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

iPSYCH; 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

doi:10.1016/j.biopsych.2021.02.972

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

iPSYCH
, 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

The Department of Psychiatry and Neuropsychology
Maastricht University
Department of Psychiatry
Massachusetts General Hospital
Harvard University
Broad Institute
Department of Biomedicine
Aarhus University
H. Lundbeck A/S
Center for Genome Analysis and Personalized Medicine
Bioinformatics Research Centre (BiRC)
Biogen IDEC
Department of Neurology and Genetics
Yale University
Department of Biomedical Sciences
Colorado State University
University of Aberdeen
Northwell Health System
The Zucker School of Medicine at Hofstra/Northwell
The Zucker Hillside Hospital
University of Queensland
Queensland Health
Schizophrenia Research Institute
University of Newcastle
Priority Centre for Translational Neuroscience and Mental Health
MRC Centre for Neuropsychiatric Genetics and Genomics
Cardiff University
Departments of Genetics and Psychiatry
University of North Carolina at Chapel Hill
Department of Medical Epidemiology and Biostatistics
Karolinska Institutet
Department of Psychiatry
Trinity College Dublin
Department of Psychiatry and Human and Molecular Genetics
Virginia Commonwealth University
Medical and Population Genetics
University of Tartu
Centre for Psychiatry Research
KG Jebsen Centre for Psychosis Research
University of Oslo
University of Helsinki
Department of Clinical Neuroscience
Max Planck Institute of Experimental Medicine
Department of Psychiatry
The University of Hong Kong
Li Ka Shing Faculty of Medicine
Department of Psychiatry
Fujita Health University
Lieber Institute for Brain Development
Department of Psychiatry
Johns Hopkins University
Department of Psychiatry and Behavioral Neuroscience
The University of Chicago
Department of Psychiatry and Behavioral Sciences
NorthShore University HealthSystem
Department of Human Genetics and Neuroscience
Icahn School of Medicine at Mount Sinai
Department of Psychiatry
Department of Psychiatry
Martin Luther University Halle-Wittenberg
Ludwig Maximilian University of Munich
Mental Health Neuroscience Research Department
University College London
King's College London
Institute for Genomic Health
SUNY Downstate Health Sciences University
Department of Psychiatry
University of Southern California
Research Division
Singapore Institute of Mental Health
National University of Singapore
Norwegian Centre for Mental Disorders Research (NORMENT)
Center for Psychopharmacology
Diakonhjemmet Hospital
Department of Pharmaceutical Bio-sciences
University Medical Center Utrecht
Utrecht University
University of California at Los Angeles
Molecular Psychiatry Laboratory
Department of Clinical Sciences
Umeå University
School of Psychology
Genetics and Computational Biology
Queensland Institute of Medical Research
Neuroscience Research Australia
University of New South Wales
Vrije Universiteit Amsterdam
University of Amsterdam

Research output: Contribution to journal › Article › peer-review

97 Citations (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.

Original language	English
Pages (from-to)	102-117
Number of pages	16
Journal	Biological Psychiatry
Volume	91
Issue number	1
DOIs	https://doi.org/10.1016/j.biopsych.2021.02.972
Publication status	Published - 23 Mar 2021
Externally published	Yes

Keywords

Affective stimuli impact
Dysphoric mood
Gender-differences
Genome-wide association
Kynurenine pathway metabolism
Ld score regression
Major depression
Paraventricular nucleus
Risk
Schizophrenia

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10.1016/j.biopsych.2021.02.972

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iPSYCH, 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 (2021). 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{0f1c6e26a6454ced96bf80edd2d1bfd0,

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{\texttimes}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{\textendash}by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 {\texttimes} 10−8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 {\texttimes} 10−6) for cross-disorder G{\texttimes}S interaction (rs7302529, p = 1.6 {\texttimes} 10−7; rs73033497, p = 8.8 {\texttimes} 10−7; rs7914279, p = 6.4 {\texttimes} 10−7), implicating various functions. Gene-based analyses identified G{\texttimes}S interaction across disorders (p = 8.97 {\texttimes} 10−7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 {\texttimes} 10−7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 {\texttimes} 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{\texttimes}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{\texttimes}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 = "Affective stimuli impact, Dysphoric mood, Gender-differences, Genome-wide association, Kynurenine pathway metabolism, Ld score regression, Major depression, Paraventricular nucleus, Risk, Schizophrenia",

