DNA methylation signature on phosphatidylethanol, not on self-reported alcohol consumption, predicts hazardous alcohol consumption in two distinct populations

Abstract

The process of diagnosing hazardous alcohol drinking (HAD) is based on self-reported data and is thereby vulnerable to bias. There has been an interest in developing epigenetic biomarkers for HAD that might complement clinical assessment. Because alcohol consumption has been previously linked to DNA methylation (DNAm), we aimed to select DNAm signatures in blood to predict HAD from two demographically and clinically distinct populations (N total = 1,549). We first separately conducted an epigenome-wide association study (EWAS) for phosphatidylethanol (PEth), an objective measure of alcohol consumption, and for self-reported alcohol consumption in Cohort 1. We identified 83 PEth-associated CpGs, including 23 CpGs previously associated with alcohol consumption or alcohol use disorder. In contrast, no CpG reached epigenome-wide significance on selfreported alcohol consumption. Using a machine learning approach, two CpG subsets from EWAS on PEth and on self-reported alcohol consumption from Cohort 1 were separately tested for the prediction of HAD in Cohort 2. We found that a subset of 143 CpGs selected from the EWAS on PEth showed an excellent prediction of HAD with the area under the receiver operating characteristic curve (AUC) of 89.4% in training set and 73.9% in validation set of Cohort 2. However, CpGs preselected from the EWAS on self-reported alcohol consumption showed a poor prediction of HAD with AUC 75.2% in training set and 57.6% in validation set. Our results demonstrate that an objective measure for alcohol consumption is a more informative phenotype than self-reported data for revealing epigenetic mechanisms. The PEth-associated DNAm signature in blood could serve as a robust biomarker for alcohol consumption.

Dual methylation and hydroxymethylation study of alcohol use disorder

“…DNAm studies are typically conducted using bulk tissue (e.g., whole blood or brain) that is composed of multiple cell types, each with a potentially different DNAm profile. In studies using bulk tissue, including some previous alcohol studies, 4,5,9–11 estimates of cell‐type proportions are included as covariates to protect against false‐positive associations 12 . By focusing only on bulk tissue, however, potentially important associations may be missed.…”

Genome-wide study of DNA methylation in Amyotrophic Lateral Sclerosis identifies differentially methylated loci and implicates metabolic, inflammatory and cholesterol pathways

“…Interestingly, cg06690548 (annotated to SLC7A11 ) has also been previously associated with alcohol intake and related factors such as GGT and phosphatidylethanol levels 11,53–55 , and the association between the alcohol PMS and ALS was primarily driven by this site. Although we did not find a significant DNA methylation-gene expression relationship (eQTM) for this site, previous work suggests that increased DNA methylation at cg06690548 is associated with downregulation of SLC7A11 in the brain.…”

Additive Effects of Stress and Alcohol Exposure on Accelerated Epigenetic Aging in Alcohol Use Disorder

“…Furthermore, the effect of the identical event can differ dramatically from one person to the next, depending on attachment to the lost object, concurrent events, personality, genotype, and culture. Analogously, alcohol assessments are mostly self-reported and more accurate measures for alcohol exposure are needed (42). In that regard, we would point out that the AUD diagnosis itself is highly reliable, having a very high kappa coefficient in interview/re-interview studies, and the diagnosis even being captured with very high ROC AUC (>.95) sensitivity/specificity with simple questionnaires such as the AUDIT.…”