Whole brain and regional hyperintense white matter volume and blood pressure: overlap of genetic loci produced by bivariate, whole-genome linkage analyses

Abstract

Background and purpose: The volume of T2-hyperintense white matter (HWM) is an important neuroimaging marker of cerebral integrity with a demonstrated high heritability. Pathophysiology studies have shown that the regional, ependymal, and subcortical HWM lesions are associated with elevated arterial pulse pressure and arterial blood pressure (BP), respectively. We performed bivariate, whole-genome linkage analyses for HWM volumes and BP measurements to identify chromosomal regions that contribute jointly to both traits in a population of healthy Mexican Americans. Our aims were to localize novel quantitative trait loci acting pleiotropically on these phenotypes and to replicate previous genetic findings on whole brain HWM volume and BP measurements.

Methods: BP measurements and volumes of whole-brain (WB), subcortical, and ependymal HWM lesions, measured from high-resolution (1 mm(3)) 3-dimensional fluid-attenuated inversion recovery images, served as focal quantitative phenotypes. Data were collected from 357 (218 females; mean age=47.9±13.2 years) members of large extended families who participated in the San Antonio Family Heart Study.

Results: Bivariate genomewide linkage analyses localized a significant quantitative trait locus influencing WB and regional (ependymal) HWM volumes and pulse pressure and systolic BP to chromosomal location 1q24 between markers D1S196 and D1S1619. Several other chromosomal regions (1q42, 10q24-q26, and 15q26) exhibited suggestive linkages. The results of the post hoc analyses that excluded 55 subjects taking antihypertensive medication showed no substantive differences from the results obtained in the full cohort.

Conclusions: This study confirms several previously observed quantitative trait loci influencing BP and cerebral integrity and identifies a novel significant quantitative trait locus at chromosome 1q24. The genetic results strongly support a role for pleiotropically acting genes jointly influencing BP and cerebral white matter integrity.

Figure 1

Bivariate linkage analysis results for WB (top), Ependymal (middle) and Subcortical (bottom) HWM volumes (bottom) and three measurements of arterial BP.