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

Identifying pleiotropy for blood pressure (BP) and cognitive performance measures may indicate mechanistic links between hypertension and Alzheimer's disease (AD).

We performed a pleiotropy genome-wide association study (GWAS) for paired measures of systolic, diastolic, pulse, and mean arterial pressure with memory, executive function, and language scores using 116,075 exam data from 25,726 participants in clinic-based and prospective cohorts. Significant findings were evaluated by Bayesian colocalization and differential gene expression in brain tissue from pathologically confirmed AD cases with and without clinical symptoms.

Genome-wide significant pleiotropy for BP and cognitive performance with JPH2, GATA3, PAX2, LOC105371656, and SUFU in the total sample; RTN4, ULK2, SORBS2, and LOC100128993 in prospective cohorts; and ADAMTS3 and LINC02946 in clinic-based cohorts. Six pleiotropic loci influence cognition directly, and six genes were differentially expressed between pathologically confirmed AD cases with and without antemortem cognitive impairment.

Our results provide insight into mechanisms underlying hypertension and AD.

Genome-wide significant pleiotropy in blood pressure (BP) and cognitive performance measures were identified with 11 novel loci: JPH2, GATA3, PAX2, LOC105371656, SUFU in the total sample; RTN4, ULK2, SORBS2, LOC100128993 in prospective cohorts; and ADAMTS3, LINC02946 in clinic-based cohorts. SUFU, RTN4, SORBS2, ADAMTS3, and GATA3 affected cognition directly rather than through BP. ACTR1A, HIF1AN, ADAMTS3, RTN4, SORBS2, and SUFU at pleiotropic loci were differentially expressed among controls and pathologically confirmed AD cases with and without clinical symptoms.