Genome-wide pleiotropy analysis of longitudinal blood pressure and harmonized cognitive performance measures.

Abstract

Background: Genome-wide association studies (GWAS) have identified over 1,000 blood pressure (BP) loci and over 80 loci for Alzheimer's disease (AD). Considering BP is an AD risk factor, identifying pleiotropy in BP and cognitive performance measures may indicate mechanistic links between BP and AD.

Methods: Genome-wide scans for pleiotropy in BP variables-systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse pressure (PP)-and co-calibrated scores for cognitive domains (executive function, language, and memory) were performed using generalized linear mixed models and 116,075 longitudinal measures from 25,726 participants of clinic-based and prospective cohorts. GWAS was conducted using PLACO to estimate each SNP's main effect and interaction with age, and their joint effect on pleiotropy. Effects of genome-wide significant (GWS) pleiotropic SNPs on cognition as direct or mediated through BP were evaluated using Mendelian randomization. Potential contribution of genes in top-ranked pleiotropic loci to cognitive resilience was assessed by comparing their expression in brain tissue from pathologically confirmed AD cases with and without clinical symptoms.

Results: Pleiotropy GWAS identified GWS associations with APOE and 11 novel loci. In the total sample, pleiotropy was identified for SBP and language with JPH2 ( P _Joint =6.09×10 ^-9 ) and GATA3 ( P _G×Age =1.42×10 ^-8 ), MAP and executive function with PAX2 ( P _G×Age =4.22×10 ^-8 ), MAP and language with LOC105371656 ( P _G×Age =1.75×10 ^-8 ), and DBP and language with SUFU ( P _G =2.10×10 ^-8 ). In prospective cohorts, pleiotropy was found for SBP and language with RTN4 ( P _G×Age =1.49×10 ^-8 ), DBP and executive function with ULK2 ( P _Joint =2.85×10 ^-8 ), PP and memory with SORBS2 ( P _G =2.33×10 ^-8 ), and DBP and memory with LOC100128993 ( P _G×Age =2.81×10 ^-8 ). In clinic-based cohorts, pleiotropy was observed for PP and language with ADAMTS3 ( P _G =2.37×10 ^-8 ) and SBP and memory with LINC02946 ( P _G×Age =3.47×10 ^-8 ). Five GWS pleiotropic loci influence cognition directly, and genes at six pleiotropic loci were differentially expressed between pathologically confirmed AD cases with and without clinical symptoms.

Conclusion: Our results provide insight into the underlying mechanisms of high BP and AD. Ongoing efforts to harmonize BP and cognitive measures across several cohorts will improve the power of discovering, replicating, and generalizing novel associations with pleiotropic loci.