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 - Klovins, Janis
N1 - Publisher Copyright:
© 2021 Society of Biological Psychiatry
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
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 -