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

TLDR: In the largest genome-wide GxS analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes, but significant sexdependent effects were enriched for genes related to neuronal development, immune and vascular functions across and within SCZ, BIP, and MDD.

Abstract: BACKGROUND Sex differences in the 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 these disorders suggest possible shared sex-dependent genetic risk. METHODS We conducted the largest to date genome-wide genotype–by–sex (GxS) interaction analysis of risk for these disorders, using data from 85,735 cases (33,403 SCZ, 19,924 BIP, 32,408 MDD) and 109,946 controls from the Psychiatric Genomics Consortium (PGC) and iPSYCH. RESULTS Across disorders, genome-wide significant SNP-by-sex interaction was detected for a locus encompassing NKAIN2 gene (rs117780815; p=3.2×10−8), that interacts with sodium/potassium-transporting ATPase enzymes important for neuronal excitability. Three additional loci showed evidence (p CONCLUSIONS In the largest genome-wide GxS analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sexdependent effects were enriched for genes related to neuronal development, immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway enrichment levels.

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Table 3. Credible SNP results for genome-wide significant NKAIN2 locus.

Frequently asked questions

Q1. What are the contributions in "Sex-dependent shared and non-shared genetic architecture across mood and psychotic disorders" ?

In this paper, the authors present the results of a study of the Schizophrenia Working Group of the Psychiatric Genomics Consortium. 

Q2. What is the significant interaction in the PGC-SCZ dataset?

Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509; p=1.1×10−7) in a locus containing IDO2, a kynureninepathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. 

Q3. What are the implications of sex-by-gene effects?

sex-by-gene effects had implications for cognitive functions, not surprising givenbrain regions implicated by some of the significant loci in this study. 

Q4. What is the reason why this is less likely for their study?

Although some haveargued this may reflect study recruitment bias or misclassification (94), this is less likely for ourstudy, given varying sample sizes across disorders (due to differing prevalences), and no geneticcorrelations by sex among SCZ compared with high correlations among MDD and BIP. 

Q5. What is the significant gene in the largest genome-wide GxS analysis of mood and?

In the largest genome-wide GxS analysis of mood and psychotic disorders todate, there was substantial genetic overlap between the sexes. 

Q6. Who has granted bioRxiv a license to display the preprint in perpetuity?

CC-BY 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. 

Q7. What is the p-value for the variants highlighted in this table?

Extended results (p < 1×10−4), including eQTL data for the variants highlighted in this table, and including secondary extended model statistics, are available in Supplementary Table 6. 

Q8. What is the sex-dependent effect of the gene in the SCZ?

significant sex-dependent effects were enriched for genes related to neuronal development, immune andvascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathwayenrichment levels.. 

Q9. who is the author/funder of bioRxiv's preprint?

CC-BY 4.0 International licenseavailable under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. 

Q10. What is the significance of timing in identifying sex-by-gene effects?

This suggests that timing is critical in identifying sex-by-gene effects, which mayhave opposing effects at different developmental periods, a fact that must be considered intranscription studies of brain regions across the lifespan.