Whole genome sequence analyses of brain imaging measures in the Framingham Study

Abstract

Objective: We sought to identify rare variants influencing brain imaging phenotypes in the Framingham Heart Study by performing whole genome sequence association analyses within the Trans-Omics for Precision Medicine Program.

Methods: We performed association analyses of cerebral and hippocampal volumes and white matter hyperintensity (WMH) in up to 2,180 individuals by testing the association of rank-normalized residuals from mixed-effect linear regression models adjusted for sex, age, and total intracranial volume with individual variants while accounting for familial relatedness. We conducted gene-based tests for rare variants using (1) a sliding-window approach, (2) a selection of functional exonic variants, or (3) all variants.

Results: We detected new loci in 1p21 for cerebral volume (minor allele frequency [MAF] 0.005, p = 10^-8) and in 16q23 for hippocampal volume (MAF 0.05, p = 2.7 × 10^-8). Previously identified associations in 12q24 for hippocampal volume (rs7294919, p = 4.4 × 10^-4) and in 17q25 for WMH (rs7214628, p = 2.0 × 10^-3) were confirmed. Gene-based tests detected associations (p ≤ 2.3 × 10^-6) in new loci for cerebral (5q13, 8p12, 9q31, 13q12-q13, 15q24, 17q12, 19q13) and hippocampal volumes (2p12) and WMH (3q13, 4p15) including Alzheimer disease- (UNC5D) and Parkinson disease-associated genes (GBA). Pathway analyses evidenced enrichment of associated genes in immunity, inflammation, and Alzheimer disease and Parkinson disease pathways.

Conclusions: Whole genome sequence-wide search reveals intriguing new loci associated with brain measures. Replication of novel loci is needed to confirm these findings.

Figure 1. Regional association plots

Regional association plots of the 12q24 hippocampal volume (HPV) (A) and the 17q25 white matter hyperintensity (WMH) (B) regions using Locuszoom software. Single nucleotide variants (SNVs) are plotted with their −log10 (p values) on the left y-axis as a function of the genomic position on the x-axis. Estimated recombination rates on the right y-axis, taken from 1000 Genomes with European panel, are plotted to reflect the local linkage disequilibrium structure around the top associated SNV in purple and correlated proxies, according to a blue to red scale from r² = 0 to 1.