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; David St Clair; Todd Lencz; Bryan J Mowry; Sathish Periyasamy; Murray J Cairns; Paul A Tooney; Jing Qin Wu; Brian Kelly; George Kirov; Patrick F Sullivan; Aiden Corvin; Brien P Riley; Tõnu Esko; Lili Milani; Erik G Jönsson; Aarno Palotie; Hannelore Ehrenreich; Martin Begemann; Agnes Steixner-Kumar; Pak C Sham; Nakao Iwata; Daniel R Weinberger; Pablo V Gejman; Alan R Sanders; Joseph D Buxbaum; Dan Rujescu; Ina Giegling; Bettina Konte; Annette M Hartmann; Elvira Bramon; Robin M Murray; Michele T Pato; Jimmy Lee; Ingrid Melle; Espen Molden; Roel A Ophoff; Andrew McQuillin; Nicholas J Bass; Rolf Adolfsson; Anil K Malhotra; Nicholas G Martin; Janice M Fullerton; Philip B Mitchell; Peter R Schofield; Schizophrenia Working 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

Gabriëlla A M Blokland^*, Jakob Grove^*, Chia-Yen Chen, Chris Cotsapas, Stuart Tobet, Robert Handa, David St Clair, Todd Lencz, Bryan J Mowry, Sathish Periyasamy, Murray J Cairns, Paul A Tooney, Jing Qin Wu, Brian Kelly, George Kirov, Patrick F Sullivan, Aiden Corvin, Brien P Riley, Tõnu Esko, Lili MilaniErik G Jönsson, Aarno Palotie, Hannelore Ehrenreich, Martin Begemann, Agnes Steixner-Kumar, Pak C Sham, Nakao Iwata, Daniel R Weinberger, Pablo V Gejman, Alan R Sanders, Joseph D Buxbaum, Dan Rujescu, Ina Giegling, Bettina Konte, Annette M Hartmann, Elvira Bramon, Robin M Murray, Michele T Pato, Jimmy Lee, Ingrid Melle, Espen Molden, Roel A Ophoff, Andrew McQuillin, Nicholas J Bass, Rolf Adolfsson, Anil K Malhotra, Nicholas G Martin, Janice M Fullerton, Philip B Mitchell, Peter R Schofield, Schizophrenia Working Group of the Psychiatric Genomics Consortium

^*Corresponding author for this work

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

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 - 1 Jan 2022

Keywords

Bipolar Disorder/genetics
Depressive Disorder, Major/genetics
Endothelial Cells
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Male
Polymorphism, Single Nucleotide
Psychotic Disorders/genetics
Receptors, Vascular Endothelial Growth Factor
Schizophrenia/genetics
Sex Characteristics
Sulfurtransferases
SCHIZOPHRENIA
RISK
MAJOR DEPRESSION
PARAVENTRICULAR NUCLEUS
DYSPHORIC MOOD
KYNURENINE PATHWAY METABOLISM
LD SCORE REGRESSION
GENDER-DIFFERENCES
GENOME-WIDE ASSOCIATION
AFFECTIVE STIMULI IMPACT

Access to Document

10.1016/j.biopsych.2021.02.972

Cite this

Blokland, G. A. M., Grove, J., Chen, C.-Y., Cotsapas, C., Tobet, S., Handa, R., St Clair, D., Lencz, T., Mowry, B. J., Periyasamy, S., Cairns, M. J., Tooney, P. A., Wu, J. Q., Kelly, B., Kirov, G., Sullivan, P. F., Corvin, A., Riley, B. P., Esko, T., ... Schizophrenia Working Group of the Psychiatric Genomics Consortium (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{9ef4e1d0ea1a49c3b8159c883eae4707,

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/genetics, Depressive Disorder, Major/genetics, Endothelial Cells, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide, Psychotic Disorders/genetics, Receptors, Vascular Endothelial Growth Factor, Schizophrenia/genetics, Sex Characteristics, Sulfurtransferases, 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 Chia-Yen Chen 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 Schofield, {Peter R} and {Schizophrenia Working Group of the Psychiatric Genomics Consortium}",

year = "2022",

month = jan,

day = "1",

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

language = "English",

volume = "91",

pages = "102--117",

journal = "Biological Psychiatry",

issn = "0006-3223",

publisher = "Elsevier Science",

number = "1",

}

Blokland, GAM, Grove, J, Chen, C-Y, Cotsapas, C, Tobet, S, Handa, R, St Clair, D, Lencz, T, Mowry, BJ, Periyasamy, S, Cairns, MJ, Tooney, PA, Wu, JQ, Kelly, B, Kirov, G, Sullivan, PF, Corvin, A, Riley, BP, Esko, T, Milani, L, Jönsson, EG, Palotie, A, Ehrenreich, H, Begemann, M, Steixner-Kumar, A, Sham, PC, Iwata, N, Weinberger, DR, Gejman, PV, Sanders, AR, Buxbaum, JD, Rujescu, D, Giegling, I, Konte, B, Hartmann, AM, Bramon, E, Murray, RM, Pato, MT, Lee, J, Melle, I, Molden, E, Ophoff, RA, McQuillin, A, Bass, NJ, Adolfsson, R, Malhotra, AK, Martin, NG, Fullerton, JM, Mitchell, PB, Schofield, PR & Schizophrenia Working Group of the Psychiatric Genomics Consortium 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

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 - 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 - Schofield, Peter R

AU - Schizophrenia Working Group of the Psychiatric Genomics Consortium

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/genetics

KW - Depressive Disorder, Major/genetics

KW - Endothelial Cells

KW - Female

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Male

KW - Polymorphism, Single Nucleotide

KW - Psychotic Disorders/genetics

KW - Receptors, Vascular Endothelial Growth Factor

KW - Schizophrenia/genetics

KW - Sex Characteristics

KW - Sulfurtransferases

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

U2 - 10.1016/j.biopsych.2021.02.972

DO - 10.1016/j.biopsych.2021.02.972

M3 - 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

Abstract

Keywords

Access to Document

Fingerprint

Cite this