Gene-set based analysis for alcohol dependence

Einleitung: Formal genetic studies have shown that the heritability of alcohol dependence is 40 – 60%, with many common variants contributing. However, as due to multiple testing these often do not pass the threshold of genome-wide significance, it is not clear which genes actually contribute. A supplementary approach is to test sets of related genes, e.g., those which are circumscribed by categories derived from prior biological knowledge. Here, we report results of a gene-set based analysis for alcohol dependence in our previously reported GWAS from the German population.

Methode: 1333 cases and 2168 controls where available for analysis after quality control. Gene-set descriptions were retrieved from KEGG, Reactome, Gene Ontology, Biocarta, microRNA targets, transcription factor targets and positional gene sets. For set-based analysis, the global test was applied.

Diskussion/Ergebnisse: Twenty-eight gene sets at FDR =< 0.1 were identified. Among the genes which contribute to these gene-sets are classical candidate genes for alcohol dependence, i.e., alcohol dehydrogenases (ADH1B, ADH1C), protein kinase C alpha (PRKCA), diacyl glycerol kinase iota (DGKI) and serotonin 6 receptor (HTR6) genes, as well as new candidates. A group of gene-sets, retrieved from the different sources, highlighted the variants mapped to the X-ray repair complementing defective repair in Chinese hamster cells 5 (XRCC5) gene.

Schlussfolgerung: A prior study has indicated that XRCC5 plays a role in the 'level of response to alcohol', which measures alcohol sensitivity and is a risk factor for developing alcohol dependence. Additionally, a gene expression study of the corresponding phenotype in rodents shows involvement of XRCC5. Testing alcohol effects on this phenotype in Drosophila mutants of Ku80, the homolog of mammalian XRCC5, support the role of this gene in response to alcohol. In conclusion, our gene-set based approach identified old and new candidates for alcohol dependence.