Genomewide Gene-by-Sex Interaction Scans Identify ADGRV1 for Sex Differences in Opioid Dependent African Americans

Bao-Zhu Yang,Henry R Kranzler,Joel Gelernter,Zhongshan Cheng,Hang Zhou

doi:10.1038/s41598-019-53560-0

Abstract

Sex differences in opioid dependence (OD) are genetically influenced. We conducted genomewide gene-by-sex interaction scans for the DSM-IV diagnosis of OD in 8,387 African-American (AA) or European-American subjects (43.6% women; 4,715 OD subjects). Among AAs, 9 SNPs were genome-wide significant at ADGRV1 (adhesion G-protein-coupled receptor V1, lead-SNP rs2366929*(C/T), p = 1.5 × 10−9) for sex-different risk of OD, with the rs2366929*C-allele increasing OD risk only for men. The top co-expressions in brain were between ADGRV1 and GRIK2 in substantia nigra and medullary inferior olivary nucleus, and between ADGRV1 and EFHC2 in frontal cortex and putamen. Significant sex-differential ADGRV1 expression from GTEx was detected in breast (Bonferroni-corrected-p < 0.002) and in heart (p < 0.0125), with nominal significance identified in brain, thyroid, lung, and stomach (p < 0.05). ADGRV1 co-expression and disease-enrichment analysis identifying the top 10 diseases showed strikingly sexually dimorphic risks. The enrichment and transcriptome analyses provided convergent support that ADGRV1 exerts a sex-different effect on OD risk. This is the first study to identify genetic variants contributing to sex differences in OD. It shows that ADGRV1 contributes to OD risk only in AA men, a finding that warrants further study.

Highlights

Sex differences in opioid dependence (OD) have a strong biological basis[1] with a genetic component[2,3]
We aimed to identify genetic variants exerting a sex difference in susceptibility to OD in a genome-wide association study (GWAS) framework using the cohort of substance use disorder we have collected; characterize and annotate the identified genetic variants using publicly available databases of co-expressed genes and enrichment analysis; and use transcriptome analysis to identify biological mechanisms consistent with sex-specific effects on OD risk for the variants identified
This increasing trend in men versus women was observed for all nine single nucleotide polymorphisms (SNPs) identified in the association analyses (Supplementary Table S1 shows the trend tests for all nine SNPs)

Summary

Introduction

Sex differences in opioid dependence (OD) have a strong biological basis[1] with a genetic component[2,3]. Systematic search for the OD genetic risk variants (regardless of sex differences) using the genome-wide association study (GWAS) design has been reported. The most compelling results in that study were the identification of genes involved in potassium signaling pathways (i.e., KCNC1 (Potassium Voltage-Gated Channel Subfamily C Member 1) and KCNG2 (Potassium Voltage-Gated Channel Modifier Subfamily G Member 2)) in the African American (AA) population, and genes involved in calcium signaling and long-term potentiation Another GWAS was conducted in an Australian cohort, in which genetic data from opioid-dependent daily injectors were compared with that from opioid misusers who never progressed to daily injection, and identified several genomewide significant variants in CNIH3 (Cornichon Family AMPA Receptor Auxiliary Protein 3)[10]. We aimed to identify genetic variants exerting a sex difference in susceptibility to OD in a GWAS framework using the cohort of substance use disorder we have collected; characterize and annotate the identified genetic variants using publicly available databases of co-expressed genes and enrichment analysis; and use transcriptome analysis to identify biological mechanisms consistent with sex-specific effects on OD risk for the variants identified

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Conclusion