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

NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, On behalf of the TOPMed Neurocognitive Working Group

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)E188-E196
Issue number3
StatePublished - Jan 2018
Externally publishedYes

ASJC Scopus subject areas

  • Clinical Neurology


Dive into the research topics of 'Whole genome sequence analyses of brain imaging measures in the Framingham Study'. Together they form a unique fingerprint.

Cite this