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

TitleWhole genome sequence analyses of brain imaging measures in the Framingham Study.
Publication TypeJournal Article
Year of Publication2018
AuthorsSarnowski C, Satizabal CL, DeCarli C, Pitsillides AN, L Cupples A, Vasan RS, Wilson JG, Bis JC, Fornage M, Beiser AS, DeStefano AL, Dupuis J
Secondary AuthorsSeshadri S
Corporate AuthorsNHLBI Trans-Omics for Precision Medicine(TOPMed) Consortium, TOPMed Neurocognitive Working Group
Date Published2018 01 16
KeywordsAged, Brain, Female, Genetic Variation, Genome-Wide Association Study, Humans, Magnetic Resonance Imaging, Male, Massachusetts, Middle Aged, Organ Size, Phenotype, Prospective Studies

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.

Alternate JournalNeurology
PubMed ID29282330
PubMed Central IDPMC5772158
Grant ListR01 NS017950 / NS / NINDS NIH HHS / United States
T32 AG000262 / AG / NIA NIH HHS / United States
HHSN268201500014C / HL / NHLBI NIH HHS / United States
P30 AG010129 / AG / NIA NIH HHS / United States
R01 HL117626 / HL / NHLBI NIH HHS / United States
U54 GM115428 / GM / NIGMS NIH HHS / United States
U01 AG049505 / AG / NIA NIH HHS / United States
R01 AG054076 / AG / NIA NIH HHS / United States
R01 HL120393 / HL / NHLBI NIH HHS / United States