Whole genome sequence analyses of brain imaging measures in the Framingham Study. (16th January 2018)

• Record Type: Journal Article
• Authors: Sarnowski, Chloé; Satizabal, Claudia L.; DeCarli, Charles; Pitsillides, Achilleas N.; Cupples, L. Adrienne; Vasan, Ramachandran S.; Wilson, James G.; Bis, Joshua C.; Fornage, Myriam; Beiser, Alexa S.; DeStefano, Anita L.; Dupuis, Josée; Seshadri, Sudha
• Is Part Of: Neurology. Volume 90:Number 3(2018)
• Publication Date: 2018-01-16
• Subjects: Neurology -- Periodicals; Neurology -- Periodicals; Neurologie -- Périodiques; 616.8
• DOI: 10.1212/WNL.0000000000004820
• Languages: English
• ISSNs: 0028-3878

Abstract

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.