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

NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Neurocognitive Working Group

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)e188-e196
JournalNeurology
Volume90
Issue number3
DOIs
StatePublished - Jan 16 2018

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Neuroimaging
Sequence Analysis
Genome
Gene Frequency
Genes
Parkinson Disease
Linear Models
Alzheimer Disease
Precision Medicine
Genome-Wide Association Study
Immunity
Inflammation
Phenotype
Brain
White Matter

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, & TOPMed Neurocognitive Working Group (2018). Whole genome sequence analyses of brain imaging measures in the Framingham Study. Neurology, 90(3), e188-e196. https://doi.org/10.1212/WNL.0000000000004820

Whole genome sequence analyses of brain imaging measures in the Framingham Study. / NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; TOPMed Neurocognitive Working Group.

In: Neurology, Vol. 90, No. 3, 16.01.2018, p. e188-e196.

Research output: Contribution to journalArticle

NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium & TOPMed Neurocognitive Working Group 2018, 'Whole genome sequence analyses of brain imaging measures in the Framingham Study', Neurology, vol. 90, no. 3, pp. e188-e196. https://doi.org/10.1212/WNL.0000000000004820
NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Neurocognitive Working Group. Whole genome sequence analyses of brain imaging measures in the Framingham Study. Neurology. 2018 Jan 16;90(3):e188-e196. https://doi.org/10.1212/WNL.0000000000004820
NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium ; TOPMed Neurocognitive Working Group. / Whole genome sequence analyses of brain imaging measures in the Framingham Study. In: Neurology. 2018 ; Vol. 90, No. 3. pp. e188-e196.
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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.",
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AU - Satizabal, Claudia L.

AU - DeCarli, Charles

AU - Pitsillides, Achilleas N.

AU - Cupples, L. Adrienne

AU - Vasan, Ramachandran S.

AU - Wilson, James G.

AU - Bis, Joshua C.

AU - Fornage, Myriam

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N2 - 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.

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