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

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

Schizophrenia Working Group of the Psychiatric Genomics Consortium

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

Abstract / Description of output

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
Early online date	22 Mar 2021
DOIs	https://doi.org/10.1016/j.biopsych.2021.02.972
Publication status	E-pub ahead of print - 22 Mar 2021

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10.1016/j.biopsych.2021.02.972

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@article{2a723b2c658c4dcab6e87d8499a41a68,

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.",

author = "{Schizophrenia Working Group of the Psychiatric Genomics Consortium} and 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 Forstner, {Andreas J} and Franziska Degenhardt and Sabrina Schaupp and Comes, {Ashley L} and Manolis Kogevinas and Jos{\'e} Guzman-Parra and Andreas Reif and Fabian Streit and Lea Sirignano and Sven Cichon and Maria Grigoroiu-Serbanescu and Joanna Hauser and Jolanta Lissowska and Fermin Mayoral and Bertram M{\"u}ller-Myhsok and Beata {\'S}wi{\c a}tkowska and Schulze, {Thomas G} and N{\"o}then, {Markus M} and Marcella Rietschel and John Kelsoe and Marion Leboyer and St{\'e}phane Jamain and Bruno Etain and Frank Bellivier and Vincent, {John B} and Martin Alda and Claire O'Donovan and Pablo Cervantes and Biernacka, {Joanna M} and Mark Frye and McElroy, {Susan L} and Scott, {Laura J} and Stahl, {Eli A} and Mikael Land{\'e}n and Hamshere, {Marian L} and Smeland, {Olav B} and Srdjan Djurovic and Vaaler, {Arne E} and Andreassen, {Ole A} and Baune, {Bernhard T} and Tracy Air and Martin Preisig and Rudolf Uher and Levinson, {Douglas F} and Weissman, {Myrna M} and Potash, {James B} and Jianxin Shi and Knowles, {James A} and Perlis, {Roy H} and Susanne Lucae and Boomsma, {Dorret I} and Penninx, {Brenda W J H} and Jouke-Jan Hottenga and {de Geus}, {Eco J C} and Gonneke Willemsen and Yuri Milaneschi and Henning Tiemeier and Grabe, {Hans J} and Alexander Teumer and {Van der Auwera}, Sandra and Uwe V{\"o}lker and Hamilton, {Steven P} and Magnusson, {Patrik K E} and Alexander Viktorin and Divya Mehta and Niamh Mullins and Adams, {Mark J} and Gerome Breen and McIntosh, {Andrew M} and Lewis, {Cathryn M} and Hougaard, {David M} and Merete Nordentoft and Ole Mors and Mortensen, {Preben B} and Thomas Werge and Als, {Thomas D} and B{\o}rglum, {Anders D} and Petryshen, {Tracey L} and Smoller, {Jordan W} and Goldstein, {Jill M}",

year = "2021",

month = mar,

day = "22",

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

language = "English",

journal = "Biological Psychiatry",

issn = "0006-3223",

publisher = "Elsevier",

}

TY - JOUR

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

AU - Schizophrenia Working 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 - Schofield, Peter R

AU - Forstner, Andreas J

AU - Degenhardt, Franziska

AU - Schaupp, Sabrina

AU - Comes, Ashley L

AU - Kogevinas, Manolis

AU - Guzman-Parra, José

AU - Reif, Andreas

AU - Streit, Fabian

AU - Sirignano, Lea

AU - Cichon, Sven

AU - Grigoroiu-Serbanescu, Maria

AU - Hauser, Joanna

AU - Lissowska, Jolanta

AU - Mayoral, Fermin

AU - Müller-Myhsok, Bertram

AU - Świątkowska, Beata

AU - Schulze, Thomas G

AU - Nöthen, Markus M

AU - Rietschel, Marcella

AU - Kelsoe, John

AU - Leboyer, Marion

AU - Jamain, Stéphane

AU - Etain, Bruno

AU - Bellivier, Frank

AU - Vincent, John B

AU - Alda, Martin

AU - O'Donovan, Claire

AU - Cervantes, Pablo

AU - Biernacka, Joanna M

AU - Frye, Mark

AU - McElroy, Susan L

AU - Scott, Laura J

AU - Stahl, Eli A

AU - Landén, Mikael

AU - Hamshere, Marian L

AU - Smeland, Olav B

AU - Djurovic, Srdjan

AU - Vaaler, Arne E

AU - Andreassen, Ole A

AU - Baune, Bernhard T

AU - Air, Tracy

AU - Preisig, Martin

AU - Uher, Rudolf

AU - Levinson, Douglas F

AU - Weissman, Myrna M

AU - Potash, James B

AU - Shi, Jianxin

AU - Knowles, James A

AU - Perlis, Roy H

AU - Lucae, Susanne

AU - Boomsma, Dorret I

AU - Penninx, Brenda W J H

AU - Hottenga, Jouke-Jan

AU - de Geus, Eco J C

AU - Willemsen, Gonneke

AU - Milaneschi, Yuri

AU - Tiemeier, Henning

AU - Grabe, Hans J

AU - Teumer, Alexander

AU - Van der Auwera, Sandra

AU - Völker, Uwe

AU - Hamilton, Steven P

AU - Magnusson, Patrik K E

AU - Viktorin, Alexander

AU - Mehta, Divya

AU - Mullins, Niamh

AU - Adams, Mark J

AU - Breen, Gerome

AU - McIntosh, Andrew M

AU - Lewis, Cathryn M

AU - Hougaard, David M

AU - Nordentoft, Merete

AU - Mors, Ole

AU - Mortensen, Preben B

AU - Werge, Thomas

AU - Als, Thomas D

AU - Børglum, Anders D

AU - Petryshen, Tracey L

AU - Smoller, Jordan W

AU - Goldstein, Jill M

PY - 2021/3/22

Y1 - 2021/3/22

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.

U2 - 10.1016/j.biopsych.2021.02.972

DO - 10.1016/j.biopsych.2021.02.972

M3 - Article

C2 - 34099189

SN - 0006-3223

JO - Biological Psychiatry

JF - Biological Psychiatry

ER -

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

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