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Original Investigation
July 26, 2017

Identification of Genetic Loci Jointly Influencing Schizophrenia Risk and the Cognitive Traits of Verbal-Numerical Reasoning, Reaction Time, and General Cognitive Function

Author Affiliations
  • 1Norwegian Centre for Mental Disorders Research, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
  • 2Norwegian Centre for Mental Disorders Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
  • 3Department of Neuroscience, University of California San Diego, La Jolla
  • 4Department of Radiology, University of California San Diego, La Jolla
  • 5Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla
  • 6Department of Radiation Sciences, Umeå University, Umeå, Sweden
  • 7Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom
  • 8Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom
  • 9Department of Cognitive Science, University of California, San Diego, La Jolla
  • 10Department of Family Medicine and Public Health, University of California, San Diego, La Jolla
  • 11Institute of Biological Psychiatry, Roskilde, Denmark
  • 12Institute of Mental Health, Singapore
  • 13Division of Psychiatry Research, Zucker Hillside Hospital, Glen Oaks, New York
  • 14Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, New York
  • 15Department of Psychiatry, Hofstra Northwell School of Medicine, Hempstead, New York
  • 16Department of Psychology, University of Oslo, Olso, Norway
  • 17Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden
  • 18Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
  • 19NORMENT, KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen, Norway
  • 20Department of Psychiatry, University of California, San Diego, La Jolla
JAMA Psychiatry. Published online July 26, 2017. doi:10.1001/jamapsychiatry.2017.1986
Key Points

Question  What genetic loci jointly influence schizophrenia and cognitive function?

Findings  In this analysis of genome-wide association studies on schizophrenia and cognitive traits in more than 250 000 participants, 21 genomic regions were found to be shared between schizophrenia and cognitive traits.

Meaning  The findings provide new insights into the common genetic basis underlying schizophrenia and cognitive function, suggesting novel molecular genetic mechanisms.

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 = 79 757 [cases, 34 486; controls, 45 271]); verbal-numerical reasoning (n = 36 035) and reaction time (n = 111 483) in the UK Biobank cohort; and general cognitive function in CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) (n = 53 949) and COGENT (Cognitive Genomics Consortium) (n = 27 888).

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 × 10−7), general cognitive function (z score, –4.43; P = 9.42 × 10−6), and verbal-numerical reasoning (z score, –5.43; P = 5.64 × 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.

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