A genome-wide association study of cocaine use disorder accounting for phenotypic heterogeneity and gene–environment interaction

Abstract

Background: Phenotypic heterogeneity and complicated gene-environment interplay in etiology are among the primary factors that hinder the identification of genetic variants associated with cocaine use disorder. Methods: To detect novel genetic variants associated with cocaine use disorder, we derived disease traits with reduced phenotypic heterogeneity using cluster analysis of a study sample (n = 9965). We then used these traits in genome-wide association tests, performed separately for 2070 African Americans and 1570 European Americans, using a new mixed model that accounted for the moderating effects of 5 childhood environmental factors. We used an independent sample (918 African Americans, 1382 European Americans) for replication. Results: The cluster analysis yielded 5 cocaine use disorder subtypes, of which subtypes 4 (n = 3258) and 5 (n = 1916) comprised heavy cocaine users, had high heritability estimates (h 2 = 0.66 and 0.64, respectively) and were used in association tests. Seven of the 13 identified genetic loci in the discovery phase were available in the replication sample. In African Americans, rs114492924 (discovery p = 1.23 × E −8), a single nucleotide polymorphism in LINC01411, was replicated in the replication sample (p = 3.63 × E −3). In a meta-analysis that combined the discovery and replication results, 3 loci in African Americans were significant genome-wide: rs10188036 in TRAK2 (p = 2.95 × E −8), del-1:15511771 in TMEM51 (p = 9.11 × E −10) and rs149843442 near LPHN2 (p = 3.50 × E −8). Limitations: Lack of data prevented us from replicating 6 of the 13 identified loci. Conclusion: Our results demonstrate the importance of considering phenotypic heterogeneity and gene-environment interplay in detecting genetic variations that contribute to cocaine use disorder, because new genetic loci have been identified using our novel analytic method.

Molecular genetics of cocaine use disorders in humans

“…Interestingly, this study estimated a SNP-based heritability (h 2 SNP ) for cocaine dependence around 0.27-0.30 using two different approaches, and very similar results were obtained using GWAS data from Gelernter et al (h 2 SNP = 0.28; Table 3) [46]. Two GWAS on CUD have been recently published, one accounting for gene-environment interactions [6], and another one evaluating time to develop dependence [47] (Table 3). In the first one, two GWS hits were found associated with DSM-5 diagnostic criterion counts in AA individuals (N = 2998) [6], only when the interactive effect of childhood environmental risk factors were considered: change in residence for rs10188036 in TRAK2 and household drinking and illicit drug use for del-13:61274071 in LINC00378 (Table 3).…”

“…In addition, a cluster analysis was performed to divide the sample in five CUD groups. For the subtypes 4 (N = 3258) and 5 (N = 1916; the highest heritable and heavy-cocaine-use clusters) they identified 11 additional GWS loci for which the effect on CUD was moderated by environmental factors (Table 3), highlighting the importance of considering environmental interactions in the statistical models [6]. In addition, this study supports the idea that CUD subjects can be decomposed into different subgroups, as previously mentioned, and the study of more homogeneous subgroups may result in more powerful genetic analyses [5].…”

Genetics of substance use disorders: a review

“…They also found positive genetic correlations with schizophrenia, ADHD, major depression, and risk-taking, in line with phenotypic correlations (despite the number of cases being less than recommended for LD score regression; Table 1 ). Another recent study used cluster analyses to identify CocUD subtypes with reduced phenotypic heterogeneity, one potential barrier to identifying significant genetic variants for psychiatric disorders (Sun, Kranzler, Gelernter, & Bi, 2020 ). Still, few genetic findings have replicated amongst GWAS of CocUD; we expect the number of robust, replicable findings to increase with larger sample sizes (similar to other SUDs).…”

Spontaneously Hypertensive Rat substrains show differences in premorbid addiction vulnerability traits and cocaine self-administration: Implications for a novel rat reduced complexity cross

“…SHR/NCrl self-administered more cocaine than SHR/NHsd under the FR1 schedule and also emitted more cocaine seeking responses and completed more cocaine seek-take cycles under the chained schedule. Heritability estimates indicated that 26% - 40% of the variances for our cocaine use traits can be explained by additive genetic factors, a key finding because cocaine use disorders in people are heritable on the order of 40% - 70% [78, 79]. As discussed in section 4.2, four of our premorbid cocaine vulnerability traits (impulsivity, compulsivity, reactivity to sucrose reward and initial sensitivity to acute 20 mg/kg cocaine) showed substrain differences, with 22% - 38% of their phenotypic variances explained by additive genetic factors.…”