Cis-meQTL for cocaine use-associated DNA methylation in an HIV-positive cohort show pleiotropic effects on multiple traits

Abstract

Abstract Background Cocaine use (CU) is associated with psychiatric and medical diseases. Little is known about the mechanisms of CU-related comorbidities. Findings from preclinical and clinical studies have suggested that CU is associated with aberrant DNA methylation (DNAm) that may be influenced by genetic variants [i.e., methylation quantitative trait loci (meQTLs)]. In this study, we mapped cis-meQTLs for CU-associated DNAm sites (CpGs) in an HIV-positive cohort (Ntotal = 811) and extended the meQTLs to multiple traits. Results We conducted cis-meQTL analysis for 224 candidate CpGs selected for their association with CU in blood. We identified 7,101 significant meQTLs [false discovery rate (FDR) < 0.05], which mostly mapped to genes involved in immunological functions and were enriched in immune pathways. We followed up the meQTLs using phenome-wide association study and trait enrichment analyses, which revealed 9 significant traits. We tested for causal effects of CU on these 9 traits using Mendelian Randomization and found evidence that CU plays a causal role in increasing hypertension (p-value = 2.35E-08) and decreasing heel bone mineral density (p-value = 1.92E-19). Conclusions These findings suggest that genetic variants for CU-associated DNAm have pleiotropic effects on other relevant traits and provide new insights into the causal relationships between cocaine use and these complex traits.

Keywords

• Cocaine use
• Cis-methylation quantitative trait loci (cis-meQTL)
• Epigenome-wide association study (EWAS)
• Mendelian randomization
• Complex trait