Genome-wide association study of problematic opioid prescription use in 132,113 23andMe research participants of European ancestry

Abstract

Rates of opioid use disorder (OUD) constitute an urgent health crisis. Ample evidence indicates that risk for OUD is heritable. As a surrogate (or proxy) for OUD, we explored the genetic basis of using opioids "not as prescribed". We hypothesized that misuse of opiates might be a heritable risk factor for OUD. To test this hypothesis, we performed a genome-wide association study (GWAS) of problematic opioid use (POU; "ever taking opioid prescriptions not as prescribed") in 132,113 23andMe research participants of European ancestry (Ncases=27,805). Our GWAS identified two genome-wide significant loci (rs3791033, an intronic variant of KDM4A; rs640561, an intergenic variant near LRRIQ3). POU showed a positive genetic correlation with opioid dependence and OUD, as measured in the largest available GWAS (rg=0.57-0.80). We also identified numerous additional genetic correlations with POU, including alcohol dependence (rg=0.74), smoking initiation (rg=0.63), pain relief medication intake (rg=0.49), major depressive disorder (rg=0.44), chronic pain (rg=0.42), insomnia (rg=0.39), and loneliness (rg=0.28). Although POU was positively genetically correlated with risk-taking (rg=0.38), conditioning POU on risk-taking did not substantially alter the magnitude or direction of these genetic correlations, suggesting that POU does not simply reflect a general tendency for risky behavior. We conclude that opioid misuse can be measured in population-based cohorts and provides a cost-effective complementary strategy for understanding the genetic basis of OUD.

CADM2is implicated in impulsive personality and numerous other traits by genome- and phenome-wide association studies in humans and mice

“…A phenotypic and genetic correlation matrix of all 9 traits is shown in Figure S22 and Tables S11-12. Consistent with the literature and our prior work (4,5,91,92), both phenotypic and genetic inter-correlations among the UPPS-P and BIS subscales were high and positive, with the exception of Sensation Seeking and Perseverance, suggesting that these traits may represent relatively different constructs (5,13,91). Drug experimentation was positively and significantly associated with all impulsive personality traits.…”

“…CADM2 mediates synaptic plasticity and is enriched in the frontal cortex and striatum, which are regions that regulate reward and inhibitory processes. We and others have implicated this gene in traits that may underlie disinhibition in humans, supporting the observed genetic correlations between impulsivity and personality (8), educational attainment (9), cognition (10), risk-taking (11), substance use (4,10,(12)(13)(14)(15), externalizing psychopathology (16), neurodevelopmental disorders (17,18), physical activity (23), reproductive health (20,21), metabolic traits (19), and BMI (22), among others (see GWAS Catalog www.ebi.ac.uk/gwas/). Cadm2 knockout mice have previously been assessed for body weight and energy homeostasis (24) but have never been behaviorally characterized for measures of impulsivity or related behaviors.…”

“…TCF4, which was significantly associated with Premeditation and Sensation Seeking and nominally associated with Perseverance in the GWAS, was only significantly associated with Premeditation in the gene-based analysis. MAPT, which has been previously associated with many traits including multiple alcohol-related behaviors (13), was implicated in Negative Urgency. Lastly, KDM4A, which was recently related to problematic opioid use and interacts with selective serotonin reuptake inhibitors and dopaminergic agents (25), was significantly associated with Drug Experimentation.…”

“…We analyzed data from a cohort of up to 133,517 male and female research participants of European ancestry, a subset of which were analyzed in our prior publications (4,13,13,25,26).…”

Genome-wide association study and multi-trait analysis of opioid use disorder identifies novel associations in 639,709 individuals of European and African ancestry

“…These identified genomic risk factors for the development of OUD and underlying biology, and highlight the need to assemble large OUD datasets that include individuals from diverse ancestral backgrounds. To advance our scientific understanding of OUD risk will require study of a range of human traits (e.g., clinically diagnosed OUD and prescription painkiller use) (47). This will be necessary to improve further our understanding of the genetic etiology of OUD and translation of genetic findings to help address the opioid public health crisis and reduce preventable deaths.…”