Title: Identification of Genetic Loci Jointly Influencing Schizophrenia Risk and the Cognitive Traits of Verbal-Numerical Reasoning, Reaction Time, and General Cognitive Function
year: 2017
Journal: JAMA Psychiatry
Volume: 74
Issue: 10
Pages: 1065-1075
date: 01/10/2001
ISSN: 2168-6238 (Electronic);2168-622X (Linking)
Legal note: PMC5710474
Article Number: 28746715
Keywords: Adult;Cognition/physiology;*Cognitive Dysfunction/diagnosis/etiology/genetics;Female;GTPase-Activating Proteins/genetics;Genetic Loci;Genetic Variation;Genome-Wide Association Study;Humans;Linkage Disequilibrium;Male;Polymorphism, Single Nucleotide;Quantitative Trait, Heritable;Reaction Time;*Schizophrenia/complications/diagnosis/genetics;alpha Catenin/genetics
Abstract: Importance: Schizophrenia is associated with widespread cognitive impairments. Although cognitive deficits are one of the factors most strongly associated with functional outcome in schizophrenia, current treatment strategies largely fail to ameliorate these impairments. To develop more efficient treatment strategies in patients with schizophrenia, a better understanding of the pathogenesis of these cognitive deficits is needed. Accumulating evidence indicates that genetic risk of schizophrenia may contribute to cognitive dysfunction. Objective: To identify genomic regions jointly influencing schizophrenia and the cognitive domains of reaction time and verbal-numerical reasoning, as well as general cognitive function, a phenotype that captures the shared variation in performance across cognitive domains. Design, Setting, and Participants: Combining data from genome-wide association studies from multiple phenotypes using conditional false discovery rate analysis provides increased power to discover genetic variants and could elucidate shared molecular genetic mechanisms. Data from the following genome-wide association studies, published from July 24, 2014, to January 17, 2017, were combined: schizophrenia in the Psychiatric Genomics Consortium cohort (n = 79757 [cases, 34486; controls, 45271]); verbal-numerical reasoning (n = 36035) and reaction time (n = 111483) in the UK Biobank cohort; and general cognitive function in CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) (n = 53949) and COGENT (Cognitive Genomics Consortium) (n = 27888). Main Outcomes and Measures: Genetic loci identified by conditional false discovery rate analysis. Brain messenger RNA expression and brain expression quantitative trait locus functionality were determined. Results: Among the participants in the genome-wide association studies, 21 loci jointly influencing schizophrenia and cognitive traits were identified: 2 loci shared between schizophrenia and verbal-numerical reasoning, 6 loci shared between schizophrenia and reaction time, and 14 loci shared between schizophrenia and general cognitive function. One locus was shared between schizophrenia and 2 cognitive traits and represented the strongest shared signal detected (nearest gene TCF20; chromosome 22q13.2), and was shared between schizophrenia (z score, 5.01; P = 5.53 x 10-7), general cognitive function (z score, -4.43; P = 9.42 x 10-6), and verbal-numerical reasoning (z score, -5.43; P = 5.64 x 10-8). For 18 loci, schizophrenia risk alleles were associated with poorer cognitive performance. The implicated genes are expressed in the developmental and adult human brain. Replicable expression quantitative trait locus functionality was identified for 4 loci in the adult human brain. Conclusions and Relevance: The discovered loci improve the understanding of the common genetic basis underlying schizophrenia and cognitive function, suggesting novel molecular genetic mechanisms.
Notes: Smeland, Olav B;Frei, Oleksandr;Kauppi, Karolina;Hill, W David;Li, Wen;Wang, Yunpeng;Krull, Florian;Bettella, Francesco;Eriksen, Jon A;Witoelar, Aree;Davies, Gail;Fan, Chun C;Thompson, Wesley K;Lam, Max;Lencz, Todd;Chen, Chi-Hua;Ueland, Torill;Jonsson, Erik G;Djurovic, Srdjan;Deary, Ian J;Dale, Anders M;Andreassen, Ole A;(Cohorts for Heart and Aging Research in Genomic Epidemiology);eng;R01 GM104400/GM/NIGMS NIH HHS/;R01 MH100351/MH/NIMH NIH HHS/;U01 MH109514/MH/NIMH NIH HHS/;2017/07/27 06:00;JAMA Psychiatry. 2017 Oct 1;74(10):1065-1075. doi: 10.1001/jamapsychiatry.2017.1986.
URL: https://www.ncbi.nlm.nih.gov/pubmed/28746715;https://jamanetwork.com/journals/jamapsychiatry/articlepdf/2645497/jamapsychiatry_Smeland_2017_oi_170050.pdf
URI: https://open-access.imh.com.sg/handle/123456789/5177
Authors Address: Norwegian Centre for Mental Disorders Research, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.;Norwegian Centre for Mental Disorders Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.;Department of Neuroscience, University of California San Diego, La Jolla.;Department of Radiology, University of California San Diego, La Jolla.;Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla.;Department of Radiation Sciences, Umea University, Umea, Sweden.;Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom.;Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom.;Department of Cognitive Science, University of California, San Diego, La Jolla.;Department of Family Medicine and Public Health, University of California, San Diego, La Jolla.;Institute of Biological Psychiatry, Roskilde, Denmark.;Institute of Mental Health, Singapore.;Division of Psychiatry Research, Zucker Hillside Hospital, Glen Oaks, New York.;Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, New York.;Department of Psychiatry, Hofstra Northwell School of Medicine, Hempstead, New York.;Department of Psychology, University of Oslo, Olso, Norway.;Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden.;Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.;NORMENT, KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen, Norway.;Department of Psychiatry, University of California, San Diego, La Jolla.
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