author = "iPSYCH 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 Blokland, \{Gabri{\"e}lla A.M.\} and Jakob Grove and Chen, \{Chia Yen\} and Chris Cotsapas and Stuart Tobet and Robert Handa and \{St Clair\}, David and Todd Lencz and Mowry, \{Bryan J.\} and Sathish Periyasamy and Cairns, \{Murray J.\} and Tooney, \{Paul A.\} and Wu, \{Jing Qin\} and Brian Kelly and George Kirov and Sullivan, \{Patrick F.\} and Aiden Corvin and Riley, \{Brien P.\} and T{\~o}nu Esko and Lili Milani and J{\"o}nsson, \{Erik G.\} and Aarno Palotie and Hannelore Ehrenreich and Martin Begemann and Agnes Steixner-Kumar and Sham, \{Pak C.\} and Nakao Iwata and Weinberger, \{Daniel R.\} and Gejman, \{Pablo V.\} and Sanders, \{Alan R.\} and Buxbaum, \{Joseph D.\} and Dan Rujescu and Ina Giegling and Bettina Konte and Hartmann, \{Annette M.\} and Elvira Bramon and Murray, \{Robin M.\} and Pato, \{Michele T.\} and Jimmy Lee and Ingrid Melle and Espen Molden and Ophoff, \{Roel A.\} and Andrew McQuillin and Bass, \{Nicholas J.\} and Rolf Adolfsson and Malhotra, \{Anil K.\} and Martin, \{Nicholas G.\} and Fullerton, \{Janice M.\} and Mitchell, \{Philip B.\} and Hottenga, \{Jouke Jan\}",

note = "Publisher Copyright: {\textcopyright} 2021 Society of Biological Psychiatry",

year = "2021",

month = mar,

day = "23",

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",

}

iPSYCH, 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 2021, 'Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders', Biological Psychiatry, vol. 91, no. 1, pp. 102-117. https://doi.org/10.1016/j.biopsych.2021.02.972

Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders. / iPSYCH; Schizophrenia Working Group of the Psychiatric Genomics Consortium; Bipolar Disorder Working Group of the Psychiatric Genomics Consortium et al.
In: Biological Psychiatry, Vol. 91, No. 1, 23.03.2021, p. 102-117.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

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

AU - iPSYCH

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 - Blokland, Gabriëlla A.M.

AU - Grove, Jakob

AU - Chen, Chia Yen

AU - Cotsapas, Chris

AU - Tobet, Stuart

AU - Handa, Robert

AU - St Clair, David

AU - Lencz, Todd

AU - Mowry, Bryan J.

AU - Periyasamy, Sathish

AU - Cairns, Murray J.

AU - Tooney, Paul A.

AU - Wu, Jing Qin

AU - Kelly, Brian

AU - Kirov, George

AU - Sullivan, Patrick F.

AU - Corvin, Aiden

AU - Riley, Brien P.

AU - Esko, Tõnu

AU - Milani, Lili

AU - Jönsson, Erik G.

AU - Palotie, Aarno

AU - Ehrenreich, Hannelore

AU - Begemann, Martin

AU - Steixner-Kumar, Agnes

AU - Sham, Pak C.

AU - Iwata, Nakao

AU - Weinberger, Daniel R.

AU - Gejman, Pablo V.

AU - Sanders, Alan R.

AU - Buxbaum, Joseph D.

AU - Rujescu, Dan

AU - Giegling, Ina

AU - Konte, Bettina

AU - Hartmann, Annette M.

AU - Bramon, Elvira

AU - Murray, Robin M.

AU - Pato, Michele T.

AU - Lee, Jimmy

AU - Melle, Ingrid

AU - Molden, Espen

AU - Ophoff, Roel A.

AU - McQuillin, Andrew

AU - Bass, Nicholas J.

AU - Adolfsson, Rolf

AU - Malhotra, Anil K.

AU - Martin, Nicholas G.

AU - Fullerton, Janice M.

AU - Mitchell, Philip B.

AU - Hottenga, Jouke Jan

PY - 2021/3/23

Y1 - 2021/3/23

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 - Affective stimuli impact

KW - Dysphoric mood

KW - Gender-differences

KW - Genome-wide association

KW - Kynurenine pathway metabolism

KW - Ld score regression

KW - Major depression

KW - Paraventricular nucleus

KW - Risk

KW - Schizophrenia

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 - Article

C2 - 34099189

AN - SCOPUS:85108284544

SN - 0006-3223

VL - 91

SP - 102

EP - 117

JO - Biological Psychiatry

JF - Biological Psychiatry

IS - 1

ER -

iPSYCH, 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. Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders. Biological Psychiatry. 2021 Mar 23;91(1):102-117. doi: 10.1016/j.biopsych.2021.02.972

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

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Keywords

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