Genomic Susceptibility Loci for Brain Atrophy in Hypertensive Sibships From the GENOA Study

We measured 366 microsatellite markers genome-wide to search for loci contributing to subcortical white matter ischemic damage (leukoariosis) and brain atrophy in 488 non-Hispanic white subjects (193 men, 295 women; mean age+/-SD=64.1+/-7.7 years; 79% hypertensive) from 223 sibships recruited through > or =2 members with essential hypertension diagnosed before age 60. Leukoariosis was quantitated by magnetic resonance imaging (MRI), brain atrophy by the difference between intracranial and brain volumes, and calculated mean arterial pressure and pulse pressure provided measures of steady-state level and pulsatile components of blood pressure. After adjustment for sex and age, variance components models estimated significant heritability of leukoariosis (0.72), brain atrophy (0.52), mean arterial pressure (0.084), and pulse pressure (0.294) (P<0.0001 for each trait). Univariate maximum logarithm of odds scores (MLS) were observed for leukoariosis on chromosome 5 (MLS=1.91; P=0.00150); for brain atrophy on 1q and 17p (MLS=2.76, P=0.00018); for mean arterial pressure on 11p (MLS=1.57; P=0.00354); and for pulse pressure on 11p (MLS=3.02; P=0.00070). Bivariate linkage analyses provided evidence of loci with pleiotropic effects on brain atrophy and pulse pressure on chromosomes 11p (MLS = 5.07 at 16 cM; P=0.00001) and 16q (MLS of 4.56 at 124 cM; P=0.00003). These results demonstrate usefulness of multivariate linkage analyses to detect loci with pleiotropic effects on genetically correlated traits and suggest overlap between the genes influencing blood pressure and those contributing to brain atrophy.