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; Stephan Ripke; Benjamin M. Neale; Aiden Corvin; James T.R. Walters; Kai How Farh; Peter A. Holmans; Phil Lee; Brendan Bulik-Sullivan; David A. Collier; Hailiang Huang; Tune H. Pers; Ingrid Agartz; Esben Agerbo; Margot Albus; Madeline Alexander; Farooq Amin; Silviu A. Bacanu; Martin Begemann; Richard A. Belliveau; Judit Bene; Sarah E. Bergen; Elizabeth Bevilacqua; Tim B. Bigdeli; Donald W. Black; Richard Bruggeman; Nancy G. Buccola; Randy L. Buckner; William Byerley; Wiepke Cahn; Guiqing Cai; Dominique Campion; Rita M. Cantor; Vaughan J. Carr; Noa Carrera; Mark Hansen; Thomas Hansen; Sandra Meier; Line Olsen; Marie Bækvad-Hansen; Thomas F. Hansen; Wesley Thompson; Shantel Marie Weinsheimer; Merete Nordentoft; Thomas Werge; 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, Stephan Ripke, Benjamin M. Neale, Aiden Corvin, James T.R. Walters, Kai How Farh, Peter A. Holmans, Phil Lee, Brendan Bulik-Sullivan, David A. Collier, Hailiang Huang, Tune H. Pers, Ingrid Agartz, Esben Agerbo, Margot AlbusMadeline Alexander, Farooq Amin, Silviu A. Bacanu, Martin Begemann, Richard A. Belliveau, Judit Bene, Sarah E. Bergen, Elizabeth Bevilacqua, Tim B. Bigdeli, Donald W. Black, Richard Bruggeman, Nancy G. Buccola, Randy L. Buckner, William Byerley, Wiepke Cahn, Guiqing Cai, Dominique Campion, Rita M. Cantor, Vaughan J. Carr, Noa Carrera, Mark Hansen, Thomas Hansen, Sandra Meier (Member of study group), Line Olsen (Member of study group), Marie Bækvad-Hansen, Thomas F. Hansen (Member of study group), Wesley Thompson (Member of study group), Shantel Marie Weinsheimer (Member of study group), Merete Nordentoft (Member of study group), Thomas Werge (Member of study group), 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 for this work

56 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
Journal	Biological Psychiatry
Volume	91
Issue number	1
Pages (from-to)	102-117
Number of pages	16
ISSN	0006-3223
DOIs	https://doi.org/10.1016/j.biopsych.2021.02.972
Publication status	Published - 1 Jan 2022

Keywords

Bipolar disorder
Genome-wide association study
Genotype-by-sex interaction
Major depressive disorder
Schizophrenia
Sex differences
Receptors, Vascular Endothelial Growth Factor
Genetic Predisposition to Disease
Genome-Wide Association Study
Endothelial Cells
Humans
Male
Sex Characteristics
Depressive Disorder, Major/genetics
Bipolar Disorder/genetics
Psychotic Disorders/genetics
Female
Sulfurtransferases
Polymorphism, Single Nucleotide
Schizophrenia/genetics

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Blokland, G. A. M., Grove, J., Chen, C. Y., Cotsapas, C., Tobet, S., Handa, R., Ripke, S., Neale, B. M., Corvin, A., Walters, J. T. R., Farh, K. H., Holmans, P. A., Lee, P., Bulik-Sullivan, B., Collier, D. A., Huang, H., Pers, T. H., Agartz, I., Agerbo, E., ... 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

Blokland, GAM, Grove, J, Chen, CY, Cotsapas, C, Tobet, S, Handa, R, Ripke, S, Neale, BM, Corvin, A, Walters, JTR, Farh, KH, Holmans, PA, Lee, P, Bulik-Sullivan, B, Collier, DA, Huang, H, Pers, TH, Agartz, I, Agerbo, E, Albus, M, Alexander, M, Amin, F, Bacanu, SA, Begemann, M, Belliveau, RA, Bene, J, Bergen, SE, Bevilacqua, E, Bigdeli, TB, Black, DW, Bruggeman, R, Buccola, NG, Buckner, RL, Byerley, W, Cahn, W, Cai, G, Campion, D, Cantor, RM, Carr, VJ, Carrera, N, Hansen, M, Hansen, T, Meier, S, Olsen, L, Bækvad-Hansen, M, Hansen, TF , Thompson, W, Weinsheimer, SM, Nordentoft, M , Werge, T, 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, vol. 91, no. 1, pp. 102-117. https://doi.org/10.1016/j.biopsych.2021.02.972

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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, Receptors, Vascular Endothelial Growth Factor, Genetic Predisposition to Disease, Genome-Wide Association Study, Endothelial Cells, Humans, Male, Sex Characteristics, Depressive Disorder, Major/genetics, Bipolar Disorder/genetics, Psychotic Disorders/genetics, Female, Sulfurtransferases, Polymorphism, Single Nucleotide, Schizophrenia/genetics",

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 Martin Begemann and Belliveau, {Richard A.} and Judit Bene and Bergen, {Sarah E.} and Elizabeth Bevilacqua and Bigdeli, {Tim B.} and Black, {Donald W.} and Richard Bruggeman and Buccola, {Nancy G.} and Buckner, {Randy L.} and William Byerley and Wiepke Cahn and Guiqing Cai and Dominique Campion and Cantor, {Rita M.} and Carr, {Vaughan J.} and Noa Carrera and Mark Hansen and Thomas Hansen and Sandra Meier and Line Olsen and Marie B{\ae}kvad-Hansen and Hansen, {Thomas F.} and Wesley Thompson and Weinsheimer, {Shantel Marie} and Merete Nordentoft and Thomas Werge 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",

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

year = "2022",

month = jan,

day = "1",

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

language = "English",

volume = "91",

pages = "102--117",

journal = "Biological Psychiatry",

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publisher = "Elsevier Inc",

number = "1",

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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 - Begemann, Martin

AU - Belliveau, Richard A.

AU - Bene, Judit

AU - Bergen, Sarah E.

AU - Bevilacqua, Elizabeth

AU - Bigdeli, Tim B.

AU - Black, Donald W.

AU - Bruggeman, Richard

AU - Buccola, Nancy G.

AU - Buckner, Randy L.

AU - Byerley, William

AU - Cahn, Wiepke

AU - Cai, Guiqing

AU - Campion, Dominique

AU - Cantor, Rita M.

AU - Carr, Vaughan J.

AU - Carrera, Noa

AU - Hansen, Mark

AU - Hansen, Thomas

AU - Bækvad-Hansen, Marie

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

A2 - Meier, Sandra

A2 - Olsen, Line

A2 - Hansen, Thomas F.

A2 - Thompson, Wesley

A2 - Weinsheimer, Shantel Marie

A2 - Nordentoft, Merete

A2 - Werge, Thomas

PY - 2022/1/1

Y1 - 2022/1/1

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 - Receptors, Vascular Endothelial Growth Factor

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Endothelial Cells

KW - Humans

KW - Male

KW - Sex Characteristics

KW - Depressive Disorder, Major/genetics

KW - Bipolar Disorder/genetics

KW - Psychotic Disorders/genetics

KW - Female

KW - Sulfurtransferases

KW - Polymorphism, Single Nucleotide

KW - Schizophrenia/genetics

UR - http://www.scopus.com/inward/record.url?scp=85108284544&partnerID=8YFLogxK

U2 - 10.1016/j.biopsych.2021.02.972

DO - 10.1016/j.biopsych.2021.02.972

M3 - Journal article

C2 - 34099189

AN - SCOPUS:85108284544

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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