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Abstract
GWAS studies have identified genetic variants associated with Alcohol Dependence (AD), but how they link to genes, their regulation and disease traits, remains largely unexplored. Here we integrated information on the 3D genome organization with expression quantitative loci (eQTLs) analysis, using CoDeS3D, to identify the functional impacts of single nucleotide polymorphisms associated with AD (p < 1 × 10−6). We report that 42% of the 285 significant tissue-specific regulatory interactions we identify were associated with four genes encoding Alcohol Dehydrogenase - ADH1A, ADH1B, ADH1C and ADH4. Identified eQTLs produced a co-ordinated regulatory action between ADH genes, especially between ADH1A and ADH1C within the subcutaneous adipose and gastrointestinal tissues. Five eQTLs were associated with regulatory motif alterations and tissue-specific histone marks consistent with these variants falling in enhancer and promoter regions. By contrast, few regulatory connections were identified in the stomach and liver. This suggests that changes in gene regulation associated with AD are linked to changes in tissues other than the primary sites of alcohol absorption and metabolism. Future work to functionally characterise the putative regulatory regions we have identified and their links to metabolic and regulatory changes in genes will improve our mechanistic understanding of AD disease development and progression.
Highlights
Genome wide association studies (GWAS) studies have identified genetic variants associated with Alcohol Dependence (AD), but how they link to genes, their regulation and disease traits, remains largely unexplored
The 34 expression quantitative trait loci (eQTL) (16 intronic, 9 intergenic, 3 exonic, 3 ncRNA intronic, 1 upstream, 2 UTR3; Supplementary Fig. 2) were involved in 274 cis- and 11 trans-acting regulatory interactions between 72 statistically significant (FDR < 0.05; Benjamini Hotchberg40) Single-nucleotide polymorphisms (SNPs)-eGene pairs across 48 different human tissues (Supplementary Table 4)
CYP4B1 is a member of the Cytochrome P450 superfamily of enzymes, which contribute to an alternative pathway for alcohol metabolism[14,18]
Summary
GWAS studies have identified genetic variants associated with Alcohol Dependence (AD), but how they link to genes, their regulation and disease traits, remains largely unexplored. We report that 42% of the 285 significant tissue-specific regulatory interactions we identify were associated with four genes encoding Alcohol Dehydrogenase - ADH1A, ADH1B, ADH1C and ADH4. Few regulatory connections were identified in the stomach and liver This suggests that changes in gene regulation associated with AD are linked to changes in tissues other than the primary sites of alcohol absorption and metabolism. AD is a clinical diagnosis and the severity of the condition presents as a continuum across populations Both genetic and environmental factors impact an individual’s likelihood of developing the condition, with twin-studies estimating the heritability of alcohol use disorders to be around 50%7. Other enzymes have minor roles in alcohol metabolism, for example CYP2E1 is part of the liver cytochrome P450 enzyme system, and catalase[14,18,19]
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