Evidence of CNIH3 involvement in opioid dependence

Abstract

Opioid dependence, a severe addictive disorder and major societal problem, has been demonstrated to be moderately heritable. We conducted a genome-wide association study in Comorbidity and Trauma Study data comparing opioid dependent daily injectors (N=1167) with opioid misusers who never progressed to daily injection (N=161). The strongest associations, observed for CNIH3 SNPs, were confirmed in two independent samples, the Yale-Penn genetic studies of opioid, cocaine, and alcohol dependence and the Study of Addiction: Genetics and Environment, which both contain non-dependent opioid misusers and opioid dependent individuals. Meta-analyses found 5 genome-wide significant CNIH3 SNPs. The A allele of rs10799590, the most highly associated SNP, was robustly protective [p=4.30E-9; OR 0.64 (95%CI 0.55 – 0.74)]. Epigenetic annotation predicts that this SNP is functional in fetal brain. Neuroimaging data from the Duke Neurogenetics Study (N=312) provide evidence of this SNP’s in vivo functionality; rs10799590 A allele carriers displayed significantly greater right amygdala habituation to threat-related facial expressions, a phenotype associated with resilience to psychopathology. Computational genetic analyses of physical dependence on morphine across 23 mouse strains yielded significant correlations for haplotypes in CNIH3 and functionally-related genes. These convergent findings support CNIH3 involvement in the pathophysiology of opioid dependence complementing prior studies implicating the AMPA glutamate system.

The genetic epidemiology of substance use disorder: A review

“…A recent GWAS reported a significant association with CNIH3, a gene whose product functions in the glutamtergic pathway and encodes for the production of cornichon family AMPA receptor auxiliary protein 3 (Nelson et al, 2016). This protein increases surface expression of AMPA ionotropic glutamate receptors and mediates channel conductance by slow deactivation and desensitation kinetics (Schwenk et al, 2009).…”

Meta-Analyses of Genome-Wide Association Data Hold New Promise for Addiction Genetics

“…We are optimistic that GWAS meta-analyses of SUDs will identify similar actionable variants for a wide range of substances in the next decade. This enthusiasm stems not only from comparisons with successes for other complex traits but also from recent discoveries for SUDs, including genome-wide significant findings for alcohol (e.g., Gelernter et al, 2014), opioids (e.g., Nelson et al, 2016), cannabis (e.g., Sherva et al, 2016), and nicotine dependence (e.g., Hancock et al, 2015).…”

A Review of Genome-Wide Association Studies of Stimulant and Opioid Use Disorders

“…CNIH3 haplotypes, as well as haplotypes for several glutamate-related signaling genes, were associated with naloxone-induced morphine withdrawal behavior. The study by Nelson et al [34] presents compelling evidence for involvement of CNIH3 in the development of OUD.…”

“…The epigenetic features associated with rs10799590 were specific to DNA isolated from human fetal brain tissue, as they were not observed in several tissues that were of non-nervous system origin. To extend the findings further, Nelson et al [34] investigated in an independent sample of EA subjects (n = 312) the association of rs10799590 with amygdala habituation, an intermediate phenotype associated with psychopathology. The allele associated with low risk for OUD was associated with greater amygdala habituation in response to threat-related facial expressions.…”

“…Nelson et al [34] reported a GWAS that compared heroin-dependent daily users (n = 1167) with heroin-exposed subjects that had never progressed to daily heroin use (n = 161). The strongest association signals were SNPs that mapped to the cornichon family AMPA receptor auxiliary protein 3 gene (CNIH3) , a glutamate receptor-associated regulatory protein encoded on chromosome 1.…”