Clinical Genomics and Experimental Therapeutics

National Institute On Alcohol Abuse And Alcoholism

Investigators

Linked publications & trials

Abstract

I. Epigenomics and multi-omics in AUD: Alcohol may influence disease outcomes through epigenetic modifications and is known to affect the acetylation and methylation of histones and the methylation of DNA (Zakhari, 2013). DNA methylation involves the addition of a methyl group, donated by the metabolite, S-adenosylmethionine (SAM), to the C of CpG dinucleotides. Chronic alcohol consumption can thus alter epigenetic signatures and subsequently may disrupt transcription and protein expression. Using epigenome-wide association studies (EWAS), we have identified CpGs that are associated with alcohol consumption and AUD (Lohoff et al., 2018, Lohoff et al., 2020, Lohoff et al., 2022). However, prior studies were somewhat limited by small sample sizes and lower capture arrays (Longley et al., 2021). In addition, only a few studies exist linking alcohol consumption and AUD EWAS data with detailed biological validation. To address these gaps in the literature, we conducted the largest EWAS analyses of alcohol consumption in a single cohort of individuals (n=8161). We are continuing to follow up top findings in AUD relevant phenotypes using a translational cross-tissue/cross-phenotypic approach to identify novel potential targets relevant to AUD. Furthermore, we have integrated proteomic and transcriptomic data with genetic architectures of problematic alcohol use and alcohol consumption behaviors to advance our understanding of AUD and to help identify novel therapeutic targets. We conducted systematic screens using genome-wise association study data from ~3,500 cortical proteins (N = 722) and ~6,100 genes in 8 canonical brain cell types (N = 192) with 4 alcohol-related outcomes (N ≤ 537,349), identifying 217 cortical proteins and 255 cell-type genes associated with these behaviors, with 36 proteins and 37 cell-type genes being new (Rosoff et al, 2025). II. Aging in AUD Studies have shown that individuals with AUD die earlier than healthy controls and are at a significantly increased risk for all-cause mortality (Westman et al., 2015, Laramée et al., 2015). Given the potential role of AUD in the aging process, it is important to understand this relationship on a molecular, epigenetic level. To better assess “biological age”, several “epigenetic clocks” that robustly correlate with chronological age have been developed. These clocks are algorithms that take the weighted average of methylation levels at specific CpG sites to calculate DNA methylation age (DNAm age), which is highly correlated with chronological age. We have previously shown that AUD is associated with epigenetic age acceleration (Rosen et al., 2018) and confirmed our finding in a larger sample. There was a 2.22-year age acceleration in AUD compared to controls after adjusting for gender and blood cell composition (p = 1.85 × 10-5)(Luo et al., 2020). We continue to work on epigenetic biomarkers of aging in individuals with AUD and have developed a methylation score of stress that tracks stress exposure in individuals with AUD (Jung et al., 2022) and have also tested novel next-generation clocks in AUD (Perlstein et al, 2025). In addition, we have conducted multi-omic analyses of aging and longevity and identified several novel targets (Mavromatis et al., 2023, Rosoff et al., 2023b, Rosoff et al., 2024c). III. PCSK9 in AUD Approximately 50% of all liver disease mortality is currently attributable to alcohol misuse (Gao and Bataller, 2011, Rehm et al., 2013, Seitz et al., 2018), yet there are no FDA approved treatment options for alcohol-associated liver disease (ALD). Thus, a substantial and increasing need is emerging for new therapeutic options capable of reducing alcohol-associated liver damage. We have recently shown that the PCSK9 inhibitor alirocumab attenuates alcohol-induced hepatic triglyceride accumulation, hepatocellular injury and hepatic inflammation in a rat model of chronic alcohol exposure (Lee et al., 2019). Given the unmet clinical need for novel treatment options for ALD, we continue to study safety and tolerability of alirocumab in heavy social drinkers. We hypothesize that alirocumab will be well tolerated and safe in this new target population and alirocumab will attenuate alcohol-induced liver damage and inflammatory biomarkers. We are currently conducting this clinical trial entitled “A Phase I, Randomized, Double-Blind, Placebo-Controlled, Study of Safety, Tolerability, and Bioeffects of alirocumab in Non-treatment Seeking Heavy Drinkers” (ClinicalTrials.gov Identifier: NCT04781322). Additional preclinical work is ongoing on the mechanisms by which PCSK9 inhibition attenuates ALD and inflammation and various other health outcomes (Rosoff et al, 2025, Arif et al, 2025).