roy, Subhojit, Bizzotto, Sara, Coulter, Michael, Dias, Caroline, D'Gama, Alissa, Ganz, Javier, Hill, Robert, Huang, August Yue, Khoshkhoo, Sattar, Kim, Sonia, Lodato, Michael, Miller, Michael, Borges-Monroy, Rebeca, Rodin, Rachel, Zhou, Zinan, Bohrson, Craig, Chu, Chong, Cortes-Ciriano, Isidro, Dou, Yanmei, Galor, Alon, Gulhan, Doga, Kwon, Minseok, Luquette, Joe, Viswanadham, Vinay, Jones, Attila, Rosenbluh, Chaggai, Cho, Sean, Langmead, Ben, Thorpe, Jeremy, Erwin, Jennifer, Jaffe, Andrew, McConnell, Michael, Narurkar, Rujuta, Paquola, Apua, Shin, Jooheon, Straub, Richard, Abyzov, Alexej, Bae, Taejeong, Jang, Yeongjun, Wang, Yifan, Gage, Fred, Linker, Sara, Reed, Patrick, Wang, Meiyan, Urban, Alexander, Zhou, Bo, Zhu, Xiaowei, Pattni, Reenal, Amero, Aitor Serres, Juan, David, Lobon, Irene, Marques-Bonet, Tomas, Moruno, Manuel Solis, Perez, Raquel Garcia, Povolotskaya, Inna, Soriano, Eduardo, Averbuj, Dan, Ball, Laurel, Breuss, Martin, Yang, Xiaoxu, Chung, Changuk, Emery, Sarah B., Flasch, Diane A., Kidd, Jeffrey M., Kopera, Huira C., Kwan, Kenneth Y., Mills, Ryan E., Moldovan, John B., Sun, Chen, Zhao, Xuefang, Zhou, Weichen, Frisbie, Trenton J., Cherskov, Adriana, Fasching, Liana, Jourdon, Alexandre, Pochareddy, Sirisha, Scuderi, Soraya, Sestan, Nenad, Maury, Eduardo A., Sherman, Maxwell A., Genovese, Giulio, Gilgenast, Thomas G., Kamath, Tushar, Burris, S.J., Rajarajan, Prashanth, Flaherty, Erin, Akbarian, Schahram, Chess, Andrew, McCarroll, Steven A., Loh, Po-Ru, Phillips-Cremins, Jennifer E., Brennand, Kristen J., Macosko, Evan Z., Walters, James T.R., O’Donovan, Michael, Sullivan, Patrick, Sebat, Jonathan, Lee, Eunjung A., and Walsh, Christopher A.

Published
2023
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16. Lack of guidelines and translational knowledge is hindering the implementation of psychiatric genetic counseling and testing within Europe – A multi-professional survey study

Author

Koido, Kati, Malmgren, Charlotta Ingvoldstad, Pojskic, Lejla, Almos, Peter Z., Bergen, Sarah E., Borg, Isabella, Božina, Nada, Coviello, Domenico A., Degenhardt, Franziska, Ganoci, Lana, Jensen, Uffe B., Durand-Lennad, Louise, Laurent-Levinson, Claudine, McQuillin, Andrew, Navickas, Alvydas, Pace, Nikolai P., Paneque, Milena, Rietschel, Marcella, Grigoroiu-Serbanescu, Maria, Soller, Maria Johansson, Suvisaari, Jaana, Utkus, Algirdas, Van Assche, Evelien, Vissouze, Lily, Zuckerman, Shachar, Chaumette, Boris, and Tammimies, Kristiina

Published
2023
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18. Genome-wide meta-analysis of problematic alcohol use in 435,563 individuals yields insights into biology and relationships with other traits

Author

Zhou, Hang, Sealock, Julia M, Sanchez-Roige, Sandra, Clarke, Toni-Kim, Levey, Daniel F, Cheng, Zhongshan, Li, Boyang, Polimanti, Renato, Kember, Rachel L, Smith, Rachel Vickers, Thygesen, Johan H, Morgan, Marsha Y, Atkinson, Stephen R, Thursz, Mark R, Nyegaard, Mette, Mattheisen, Manuel, Børglum, Anders D, Johnson, Emma C, Justice, Amy C, Palmer, Abraham A, McQuillin, Andrew, Davis, Lea K, Edenberg, Howard J, Agrawal, Arpana, Kranzler, Henry R, and Gelernter, Joel

Subjects
Biological Psychology, Psychology, Genetics, Alcoholism, Alcohol Use and Health, Substance Misuse, Brain Disorders, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Cardiovascular, Mental health, Good Health and Well Being, Alcohol Drinking, Alcoholism, Datasets as Topic, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Multifactorial Inheritance, Neurosciences, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

Problematic alcohol use (PAU) is a leading cause of death and disability worldwide. Although genome-wide association studies have identified PAU risk genes, the genetic architecture of this trait is not fully understood. We conducted a proxy-phenotype meta-analysis of PAU, combining alcohol use disorder and problematic drinking, in 435,563 European-ancestry individuals. We identified 29 independent risk variants, 19 of them novel. PAU was genetically correlated with 138 phenotypes, including substance use and psychiatric traits. Phenome-wide polygenic risk score analysis in an independent biobank sample (BioVU, n = 67,589) confirmed the genetic correlations between PAU and substance use and psychiatric disorders. Genetic heritability of PAU was enriched in brain and in conserved and regulatory genomic regions. Mendelian randomization suggested causal effects on liability to PAU of substance use, psychiatric status, risk-taking behavior and cognitive performance. In summary, this large PAU meta-analysis identified novel risk loci and revealed genetic relationships with numerous other traits.

Published
2020

19. Using brain cell-type-specific protein interactomes to interpret neurodevelopmental genetic signals in schizophrenia

Author

Ripke, Stephan, Neale, Benjamin M., Corvin, Aiden, Walters, James T.R., 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, Kimberley D., Chan, Raymond C.K., Chan, Ronald Y.L., Chen, Eric Y.H., 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-Rodríguez, 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, Joa, Inge, Julià, Antonio, Kahn, René S., Kalaydjieva, Luba, Karachanak-Yankova, Sena, Karjalainen, Juha, Kavanagh, David, Keller, Matthew C., Kennedy, James L., Khrunin, Andrey, Kim, Yunjung, Klovins, Janis, Knowles, James A., Konte, Bettina, Kucinskas, Vaidutis, Kucinskiene, Zita Ausrele, Kuzelova-Ptackova, Hana, Kähler, Anna K., Laurent, Claudine, Lee, Jimmy, Lee, S. Hong, Legge, Sophie E., Lerer, Bernard, Li, Miaoxin, Li, Tao, Liang, Kung-Yee, Lieberman, Jeffrey, Limborska, Svetlana, Loughland, Carmel M., Lubinski, Jan, Lönnqvist, Jouko, Macek, Milan, Magnusson, Patrik K.E., Maher, Brion S., Maier, Wolfgang, Mallet, Jacques, Marsal, Sara, Mattheisen, Manuel, Mattingsdal, Morten, McCarley, Robert W., McDonald, Colm, McIntosh, Andrew M., Meier, Sandra, Meijer, Carin J., Melegh, Bela, Melle, Ingrid, Mesholam-Gately, Raquelle I., Metspalu, Andres, Michie, Patricia T., Milani, Lili, Milanova, Vihra, Mokrab, Younes, Morris, Derek W., Mors, Ole, Murphy, Kieran C., Murray, Robin M., Myin-Germeys, Inez, Müller-Myhsok, Bertram, Nelis, Mari, Nenadic, Igor, Nertney, Deborah A., Nestadt, Gerald, Nicodemus, Kristin K., Nikitina-Zake, Liene, Nisenbaum, Laura, Nordin, Annelie, O'Callaghan, Eadbhard, O'Dushlaine, Colm, O'Neill, F. Anthony, Oh, Sang-Yun, Olincy, Ann, Olsen, Line, Van Os, Jim, Pantelis, Christos, Papadimitriou, George N., Papiol, Sergi, Parkhomenko, Elena, Pato, Michele T., Paunio, Tiina, Pejovic-Milovancevic, Milica, Perkins, Diana O., Pietiläinen, Olli, Pimm, Jonathan, Pocklington, Andrew J., Powell, John, Price, Alkes, Pulver, Ann E., Purcell, Shaun M., Quested, Digby, Rasmussen, Henrik B., Reichenberg, Abraham, Reimers, Mark A., Richards, Alexander L., Roffman, Joshua L., Roussos, Panos, Ruderfer, Douglas M., Salomaa, Veikko, Sanders, Alan R., Schall, Ulrich, Schubert, Christian R., Schulze, Thomas G., Schwab, Sibylle G., Scolnick, Edward M., Scott, Rodney J., Seidman, Larry J., Shi, Jianxin, Sigurdsson, Engilbert, Silagadze, Teimuraz, Silverman, Jeremy M., Sim, Kang, Slominsky, Petr, Smoller, Jordan W., So, Hon-Cheong, Spencer, Chris C.A., Stahl, Eli A., Stefansson, Hreinn, Steinberg, Stacy, Stogmann, Elisabeth, Straub, Richard E., Strengman, Eric, Strohmaier, Jana, Stroup, T Scott, Subramaniam, Mythily, Suvisaari, Jaana, Svrakic, Dragan M., Szatkiewicz, Jin P., Söderman, Erik, Thirumalai, Srinivas, Toncheva, Draga, Tosato, Sarah, Veijola, Juha, Waddington, John, Walsh, Dermot, Wang, Dai, Wang, Qiang, Webb, Bradley T., Weiser, Mark, Wildenauer, Dieter B., Williams, Nigel M., Williams, Stephanie, Witt, Stephanie H., Wolen, Aaron R., Wong, Emily H.M., Wormley, Brandon K., Xi, Hualin Simon, Zai, Clement C., Zheng, Xuebin, Zimprich, Fritz, Wray, Naomi R., Stefansson, Kari, Visscher, Peter M., Adolfsson, Rolf, Andreassen, Ole A., Blackwood, Douglas H.R., Bramon, Elvira, Buxbaum, Joseph D., Børglum, Anders D., Cichon, Sven, Darvasi, Ariel, Domenici, Enrico, Ehrenreich, Hannelore, Esko, Tõnu, Gejman, Pablo V., Gill, Michael, Gurling, Hugh, Hultman, Christina M., Iwata, Nakao, Jablensky, Assen V., Jönsson, Erik G., Kendler, Kenneth S., Kirov, George, Knight, Jo, Lencz, Todd, Levinson, Douglas F., Li, Qingqin S., Liu, Jianjun, Malhotra, Anil K., McCarroll, Steven A., McQuillin, Andrew, Moran, Jennifer L., Mortensen, Preben B., Mowry, Bryan J., Nöthen, Markus M., Ophoff, Roel A., Owen, Michael J., Palotie, Aarno, Pato, Carlos N., Petryshen, Tracey L., Posthuma, Danielle, Rietschel, Marcella, Riley, Brien P., Rujescu, Dan, Sham, Pak C., Sklar, Pamela, St Clair, David, Weinberger, Daniel R., Wendland, Jens R., Werge, Thomas, Daly, Mark J., Sullivan, Patrick F., O'Donovan, Michael C., Qin, Shengying, Sawa, Akira, Kahn, Rene, Hong, Kyung Sue, Shi, Wenzhao, Tsuang, Ming, Itokawa, Masanari, Feng, Gang, Glatt, Stephen J., Ma, Xiancang, Tang, Jinsong, Ruan, Yunfeng, Liu, Ruize, Zhu, Feng, Horiuchi, Yasue, Lee, Byung Dae, Joo, Eun-Jeong, Myung, Woojae, Ha, Kyooseob, Won, Hong-Hee, Baek, Ji Hyung, Chung, Young Chul, Kim, Sung-Wan, Kusumawardhani, Agung, Chen, Wei J., Hwu, Hai-Gwo, Hishimoto, Akitoyo, Otsuka, Ikuo, Sora, Ichiro, Toyota, Tomoko, Yoshikawa, Takeo, Kunugi, Hiroshi, Hattori, Kotaro, Ishiwata, Sayuri, Numata, Shusuke, Ohmori, Tetsuro, Arai, Makoto, Ozeki, Yuji, Fujii, Kumiko, Kim, Se Joo, Lee, Heon-Jeong, Ahn, Yong Min, Kim, Se Hyun, Akiyama, Kazufumi, Shimoda, Kazutaka, Kinoshita, Makoto, Hsu, Yu-Han H., Pintacuda, Greta, Nacu, Eugeniu, Kim, April, Tsafou, Kalliopi, Petrossian, Natalie, Crotty, William, Suh, Jung Min, Riseman, Jackson, Martin, Jacqueline M., Biagini, Julia C., Mena, Daya, Ching, Joshua K.T., Malolepsza, Edyta, Li, Taibo, Singh, Tarjinder, Ge, Tian, Egri, Shawn B., Tanenbaum, Benjamin, Stanclift, Caroline R., Apffel, Annie M., Carr, Steven A., Schenone, Monica, Jaffe, Jake, Fornelos, Nadine, Eggan, Kevin C., and Lage, Kasper

