Juraeva et al. (2015) combined pathway analysis with functional follow-up studies in a Drosophila model and a human sample to identify AD risk genes. They conducted gene set analysis on 1,333 AD cases and 2,168 controls from the German GWAS sample (Frank et al., 2012) using the R package globaltest (Goeman et al., 2004). Gene sets were constructed using multiple sources such as KEGG, Reactome, Gene Ontology, Biocarta, microRNA targets, transcription factor targets, and positional information. The analysis identified 19 significant gene sets (FDR ≤ 0.05), with the gene XRCC5 present in six of these. In a Drosophila knockdown model of the XRCC5 ortholog, Ku80, the mutants had lower sensitivity to ethanol than controls. An alcohol intravenous self-administration study in 85 healthy humans showed a significant association between maximum blood alcohol concentration and XRCC5 genotype for the top SNP from their GWAS, rs828701 (P=0.03), indicating that XRCC5 may be an AD candidate gene.
