Concordant and antagonistic associations of genetic variants with Alzheimer’s disease and diabetes mellitus through blood glucose and body‐mass index

Abstract

AbstractBackgroundMounting evidence suggests common etiologies of Alzheimer’s disease (AD) and diabetes mellitus (DM). Genetic mechanisms underlying the risks of AD and DM remain elusive.MethodWe used individual‐level data from four longitudinal studies,—the Atherosclerosis Risk in Communities study, Cardiovascular Health Study, Framingham Heart Study, and UK Biobank,—to examine causal mediation effects in the associations of single nucleotide polymorphisms (SNPs) with AD and DM. We selected 178 lead SNPs representing 74 previously identified AD‐ and/or DM‐associated loci on 20 chromosomes (excluding chromosomes 6 and 21). First, we used marginal structural models to perform a univariate mediation meta‐analysis considering AD or DM as an outcome and blood glucose (BG) or body mass index (BMI) measured before the onset of AD and DM as a mediator. Then, we utilized summary statistics from these univariate analyses to examine pleiotropic mediation effects on AD and DM using an omnibus test.ResultWe identified 56 SNPs in 26 loci on 12 chromosomes attaining p<0.05 in the univariate mediation meta‐analyses and genome‐wide significance (p<5×10−8) in the pleiotropic meta‐analysis of indirect effects on AD and DM through BG and BMI. BG and BMI mediated associations of 27 SNPs—14 loci on nine chromosomes; none in the APOE locus— and 33 SNPs—14 loci on eight chromosomes, including the APOE locus—, respectively. SNPs only from two of 26 loci on chromosomes 7p15.1 (JAZF1 gene) and 10q25.2 (TCF7L2 gene) showed pleiotropic effects through both BG and BMI. Directions of the mediation effects on AD and DM were the same for the same alleles through BG and the opposite through BMI. The exclusion of DM‐affected subjects explained mediation effects on AD through BG in all 14 loci. In contrast, this exclusion improved the significance of the mediation effects on AD through BMI also in all loci by decreasing p‐values 0.5 to 2 orders of magnitude.ConclusionMost of the identified genetic variants increase susceptibility to AD and DM through different mechanisms. The BG‐associated genetic mechanism is common for AD and DM, whereas the BMI‐related genetic mechanism mediates the AD and DM risks in an antagonistic manner.