Published
2023
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20. Examining Youth Mentoring Services across America: Findings from the 2016 National Mentoring Program Survey

Author

MENTOR: The National Mentoring Partnership, Garringer, Michael, McQuillin, Sam, and McDaniel, Heather

Abstract

In 2016, MENTOR and its affiliates led the largest data collection effort in almost 20 years to examine the prevalence and practices of youth mentoring programs across America. The effort had had three major goals: (1) Better understand the structure, services, and challenges of mentoring programs so that MENTOR and its affiliates could provide them with appropriate professional development, training, and technical assistance; (2) Identify what programs are serving and the groups of adults that are stepping up to mentor youth in programs so that they might boost mentor recruitment and ensure that youth with the most needs are being served adequately; and (3) Provide MENTOR with a baseline understanding of the field that can be monitored for trends and used to inform a growth strategy. In the end, the national survey captured information on: (1) 1,271 mentoring agencies and 1,451 distinct mentoring programs; (2) 413,237 youth served by 193,823 mentors and supported by 10,804 staff members; and (3) The services, practices, settings, goals, challenges, and financial resources of these programs. MENTOR believes this to be the largest and most comprehensive data set about youth mentoring programs ever developed and the remainder of this report details the main findings and conclusions from the survey results. The authors think this information sheds considerable light on the current state of mentoring programs in the United States and highlights paths forward that can strengthen this field over time. [Funding for this report was provided by Altria Group, Inc.]

Published
2017

21. 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

22. 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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23. Investigating the association between schizophrenia and distance visual acuity: Mendelian randomisation study

Author

Natalie Shoham, Diana Dunca, Claudia Cooper, Joseph F. Hayes, Andrew McQuillin, Nick Bass, Gemma Lewis, and Karoline Kuchenbaecker

Subjects
Psychiatric epidemiology, visual impairment, schizophrenia, psychosis, Mendelian randomisation, Psychiatry, RC435-571
Abstract

Background Increased rates of visual impairment are observed in people with schizophrenia. Aims We assessed whether genetically predicted poor distance acuity is causally associated with schizophrenia, and whether genetically predicted schizophrenia is causally associated with poorer visual acuity. Method We used bidirectional, two-sample Mendelian randomisation to assess the effect of poor distance acuity on schizophrenia risk, poorer visual acuity on schizophrenia risk and schizophrenia on visual acuity, in European and East Asian ancestry samples ranging from approximately 14 000 to 500 000 participants. Genetic instrumental variables were obtained from the largest available summary statistics: for schizophrenia, from the Psychiatric Genomics Consortium; for visual acuity, from the UK Biobank; and for poor distance acuity, from a meta-analysis of case–control samples. We used the inverse variance-weighted method and sensitivity analyses to test validity of results. Results We found little evidence that poor distance acuity was causally associated with schizophrenia (odds ratio 1.00, 95% CI 0.91–1.10). Genetically predicted schizophrenia was associated with poorer visual acuity (mean difference in logMAR score: 0.024, 95% CI 0.014–0.033) in European ancestry samples, with a similar but less precise effect that in smaller East Asian ancestry samples (mean difference: 0.186, 95% CI –0.008 to 0.379). Conclusions Genetic evidence supports schizophrenia being a causal risk factor for poorer visual acuity, but not the converse. This highlights the importance of visual care for people with psychosis and refutes previous hypotheses that visual impairment is a potential target for prevention of schizophrenia.

Published
2023
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24. Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Author

Trubetskoy, Vassily, Pardiñas, Antonio F., Qi, Ting, Panagiotaropoulou, Georgia, Awasthi, Swapnil, Bigdeli, Tim B., Bryois, Julien, Chen, Chia-Yen, Dennison, Charlotte A., Hall, Lynsey S., Lam, Max, Watanabe, Kyoko, Frei, Oleksandr, Ge, Tian, Harwood, Janet C., Koopmans, Frank, Magnusson, Sigurdur, Richards, Alexander L., Sidorenko, Julia, Wu, Yang, Zeng, Jian, Grove, Jakob, Kim, Minsoo, Li, Zhiqiang, Voloudakis, Georgios, Zhang, Wen, Adams, Mark, Agartz, Ingrid, Atkinson, Elizabeth G., Agerbo, Esben, Al Eissa, Mariam, Albus, Margot, Alexander, Madeline, Alizadeh, Behrooz Z., Alptekin, Köksal, Als, Thomas D., Amin, Farooq, Arolt, Volker, Arrojo, Manuel, Athanasiu, Lavinia, Azevedo, Maria Helena, Bacanu, Silviu A., Bass, Nicholas J., Begemann, Martin, Belliveau, Richard A., Bene, Judit, Benyamin, Beben, Bergen, Sarah E., Blasi, Giuseppe, Bobes, Julio, Bonassi, Stefano, Braun, Alice, Bressan, Rodrigo Affonseca, Bromet, Evelyn J., Bruggeman, Richard, Buckley, Peter F., Buckner, Randy L., Bybjerg-Grauholm, Jonas, Cahn, Wiepke, Cairns, Murray J., Calkins, Monica E., Carr, Vaughan J., Castle, David, Catts, Stanley V., Chambert, Kimberley D., Chan, Raymond C. K., Chaumette, Boris, Cheng, Wei, Cheung, Eric F. C., Chong, Siow Ann, Cohen, David, Consoli, Angèle, Cordeiro, Quirino, Costas, Javier, Curtis, Charles, Davidson, Michael, Davis, Kenneth L., de Haan, Lieuwe, Degenhardt, Franziska, DeLisi, Lynn E., Demontis, Ditte, Dickerson, Faith, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Duan, Jubao, Ducci, Giuseppe, Dudbridge, Frank, Eriksson, Johan G., Fañanás, Lourdes, Faraone, Stephen V., Fiorentino, Alessia, Forstner, Andreas, Frank, Josef, Freimer, Nelson B., Fromer, Menachem, Frustaci, Alessandra, Gadelha, Ary, Genovese, Giulio, Gershon, Elliot S., Giannitelli, Marianna, Giegling, Ina, Giusti-Rodríguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I., González Peñas, Javier, González-Pinto, Ana, Gopal, Srihari, Gratten, Jacob, Green, Michael F., Greenwood, Tiffany A., Guillin, Olivier, Gülöksüz, Sinan, Gur, Raquel E., Gur, Ruben C., Gutiérrez, Blanca, Hahn, Eric, Hakonarson, Hakon, Haroutunian, Vahram, Hartmann, Annette M., Harvey, Carol, Hayward, Caroline, Henskens, Frans A., Herms, Stefan, Hoffmann, Per, Howrigan, Daniel P., Ikeda, Masashi, Iyegbe, Conrad, Joa, Inge, Julià, Antonio, Kähler, Anna K., Kam-Thong, Tony, Kamatani, Yoichiro, Karachanak-Yankova, Sena, Kebir, Oussama, Keller, Matthew C., Kelly, Brian J., Khrunin, Andrey, Kim, Sung-Wan, Klovins, Janis, Kondratiev, Nikolay, Konte, Bettina, Kraft, Julia, Kubo, Michiaki, Kučinskas, Vaidutis, Kučinskiene, Zita Ausrele, Kusumawardhani, Agung, Kuzelova-Ptackova, Hana, Landi, Stefano, Lazzeroni, Laura C., Lee, Phil H., Legge, Sophie E., Lehrer, Douglas S., Lencer, Rebecca, Lerer, Bernard, Li, Miaoxin, Lieberman, Jeffrey, Light, Gregory A., Limborska, Svetlana, Liu, Chih-Min, Lönnqvist, Jouko, Loughland, Carmel M., Lubinski, Jan, Luykx, Jurjen J., Lynham, Amy, Macek, Jr, Milan, Mackinnon, Andrew, Magnusson, Patrik K. E., Maher, Brion S., Maier, Wolfgang, Malaspina, Dolores, Mallet, Jacques, Marder, Stephen R., Marsal, Sara, Martin, Alicia R., Martorell, Lourdes, Mattheisen, Manuel, McCarley, Robert W., McDonald, Colm, McGrath, John J., Medeiros, Helena, Meier, Sandra, Melegh, Bela, Melle, Ingrid, Mesholam-Gately, Raquelle I., Metspalu, Andres, Michie, Patricia T., Milani, Lili, Milanova, Vihra, Mitjans, Marina, Molden, Espen, Molina, Esther, Molto, María Dolores, Mondelli, Valeria, Moreno, Carmen, Morley, Christopher P., Muntané, Gerard, Murphy, Kieran C., Myin-Germeys, Inez, Nenadić, Igor, Nestadt, Gerald, Nikitina-Zake, Liene, Noto, Cristiano, Nuechterlein, Keith H., O’Brien, Niamh Louise, O’Neill, F. Anthony, Oh, Sang-Yun, Olincy, Ann, Ota, Vanessa Kiyomi, Pantelis, Christos, Papadimitriou, George N., Parellada, Mara, Paunio, Tiina, Pellegrino, Renata, Periyasamy, Sathish, Perkins, Diana O., Pfuhlmann, Bruno, Pietiläinen, Olli, Pimm, Jonathan, Porteous, David, Powell, John, Quattrone, Diego, Quested, Digby, Radant, Allen D., Rampino, Antonio, Rapaport, Mark H., Rautanen, Anna, Reichenberg, Abraham, Roe, Cheryl, Roffman, Joshua L., Roth, Julian, Rothermundt, Matthias, Rutten, Bart P. F., Saker-Delye, Safaa, Salomaa, Veikko, Sanjuan, Julio, Santoro, Marcos Leite, Savitz, Adam, Schall, Ulrich, Scott, Rodney J., Seidman, Larry J., Sharp, Sally Isabel, Shi, Jianxin, Siever, Larry J., Sigurdsson, Engilbert, Sim, Kang, Skarabis, Nora, Slominsky, Petr, So, Hon-Cheong, Sobell, Janet L., Söderman, Erik, Stain, Helen J., Steen, Nils Eiel, Steixner-Kumar, Agnes A., Stögmann, Elisabeth, Stone, William S., Straub, Richard E., Streit, Fabian, Strengman, Eric, Stroup, T. Scott, Subramaniam, Mythily, Sugar, Catherine A., Suvisaari, Jaana, Svrakic, Dragan M., Swerdlow, Neal R., Szatkiewicz, Jin P., Ta, Thi Minh Tam, Takahashi, Atsushi, Terao, Chikashi, Thibaut, Florence, Toncheva, Draga, Tooney, Paul A., Torretta, Silvia, Tosato, Sarah, Tura, Gian Battista, Turetsky, Bruce I., Üçok, Alp, Vaaler, Arne, van Amelsvoort, Therese, van Winkel, Ruud, Veijola, Juha, Waddington, John, Walter, Henrik, Waterreus, Anna, Webb, Bradley T., Weiser, Mark, Williams, Nigel M., Witt, Stephanie H., Wormley, Brandon K., Wu, Jing Qin, Xu, Zhida, Yolken, Robert, Zai, Clement C., Zhou, Wei, Zhu, Feng, Zimprich, Fritz, Atbaşoğlu, Eşref Cem, Ayub, Muhammad, Benner, Christian, Bertolino, Alessandro, Black, Donald W., Bray, Nicholas J., Breen, Gerome, Buccola, Nancy G., Byerley, William F., Chen, Wei J., Cloninger, C. Robert, Crespo-Facorro, Benedicto, Donohoe, Gary, Freedman, Robert, Galletly, Cherrie, Gandal, Michael J., Gennarelli, Massimo, Hougaard, David M., Hwu, Hai-Gwo, Jablensky, Assen V., McCarroll, Steven A., Moran, Jennifer L., Mors, Ole, Mortensen, Preben B., Müller-Myhsok, Bertram, Neil, Amanda L., Nordentoft, Merete, Pato, Michele T., Petryshen, Tracey L., Pirinen, Matti, Pulver, Ann E., Schulze, Thomas G., Silverman, Jeremy M., Smoller, Jordan W., Stahl, Eli A., Tsuang, Debby W., Vilella, Elisabet, Wang, Shi-Heng, Xu, Shuhua, Adolfsson, Rolf, Arango, Celso, Baune, Bernhard T., Belangero, Sintia Iole, Børglum, Anders D., Braff, David, Bramon, Elvira, Buxbaum, Joseph D., Campion, Dominique, Cervilla, Jorge A., Cichon, Sven, Collier, David A., Corvin, Aiden, Curtis, David, Forti, Marta Di, Domenici, Enrico, Ehrenreich, Hannelore, Escott-Price, Valentina, Esko, Tõnu, Fanous, Ayman H., Gareeva, Anna, Gawlik, Micha, Gejman, Pablo V., Gill, Michael, Glatt, Stephen J., Golimbet, Vera, Hong, Kyung Sue, Hultman, Christina M., Hyman, Steven E., Iwata, Nakao, Jönsson, Erik G., Kahn, René S., Kennedy, James L., Khusnutdinova, Elza, Kirov, George, Knowles, James A., Krebs, Marie-Odile, Laurent-Levinson, Claudine, Lee, Jimmy, Lencz, Todd, Levinson, Douglas F., Li, Qingqin S., Liu, Jianjun, Malhotra, Anil K., Malhotra, Dheeraj, McIntosh, Andrew, McQuillin, Andrew, Menezes, Paulo R., Morgan, Vera A., Morris, Derek W., Mowry, Bryan J., Murray, Robin M., Nimgaonkar, Vishwajit, Nöthen, Markus M., Ophoff, Roel A., Paciga, Sara A., Palotie, Aarno, Pato, Carlos N., Qin, Shengying, Rietschel, Marcella, Riley, Brien P., Rivera, Margarita, Rujescu, Dan, Saka, Meram C., Sanders, Alan R., Schwab, Sibylle G., Serretti, Alessandro, Sham, Pak C., Shi, Yongyong, St Clair, David, Stefánsson, Hreinn, Stefansson, Kari, Tsuang, Ming T., van Os, Jim, Vawter, Marquis P., Weinberger, Daniel R., Werge, Thomas, Wildenauer, Dieter B., Yu, Xin, Yue, Weihua, Holmans, Peter A., Pocklington, Andrew J., Roussos, Panos, Vassos, Evangelos, Verhage, Matthijs, Visscher, Peter M., Yang, Jian, Posthuma, Danielle, Andreassen, Ole A., Kendler, Kenneth S., Owen, Michael J., Wray, Naomi R., Daly, Mark J., Huang, Hailiang, Neale, Benjamin M., Sullivan, Patrick F., Ripke, Stephan, Walters, James T. R., and O’Donovan, Michael C.

