Serum cholesterol and variant in cholesterol-related gene CETP predict white matter microstructure

Abstract

Several common genetic variants influence cholesterol levels, which play a key role in overall health. Myelin synthesis and maintenance are highly sensitive to cholesterol concentrations, and abnormal cholesterol levels increase the risk for various brain diseases, including Alzheimer's disease. We report significant associations between higher serum cholesterol (CHOL) and high-density lipoprotein levels and higher fractional anisotropy in 403 young adults (23.8 ± 2.4 years) scanned with diffusion imaging and anatomic magnetic resonance imaging at 4 Tesla. By fitting a multi-locus genetic model within white matter areas associated with CHOL, we found that a set of 18 cholesterol-related, single-nucleotide polymorphisms implicated in Alzheimer's disease risk predicted fractional anisotropy. We focused on the single-nucleotide polymorphism with the largest individual effects, CETP (rs5882), and found that increased G-allele dosage was associated with higher fractional anisotropy and lower radial and mean diffusivities in voxel-wise analyses of the whole brain. A follow-up analysis detected white matter associations with rs5882 in the opposite direction in 78 older individuals (74.3 ± 7.3 years). Cholesterol levels may influence white matter integrity, and cholesterol-related genes may exert age-dependent effects on the brain.

Keywords: Aging; Brain structure; Cholesterol; DTI; Development; Imaging genetics.

Figure 1

Several known relationships (solid black arrows) motivated our study. Both serum cholesterol levels and brain structure are highly heritable. In our initial analysis, we tested whether serum cholesterol levels effected WM microstructure (?¹). Brain and serum cholesterol pools are largely independent, so we hypothesized that certain genes might exhibit pleiotropic effects on both serum and brain cholesterol pools and, thus, brain integrity. As cholesterol genes maintain serum cholesterol levels and AD genes influence brain structure, we analyzed the effects of a subset of cholesterol genes implicated in AD pathology on WM microstructure (?²).

Figure 2

Associations between white matter microstructure (FA) and total cholesterol (CHOL) and high-density lipoprotein (HDL) in the QTIM sample. Higher adolescent serum levels of both CHOL and HDL were associated with higher FA in early adulthood. For total cholesterol, light blue areas correspond to stronger beta-values (regression coefficients more positive); for high-density lipoprotein, yellow areas correspond to stronger beta-values (more positive). Even though both measures positively associate with FA, they are represented in different colors to capture the specific beta-value ranges for each test. CC=corpus callosum, CR=corona radiata, IC=internal capsule, G=genu, IFOF=inferior fronto-occipital fasciculus, UNC=uncinate, ILF=inferior longitudinal fasciculus, FX=fornix, AF=arcuate fasciculus, SP=splenium. Left in the image is right in the brain.

Figure 3

Multi-SNP results: Associations between FA and SNPs linked with CHOL. R² values are combined predictive value of our SNPs, white areas are areas with higher R² values, as shown by the color bar. The blue underlay corresponds to the p-values of the CHOL analysis; these were used to define a search region for the multi-SNP analysis. Thus, blue regions visible represent the only regions of the CHOL FA mask where the multi-SNP analysis did not find significant associations. Left in the image is right in the brain, coordinates are in MNI space.

Figure 4

Association between whole brain voxel-wise FA and CETP (rs5882) risk allele dosage in the QTIM and ADNI samples. In QTIM (a), increased G-allele dosage was associated with higher FA in statistically significant regions. Yellow corresponds to stronger b-values (more positive). In ADNI (b), increased G-allele dosage was associated with lower FA in statistically significant regions. Pink corresponds to stronger beta-values (more negative). Only areas surviving FDR across the brain are shown. CR=corona radiata, CC=corpus callosum, IC=internal capsule, IFG=inferior frontal gyrus, G=genu, SP=splenium, AF=arcuate fasciculus, IFOF=inferior fronto-occipital fasciculus, UNC=uncinate, ILF=inferior longitudinal fasciculus, FX=fornix. Left in the image is right in the brain, coordinates are in MNI space.