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Strategies to design and analyze targeted sequencing data: cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.

Wednesday,2015-03-04 13:00 America/Los_Angeles — zdrager
TitleStrategies to design and analyze targeted sequencing data: cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.
Publication TypeJournal Article
Year of Publication2014
AuthorsLin, H, Wang, M, Brody, JA, Bis, JC, Dupuis, J, Lumley, T, McKnight, B, Rice, KM, Sitlani, CM, Reid, JG, Bressler, J, Liu, X, Davis, BC, Johnson, AD, O'Donnell, CJ, Kovar, CL, Dinh, H, Wu, Y, Newsham, I, Chen, H, Broka, A, DeStefano, AL, Gupta, M, Lunetta, KL, Liu, C-T, White, CC, Xing, C, Zhou, Y, Benjamin, EJ, Schnabel, RB, Heckbert, SR, Psaty, BM, Muzny, DM, Cupples, AL, Morrison, AC, Boerwinkle, E
JournalCirc Cardiovasc Genet
Volume7
Issue3
Pagination335-43
Date Published2014 Jun
ISSN1942-3268
KeywordsAdult, Aged, Aged, 80 and over, Aging, Cohort Studies, Female, Genetic Variation, Genome-Wide Association Study, Genomics, Heart Diseases, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Research Design, Sequence Analysis, DNA
Abstract<p><b>BACKGROUND: </b>Genome-wide association studies have identified thousands of genetic variants that influence a variety of diseases and health-related quantitative traits. However, the causal variants underlying the majority of genetic associations remain unknown. Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study aims to follow up genome-wide association study signals and identify novel associations of the allelic spectrum of identified variants with cardiovascular-related traits.</p><p><b>METHODS AND RESULTS: </b>The study included 4231 participants from 3 CHARGE cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, and the Framingham Heart Study. We used a case-cohort design in which we selected both a random sample of participants and participants with extreme phenotypes for each of 14 traits. We sequenced and analyzed 77 genomic loci, which had previously been associated with ≥1 of 14 phenotypes. A total of 52 736 variants were characterized by sequencing and passed our stringent quality control criteria. For common variants (minor allele frequency ≥1%), we performed unweighted regression analyses to obtain P values for associations and weighted regression analyses to obtain effect estimates that accounted for the sampling design. For rare variants, we applied 2 approaches: collapsed aggregate statistics and joint analysis of variants using the sequence kernel association test.</p><p><b>CONCLUSIONS: </b>We sequenced 77 genomic loci in participants from 3 cohorts. We established a set of filters to identify high-quality variants and implemented statistical and bioinformatics strategies to analyze the sequence data and identify potentially functional variants within genome-wide association study loci.</p>
DOI10.1161/CIRCGENETICS.113.000350
Alternate JournalCirc Cardiovasc Genet
PubMed ID24951659
PubMed Central IDPMC4176824
Grant ListHHSN268201100012C / HL / NHLBI NIH HHS / United States
HHSN268201000010C / HL / NHLBI NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
RC2 HL102419 / HL / NHLBI NIH HHS / United States
HHSN268201100001I / HL / NHLBI NIH HHS / United States
HHSN268201100009I / HL / NHLBI NIH HHS / United States
5RC2HL102419 / HL / NHLBI NIH HHS / United States
N01 HC085081 / HC / NHLBI NIH HHS / United States
ZIA HL006002-05 / / Intramural NIH HHS / United States
R01HL59367 / HL / NHLBI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
HHSN2682011000010C / / PHS HHS / United States
R01 AG015928 / AG / NIA NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
HHSN268201100005G / HL / NHLBI NIH HHS / United States
N01 HC075150 / HC / NHLBI NIH HHS / United States
HHSN268201100008I / HL / NHLBI NIH HHS / United States
N01-HC-85081 / HC / NHLBI NIH HHS / United States
HHSN268201100005C / / PHS HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
HL105756 / HL / NHLBI NIH HHS / United States
N01 HC015103 / HC / NHLBI NIH HHS / United States
R56 AG020098 / AG / NIA NIH HHS / United States
N01 HC025195 / HC / NHLBI NIH HHS / United States
HHSN268201100009C / / PHS HHS / United States
HHSN268201100011I / HL / NHLBI NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
N02 HL64278 / HL / NHLBI NIH HHS / United States
N01 HC085085 / HC / NHLBI NIH HHS / United States
R01 HL087652 / HL / NHLBI NIH HHS / United States
AG-20098 / AG / NIA NIH HHS / United States
HHSN268201000011C / HL / NHLBI NIH HHS / United States
HL087652 / HL / NHLBI NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
N01-HC-85086 / HC / NHLBI NIH HHS / United States
N01HC85086 / HL / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
AG-027058 / AG / NIA NIH HHS / United States
N01-HC-85082 / HC / NHLBI NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
N01 HC-55222 / HC / NHLBI NIH HHS / United States
HHSN268201200036C / HL / NHLBI NIH HHS / United States
HHSN268201100008C / / PHS HHS / United States
R01HL087641 / HL / NHLBI NIH HHS / United States
HHSN268201100005I / HL / NHLBI NIH HHS / United States
N01-HC-85083 / HC / NHLBI NIH HHS / United States
N01-HC-75150 / HC / NHLBI NIH HHS / United States
HHSN268201100002C / WH / WHI NIH HHS / United States
N01-HC-85080 / HC / NHLBI NIH HHS / United States
HHSN2682011000012C / / PHS HHS / United States
R01 HL080295 / HL / NHLBI NIH HHS / United States
ZIA HL006002-06 / / Intramural NIH HHS / United States
HHSN268201100007C / / PHS HHS / United States
N01 HC085084 / HC / NHLBI NIH HHS / United States
R01 AG020098 / AG / NIA NIH HHS / United States
N01HC85082 / HL / NHLBI NIH HHS / United States
N01HC75150 / HL / NHLBI NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
N01HC85083 / HL / NHLBI NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
Z99 HL999999 / / Intramural NIH HHS / United States
HHSN268201100007I / HL / NHLBI NIH HHS / United States
N01-HC-85079 / HC / NHLBI NIH HHS / United States
HHSN268201200036C / / PHS HHS / United States
HHSN268201100002I / HL / NHLBI NIH HHS / United States
HL080295 / HL / NHLBI NIH HHS / United States
HHSN268201000012C / HL / NHLBI NIH HHS / United States
N01-HC-85239 / HC / NHLBI NIH HHS / United States
AG-023629 / AG / NIA NIH HHS / United States
N01HC85079 / HL / NHLBI NIH HHS / United States
HHSN268201100006C / / PHS HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
R01 AG027058 / AG / NIA NIH HHS / United States
N01 HC045133 / HC / NHLBI NIH HHS / United States
N01HC85080 / HL / NHLBI NIH HHS / United States
N01 HC035129 / HC / NHLBI NIH HHS / United States
R56 AG023629 / AG / NIA NIH HHS / United States
HHSN268201100001C / WH / WHI NIH HHS / United States
N01HC85081 / HL / NHLBI NIH HHS / United States
R01HL086694 / HL / NHLBI NIH HHS / United States
HHSN2682011000011C / / PHS HHS / United States

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