Published
2022
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25. Analysis of shared heritability in common disorders of the brain

Author

Consortium, The Brainstorm, Anttila, Verneri, Bulik-Sullivan, Brendan, Finucane, Hilary K, Walters, Raymond K, Bras, Jose, Duncan, Laramie, Escott-Price, Valentina, Falcone, Guido J, Gormley, Padhraig, Malik, Rainer, Patsopoulos, Nikolaos A, Ripke, Stephan, Wei, Zhi, Yu, Dongmei, Lee, Phil H, Turley, Patrick, Grenier-Boley, Benjamin, Chouraki, Vincent, Kamatani, Yoichiro, Berr, Claudine, Letenneur, Luc, Hannequin, Didier, Amouyel, Philippe, Boland, Anne, Deleuze, Jean-François, Duron, Emmanuelle, Vardarajan, Badri N, Reitz, Christiane, Goate, Alison M, Huentelman, Matthew J, Kamboh, M Ilyas, Larson, Eric B, Rogaeva, Ekaterina, St George-Hyslop, Peter, Hakonarson, Hakon, Kukull, Walter A, Farrer, Lindsay A, Barnes, Lisa L, Beach, Thomas G, Demirci, F Yesim, Head, Elizabeth, Hulette, Christine M, Jicha, Gregory A, Kauwe, John SK, Kaye, Jeffrey A, Leverenz, James B, Levey, Allan I, Lieberman, Andrew P, Pankratz, Vernon S, Poon, Wayne W, Quinn, Joseph F, Saykin, Andrew J, Schneider, Lon S, Smith, Amanda G, Sonnen, Joshua A, Stern, Robert A, Van Deerlin, Vivianna M, Van Eldik, Linda J, Harold, Denise, Russo, Giancarlo, Rubinsztein, David C, Bayer, Anthony, Tsolaki, Magda, Proitsi, Petra, Fox, Nick C, Hampel, Harald, Owen, Michael J, Mead, Simon, Passmore, Peter, Morgan, Kevin, Nöthen, Markus M, Schott, Jonathan M, Rossor, Martin, Lupton, Michelle K, Hoffmann, Per, Kornhuber, Johannes, Lawlor, Brian, McQuillin, Andrew, Al-Chalabi, Ammar, Bis, Joshua C, Ruiz, Agustin, Boada, Mercè, Seshadri, Sudha, Beiser, Alexa, Rice, Kenneth, van der Lee, Sven J, De Jager, Philip L, Geschwind, Daniel H, Riemenschneider, Matthias, Riedel-Heller, Steffi, Rotter, Jerome I, Ransmayr, Gerhard, Hyman, Bradley T, Cruchaga, Carlos, Alegret, Montserrat, Winsvold, Bendik, Palta, Priit, Farh, Kai-How, and Cuenca-Leon, Ester

Subjects
Biological Sciences, Genetics, Biological Psychology, Health Sciences, Psychology, Clinical Research, Mental Health, Human Genome, Brain Disorders, Neurosciences, Mental Illness, 2.1 Biological and endogenous factors, Neurological, Mental health, Brain Diseases, Genetic Variation, Genome-Wide Association Study, Humans, Mental Disorders, Phenotype, Quantitative Trait, Heritable, Risk Factors, Brainstorm Consortium, General Science & Technology
Abstract

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

Published
2018

26. Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

Author

Consortium, Bipolar Disorder and Schizophrenia Working Group of the Psychiatric Genomics, Ruderfer, Douglas M, Ripke, Stephan, McQuillin, Andrew, Boocock, James, Stahl, Eli A, Pavlides, Jennifer M Whitehead, Mullins, Niamh, Charney, Alexander W, Ori, Anil PS, Loohuis, Loes M Olde, Domenici, Enrico, Di Florio, Arianna, Papiol, Sergi, Kalman, Janos L, Trubetskoy, Vassily, Adolfsson, Rolf, Agartz, Ingrid, Agerbo, Esben, Akil, Huda, Albani, Diego, Albus, Margot, Alda, Martin, Alexander, Madeline, Alliey-Rodriguez, Ney, Als, Thomas D, Amin, Farooq, Anjorin, Adebayo, Arranz, Maria J, Awasthi, Swapnil, Bacanu, Silviu A, Badner, Judith A, Baekvad-Hansen, Marie, Bakker, Steven, Band, Gavin, Barchas, Jack D, Barroso, Ines, Bass, Nicholas, Bauer, Michael, Baune, Bernhard T, Begemann, Martin, Bellenguez, Celine, Belliveau, Richard A, Bellivier, Frank, Bender, Stephan, Bene, Judit, Bergen, Sarah E, Berrettini, Wade H, Bevilacqua, Elizabeth, Biernacka, Joanna M, Bigdeli, Tim B, Black, Donald W, Blackburn, Hannah, Blackwell, Jenefer M, Blackwood, Douglas HR, Pedersen, Carsten Bocker, Boehnke, Michael, Boks, Marco, Borglum, Anders D, Bramon, Elvira, Breen, Gerome, Brown, Matthew A, Bruggeman, Richard, Buccola, Nancy G, Buckner, Randy L, Budde, Monika, Bulik-Sullivan, Brendan, Bumpstead, Suzannah J, Bunney, William, Burmeister, Margit, Buxbaum, Joseph D, Bybjerg-Grauholm, Jonas, Byerley, William, Cahn, Wiepke, Cai, Guiqing, Cairns, Murray J, Campion, Dominique, Cantor, Rita M, Carr, Vaughan J, Carrera, Noa, Casas, Juan P, Casas, Miquel, Catts, Stanley V, Cervantes, Pablo, Chambert, Kimberley D, Chan, Raymond CK, Chen, Eric YH, Chen, Ronald YL, Cheng, Wei, Cheung, Eric FC, Chong, Siow Ann, Clarke, Toni-Kim, Cloninger, C Robert, Cohen, David, Cohen, Nadine, Coleman, Jonathan RI, Collier, David A, Cormican, Paul, Coryell, William, and Craddock, Nicholas

Subjects
Human Genome, Neurosciences, Serious Mental Illness, Bipolar Disorder, Biotechnology, Schizophrenia, Brain Disorders, Genetics, Mental Health, Mental health, Good Health and Well Being, Case-Control Studies, Genetic Loci, Genome-Wide Association Study, Humans, Multifactorial Inheritance, Odds Ratio, Phenotype, Risk, White People, Bipolar Disorder and Schizophrenia Working Group of the Psychiatric Genomics Consortium. Electronic address: douglas.ruderfer@vanderbilt.edu, Bipolar Disorder and Schizophrenia Working Group of the Psychiatric Genomics Consortium, bipolar disorder, polygenic risk, psychosis, schizophrenia, subphenotypes, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Schizophrenia and bipolar disorder are two distinct diagnoses that share symptomology. Understanding the genetic factors contributing to the shared and disorder-specific symptoms will be crucial for improving diagnosis and treatment. In genetic data consisting of 53,555 cases (20,129 bipolar disorder [BD], 33,426 schizophrenia [SCZ]) and 54,065 controls, we identified 114 genome-wide significant loci implicating synaptic and neuronal pathways shared between disorders. Comparing SCZ to BD (23,585 SCZ, 15,270 BD) identified four genomic regions including one with disorder-independent causal variants and potassium ion response genes as contributing to differences in biology between the disorders. Polygenic risk score (PRS) analyses identified several significant correlations within case-only phenotypes including SCZ PRS with psychotic features and age of onset in BD. For the first time, we discover specific loci that distinguish between BD and SCZ and identify polygenic components underlying multiple symptom dimensions. These results point to the utility of genetics to inform symptomology and potential treatment.

