Mendelian randomization study using paired SNPs as instruments supports casual protective effect of overweight on Alzheimer’s disease

Abstract

AbstractBackgroundMendelian Randomization (MR) is a powerful method of detecting causal effects in observational studies. However, choosing an appropriate SNP as an instrumental variable (IVar) is challenging because of difficulties in satisfying all assumption criteria. We proposed a novel strategy of creating IVar using paired SNPs between genes of interest, and tested this strategy in MR study examining causal relationships between being overweight and onset of Alzheimer’s disease (AD).MethodWe performed MR in the Health and Retirement Study (HRS) subsample of participants aged 75+, using the following binary variables: (1) ‘overweight’ BMI 25‐30 vs. (0) ‘normal’ BMI 18.5‐25, at ages 65‐75, as exposure; and (1) no AD vs. (0) AD onset at ages 75+, as outcome. We found significant association between ‘overweight’ BMI and lower odds of AD in logistic regression, and used MR to test causality. For IVar, we selected eight obesity‐related genes from the literature (ADIPOQ, FTO, LEP, LEPR, INSIG2, MC4R, PCSK1, PPARG), cross‐paired their SNPs, and used counts of minor alleles of the paired SNPs to create new ‘composite SNP’s. Analyses were stratified by sex and race, and non‐stratified. Initial models were estimated in SAS. Resulting summary statistics were used in R‐package MendelianRandomization. F‐value>10 criteria was applied to ensure the IVar strength. The causal effect was evaluated using weighted median, Inverse‐Variance Weighted (IVW), and maximum likelihood (ML).ResultBeing overweight at ages 65‐75 had significant causal protective effect on AD onset after age 75 in White females (logistic regression: OR = 1.99 [higher odds for ‘overweight’ individuals to be in ‘no AD’ group], p‐value = 8.26E‐5; MR: number of instrument ‘SNP’s = 13, weighted median causal estimate = 1.27, p‐value = 1.91E‐5; IVW causal estimate = 1.14, p‐value = 2.30E‐08; ML causal estimate = 1.20, p‐value = 7.67E‐7). No causal effects were detected using single SNPs in the same genes.ConclusionThe proposed novel strategy of creating IVar for MR analysis, based on pairing SNPs between candidate genes, substantially improves the critical step of MR analysis: choosing efficient instrument SNPs. We successfully tested this new strategy in HRS data, and confirmed causal relationship between BMI and AD, specifically, significant causal protective effect of being overweight on AD onset later in life in white females.