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

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 vol...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5772158/
https://www.ncbi.nlm.nih.gov/pubmed/29282330
http://dx.doi.org/10.1212/WNL.0000000000004820
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author 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
author_facet 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
author_sort Sarnowski, Chloé
collection PubMed
description 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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spelling pubmed-57721582018-01-22 Whole genome sequence analyses of brain imaging measures in the Framingham Study 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 Neurology Article 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. Lippincott Williams & Wilkins 2018-01-16 /pmc/articles/PMC5772158/ /pubmed/29282330 http://dx.doi.org/10.1212/WNL.0000000000004820 Text en Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
spellingShingle Article
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
Whole genome sequence analyses of brain imaging measures in the Framingham Study
title Whole genome sequence analyses of brain imaging measures in the Framingham Study
title_full Whole genome sequence analyses of brain imaging measures in the Framingham Study
title_fullStr Whole genome sequence analyses of brain imaging measures in the Framingham Study
title_full_unstemmed Whole genome sequence analyses of brain imaging measures in the Framingham Study
title_short Whole genome sequence analyses of brain imaging measures in the Framingham Study
title_sort whole genome sequence analyses of brain imaging measures in the framingham study
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5772158/
https://www.ncbi.nlm.nih.gov/pubmed/29282330
http://dx.doi.org/10.1212/WNL.0000000000004820
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