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

Olav B. Smeland, Shahram Bahrami, Oleksandr Frei, Alexey Shadrin, Kevin O’Connell, Jeanne Savage, Kyoko Watanabe, Florian Krull, Francesco Bettella, Nils Eiel Steen, Torill Ueland, Danielle Posthuma, Srdjan Djurovic, Anders M. Dale, Ole A. Andreassen

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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.

Original languageEnglish
Pages (from-to)1-10
Number of pages10
JournalMolecular Psychiatry
DOIs
Publication statusE-pub ahead of print - 4 Jan 2019

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Intelligence
Bipolar Disorder
Schizophrenia
Genome
Alleles
Biological Phenomena
Genome-Wide Association Study
Mental Disorders
Synaptic Transmission
Cognition
Genes

Cite this

Smeland, Olav B. ; Bahrami, Shahram ; Frei, Oleksandr ; Shadrin, Alexey ; O’Connell, Kevin ; Savage, Jeanne ; Watanabe, Kyoko ; Krull, Florian ; Bettella, Francesco ; Steen, Nils Eiel ; Ueland, Torill ; Posthuma, Danielle ; Djurovic, Srdjan ; Dale, Anders M. ; Andreassen, Ole A. / Genome-wide analysis reveals extensive genetic overlap between schizophrenia, bipolar disorder, and intelligence. In: Molecular Psychiatry. 2019 ; pp. 1-10.
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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.",
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Smeland, OB, Bahrami, S, Frei, O, Shadrin, A, O’Connell, K, Savage, J, Watanabe, K, Krull, F, Bettella, F, Steen, NE, Ueland, T, Posthuma, D, Djurovic, S, Dale, AM & Andreassen, OA 2019, 'Genome-wide analysis reveals extensive genetic overlap between schizophrenia, bipolar disorder, and intelligence' Molecular Psychiatry, pp. 1-10. https://doi.org/10.1038/s41380-018-0332-x

Genome-wide analysis reveals extensive genetic overlap between schizophrenia, bipolar disorder, and intelligence. / Smeland, Olav B.; Bahrami, Shahram; Frei, Oleksandr; Shadrin, Alexey; O’Connell, Kevin; Savage, Jeanne; Watanabe, Kyoko; Krull, Florian; Bettella, Francesco; Steen, Nils Eiel; Ueland, Torill; Posthuma, Danielle; Djurovic, Srdjan; Dale, Anders M.; Andreassen, Ole A.

In: Molecular Psychiatry, 04.01.2019, p. 1-10.

Research output: Contribution to JournalArticleAcademicpeer-review

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AU - Bahrami, Shahram

AU - Frei, Oleksandr

AU - Shadrin, Alexey

AU - O’Connell, Kevin

AU - Savage, Jeanne

AU - Watanabe, Kyoko

AU - Krull, Florian

AU - Bettella, Francesco

AU - Steen, Nils Eiel

AU - Ueland, Torill

AU - Posthuma, Danielle

AU - Djurovic, Srdjan

AU - Dale, Anders M.

AU - Andreassen, Ole A.

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AB - 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.

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