Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer's disease.
Broce IJ, Tan CH, Fan CC et al.
Publication Details
Comprehensive information about this research publication
Abstract
Summary of the research findings
Cardiovascular (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. Beyond APOE, 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 within MBLAC1 (chromosome 7, meta-p = 1.44 × 10-9), MINK1 (chromosome 17, meta-p = 1.98 × 10-7) and two chromosome 11 SNPs within the MTCH2/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' cohort from the UK Biobank, we replicated three of the four novel AD/CV pleiotropic SNPs, namely variants within MINK1, MBLAC1, and DDB2. Expression of MBLAC1, SPI1, MINK1 and DDB2 was differentially altered within postmortem AD brains. Beyond APOE, we show that the polygenic component of AD is enriched for lipid-associated RFs. We pinpoint a subset of cardiovascular-associated genes that strongly increase the risk for AD. Our collective findings support a disease model in which cardiovascular biology is integral to the development of clinical AD in a subset of individuals.
17,008 European ancestry Alzheimer's disease cases, 48,286 European ancestry type 2 diabetes cases, 17,283 European ancestry coronary artery disease cases, 425,739 European ancestry controls, 923,864 European ancestry individuals
Study Statistics
Key metrics and study information
Analysis
Comprehensive review of health and genetic findings
Important Disclaimer: This review has been performed semi-automatically and is provided for informational purposes only. While we strive for accuracy, this analysis may contain errors, omissions, or misinterpretations of the original research. DNA Genics disclaims all liability for any inaccuracies, errors, or consequences arising from the use of this information. Users should independently verify all information and consult original research publications before making any decisions based on this content. This analysis is not intended as a substitute for professional scientific review or medical advice.
Analysis In Progress
Our analysis of this publication is currently being prepared. Please check back soon for comprehensive insights into the health and genetic findings discussed in this research.