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• W4387501426 abstract "The phenotypic heterogeneity of multiple substance use patterns presents a major challenge in the identification of biological underpinnings of polysubstance use disorder (pSUD). Therefore, this study identified patterns of pSUD in subjects who were diagnosed with multiple SUDs by applying a latent class analysis (LCA). Due to the role of DNA-methylation (DNAm) implicated in SUDs, understanding how DNAm associates with distinct SUD combinations may help identify targets with biological implications. Latent classes were identified using the lowest Akaike Information Criterion, Bayesian Information Criterion, C-squared, Chi-squared metrics for the five SUDs: alcohol, cannabis, cocaine, opioid, and tobacco use disorders (AUD, CanUD, CoUD, OUD, TUD) using DSM-IV criteria in 31,197 individuals from six cohorts (five dbGaP cohorts and Yale-Penn; Age=42.1 yrs ± 11; Females = 49.3%). For each class, we assigned the profiles based on >70% probability of case status. The DNA methylation assay was performed using the Illumina EPIC array in a subset of the individuals (European (EUR), n=231; African (AFR), n= 501, Hispanic (HIS), n= 175) of the Yale-Penn cohort. We conducted an epigenome-wide association study (EWAS) analysis at 657,226 CpG sites using regression models, with adjustment for slide, array, age, sex, blood cell type proportion, and ten principal components of within-genetic ancestry. The LCA identified a five-class model: Class1 (AUD-TUD, n= 6487), Class 2 (CoUD-TUD, n=1170), Class 3 (Polysubstance use (PSU): AUD, CoUD, OUD, TUD, n= 2090), Class 4 (Controls, n= 11759), and Class 5 (TUD, n = 1162). Comparing the latent-class control sample with the PSU latent class, we found 2, 1, and 0 differentially methylated sites in EUR, AFR, and HIS populations, respectively. The cg05575921 in AHRR (5p15.33) was significantly hypomethylated in the PSU class (AFR p = 3.63e-09; EUR p= 7.35e-09). Due to the known role of AHRR in affecting DNA methylation from smoking, we further adjusted for methylation smoking score; these associations were then no longer significant. Comparing the control latent-class with the alcohol-tobacco class, we found 2, 80, and 1 differentially methylated sites in EUR, AFR, and HIS populations, respectively. The cg02833127 in SPATA4 (4q34.2) was significantly hypomethylated in alcohol and tobacco class (AFR p = 6.05e-08; EUR p= 3.668915e-26; HIS p= 1.00e-17). This association remains significant even after adjustment of methylation smoking score in all three ancestries. In AFR, we additionally observed cg07395074 (12q24.11), and cg21911711 (9p13.11) in F2RL3; other associations were no longer significant after methylation smoking score adjustment. We also observed differentially methylated regions in PRRT1 (AFR) and WRAP73 (HIS) that remained significant after methylation smoking score adjustment. No sites were significant for other class comparisons. Overall, we identified several genes differentially methylated in the AUD-TUD class, for eg. F2RL3 has been linked to methylation profile of smoking in African Americans, and PRRT1 is involved in long-term synaptic regulation and AMPA activity and has been linked with chronic alcohol consumption in animal models. These findings highlight the role of methylation in pSUD profiles in multiple population groups." @default.
• W4387501426 created "2023-10-11" @default.
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• W4387501426 date "2023-10-01" @default.
• W4387501426 modified "2023-10-12" @default.
• W4387501426 title "W101. EPIGENETIC PROFILES OF LATENT CLASSES FOR POLYSUBSTANCE USE DISORDER" @default.
• W4387501426 doi "https://doi.org/10.1016/j.euroneuro.2023.08.287" @default.
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