Published
2018

27. Analysis of shared heritability in common disorders of the brain.

Author

Brainstorm Consortium, Anttila, Verneri, Bulik-Sullivan, Brendan, Finucane, Hilary K, Walters, Raymond K, Bras, Jose, Duncan, Laramie, Escott-Price, Valentina, Falcone, Guido J, Gormley, Padhraig, Malik, Rainer, Patsopoulos, Nikolaos A, Ripke, Stephan, Wei, Zhi, Yu, Dongmei, Lee, Phil H, Turley, Patrick, Grenier-Boley, Benjamin, Chouraki, Vincent, Kamatani, Yoichiro, Berr, Claudine, Letenneur, Luc, Hannequin, Didier, Amouyel, Philippe, Boland, Anne, Deleuze, Jean-François, Duron, Emmanuelle, Vardarajan, Badri N, Reitz, Christiane, Goate, Alison M, Huentelman, Matthew J, Kamboh, M Ilyas, Larson, Eric B, Rogaeva, Ekaterina, St George-Hyslop, Peter, Hakonarson, Hakon, Kukull, Walter A, Farrer, Lindsay A, Barnes, Lisa L, Beach, Thomas G, Demirci, F Yesim, Head, Elizabeth, Hulette, Christine M, Jicha, Gregory A, Kauwe, John SK, Kaye, Jeffrey A, Leverenz, James B, Levey, Allan I, Lieberman, Andrew P, Pankratz, Vernon S, Poon, Wayne W, Quinn, Joseph F, Saykin, Andrew J, Schneider, Lon S, Smith, Amanda G, Sonnen, Joshua A, Stern, Robert A, Van Deerlin, Vivianna M, Van Eldik, Linda J, Harold, Denise, Russo, Giancarlo, Rubinsztein, David C, Bayer, Anthony, Tsolaki, Magda, Proitsi, Petra, Fox, Nick C, Hampel, Harald, Owen, Michael J, Mead, Simon, Passmore, Peter, Morgan, Kevin, Nöthen, Markus M, Rossor, Martin, Lupton, Michelle K, Hoffmann, Per, Kornhuber, Johannes, Lawlor, Brian, McQuillin, Andrew, Al-Chalabi, Ammar, Bis, Joshua C, Ruiz, Agustin, Boada, Mercè, Seshadri, Sudha, Beiser, Alexa, Rice, Kenneth, van der Lee, Sven J, De Jager, Philip L, Geschwind, Daniel H, Riemenschneider, Matthias, Riedel-Heller, Steffi, Rotter, Jerome I, Ransmayr, Gerhard, Hyman, Bradley T, Cruchaga, Carlos, Alegret, Montserrat, Winsvold, Bendik, Palta, Priit, Farh, Kai-How, Cuenca-Leon, Ester, and Furlotte, Nicholas

Subjects
Brainstorm Consortium, Humans, Brain Diseases, Risk Factors, Mental Disorders, Quantitative Trait, Heritable, Phenotype, Genetic Variation, Genome-Wide Association Study, Clinical Research, Neurosciences, Rare Diseases, Human Genome, Brain Disorders, Genetics, Mental Health, 2.1 Biological and endogenous factors, Mental health, Neurological, General Science & Technology
Abstract

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

Published
2018

29. A machine learning case–control classifier for schizophrenia based on DNA methylation in blood

Author

Chathura J. Gunasekara, Eilis Hannon, Harry MacKay, Cristian Coarfa, Andrew McQuillin, David St. Clair, Jonathan Mill, and Robert A. Waterland

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Epigenetic dysregulation is thought to contribute to the etiology of schizophrenia (SZ), but the cell type-specificity of DNA methylation makes population-based epigenetic studies of SZ challenging. To train an SZ case–control classifier based on DNA methylation in blood, therefore, we focused on human genomic regions of systemic interindividual epigenetic variation (CoRSIVs), a subset of which are represented on the Illumina Human Methylation 450K (HM450) array. HM450 DNA methylation data on whole blood of 414 SZ cases and 433 non-psychiatric controls were used as training data for a classification algorithm with built-in feature selection, sparse partial least squares discriminate analysis (SPLS-DA); application of SPLS-DA to HM450 data has not been previously reported. Using the first two SPLS-DA dimensions we calculated a “risk distance” to identify individuals with the highest probability of SZ. The model was then evaluated on an independent HM450 data set on 353 SZ cases and 322 non-psychiatric controls. Our CoRSIV-based model classified 303 individuals as cases with a positive predictive value (PPV) of 80%, far surpassing the performance of a model based on polygenic risk score (PRS). Importantly, risk distance (based on CoRSIV methylation) was not associated with medication use, arguing against reverse causality. Risk distance and PRS were positively correlated (Pearson r = 0.28, P = 1.28 × 10−12), and mediational analysis suggested that genetic effects on SZ are partially mediated by altered methylation at CoRSIVs. Our results indicate two innate dimensions of SZ risk: one based on genetic, and the other on systemic epigenetic variants.

Published
2021
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30. Genetic Overlap Between Attention-Deficit/Hyperactivity Disorder and Bipolar Disorder: Evidence From Genome-wide Association Study Meta-analysis.

Author

van Hulzen, Kimm JE, Scholz, Claus J, Franke, Barbara, Ripke, Stephan, Klein, Marieke, McQuillin, Andrew, Sonuga-Barke, Edmund J, PGC ADHD Working Group, Kelsoe, John R, Landén, Mikael, Andreassen, Ole A, PGC Bipolar Disorder Working Group, Lesch, Klaus-Peter, Weber, Heike, Faraone, Stephen V, Arias-Vasquez, Alejandro, and Reif, Andreas

Subjects
PGC ADHD Working Group, PGC Bipolar Disorder Working Group, Humans, Attention Deficit Disorder with Hyperactivity, Bipolar Disorder, Comorbidity, Genome-Wide Association Study, Attention-deficit/hyperactivity disorder, GWAS, bipolar disorder, cross-disorder meta-analysis, genetic correlation, genetic overlap, Human Genome, Pediatric, Genetics, Attention Deficit Hyperactivity Disorder (ADHD), Mental Health, Brain Disorders, Aetiology, 2.1 Biological and endogenous factors, Mental health, Good Health and Well Being, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

BackgroundAttention-deficit/hyperactivity disorder (ADHD) and bipolar disorder (BPD) are frequently co-occurring and highly heritable mental health conditions. We hypothesized that BPD cases with an early age of onset (≤21 years old) would be particularly likely to show genetic covariation with ADHD.MethodsGenome-wide association study data were available for 4609 individuals with ADHD, 9650 individuals with BPD (5167 thereof with early-onset BPD), and 21,363 typically developing controls. We conducted a cross-disorder genome-wide association study meta-analysis to identify whether the observed comorbidity between ADHD and BPD could be due to shared genetic risks.ResultsWe found a significant single nucleotide polymorphism-based genetic correlation between ADHD and BPD in the full and age-restricted samples (rGfull = .64, p = 3.13 × 10-14; rGrestricted = .71, p = 4.09 × 10-16). The meta-analysis between the full BPD sample identified two genome-wide significant (prs7089973 = 2.47 × 10-8; prs11756438 = 4.36 × 10-8) regions located on chromosomes 6 (CEP85L) and 10 (TAF9BP2). Restricting the analyses to BPD cases with an early onset yielded one genome-wide significant association (prs58502974 = 2.11 × 10-8) on chromosome 5 in the ADCY2 gene. Additional nominally significant regions identified contained known expression quantitative trait loci with putative functional consequences for NT5DC1, NT5DC2, and CACNB3 expression, whereas functional predictions implicated ABLIM1 as an allele-specific expressed gene in neuronal tissue.ConclusionsThe single nucleotide polymorphism-based genetic correlation between ADHD and BPD is substantial, significant, and consistent with the existence of genetic overlap between ADHD and BPD, with potential differential genetic mechanisms involved in early and later BPD onset.

Published
2017

31. Genome-wide association study of borderline personality disorder reveals genetic overlap with bipolar disorder, major depression and schizophrenia.

Author

Witt, SH, Streit, F, Jungkunz, M, Frank, J, Awasthi, S, Reinbold, CS, Treutlein, J, Degenhardt, F, Forstner, AJ, Heilmann-Heimbach, S, Dietl, L, Schwarze, CE, Schendel, D, Strohmaier, J, Abdellaoui, A, Adolfsson, R, Air, TM, Akil, H, Alda, M, Alliey-Rodriguez, N, Andreassen, OA, Babadjanova, G, Bass, NJ, Bauer, M, Baune, BT, Bellivier, F, Bergen, S, Bethell, A, Biernacka, JM, Blackwood, DHR, Boks, MP, Boomsma, DI, Børglum, AD, Borrmann-Hassenbach, M, Brennan, P, Budde, M, Buttenschøn, HN, Byrne, EM, Cervantes, P, Clarke, T-K, Craddock, N, Cruceanu, C, Curtis, D, Czerski, PM, Dannlowski, U, Davis, T, de Geus, EJC, Di Florio, A, Djurovic, S, Domenici, E, Edenberg, HJ, Etain, B, Fischer, SB, Forty, L, Fraser, C, Frye, MA, Fullerton, JM, Gade, K, Gershon, ES, Giegling, I, Gordon, SD, Gordon-Smith, K, Grabe, HJ, Green, EK, Greenwood, TA, Grigoroiu-Serbanescu, M, Guzman-Parra, J, Hall, LS, Hamshere, M, Hauser, J, Hautzinger, M, Heilbronner, U, Herms, S, Hitturlingappa, S, Hoffmann, P, Holmans, P, Hottenga, J-J, Jamain, S, Jones, I, Jones, LA, Juréus, A, Kahn, RS, Kammerer-Ciernioch, J, Kirov, G, Kittel-Schneider, S, Kloiber, S, Knott, SV, Kogevinas, M, Landén, M, Leber, M, Leboyer, M, Li, QS, Lissowska, J, Lucae, S, Martin, NG, Mayoral-Cleries, F, McElroy, SL, McIntosh, AM, McKay, JD, and McQuillin, A

