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Mol Psychiatry. 2019 Jan 4. doi: 10.1038/s41380-018-0332-x. [Epub ahead of print]

Genome-wide analysis reveals extensive genetic overlap between schizophrenia, bipolar disorder, and intelligence.

Author information

1
NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, 0407, Oslo, Norway. o.b.smeland@medisin.uio.no.
2
NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, 0407, Oslo, Norway.
3
Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, Amsterdam, The Netherlands.
4
Department of Psychology, University of Oslo, Oslo, Norway.
5
Department of Clinical Genetics, section Complex Trait Genetics, Neuroscience Campus Amsterdam, VU Medical Center, Amsterdam, the Netherlands.
6
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
7
NORMENT, KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen, Norway.
8
Department of Cognitive Science, University of California, San Diego, La Jolla, CA, 92093, USA.
9
Department of Neuroscience, University of California San Diego, La Jolla, CA, 92093, USA.
10
Department of Radiology, University of California, San Diego, La Jolla, CA, 92093, USA.
11
Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA, 92093, USA.
12
NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, 0407, Oslo, Norway. o.a.andreassen@medisin.uio.no.

Abstract

Schizophrenia (SCZ) and bipolar disorder (BD) are severe mental disorders associated with cognitive impairment, which is considered a major determinant of functional outcome. Despite this, the etiology of the cognitive impairment is poorly understood, and no satisfactory cognitive treatments exist. Increasing evidence indicates that genetic risk for SCZ may contribute to cognitive impairment, whereas the genetic relationship between BD and cognitive function remains unclear. Here, we combined large genome-wide association study data on SCZ (n = 82,315), BD (n = 51,710), and general intelligence (n = 269,867) to investigate overlap in common genetic variants using conditional false discovery rate (condFDR) analysis. We observed substantial genetic enrichment in both SCZ and BD conditional on associations with intelligence indicating polygenic overlap. Using condFDR analysis, we leveraged this enrichment to increase statistical power and identified 75 distinct genomic loci associated with both SCZ and intelligence, and 12 loci associated with both BD and intelligence at conjunctional FDR < 0.01. Among these loci, 20 are novel for SCZ, and four are novel for BD. Most SCZ risk alleles (61 of 75, 81%) were associated with poorer cognitive performance, whereas most BD risk alleles (9 of 12, 75%) were associated with better cognitive performance. A gene set analysis of the loci shared between SCZ and intelligence implicated biological processes related to neurodevelopment, synaptic integrity, and neurotransmission; the same analysis for BD was underpowered. Altogether, the study demonstrates that both SCZ and BD share genetic influences with intelligence, albeit in a different manner, providing new insights into their genetic architectures.

PMID:
30610197
DOI:
10.1038/s41380-018-0332-x

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