Gelernter, Joel E.

Abstract Background In two 12‐week, randomized, placebo‐controlled trials (RCTs) in individuals with alcohol use disorder (AUD), topiramate significantly reduced heavy drinking days (HDDs), and alcohol‐related problems. In a secondary analysis of those findings, we examined four broad measures of genetic risk—polygenic scores (PGS)—of problematic alcohol use (PAU), drinks per week (DPW), and time to relapse to any drinking (TR) and heavy drinking (THR) as moderators of topiramate's effect on HDDs and alcohol‐related problems. Methods We analyzed data from 285 individuals with AUD (65.6% male) of European‐like ancestry, who were treated with either topiramate (49.1%) or placebo (50.9%). All patients underwent genome‐wide array genotyping, and PGS were calculated using summary statistics from genome‐wide association studies of PAU, DPW, and TR and THR (two time‐to‐event outcomes among patients treated in AUD pharmacotherapy trials). We hypothesized an interaction effect in which greater genetic risk—particularly for PAU—would be associated with a greater therapeutic response to topiramate than placebo. Results As shown previously, topiramate significantly reduced both HDDs (odds ratio [OR] = 0.50, p < 0.001) and Short Index of Problems (SIP) scores ( b = −3.04, p < 0.001) more than placebo. There were nonsignificant associations of higher PGS with more HDDs (OR = 1.17, 95% CI = 0.98–1.41, p = 0.091) and a greater reduction in HDDs in the topiramate group (OR = 0.80, 95% CI = 0.62–1.03, p = 0.089). There were also significant interaction effects with treatment on SIP score by PGS for PAU ( b = −1.64, SE = 0.78, p = 0.033), TR ( b = −2.16, SE = 0.72, p = 0.003), and TRH ( b = −2.17, SE = 0.72, p = 0.003). Conclusions These findings provide proof of principle for the use of alcohol‐related PGS as moderators of the effects of topiramate for treating AUD. Larger RCTs of topiramate are needed to provide adequate statistical power to validate this pharmacogenetic approach to precision AUD treatment.

Abstract Eating disorders and substance use disorders frequently co‐occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [ r g ], twin‐based = 0.23‐0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome‐wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance‐use‐related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism‐based genetic correlations between eating disorder‐ and substance‐use‐related phenotypes. Significant positive genetic associations emerged between AUD and AN ( r g = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN ( r g = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating ( r g = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating ( r gs = −0.19 to −0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co‐varying for major depressive disorder loci. The patterns of association between eating disorder‐ and substance‐use‐related phenotypes highlights the potentially complex and substance‐specific relationships among these behaviors.

BackgroundEfforts to promote the cessation of harmful alcohol use are hindered by the affective and physiological components of alcohol withdrawal (AW), which can include life‐threatening seizures. Although previous studies ofAWand relapse have highlighted the detrimental role of stress, little is known about genetic risk factors.MethodsWe conducted a genome‐wide association study ofAWsymptom count in uniformly assessed subjects with histories of seriousAW, followed by additional genotyping in independentAWsubjects.ResultsThe top association signal forAWseverity was in sortilin family neurotrophin receptor geneSORCS2on chromosome 4 (European American meta‐analysisn = 1,478,p = 4.3 × 10−9). There were no genome‐wide significant findings in African Americans (n = 1,231). Bioinformatic analyses were conducted using publicly available high‐throughput transcriptomic and epigenomic data sets, showing that in humansSORCS2is most highly expressed in the nervous system. The identifiedSORCS2risk haplotype is predicted to disrupt a stress hormone‐modulated regulatory element that has tissue‐specific activity in human hippocampus. We used human neural lineage cells to demonstrate in vitro a causal relationship between stress hormone levels andSORCS2expression, and show thatSORCS2levels in culture are increased upon ethanol exposure and withdrawal.ConclusionsTaken together, these findings indicate that the pathophysiology of withdrawal may involve the effects of stress hormones on neurotrophic factor signaling. Further investigation of these pathways could produce new approaches to managing the aversive consequences of abrupt alcohol cessation.