Subjects
Bipolar Disorders Working Group of the Psychiatric Genomics Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Humans, Genetic Predisposition to Disease, Case-Control Studies, Bipolar Disorder, Depressive Disorder, Major, Borderline Personality Disorder, Schizophrenia, Genotype, Multifactorial Inheritance, Adolescent, Adult, Aged, Middle Aged, Female, Male, Genome-Wide Association Study, Young Adult, Depressive Disorder, Major, Clinical Sciences, Public Health and Health Services, Psychology
Abstract

Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case-control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, major depression (MDD) and schizophrenia (SCZ) and a high comorbidity of BOR and MDD, we also analyzed the genetic overlap of BOR with SCZ and MDD. GWAS, gene-based tests and gene-set analyses were performed in 998 BOR patients and 1545 controls. Linkage disequilibrium score regression was used to detect the genetic overlap between BOR and these disorders. Single marker analysis revealed no significant association after correction for multiple testing. Gene-based analysis yielded two significant genes: DPYD (P=4.42 × 10-7) and PKP4 (P=8.67 × 10-7); and gene-set analysis yielded a significant finding for exocytosis (GO:0006887, PFDR=0.019; FDR, false discovery rate). Prior studies have implicated DPYD, PKP4 and exocytosis in BIP and SCZ. The most notable finding of the present study was the genetic overlap of BOR with BIP (rg=0.28 [P=2.99 × 10-3]), SCZ (rg=0.34 [P=4.37 × 10-5]) and MDD (rg=0.57 [P=1.04 × 10-3]). We believe our study is the first to demonstrate that BOR overlaps with BIP, MDD and SCZ on the genetic level. Whether this is confined to transdiagnostic clinical symptoms should be examined in future studies.

Published
2017

32. Meta-analysis of epigenetic aging in schizophrenia reveals multifaceted relationships with age, sex, illness duration, and polygenic risk

Author

Onderzoeksgroep 11, Brain, Hersenen-Bedrijfsvoering, Ori, Anil P.S., Olde Loohuis, Loes M., Guintivano, Jerry, Hannon, Eilis, Dempster, Emma, St. Clair, David, Bass, Nick J., McQuillin, Andrew, Mill, Jonathan, Sullivan, Patrick F., Kahn, Rene S., Horvath, Steve, Ophoff, Roel A., Onderzoeksgroep 11, Brain, Hersenen-Bedrijfsvoering, Ori, Anil P.S., Olde Loohuis, Loes M., Guintivano, Jerry, Hannon, Eilis, Dempster, Emma, St. Clair, David, Bass, Nick J., McQuillin, Andrew, Mill, Jonathan, Sullivan, Patrick F., Kahn, Rene S., Horvath, Steve, and Ophoff, Roel A.

Published
2024

33. Meta-analysis of epigenetic aging in schizophrenia reveals multifaceted relationships with age, sex, illness duration, and polygenic risk

Author

Ori, Anil P.S., Olde Loohuis, Loes M., Guintivano, Jerry, Hannon, Eilis, Dempster, Emma, St. Clair, David, Bass, Nick J., McQuillin, Andrew, Mill, Jonathan, Sullivan, Patrick F., Kahn, Rene S., Horvath, Steve, Ophoff, Roel A., Ori, Anil P.S., Olde Loohuis, Loes M., Guintivano, Jerry, Hannon, Eilis, Dempster, Emma, St. Clair, David, Bass, Nick J., McQuillin, Andrew, Mill, Jonathan, Sullivan, Patrick F., Kahn, Rene S., Horvath, Steve, and Ophoff, Roel A.

Abstract

Background: The study of biological age acceleration may help identify at-risk individuals and reduce the rising global burden of age-related diseases. Using DNA methylation (DNAm) clocks, we investigated biological aging in schizophrenia (SCZ), a mental illness that is associated with an increased prevalence of age-related disabilities and morbidities. In a whole blood DNAm sample of 1090 SCZ cases and 1206 controls across four European cohorts, we performed a meta-analysis of differential aging using three DNAm clocks (i.e., Hannum, Horvath, and Levine). To dissect how DNAm aging contributes to SCZ, we integrated information on duration of illness and SCZ polygenic risk, as well as stratified our analyses by chronological age and biological sex. Results: We found that blood-based DNAm aging is significantly altered in SCZ independent from duration of the illness since onset. We observed sex-specific and nonlinear age effects that differed between clocks and point to possible distinct age windows of altered aging in SCZ. Most notably, intrinsic cellular age (Horvath clock) is decelerated in SCZ cases in young adulthood, while phenotypic age (Levine clock) is accelerated in later adulthood compared to controls. Accelerated phenotypic aging was most pronounced in women with SCZ carrying a high polygenic burden with an age acceleration of + 3.82 years (CI 2.02–5.61, P = 1.1E−03). Phenotypic aging and SCZ polygenic risk contributed additively to the illness and together explained up to 14.38% of the variance in disease status. Conclusions: Our study contributes to the growing body of evidence of altered DNAm aging in SCZ and points to intrinsic age deceleration in younger adulthood and phenotypic age acceleration in later adulthood in SCZ. Since increased phenotypic age is associated with increased risk of all-cause mortality, our findings indicate that specific and identifiable patient groups are at increased mortality risk as measured by the Levine clock. Our stud

Published
2024

34. Fine-mapping genomic loci refines bipolar disorder risk genes

Author

Koromina, Maria, Ravi, Ashvin, Panagiotaropoulou, Georgia, Schilder, Brian M., Humphrey, Jack, Braun, Alice, Bidgeli, Tim, Chatzinakos, Chris, Coombes, Brandon, Kim, Jaeyoung, Liu, Xiaoxi, Terao, Chikashi, O'Connell, Kevin S., Adams, Mark, Adolfsson, Rolf, Alda, Martin, Alfredsson, Lars, Andlauer, Till, Andreassen, Ole A., Antoniou, Anastasia, Baune, Bernhard T., Bengesser, Susanne, Biernacka, Joanna, Boehnke, Michael, Bosch, Rosa, Cairns, Murray, Carr, Vaughan J., Casas Brugué, Miquel, Catts, Stanley, Cichon, Sven, Corvin, Aiden, Craddock, Nicholas, Dafnas, Konstantinos, Dalkner, Nina, Dannlowski, Udo, Degenhardt, Franziska, Di Florio, Arianna, Dikeos, Dimitris, Fellendorf, Frederike Tabea, Ferentinos, Panagiotis, Forstner, Andreas Josef, Forty, Liz, Frye, Mark, Fullerton, Janice M., Gawlik, Micha, Gizer, Ian R., Gordon-Smith, Katherine, Green, Melissa J., Grigoroiu-Serbanescu, Maria, Guzman-Parra, José, Hahn, Tim, Henskens, Frans, Hillert, Jan, Jablensky, Assen V., Jones, Lisa, Jones, Ian, Jonsson, Lina, Kelsoe, John R., Kircher, Tilo, Kirov, George, Kittel-Schneider, Sarah, Kogevinas, Manolis, Landén, Mikael, Leboyer, Marion, Lenger, Melanie, Lissowska, Jolanta, Lochner, Christine, Loughland, Carmel, MacIntyre, Donald, Martin, Nicholas G., Maratou, Eirini, Mathews, Carol A., Mayoral, Fermı́n, McElroy, Susan L., McGregor, Nathaniel W., McIntosh, Andrew M., McQuillin, Andrew, Michie, Patricia, Milanova, Vihra, Mitchell, Philip B., Moutsatsou, Paraskevi, Mowry, Bryan, Müller-Myhsok, Bertram, Myers, Richard M., Nenadić, Igor, Nöthen, Markus Maria, O'Donovan, Claire, O'Donovan, Michael, Ophoff, Roel André, Owen, Michael J., Pantelis, Christos, Pato, Carlos, Pato, Michele T., Patrinos, George P., Pawlak, Joanna M., Perlis, Roy H., Porichi, Evgenia, Posthuma, Danielle, Ramos-Quiroga, Josep Antoni, Reif, Andreas, Reininghaus, Eva Z., Ribasés, Marta, Rietschel, Marcella, Schall, Ulrich, Schulze, Thomas Gerd, Scott, Laura J., Scott, Rodney J., Serretti, Alessandro, Shannon Weickert, Cynthia, Smoller, Jordan W., Soler Artigas, Marı́a, Stein, Dan J., Streit, Fabian, Toma, Claudio, Tooney, Paul, Vieta, Eduard, Vincent, John B., Waldman, Irwin D., Weickert, Thomas, Witt, Stephanie H., Hong, Kyung Sue, Ikeda, Masashi, Iwata, Nakao, Świątkowska, Beata, Won, Hong-Hee, Edenberg, Howard J., Ripke, Stephan, Raj, Towfique, Coleman, Jonathan R. I., Mullins, Niamh, Koromina, Maria, Ravi, Ashvin, Panagiotaropoulou, Georgia, Schilder, Brian M., Humphrey, Jack, Braun, Alice, Bidgeli, Tim, Chatzinakos, Chris, Coombes, Brandon, Kim, Jaeyoung, Liu, Xiaoxi, Terao, Chikashi, O'Connell, Kevin S., Adams, Mark, Adolfsson, Rolf, Alda, Martin, Alfredsson, Lars, Andlauer, Till, Andreassen, Ole A., Antoniou, Anastasia, Baune, Bernhard T., Bengesser, Susanne, Biernacka, Joanna, Boehnke, Michael, Bosch, Rosa, Cairns, Murray, Carr, Vaughan J., Casas Brugué, Miquel, Catts, Stanley, Cichon, Sven, Corvin, Aiden, Craddock, Nicholas, Dafnas, Konstantinos, Dalkner, Nina, Dannlowski, Udo, Degenhardt, Franziska, Di Florio, Arianna, Dikeos, Dimitris, Fellendorf, Frederike Tabea, Ferentinos, Panagiotis, Forstner, Andreas Josef, Forty, Liz, Frye, Mark, Fullerton, Janice M., Gawlik, Micha, Gizer, Ian R., Gordon-Smith, Katherine, Green, Melissa J., Grigoroiu-Serbanescu, Maria, Guzman-Parra, José, Hahn, Tim, Henskens, Frans, Hillert, Jan, Jablensky, Assen V., Jones, Lisa, Jones, Ian, Jonsson, Lina, Kelsoe, John R., Kircher, Tilo, Kirov, George, Kittel-Schneider, Sarah, Kogevinas, Manolis, Landén, Mikael, Leboyer, Marion, Lenger, Melanie, Lissowska, Jolanta, Lochner, Christine, Loughland, Carmel, MacIntyre, Donald, Martin, Nicholas G., Maratou, Eirini, Mathews, Carol A., Mayoral, Fermı́n, McElroy, Susan L., McGregor, Nathaniel W., McIntosh, Andrew M., McQuillin, Andrew, Michie, Patricia, Milanova, Vihra, Mitchell, Philip B., Moutsatsou, Paraskevi, Mowry, Bryan, Müller-Myhsok, Bertram, Myers, Richard M., Nenadić, Igor, Nöthen, Markus Maria, O'Donovan, Claire, O'Donovan, Michael, Ophoff, Roel André, Owen, Michael J., Pantelis, Christos, Pato, Carlos, Pato, Michele T., Patrinos, George P., Pawlak, Joanna M., Perlis, Roy H., Porichi, Evgenia, Posthuma, Danielle, Ramos-Quiroga, Josep Antoni, Reif, Andreas, Reininghaus, Eva Z., Ribasés, Marta, Rietschel, Marcella, Schall, Ulrich, Schulze, Thomas Gerd, Scott, Laura J., Scott, Rodney J., Serretti, Alessandro, Shannon Weickert, Cynthia, Smoller, Jordan W., Soler Artigas, Marı́a, Stein, Dan J., Streit, Fabian, Toma, Claudio, Tooney, Paul, Vieta, Eduard, Vincent, John B., Waldman, Irwin D., Weickert, Thomas, Witt, Stephanie H., Hong, Kyung Sue, Ikeda, Masashi, Iwata, Nakao, Świątkowska, Beata, Won, Hong-Hee, Edenberg, Howard J., Ripke, Stephan, Raj, Towfique, Coleman, Jonathan R. I., and Mullins, Niamh

Abstract

Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).

