LRRTM4 and PCSK5 Genetic Polymorphisms as Markers for Cognitive Impairment in A Hypotensive Aging Population: A Genome-Wide Association Study in Taiwan

Abstract

Hypotension can affect cerebral perfusion and worsen cognitive outcomes. The prevalence of low blood pressure (BP) rises with increasing age. To our knowledge, no study has examined the genetic biomarkers for hypotension-related cognitive impairment (CI) yet. Utilizing the population-based genome-wide study of the Taiwan Biobank containing the data of 2533 healthy aging subjects, we found after adjustments for age, sex, education years, and principal components at a suggestive level of 1 × 10^-5 that minor alleles of leucine rich repeat transmembrane neuronal 4 (LRRTM4) (rs13388459, rs1075716, rs62171995, rs17406146, rs2077823, and rs62170897), proprotein convertase subtilisin/kexin type 5 (PCSK5) (rs10521467), and the intergenic variation rs117129097 (the nearby gene: TMEM132C) are risk factors for CI in hypotensive subjects. Except for rs117129097, these single nucleotide polymorphisms (SNPs) were not markers per se for CI or for BP regulation. However, we found a suggestive interaction effect between each of the eight SNPs and hypotension on CI risk. In the hypotensive participants, those carrying minor alleles were associated with a higher incidence of CI in an additive manner than were those carrying major alleles (2 × 10^-4 to 9 × 10^-7). Intensive BP lowering in elderly patients carrying a minor allele of the eight identified SNPs should raise cautions to prevent a potential treatment-induced neurodegeneration.

Keywords: cognitive impairment; dementia; hypotension; single nucleotide polymorphism.

Figure 1

Manhattan plots of the genome-wide association scan. Manhattan plots of the genome-wide association scan for regions associated with the coexistence of cognitive impairment (CI) and hypotension shows the clusters of suggestive single nucleotide polymorphisms (SNPs) within the loci of chromosome 2p12, 77.09 M to 77.33 M, and two spots at chromosome 9q21.13 and 12q24.32 at a significance level of 1 × 10⁻⁵. Eight SNPs within three genes (six in leucine rich repeat transmembrane neuronal 4 (LRRTM4), one in proprotein convertase subtilisin/kexin type 5 (PCSK5), and one unknown (the nearby gene is TMEM132C)) were identified to be associated with the concurrent presence of hypotension and CI.

Figure 2

Linkage disequilibrium coefficients (D’) of the pairwise loci constructed by the six SNPs in LRRTM4. Linkage disequilibrium coefficients (D’) of the pairwise loci constructed by the six SNPs in LRRTM4 show no difference between cases and controls (Haploview version 4.2 software). A D’ value of “1” indicates that the examined two loci exhibit a complete linkage while a value of “0” demonstrates their independence. The most common haplotypes were CTGAAA with 69.9% and TCAGGGG with 30.4% in the group with coexisting hypotension and cognitive impairment, whereas 85.7% CTGAAA and 13.4% TCAGGGG were determined in the control group.

Figure 3

Interactive effects of the discovered SNPs and hypotension on CI in the whole cohort. There was a suggestive interactive effect between rs13388459 and hypotension on cognitive impairment (CI) risk (p = 0.0004). Hypotensive subjects carrying the rs13388459 T allele were associated with a higher incidence of CI in an additive manner compared to those carrying the C allele (panel A). By contrast, in the non-hypotensive group, there was no difference in CI incidence between the rs13388459 genotypes. Similarly, there was a suggestive interaction effect between PCSK5 rs10521467 and hypotension on CI risk (p = 9 × 10⁻⁷; panel B). The SNP rs117129097 was associated with hypotension (p = 0.0005). An additional suggestive interaction effect was found between rs10521467 and hypotension on CI risk (p = 0.003; panel C).