|Title||Whole genome sequence analyses of brain imaging measures in the Framingham Study.|
|Publication Type||Journal Article|
|Year of Publication||2018|
|Authors||Sarnowski 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 Authors||Seshadri S|
|Corporate Authors||NHLBI Trans-Omics for Precision Medicine(TOPMed) Consortium, TOPMed Neurocognitive Working Group|
|Date Published||2018 01 16|
|Keywords||Aged, 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.
|PubMed Central ID||PMC5772158|
|Grant List||R01 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