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

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, = 10) and in 16q23 for hippocampal volume (MAF 0.05, = 2.7 × 10). Previously identified associations in 12q24 for hippocampal volume (rs7294919, = 4.4 × 10) and in 17q25 for WMH (rs7214628, = 2.0 × 10) were confirmed. Gene-based tests detected associations ( ≤ 2.3 × 10) in new loci for cerebral (5q13, 8p12, 9q31, 13q12-q13, 15q24, 17q12, 19q13) and hippocampal volumes (2p12) and WMH (3q13, 4p15) including Alzheimer disease- () and Parkinson disease-associated genes (). 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.