Epigenetic aging is accelerated in alcohol use disorder and regulated by genetic variation in APOL2

Audrey Luo, Jeesun Jung, Martha Longley, Daniel B. Rosoff, Katrin Charlet, Christine Muench, Jisoo Lee, Colin A. Hodgkinson, David Goldman, Steve Horvath, Zachary A Kaminsky, Falk W. Lohoff

Research output: Contribution to journalArticle

Abstract

To investigate the potential role of alcohol use disorder (AUD) in aging processes, we employed Levine’s epigenetic clock (DNAm PhenoAge) to estimate DNA methylation age in 331 individuals with AUD and 201 healthy controls (HC). We evaluated the effects of heavy, chronic alcohol consumption on epigenetic age acceleration (EAA) using clinical biomarkers, including liver function test enzymes (LFTs) and clinical measures. To characterize potential underlying genetic variation contributing to EAA in AUD, we performed genome-wide association studies (GWAS) on EAA, including pathway analyses. We followed up on relevant top findings with in silico expression quantitative trait loci (eQTL) analyses for biological function using the BRAINEAC database. 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). This association remained significant after adjusting for race, body mass index, and smoking status (1.38 years, p = 0.02). Secondary analyses showed more pronounced EAA in individuals with more severe AUD-associated phenotypes, including elevated gamma-glutamyl transferase (GGT) and alanine aminotransferase (ALT), and higher number of heavy drinking days (all ps < 0.05). The genome-wide meta-analysis of EAA in AUD revealed a significant single nucleotide polymorphism (SNP), rs916264 (p = 5.43 × 10−8), in apolipoprotein L2 (APOL2) at the genome-wide level. The minor allele A of rs916264 was associated with EAA and with increased mRNA expression in hippocampus (p = 0.0015). Our data demonstrate EAA in AUD and suggest that disease severity further accelerates epigenetic aging. EAA was associated with genetic variation in APOL2, suggesting potential novel biological mechanisms for age acceleration in AUD.

Original languageEnglish (US)
JournalNeuropsychopharmacology
DOIs
StateAccepted/In press - Jan 1 2019

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Apolipoproteins
Epigenomics
Alcohols
Genome
Quantitative Trait Loci
Genome-Wide Association Study
Liver Function Tests
DNA Methylation
Transferases
Alanine Transaminase
Alcohol Drinking
Computer Simulation
Drinking
Single Nucleotide Polymorphism
Meta-Analysis
Hippocampus
Blood Cells
Body Mass Index
Biomarkers
Smoking

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

Cite this

Luo, A., Jung, J., Longley, M., Rosoff, D. B., Charlet, K., Muench, C., ... Lohoff, F. W. (Accepted/In press). Epigenetic aging is accelerated in alcohol use disorder and regulated by genetic variation in APOL2. Neuropsychopharmacology. https://doi.org/10.1038/s41386-019-0500-y

Epigenetic aging is accelerated in alcohol use disorder and regulated by genetic variation in APOL2. / Luo, Audrey; Jung, Jeesun; Longley, Martha; Rosoff, Daniel B.; Charlet, Katrin; Muench, Christine; Lee, Jisoo; Hodgkinson, Colin A.; Goldman, David; Horvath, Steve; Kaminsky, Zachary A; Lohoff, Falk W.

In: Neuropsychopharmacology, 01.01.2019.

Research output: Contribution to journalArticle

Luo, A, Jung, J, Longley, M, Rosoff, DB, Charlet, K, Muench, C, Lee, J, Hodgkinson, CA, Goldman, D, Horvath, S, Kaminsky, ZA & Lohoff, FW 2019, 'Epigenetic aging is accelerated in alcohol use disorder and regulated by genetic variation in APOL2', Neuropsychopharmacology. https://doi.org/10.1038/s41386-019-0500-y
Luo, Audrey ; Jung, Jeesun ; Longley, Martha ; Rosoff, Daniel B. ; Charlet, Katrin ; Muench, Christine ; Lee, Jisoo ; Hodgkinson, Colin A. ; Goldman, David ; Horvath, Steve ; Kaminsky, Zachary A ; Lohoff, Falk W. / Epigenetic aging is accelerated in alcohol use disorder and regulated by genetic variation in APOL2. In: Neuropsychopharmacology. 2019.
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AU - Muench, Christine

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