Published
2024

35. Distinct genetic liability profiles define clinically relevant patient strata across common diseases.

Author

Trastulla, Lucia, Dolgalev, Georgii, Moser, Sylvain, Jiménez-Barrón, Laura T., Andlauer, Till F. M., von Scheidt, Moritz, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Ruderfer, Douglas M., Ripke, Stephan, McQuillin, Andrew, Stahl, Eli A., Domenici, Enrico, Adolfsson, Rolf, Agartz, Ingrid, Agerbo, Esben, Albus, Margot, Alexander, Madeline, Amin, Farooq, Bacanu, Silviu A., and Begemann, Martin

Subjects
CORONARY artery disease, GENE expression profiling, INDIVIDUALIZED medicine, OLANZAPINE
Abstract

Stratified medicine holds great promise to tailor treatment to the needs of individual patients. While genetics holds great potential to aid patient stratification, it remains a major challenge to operationalize complex genetic risk factor profiles to deconstruct clinical heterogeneity. Contemporary approaches to this problem rely on polygenic risk scores (PRS), which provide only limited clinical utility and lack a clear biological foundation. To overcome these limitations, we develop the CASTom-iGEx approach to stratify individuals based on the aggregated impact of their genetic risk factor profiles on tissue specific gene expression levels. The paradigmatic application of this approach to coronary artery disease or schizophrenia patient cohorts identified diverse strata or biotypes. These biotypes are characterized by distinct endophenotype profiles as well as clinical parameters and are fundamentally distinct from PRS based groupings. In stark contrast to the latter, the CASTom-iGEx strategy discovers biologically meaningful and clinically actionable patient subgroups, where complex genetic liabilities are not randomly distributed across individuals but rather converge onto distinct disease relevant biological processes. These results support the notion of different patient biotypes characterized by partially distinct pathomechanisms. Thus, the universally applicable approach presented here has the potential to constitute an important component of future personalized medicine paradigms. Stratified medicine promises to tailor treatment for individual patients, however it remains a major challenge to leverage genetic risk data to aid patient stratification. Here the authors introduce an approach to stratify individuals based on the aggregated impact of their genetic risk factor profiles on tissue-specific gene expression levels, and highlight its ability to identify biologically meaningful and clinically actionable patient subgroups, supporting the notion of different patient 'biotypes' characterized by partially distinct disease mechanisms. [ABSTRACT FROM AUTHOR]

Published
2024
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36. Evidence for Genetic Overlap Between Schizophrenia and Age at First Birth in Women

Author

Mehta, Divya, Tropf, Felix C, Gratten, Jacob, Bakshi, Andrew, Zhu, Zhihong, Bacanu, Silviu-Alin, Hemani, Gibran, Magnusson, Patrik KE, Barban, Nicola, Esko, Tõnu, Metspalu, Andres, Snieder, Harold, Mowry, Bryan J, Kendler, Kenneth S, Yang, Jian, Visscher, Peter M, McGrath, John J, Mills, Melinda C, Wray, Naomi R, Lee, S Hong, Andreassen, Ole A, Bramon, Elvira, Bruggeman, Richard, Buxbaum, Joseph D, Cairns, Murray J, Cantor, Rita M, Cloninger, C Robert, Cohen, David, Crespo-Facorro, Benedicto, Darvasi, Ariel, DeLisi, Lynn E, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Escott-Price, Valentina, Freimer, Nelson B, Georgieva, Lyudmila, de Haan, Lieuwe, Henskens, Frans A, Joa, Inge, Julià, Antonio, Khrunin, Andrey, Lerer, Bernard, Limborska, Svetlana, Loughland, Carmel M, Macek, Milan, Marsal, Sara, McCarley, Robert W, McIntosh, Andrew M, McQuillin, Andrew, Melegh, Bela, Michie, Patricia T, Morris, Derek W, Murphy, Kieran C, Myin-Germeys, Inez, Olincy, Ann, Van Os, Jim, Pantelis, Christos, Posthuma, Danielle, Quested, Digby, Schall, Ulrich, Scott, Rodney J, Seidman, Larry J, Toncheva, Draga, Tooney, Paul A, Waddington, John, Weinberger, Daniel R, Weiser, Mark, and Wu, Jing Qin

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Epidemiology, Health Sciences, Human Genome, Prevention, Brain Disorders, Serious Mental Illness, Mental Health, Schizophrenia, Clinical Research, Mental health, Adult, Alleles, Birth Order, Cohort Studies, Denmark, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Maternal Age, Phenotype, Pregnancy, Risk, Schizophrenia Working Group of the Psychiatric Genomics Consortium, LifeLines Cohort Study, and TwinsUK, Other Medical and Health Sciences, Psychology, Cognitive Sciences, Clinical sciences, Clinical and health psychology
Abstract

ImportanceA recently published study of national data by McGrath et al in 2014 showed increased risk of schizophrenia (SCZ) in offspring associated with both early and delayed parental age, consistent with a U-shaped relationship. However, it remains unclear if the risk to the child is due to psychosocial factors associated with parental age or if those at higher risk for SCZ tend to have children at an earlier or later age.ObjectiveTo determine if there is a genetic association between SCZ and age at first birth (AFB) using genetically informative but independently ascertained data sets.Design, setting, and participantsThis investigation used multiple independent genome-wide association study data sets. The SCZ sample comprised 18 957 SCZ cases and 22 673 controls in a genome-wide association study from the second phase of the Psychiatric Genomics Consortium, and the AFB sample comprised 12 247 genotyped women measured for AFB from the following 4 community cohorts: Estonia (Estonian Genome Center Biobank, University of Tartu), the Netherlands (LifeLines Cohort Study), Sweden (Swedish Twin Registry), and the United Kingdom (TwinsUK). Schizophrenia genetic risk for each woman in the AFB community sample was estimated using genetic effects inferred from the SCZ genome-wide association study.Main outcomes and measuresWe tested if SCZ genetic risk was a significant predictor of response variables based on published polynomial functions that described the relationship between maternal age and SCZ risk in offspring in Denmark. We substituted AFB for maternal age in these functions, one of which was corrected for the age of the father, and found that the fit was superior for the model without adjustment for the father's age.ResultsWe observed a U-shaped relationship between SCZ risk and AFB in the community cohorts, consistent with the previously reported relationship between SCZ risk in offspring and maternal age when not adjusted for the age of the father. We confirmed that SCZ risk profile scores significantly predicted the response variables (coefficient of determination R2 = 1.1E-03, P = 4.1E-04), reflecting the published relationship between maternal age and SCZ risk in offspring by McGrath et al in 2014.Conclusions and relevanceThis study provides evidence for a significant overlap between genetic factors associated with risk of SCZ and genetic factors associated with AFB. It has been reported that SCZ risk associated with increased maternal age is explained by the age of the father and that de novo mutations that occur more frequently in the germline of older men are the underlying causal mechanism. This explanation may need to be revised if, as suggested herein and if replicated in future studies, there is also increased genetic risk of SCZ in older mothers.

Published
2016

37. 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

38. Genetic risk scores and dementia risk across different ethnic groups in UK Biobank.

Author

Naaheed Mukadam, Olga Giannakopoulou, Nick Bass, Karoline Kuchenbaecker, and Andrew McQuillin

Subjects
Medicine, Science
Abstract

BackgroundGenetic Risk Scores (GRS) for predicting dementia risk have mostly been used in people of European ancestry with limited testing in other ancestry groups.MethodsWe conducted a logistic regression with all-cause dementia as the outcome and z-standardised GRS as the exposure across diverse ethnic groups.FindingsThere was variation in frequency of APOE alleles across ethnic groups. Per standard deviation (SD) increase in z-GRS including APOE, the odds ratio (OR) for dementia was 1.73 (95%CI 1.69-1.77). Z-GRS excluding APOE also increased dementia risk (OR 1.21 per SD increase, 95% CI 1.18-1.24) and there was no evidence that ethnicity modified this association. Prediction of secondary outcomes was less robust in those not of European ancestry when APOE was excluded from the GRS.Interpretationz-GRS derived from studies in people of European ancestry can be used to quantify genetic risk in people from more diverse ancestry groups. Urgent work is needed to include people from diverse ancestries in future genetic risk studies to make this field more inclusive.

Published
2022
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40. 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

41. Black hole wind speeds and the M-sigma relation

Author

McQuillin, Rachael C and McLaughlin, Dean E

Subjects
Astrophysics - Cosmology and Nongalactic Astrophysics
Abstract

We derive an M_bh-sigma relation between supermassive black hole mass and stellar velocity dispersion in galaxy bulges, that results from self-regulated, energy-conserving feedback. The relation is of the form M_bh v_w \propto sigma^5, where v_w is the velocity of the wind driven by the black hole. We take a sample of quiescent early-type galaxies and bulges with measured black hole masses and velocity dispersions and use our model to infer the wind speeds they would have had during an active phase. This approach, in effect, translates the scatter in the observed M_bh-sigma relation into a distribution of v_w. There are some remarkable similarities between the distribution of black hole wind speeds that we obtain and the distributions of outflow speeds observed in local AGN, including a comparable median of v_w = 0.035 c., Comment: 8 pages, 4 figures. Accepted for publication in MNRAS

Published
2013
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42. A rare functional noncoding variant at the GWAS-implicated MIR137/MIR2682 locus might confer risk to schizophrenia and bipolar disorder.

