Genetic heterogeneity of Alzheimer's disease in subjects with and without hypertension.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder caused by the interplay of multiple genetic and non-genetic factors. Hypertension is one of the AD risk factors that has been linked to underlying pathological changes like senile plaques and neurofibrillary tangles formation as well as hippocampal atrophy. In this study, we investigated the differences in the genetic architecture of AD between hypertensive and non-hypertensive subjects in four independent cohorts. Our genome-wide association analyses revealed significant associations of 15 novel potentially AD-associated polymorphisms (P < 5E-06) that were located outside the chromosome 19q13 region and were significant either in hypertensive or non-hypertensive groups. The closest genes to 14 polymorphisms were not associated with AD at P < 5E-06 in previous genome-wide association studies (GWAS). Also, four of them were located within two chromosomal regions (i.e., 3q13.11 and 17q21.2) that were not associated with AD at P < 5E-06 before. In addition, 30 genes demonstrated evidence of group-specific associations with AD at the false discovery rates (FDR) < 0.05 in our gene-based and transcriptome-wide association analyses. The chromosomal regions corresponding to four genes (i.e., 2p13.1, 9p13.3, 17q12, and 18q21.1) were not associated with AD at P < 5E-06 in previous GWAS. These genes may serve as a list of prioritized candidates for future functional studies. Our pathway-enrichment analyses revealed the associations of 11 non-group-specific and four group-specific pathways with AD at FDR < 0.05. These findings provided novel insights into the potential genetic heterogeneity of AD among subjects with and without hypertension.

796 European ancestry cases, 4,010 European ancestry controls