OPRD1 SNPs associated with opioid addiction are cis-eQTLs for the phosphatase and actin regulator 4 gene, PHACTR4, a mediator of cytoskeletal dynamics

Abstract

Several OPRD1 intronic variants were associated with opioid addiction (OD) in a population-specific manner. This follow-up study aims to further characterize the OPRD1 haplotype pattern of the risk variants in different populations and apply in silico analysis to identify potential causal variants. A population-specific haplotype pattern was revealed based on six OPRD1 eQTL SNPs and five common haplotypes were identified in a sample of European ancestry (CEU). A European-specific haplotype (‘Hap 3’) that includes SNPs previously associated with OD and is tagged by SNP rs2236861 is more common in subjects with OD. It is quite common (10%) in CEU but is absent in the African sample (YRI) and extends upstream of OPRD1. SNP rs2236857 is most probably a non-causal variant in LD with the causal SNP/s in a population-specific manner. The study provides an explanation for the lack of association in African Americans, despite its high frequency in this population. OD samples homozygous for ‘Hap 3’ were reanalyzed using a denser coverage of the region and revealed at least 25 potentially regulatory SNPs in high LD. Notably, GTEx data indicate that some of the SNPs are eQTLs for the upstream phosphatase and actin regulator 4 (PHACTR4), in the cortex, and others are eQTLs for OPRD1 and the upstream lncRNA ENSG00000270605, in the cerebellum. The study highlights the limitation of single SNP analysis and the sensitivity of association studies of OPRD1 to a genetic background. It proposes a long-range functional connection between OPRD1 and PHACTR4. PHACTR4, a mediator of cytoskeletal dynamics, may contribute to drug addiction by modulating synaptic plasticity.

Genome-wide meta-analyses of cross substance use disorders in European, African, and Latino ancestry populations

“…Some genes are worth noting. For instance, OPRD1, which was identi ed by positional mapping, is a member of opioid receptor signaling pathway and was nominated as SUD-related in some small studies [39][40][41] , but was not reported as SUD-related in the GWAS catalog 36 .…”

Tackling the opioid crisis: Novel mechanisms and clinical perspectives

“…In a retrospective study, Agrawal et al (2020) report that subjective responses to initial opioid exposure differ between people who progress to developing opioid use disorder and those who do not. This inter-individual variability in opioid responses and addiction liability has a significant genetic component (Glatt et al, 2007;Goldman et al, 2005;Levran et al, 2021;Reed & Kreek, 2021). Indeed, several genes have been associated with altered opioid response, including those that encode for opioid receptors, metabolizing enzymes, drug transporters, and proteins involved in other modulating systems such as descending adrenergic and serotonergic inputs (Klepstad et al, 2005;Nielsen et al, 2015;Stamer et al, 2005).…”