Author

Duan, Jubao, Shi, Jianxin, Fiorentino, Alessia, Leites, Catherine, Chen, Xiangning, Moy, Winton, Chen, Jingchun, Alexandrov, Boian S, Usheva, Anny, He, Deli, Freda, Jessica, O'Brien, Niamh L, Molecular Genetics of Schizophrenia collaboration, Genomic Psychiatric Cohort consortium, McQuillin, Andrew, Sanders, Alan R, Gershon, Elliot S, DeLisi, Lynn E, Bishop, Alan R, Gurling, Hugh MD, Pato, Michele T, Levinson, Douglas F, Kendler, Kenneth S, Pato, Carlos N, and Gejman, Pablo V

Subjects
Molecular Genetics of Schizophrenia collaboration, Genomic Psychiatric Cohort consortium, Cell Line, Tumor, Humans, Genetic Predisposition to Disease, MicroRNAs, Risk, Sequence Analysis, DNA, Bipolar Disorder, Schizophrenia, Gene Expression Regulation, Base Sequence, Gene Frequency, Polymorphism, Single Nucleotide, Alleles, Genes, Reporter, Molecular Sequence Data, Promoter Regions, Genetic, Genetic Variation, Genome-Wide Association Study, Genetic Loci, Biotechnology, Serious Mental Illness, Clinical Research, Genetics, Mental Health, Brain Disorders, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Mental health, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Schizophrenia (SZ) genome-wide association studies (GWASs) have identified common risk variants in >100 susceptibility loci; however, the contribution of rare variants at these loci remains largely unexplored. One of the strongly associated loci spans MIR137 (miR137) and MIR2682 (miR2682), two microRNA genes important for neuronal function. We sequenced ∼6.9 kb MIR137/MIR2682 and upstream regulatory sequences in 2,610 SZ cases and 2,611 controls of European ancestry. We identified 133 rare variants with minor allele frequency (MAF) T, presented exclusively in 11 SZ cases (nominal p = 4.8 × 10(-4)). We further identified its risk allele T in 2 of 2,434 additional SZ cases, 11 of 4,339 bipolar (BP) cases, and 3 of 3,572 SZ/BP study controls and 1,688 population controls; yielding combined p values of 0.0007, 0.0013, and 0.0001 for SZ, BP, and SZ/BP, respectively. The risk allele T of 1:g.98515539A>T reduced enhancer activity of its flanking sequence by >50% in human neuroblastoma cells, predicting lower expression of MIR137/MIR2682. Both empirical and computational analyses showed weaker transcription factor (YY1) binding by the risk allele. Chromatin conformation capture (3C) assay further indicated that 1:g.98515539A>T influenced MIR137/MIR2682, but not the nearby DPYD or LOC729987. Our results suggest that rare noncoding risk variants are associated with SZ and BP at MIR137/MIR2682 locus, with risk alleles decreasing MIR137/MIR2682 expression.

Published
2014

43. Outflows from galaxy nuclei : dynamics and implications for scaling relations

Author

McQuillin, Rachael C.

Subjects
500, QB Astronomy
Abstract

The M–σ relations observed between the masses of central massive objects (CMOs: either a nuclear star cluster or a supermassive black hole) in galaxy nuclei and the stellar velocity dispersion of their host galaxy bulges strongly suggest that the evolution of CMOs and their host galaxies are closely related. Self-regulated feedback from CMOs sweeps the surrounding ambient medium into a shell and when the CMO is at a critical mass the shell is driven from the galaxy, cutting off fuel to the CMO for further growth and locking in the M–σ relations. We investigate the M–σ relations that result from either momentum- or energy-conserving feedback. In the case of momentum-conserving feedback in an isothermal halo, we find the previously derived critical mass is not by itself sufficient to drive the shell to large radius and it takes a CMO with a mass three times the critical value to drive the shell to the escape speed of the halo. In non-isothermal haloes both of these issues are mitigated as the critical mass is sufficient to drive any shell to large radius where it will accelerate and escape the halo. For energy-conserving feedback, we focus on the case that the CMO is a black hole and we find Mvw ∝ σ5, where vw is the black hole wind speed. This relation allows us to infer the wind speeds a sample of now quiescent galaxies would have had during an active phase, and we find good agreement with distributions of observed wind speeds in local active galaxies. We discuss the possibility of a transition from momentum- to energy-driving, the implications of relaxing the assumption of steady CMO winds and the effects these may have on the derived M–σ relations.

Published
2014

44. Momentum-driven feedback and the Mass-sigma relation in non-isothermal galaxies

Author

McQuillin, Rachael C. and McLaughlin, Dean E.

Subjects
Astrophysics - Cosmology and Extragalactic Astrophysics
Abstract

We solve for the velocity fields of momentum-conserving supershells driven from galaxy centres by steady winds from supermassive black holes or nuclear star clusters (central massive objects: CMOs). We look for the critical CMO mass that allows such a shell to escape from its host galaxy. In the case that the host galaxy dark matter halo is a singular isothermal sphere, we find that the critical CMO mass derived by King, which scales with the halo velocity dispersion as M_crit \propto \sigma^4, is necessary, but not by itself sufficient, to drive shells to large radii in the halo. Furthermore, a CMO mass at least 3 times the King value is required to drive the shell to the escape speed of the halo. In the case of CMOs embedded in protogalaxies with non-isothermal dark matter haloes, which we treat here for the first time, we find a critical CMO mass that \textit{is sufficient} to drive \textit{any} shell (under a steady wind) to escape \textit{any} galaxy with a peaked circular speed profile. In the limit of large halo mass, relevant to real galaxies, this critical CMO mass depends only on the value of the peak circular speed of the halo, scaling as M_crit \propto V_c,pk^4. Our results therefore relate to observational scalings between black hole mass and asymptotic circular speed in galaxy spheroids. They also suggest a natural way of extending analyses of M-\sigma relations for black holes in massive bulges, to include similar relations for nuclear clusters in lower-mass and disc galaxies., Comment: 16 pages, 7 figures, accepted for publication in MNRAS. Typos corrected, bibliography amended

Published
2012
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45. Polygenic dissection of diagnosis and clinical dimensions of bipolar disorder and schizophrenia

Author

Ruderfer, DM, Fanous, AH, Ripke, S, McQuillin, A, Amdur, RL, Gejman, PV, O'Donovan, MC, Andreassen, OA, Djurovic, S, Hultman, CM, Kelsoe, JR, Jamain, S, Landén, M, Leboyer, M, Nimgaonkar, V, Nurnberger, J, Smoller, JW, Craddock, N, Corvin, A, Sullivan, PF, Holmans, P, Sklar, P, and Kendler, KS

Subjects
Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Brain Disorders, Serious Mental Illness, Genetics, Schizophrenia, Prevention, Mental Health, Bipolar Disorder, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Mental health, Calcium Channels, L-Type, Case-Control Studies, Cell Cycle Proteins, Factor Analysis, Statistical, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Nuclear Proteins, Odds Ratio, Phenotype, Phosphatidylinositol 3-Kinases, Polymorphism, Single Nucleotide, Schizophrenic Psychology, bipolar, clinical symptoms, cross disorder, polygenic, schizophrenia, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Cross-Disorder Working Group of the Psychiatric Genomics Consortium, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Biological psychology, Clinical and health psychology
Abstract

Bipolar disorder and schizophrenia are two often severe disorders with high heritabilities. Recent studies have demonstrated a large overlap of genetic risk loci between these disorders but diagnostic and molecular distinctions still remain. Here, we perform a combined genome-wide association study (GWAS) of 19 779 bipolar disorder (BP) and schizophrenia (SCZ) cases versus 19 423 controls, in addition to a direct comparison GWAS of 7129 SCZ cases versus 9252 BP cases. In our case-control analysis, we identify five previously identified regions reaching genome-wide significance (CACNA1C, IFI44L, MHC, TRANK1 and MAD1L1) and a novel locus near PIK3C2A. We create a polygenic risk score that is significantly different between BP and SCZ and show a significant correlation between a BP polygenic risk score and the clinical dimension of mania in SCZ patients. Our results indicate that first, combining diseases with similar genetic risk profiles improves power to detect shared risk loci and second, that future direct comparisons of BP and SCZ are likely to identify loci with significant differential effects. Identifying these loci should aid in the fundamental understanding of how these diseases differ biologically. These findings also indicate that combining clinical symptom dimensions and polygenic signatures could provide additional information that may someday be used clinically.

Published
2014

46. Early negative affect in males and females with fragile X syndrome: implications for anxiety and autism

Author

Carla A. Wall, Abigail L. Hogan, Elizabeth A. Will, Samuel McQuillin, Bridgette L. Kelleher, and Jane E. Roberts

Subjects
Fragile X syndrome, Autism spectrum disorder, Anxiety, Negative affect, Sex differences, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Background Fragile X syndrome (FXS) is a genetic disorder that is highly comorbid with anxiety and autism spectrum disorder (ASD). Elevated negative affect in young children has been associated with increased risk for both anxiety and ASD; however, these relations remain poorly understood in FXS. Methods The present prospective longitudinal study examined the trajectory of negative affect from infancy through preschool in males and females with FXS and typical development and its relation to anxiety and ASD. Results Results indicate a complex association reflecting group, developmental, and sex effects. Specifically, the group with FXS displayed a trajectory of increasing negative affect across age that was distinct from the typical controls. This atypical trajectory of negative affect in FXS was driven by sex effects in that males showed lower negative affect during infancy followed by steep increases across the toddler and preschool years whereas the females displayed a flatter trajectory. Finally, elevated negative affect predicted anxiety symptoms in males, but not females, with no relationship to ASD in males or females with FXS. Conclusions The current work addresses the importance of studying the development of psychopathology in a specific neurogenetic population. Temperamental negative affect was shown to be an important early marker for anxiety in young children with FXS, with subtle differences observed between males and females.

Published
2019
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48. DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia

Author

Eilis Hannon, Emma L Dempster, Georgina Mansell, Joe Burrage, Nick Bass, Marc M Bohlken, Aiden Corvin, Charles J Curtis, David Dempster, Marta Di Forti, Timothy G Dinan, Gary Donohoe, Fiona Gaughran, Michael Gill, Amy Gillespie, Cerisse Gunasinghe, Hilleke E Hulshoff, Christina M Hultman, Viktoria Johansson, René S Kahn, Jaakko Kaprio, Gunter Kenis, Kaarina Kowalec, James MacCabe, Colm McDonald, Andrew McQuillin, Derek W Morris, Kieran C Murphy, Colette J Mustard, Igor Nenadic, Michael C O'Donovan, Diego Quattrone, Alexander L Richards, Bart PF Rutten, David St Clair, Sebastian Therman, Timothea Toulopoulou, Jim Van Os, John L Waddington, Wellcome Trust Case Control Consortium (WTCCC), CRESTAR consortium, Patrick Sullivan, Evangelos Vassos, Gerome Breen, David Andrew Collier, Robin M Murray, Leonard S Schalkwyk, and Jonathan Mill

Subjects
epigenetics, DNA methylation, psychosis, schizophrenia, clozapine, Medicine, Science, Biology (General), QH301-705.5
Abstract

We performed a systematic analysis of blood DNA methylation profiles from 4483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia, and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.

