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ADAM19 and HTR4 variants and pulmonary function: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.

Wednesday,2015-03-04 13:01 America/Los_Angeles — zdrager
TitleADAM19 and HTR4 variants and pulmonary function: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.
Publication TypeJournal Article
Year of Publication2014
AuthorsLondon, SJ, Gao, W, Gharib, SA, Hancock, DB, Wilk, JB, House, JS, Gibbs, RA, Muzny, DM, Lumley, T, Franceschini, N, North, KE, Psaty, BM, Kovar, CL, Coresh, J, Zhou, Y, Heckbert, SR, Brody, JA, Morrison, AC, Dupuis, J
JournalCirc Cardiovasc Genet
Volume7
Issue3
Pagination350-8
Date Published2014 Jun
ISSN1942-3268
KeywordsADAM Proteins, Aged, Aged, 80 and over, Aging, Cohort Studies, Female, Genetic Variation, Genome-Wide Association Study, Genomics, Heart Diseases, Humans, Lung, Male, Middle Aged, Polymorphism, Single Nucleotide, Sequence Analysis, DNA
Abstract<p><b>BACKGROUND: </b>The pulmonary function measures of forced expiratory volume in 1 second (FEV1) and its ratio to forced vital capacity (FVC) are used in the diagnosis and monitoring of lung diseases and predict cardiovascular mortality in the general population. Genome-wide association studies (GWASs) have identified numerous loci associated with FEV1 and FEV1/FVC, but the causal variants remain uncertain. We hypothesized that novel or rare variants poorly tagged by GWASs may explain the significant associations between FEV1/FVC and 2 genes: ADAM19 and HTR4.</p><p><b>METHODS AND RESULTS: </b>We sequenced ADAM19 and its promoter region along with the ≈21-kb portion of HTR4 harboring GWAS single-nucleotide polymorphisms for pulmonary function and analyzed associations with FEV1/FVC among 3983 participants of European ancestry from Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Meta-analysis of common variants in each region identified statistically significant associations (316 tests; P<1.58×10(-4)) with FEV1/FVC for 14 ADAM19 single-nucleotide polymorphisms and 24 HTR4 single-nucleotide polymorphisms. After conditioning on the sentinel GWASs hit in each gene (ADAM19 rs1422795, minor allele frequency=0.33 and HTR4 rs11168048, minor allele frequency=0.40], 1 single-nucleotide polymorphism remained statistically significant (ADAM19 rs13155908, minor allele frequency=0.12; P=1.56×10(-4)). Analysis of rare variants (minor allele frequency <1%) using sequence kernel association test did not identify associations with either region.</p><p><b>CONCLUSIONS: </b>Sequencing identified 1 common variant associated with FEV1/FVC independent of the sentinel ADAM19 GWAS hit and supports the original HTR4 GWAS findings. Rare variants do not seem to underlie GWAS associations with pulmonary function for common variants in ADAM19 and HTR4.</p>
DOI10.1161/CIRCGENETICS.113.000066
Alternate JournalCirc Cardiovasc Genet
PubMed ID24951661
PubMed Central IDPMC4136502
Grant ListHHSN268201100012C / HL / NHLBI NIH HHS / United States
N01HC55222 / HC / NHLBI NIH HHS / United States
HHSN268201000010C / HL / NHLBI NIH HHS / United States
UL1RR025005 / RR / NCRR NIH HHS / United States
N02-HL-6-4278 / HL / NHLBI NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
RC2 HL102419 / HL / NHLBI NIH HHS / United States
N01 HC085086 / HC / NHLBI NIH HHS / United States
HHSN268201100001I / HL / NHLBI NIH HHS / United States
HHSN268201100009I / HL / NHLBI NIH HHS / United States
ZIA ES043012-15 / / Intramural NIH HHS / United States
5RC2HL102419 / HL / NHLBI NIH HHS / United States
N01 HC085081 / HC / NHLBI NIH HHS / United States
R01HL59367 / HL / NHLBI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
N01HC85080 / HC / NHLBI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
HHSN2682011000010C / / PHS HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
UL1 TR001079 / TR / NCATS NIH HHS / United States
HHSN268201100005G / HL / NHLBI NIH HHS / United States
HHSN268201100008I / HL / 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
HHSN268200800007C / HL / NHLBI NIH HHS / United States
N01 HC085083 / HC / NHLBI 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
R01 HL087652 / HL / NHLBI NIH HHS / United States
HHSN268200625226C / / PHS HHS / United States
U01 HG004402 / HG / NHGRI 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
N01HC85086 / HL / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
U01HG004402 / HG / NHGRI NIH HHS / United States
N01 HC085082 / HC / NHLBI NIH HHS / United States
N01HC85081 / HC / NHLBI NIH HHS / United States
N01 HC085080 / HC / NHLBI NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
N01HC85079 / 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
N01HC85086 / HC / NHLBI NIH HHS / United States
HHSN268201100002C / WH / WHI NIH HHS / United States
HHSN2682011000012C / / PHS HHS / United States
R01 HL080295 / HL / NHLBI NIH HHS / United States
N01HC85082 / HC / NHLBI NIH HHS / United States
HHSN268201100007C / / PHS HHS / United States
HHSN268200800007C / / PHS HHS / United States
N01HC85082 / 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
HHSN268201100007I / HL / NHLBI NIH HHS / United States
HHSN268201200036C / / PHS HHS / United States
HHSN268201100002I / HL / NHLBI NIH HHS / United States
HL080295 / HL / NHLBI NIH HHS / United States
N01HC85083 / HC / NHLBI NIH HHS / United States
HHSN268201000012C / HL / NHLBI NIH HHS / United States
N01HC85079 / HL / NHLBI NIH HHS / United States
N01 HC085079 / HC / 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
N01HC85080 / HL / NHLBI NIH HHS / United States
AG023629 / AG / NIA 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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