Linking Alzheimer's disease and type 2 diabetes: Novel shared susceptibility genes detected by cFDR approach

Both type 2 diabetes (T2D) and Alzheimer's disease (AD) occur commonly in the aging populations and T2D has been considered as an important risk factor for AD. The heritability of both diseases is estimated to be over 50%. However, common pleiotropic single-nucleotide polymorphisms (SNPs)/loci have not been well-defined. The aim of this study is to analyze two large public accessible GWAS datasets to identify novel common genetic loci for T2D and/or AD.

The recently developed novel conditional false discovery rate (cFDR) approach was used to analyze the summary GWAS datasets from International Genomics of Alzheimer's Project (IGAP) and Diabetes Genetics Replication And Meta-analysis (DIAGRAM) to identify novel susceptibility genes for AD and T2D.

We identified 78 SNPs (including 58 novel SNPs) that were associated with AD in Europeans conditional on T2D (cFDR<0.05). 66 T2D SNPs (including 40 novel SNPs) were identified by conditioning on SNPs association with AD (cFDR<0.05). A conjunction-cFDR (ccFDR) analysis detected 8 pleiotropic SNPs with a significance threshold of ccFDR<0.05 for both AD and T2D, of which 5 SNPs (rs6982393, rs4734295, rs7812465, rs10510109, rs2421016) were novel findings. Furthermore, among the 8 SNPs annotated at 6 different genes, 3 corresponding genes TP53INP1, TOMM40 and C8orf38 were related to mitochondrial dysfunction, critically involved in oxidative stress, which potentially contribute to the etiology of both AD and T2D.

Our study provided evidence for shared genetic loci between T2D and AD in European subjects by using cFDR and ccFDR analyses. These results may provide novel insight into the etiology and potential therapeutic targets of T2D and/or AD.