Published
2021
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49. Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

Author

Maury, Eduardo A., primary, Sherman, Maxwell A., additional, Genovese, Giulio, additional, Gilgenast, Thomas G., additional, Kamath, Tushar, additional, Burris, S.J., additional, Rajarajan, Prashanth, additional, Flaherty, Erin, additional, Akbarian, Schahram, additional, Chess, Andrew, additional, McCarroll, Steven A., additional, Loh, Po-Ru, additional, Phillips-Cremins, Jennifer E., additional, Brennand, Kristen J., additional, Macosko, Evan Z., additional, Walters, James T.R., additional, O’Donovan, Michael, additional, Sullivan, Patrick, additional, Sebat, Jonathan, additional, Lee, Eunjung A., additional, Walsh, Christopher A., additional, Marshall, Christian R., additional, Merico, Daniele, additional, Thiruvahindrapuram, Bhooma, additional, Wang, Zhouzhi, additional, Scherer, Stephen W., additional, Howrigan, Daniel P, additional, Ripke, Stephan, additional, Bulik-Sullivan, Brendan, additional, Farh, Kai-How, additional, Fromer, Menachem, additional, Goldstein, Jacqueline I., additional, Huang, Hailiang, additional, Lee, Phil, additional, Daly, Mark J., additional, Neale, Benjamin M., additional, Belliveau, Richard A., additional, Bergen, Sarah E., additional, Bevilacqua, Elizabeth, additional, Chambert, Kimberley D., additional, O'Dushlaine, Colm, additional, Scolnick, Edward M., additional, Smoller, Jordan W., additional, Moran, Jennifer L., additional, Palotie, Aarno, additional, Petryshen, Tracey L., additional, Wu, Wenting, additional, Greer, Douglas S., additional, Antaki, Danny, additional, Shetty, Aniket, additional, Gujral, Madhusudan, additional, Brandler, William M., additional, Malhotra, Dheeraj, additional, Fuentes Fajarado, Karin V., additional, Maile, Michelle S., additional, Holmans, Peter A., additional, Carrera, Noa, additional, Craddock, Nick, additional, Escott-Price, Valentina, additional, Georgieva, Lyudmila, additional, Hamshere, Marian L., additional, Kavanagh, David, additional, Legge, Sophie E., additional, Pocklington, Andrew J., additional, Richards, Alexander L., additional, Ruderfer, Douglas M., additional, Williams, Nigel M., additional, Kirov, George, additional, Owen, Michael J., additional, Pinto, Dalila, additional, Cai, Guiqing, additional, Davis, Kenneth L., additional, Drapeau, Elodie, additional, Friedman, Joseph I, additional, Haroutunian, Vahram, additional, Parkhomenko, Elena, additional, Reichenberg, Abraham, additional, Silverman, Jeremy M., additional, Buxbaum, Joseph D., additional, Domenici, Enrico, additional, Agartz, Ingrid, additional, Djurovic, Srdjan, additional, Mattingsdal, Morten, additional, Melle, Ingrid, additional, Andreassen, Ole A., additional, Jönsson, Erik G., additional, Söderman, Erik, additional, Albus, Margot, additional, Alexander, Madeline, additional, Laurent, Claudine, additional, Levinson, Douglas F., additional, Amin, Farooq, additional, Atkins, Joshua, additional, Cairns, Murray J., additional, Scott, Rodney J., additional, Tooney, Paul A., additional, Wu, Jing Qin, additional, Bacanu, Silviu A., additional, Bigdeli, Tim B., additional, Reimers, Mark A., additional, Webb, Bradley T., additional, Wolen, Aaron R., additional, Wormley, Brandon K., additional, Kendler, Kenneth S., additional, Riley, Brien P., additional, Kähler, Anna K., additional, Magnusson, Patrik K.E., additional, Hultman, Christina M., additional, Bertalan, Marcelo, additional, Hansen, Thomas, additional, Olsen, Line, additional, Rasmussen, Henrik B., additional, Werge, Thomas, additional, Mattheisen, Manuel, additional, Black, Donald W., additional, Bruggeman, Richard, additional, Buccola, Nancy G., additional, Buckner, Randy L., additional, Roffman, Joshua L., additional, Byerley, William, additional, Cahn, Wiepke, additional, Kahn, René S, additional, Strengman, Eric, additional, Ophoff, Roel A., additional, Carr, Vaughan J., additional, Catts, Stanley V., additional, Henskens, Frans A., additional, Loughland, Carmel M., additional, Michie, Patricia T., additional, Pantelis, Christos, additional, Schall, Ulrich, additional, Jablensky, Assen V., additional, Kelly, Brian J., additional, Campion, Dominique, additional, Cantor, Rita M., additional, Cheng, Wei, additional, Cloninger, C. Robert, additional, Svrakic, Dragan M, additional, Cohen, David, additional, Cormican, Paul, additional, Donohoe, Gary, additional, Morris, Derek W., additional, Corvin, Aiden, additional, Gill, Michael, additional, Crespo-Facorro, Benedicto, additional, Crowley, James J., additional, Farrell, Martilias S., additional, Giusti-Rodríguez, Paola, additional, Kim, Yunjung, additional, Szatkiewicz, Jin P., additional, Williams, Stephanie, additional, Curtis, David, additional, Pimm, Jonathan, additional, Gurling, Hugh, additional, McQuillin, Andrew, additional, Davidson, Michael, additional, Weiser, Mark, additional, Degenhardt, Franziska, additional, Forstner, Andreas J., additional, Herms, Stefan, additional, Hoffmann, Per, additional, Hofman, Andrea, additional, Cichon, Sven, additional, Nöthen, Markus M., additional, Del Favero, Jurgen, additional, DeLisi, Lynn E., additional, McCarley, Robert W., additional, Levy, Deborah L., additional, Mesholam-Gately, Raquelle I., additional, Seidman, Larry J., additional, Dikeos, Dimitris, additional, Papadimitriou, George N., additional, Dinan, Timothy, additional, Duan, Jubao, additional, Sanders, Alan R., additional, Gejman, Pablo V., additional, Gershon, Elliot S., additional, Dudbridge, Frank, additional, Eichhammer, Peter, additional, Eriksson, Johan, additional, Salomaa, Veikko, additional, Essioux, Laurent, additional, Fanous, Ayman H., additional, Knowles, James A., additional, Pato, Michele T., additional, Pato, Carlos N., additional, Frank, Josef, additional, Meier, Sandra, additional, Schulze, Thomas G., additional, Strohmaier, Jana, additional, Witt, Stephanie H., additional, Rietschel, Marcella, additional, Franke, Lude, additional, Karjalainen, Juha, additional, Freedman, Robert, additional, Olincy, Ann, additional, Freimer, Nelson B., additional, Purcell, Shaun M., additional, Roussos, Panos, additional, Stahl, Eli A., additional, Sklar, Pamela, additional, Giegling, Ina, additional, Hartmann, Annette M., additional, Konte, Bettina, additional, Rujescu, Dan, additional, Godard, Stephanie, additional, Hirschhorn, Joel N., additional, Pers, Tune H., additional, Price, Alkes, additional, Esko, Tõnu, additional, Gratten, Jacob, additional, Lee, S. Hong, additional, Visscher, Peter M., additional, Wray, Naomi R., additional, Mowry, Bryan J., additional, de Haan, Lieuwe, additional, Meijer, Carin J., additional, Hansen, Mark, additional, Ikeda, Masashi, additional, Iwata, Nakao, additional, Joa, Inge, additional, Kalaydjieva, Luba, additional, Keller, Matthew C., additional, Kennedy, James L., additional, Zai, Clement C., additional, Knight, Jo, additional, Lerer, Bernard, additional, Liang, Kung-Yee, additional, Lieberman, Jeffrey, additional, Stroup, T. Scott, additional, Lönnqvist, Jouko, additional, Suvisaari, Jaana, additional, Maher, Brion S., additional, Maier, Wolfgang, additional, Mallet, Jacques, additional, McDonald, Colm, additional, McIntosh, Andrew M., additional, Blackwood, Douglas H.R., additional, Metspalu, Andres, additional, Milani, Lili, additional, Milanova, Vihra, additional, Mokrab, Younes, additional, Collier, David A., additional, Müller-Myhsok, Bertram, additional, Murphy, Kieran C., additional, Murray, Robin M., additional, Powell, John, additional, Myin-Germeys, Inez, additional, Van Os, Jim, additional, Nenadic, Igor, additional, Nertney, Deborah A., additional, Nestadt, Gerald, additional, Pulver, Ann E., additional, Nicodemus, Kristin K., additional, Nisenbaum, Laura, additional, Nordin, Annelie, additional, Adolfsson, Rolf, additional, O'Callaghan, Eadbhard, additional, Oh, Sang-Yun, additional, O'Neill, F. Anthony, additional, Paunio, Tiina, additional, Pietiläinen, Olli, additional, Perkins, Diana O., additional, Quested, Digby, additional, Savitz, Adam, additional, Li, Qingqin S., additional, Schwab, Sibylle G., additional, Shi, Jianxin, additional, Spencer, Chris C.A., additional, Thirumalai, Srinivas, additional, Veijola, Juha, additional, Waddington, John, additional, Walsh, Dermot, additional, Wildenauer, Dieter B., additional, Bramon, Elvira, additional, Darvasi, Ariel, additional, Posthuma, Danielle, additional, St. Clair, David, additional, Shanta, Omar, additional, Klein, Marieke, additional, Park, Peter J., additional, Weinberger, Daniel, additional, Moran, John V., additional, Gage, Fred H., additional, Vaccarino, Flora M., additional, Gleeson, Joseph, additional, Mathern, Gary, additional, Courchesne, Eric, additional, Roy, Subhojit, additional, Bizzotto, Sara, additional, Coulter, Michael, additional, Dias, Caroline, additional, D'Gama, Alissa, additional, Ganz, Javier, additional, Hill, Robert, additional, Huang, August Yue, additional, Khoshkhoo, Sattar, additional, Kim, Sonia, additional, Lodato, Michael, additional, Miller, Michael, additional, Borges-Monroy, Rebeca, additional, Rodin, Rachel, additional, Zhou, Zinan, additional, Bohrson, Craig, additional, Chu, Chong, additional, Cortes-Ciriano, Isidro, additional, Dou, Yanmei, additional, Galor, Alon, additional, Gulhan, Doga, additional, Kwon, Minseok, additional, Luquette, Joe, additional, Viswanadham, Vinay, additional, Jones, Attila, additional, Rosenbluh, Chaggai, additional, Cho, Sean, additional, Langmead, Ben, additional, Thorpe, Jeremy, additional, Erwin, Jennifer, additional, Jaffe, Andrew, additional, McConnell, Michael, additional, Narurkar, Rujuta, additional, Paquola, Apua, additional, Shin, Jooheon, additional, Straub, Richard, additional, Abyzov, Alexej, additional, Bae, Taejeong, additional, Jang, Yeongjun, additional, Wang, Yifan, additional, Gage, Fred, additional, Linker, Sara, additional, Reed, Patrick, additional, Wang, Meiyan, additional, Urban, Alexander, additional, Zhou, Bo, additional, Zhu, Xiaowei, additional, Pattni, Reenal, additional, Amero, Aitor Serres, additional, Juan, David, additional, Lobon, Irene, additional, Marques-Bonet, Tomas, additional, Moruno, Manuel Solis, additional, Perez, Raquel Garcia, additional, Povolotskaya, Inna, additional, Soriano, Eduardo, additional, Averbuj, Dan, additional, Ball, Laurel, additional, Breuss, Martin, additional, Yang, Xiaoxu, additional, Chung, Changuk, additional, Emery, Sarah B., additional, Flasch, Diane A., additional, Kidd, Jeffrey M., additional, Kopera, Huira C., additional, Kwan, Kenneth Y., additional, Mills, Ryan E., additional, Moldovan, John B., additional, Sun, Chen, additional, Zhao, Xuefang, additional, Zhou, Weichen, additional, Frisbie, Trenton J., additional, Cherskov, Adriana, additional, Fasching, Liana, additional, Jourdon, Alexandre, additional, Pochareddy, Sirisha, additional, Scuderi, Soraya, additional, and Sestan, Nenad, additional

Published
2023
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