Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer ’s disease

AbstractCardiovascular (CV)- and lifestyle-associated risk factors (RFs) are increasingly recognized as important for Alzheimer ’s disease (AD) pathogenesis. Beyond the ε4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV-associated genes also increase risk for AD. Using large genome-wide association studies and validated  tools to quantify genetic overlap, we systematically identified single nucleotide polymorphisms (SNPs)jointly associated with AD and one or more CV-associated RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), triglycerides (TG), low-density (LDL) and high-density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TG, TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. BeyondAPOE, at conjunction FDR  <  0.05 we identified 90 SNPs on 19 different chromosomes that were jointly associated with AD and CV-associated outcomes. In meta-analyses across three independent cohorts, we found four novel loci withinMBLAC1 (chromosome 7, meta-p = 1.44 × 10−9),MINK1 (chromosome 17, meta-p = 1.98 × 10−7) and two chromosome 11 SNPs within theMTCH2/SPI1 region (closest gene  = DDB2, meta-p = 7.01 × 10−7 and closest gene  = MYBPC3, meta-p = 5.62 × 10−8). In a large ‘AD-by-proxy’ coho...
Source: Acta Neuropathologica - Category: Neurology Source Type: research