Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders

Gabriëlla A.M. Blokland; Jakob Grove; Chia Yen Chen; Chris Cotsapas; Stuart Tobet; Robert Handa; 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

doi:10.1016/j.biopsych.2021.02.972

Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders

Gabriëlla A.M. Blokland^*, Jakob Grove, Chia Yen Chen, Chris Cotsapas, Stuart Tobet, Robert Handa, 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

^*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

80 Citationer (Scopus)

Abstract

BACKGROUND: Sex 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.

METHODS: We 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.

RESULTS: Across 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).

CONCLUSIONS: In 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.

Originalsprog	Engelsk
Tidsskrift	Biological Psychiatry
Vol/bind	91
Nummer	1
Sider (fra-til)	102-117
Antal sider	16
ISSN	0006-3223
DOI	https://doi.org/10.1016/j.biopsych.2021.02.972
Status	Udgivet - jan. 2022

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10.1016/j.biopsych.2021.02.972

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8458480/pdf/nihms-1685139.pdf

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Blokland, G. A. M., Grove, J., Chen, C. Y., Cotsapas, C., Tobet, S., Handa, R., 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 (2022). Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders. Biological Psychiatry, 91(1), 102-117. https://doi.org/10.1016/j.biopsych.2021.02.972

@article{681d848f22824fb9808cda9953f43dc9,

title = "Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders",

abstract = "BACKGROUND: Sex 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.METHODS: We 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.RESULTS: Across 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).CONCLUSIONS: In 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.",

keywords = "Bipolar disorder, Genome-wide association study, Genotype-by-sex interaction, Major depressive disorder, Schizophrenia, Sex differences, SCHIZOPHRENIA, RISK, MAJOR DEPRESSION, PARAVENTRICULAR NUCLEUS, DYSPHORIC MOOD, KYNURENINE PATHWAY METABOLISM, LD SCORE REGRESSION, GENDER-DIFFERENCES, GENOME-WIDE ASSOCIATION, AFFECTIVE STIMULI IMPACT",

author = "Blokland, \{Gabri{\"e}lla A.M.\} and Jakob Grove and Chen, \{Chia Yen\} and Chris Cotsapas and Stuart Tobet and Robert Handa and Stephan Ripke and Neale, \{Benjamin M.\} and Aiden Corvin and Walters, \{James T.R.\} and Farh, \{Kai How\} and Holmans, \{Peter A.\} and Phil Lee and Brendan Bulik-Sullivan and Collier, \{David A.\} and Hailiang Huang and Pers, \{Tune H.\} and Ingrid Agartz and Esben Agerbo and Margot Albus and Madeline Alexander and Farooq Amin and Bacanu, \{Silviu A.\} and Ditte Demontis and Thomas Hansen and Hollegaard, \{Mads V.\} and Manuel Mattheisen and Ole Mors and Als, \{Thomas D.\} and Pedersen, \{Carsten B{\o}cker\} and Pedersen, \{Marianne Gi{\o}rtz\} and Li, \{Jun Z.\} and Buttensch{\o}n, \{Henriette N.\} and Christensen, \{Jane Hvarregaard\} and Thomas Hansen and Per Qvist and Wesley Thompson and Mortensen, \{Preben Bo\} and B{\o}rglum, \{Anders D.\} and Christopher H{\"u}bel and Kristjar Skajaa and \{Schizophrenia Working Group of the Psychiatric Genomics Consortium\} and \{Bipolar Disorder Working Group of the Psychiatric Genomics Consortium\} and \{Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium\} and \{Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium\} and iPSYCH",

year = "2022",

month = jan,

doi = "10.1016/j.biopsych.2021.02.972",

language = "English",

volume = "91",

pages = "102--117",

journal = "Biological Psychiatry",

issn = "0006-3223",

publisher = "Elsevier Inc.",

number = "1",

}

Blokland, GAM, Grove, J, Chen, CY, Cotsapas, C, Tobet, S, Handa, R, 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 2022, 'Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders', Biological Psychiatry, bind 91, nr. 1, s. 102-117. https://doi.org/10.1016/j.biopsych.2021.02.972

TY - JOUR

T1 - Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders

AU - Blokland, Gabriëlla A.M.

AU - Grove, Jakob

AU - Chen, Chia Yen

AU - Cotsapas, Chris

AU - Tobet, Stuart

AU - Handa, Robert

AU - Ripke, Stephan

AU - Neale, Benjamin M.

AU - Corvin, Aiden

AU - Walters, James T.R.

AU - Farh, Kai How

AU - Holmans, Peter A.

AU - Lee, Phil

AU - Bulik-Sullivan, Brendan

AU - Collier, David A.

AU - Huang, Hailiang

AU - Pers, Tune H.

AU - Agartz, Ingrid

AU - Agerbo, Esben

AU - Albus, Margot

AU - Alexander, Madeline

AU - Amin, Farooq

AU - Bacanu, Silviu A.

AU - Demontis, Ditte

AU - Hansen, Thomas

AU - Hollegaard, Mads V.

AU - Mattheisen, Manuel

AU - Mors, Ole

AU - Als, Thomas D.

AU - Pedersen, Carsten Bøcker

AU - Pedersen, Marianne Giørtz

AU - Li, Jun Z.

AU - Buttenschøn, Henriette N.

AU - Christensen, Jane Hvarregaard

AU - Hansen, Thomas

AU - Qvist, Per

AU - Thompson, Wesley

AU - Mortensen, Preben Bo

AU - Børglum, Anders D.

AU - Hübel, Christopher

AU - Skajaa, Kristjar

AU - Schizophrenia Working Group of the Psychiatric Genomics Consortium

AU - Bipolar Disorder Working Group of the Psychiatric Genomics Consortium

AU - Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

AU - Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium

AU - iPSYCH

PY - 2022/1

Y1 - 2022/1

N2 - BACKGROUND: Sex 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.METHODS: We 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.RESULTS: Across 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).CONCLUSIONS: In 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.

AB - BACKGROUND: Sex 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.METHODS: We 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.RESULTS: Across 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).CONCLUSIONS: In 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.

KW - Bipolar disorder

KW - Genome-wide association study

KW - Genotype-by-sex interaction

KW - Major depressive disorder

KW - Schizophrenia

KW - Sex differences

KW - SCHIZOPHRENIA

KW - RISK

KW - MAJOR DEPRESSION

KW - PARAVENTRICULAR NUCLEUS

KW - DYSPHORIC MOOD

KW - KYNURENINE PATHWAY METABOLISM

KW - LD SCORE REGRESSION

KW - GENDER-DIFFERENCES

KW - GENOME-WIDE ASSOCIATION

KW - AFFECTIVE STIMULI IMPACT

UR - https://www.scopus.com/pages/publications/85108284544

U2 - 10.1016/j.biopsych.2021.02.972

DO - 10.1016/j.biopsych.2021.02.972

M3 - Journal article

C2 - 34099189

SN - 0006-3223

VL - 91

SP - 102

EP - 117

JO - Biological Psychiatry

JF - Biological Psychiatry

IS - 1

ER -

Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders

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