A weighted false discovery rate control procedure reveals alleles at FOXA2 that influence fasting glucose levels.

TitleA weighted false discovery rate control procedure reveals alleles at FOXA2 that influence fasting glucose levels.
Publication TypeJournal Article
Year of Publication2010
AuthorsXing, C, Cohen, JC, Boerwinkle, E
JournalAm J Hum Genet
Volume86
Issue3
Pagination440-6
Date Published2010 Mar 12
ISSN1537-6605
KeywordsAfrican Americans, Alleles, Biostatistics, Blood Glucose, European Continental Ancestry Group, Fasting, Gene Frequency, Genome-Wide Association Study, Hepatocyte Nuclear Factor 3-beta, Humans, Linkage Disequilibrium, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide
Abstract

Association signals in GWAS are usually prioritized solely by p values. Here, we attempt to improve the power of GWAS by using a weighted false discovery rate control procedure to detect associations of low-frequency variants with effect sizes similar to or even larger than those of common variants. We used the Affymetrix Genome-Wide Human SNP Array 6.0 to test for association with fasting glucose levels in the Atherosclerosis Risk in Communities Study (ARIC) population. In addition to finding several previously identified sequence variations, we identified a low-frequency variant (rs1209523; minor allele frequency = 0.043) near FOXA2 that was associated with fasting glucose levels in European Americans (EAs) (n = 7428, p value = 1.3 x 10(-5)). The association between rs1209523 and glucose levels was also significant in African Americans (AAs) (n = 2029, p value = 6.7 x 10(-3)) of the ARIC and was confirmed by replication in both EAs and AAs of the Dallas Heart Study (n = 963 and 1571, respectively; p values = 5.3 x 10(-3) and 5.8 x 10(-4), respectively) and in EAs of the Cooper Center Longitudinal Study (n = 2862; p value = 1.6 x 10(-2)). A meta-analysis of these five populations yielded an estimated effect size of -1.31 mg/dl per minor allele (p value = 2.2 x 10(-11)). This study reveals that there is a cache of less-frequent variants in GWAS arrays that can be identified via analytical approaches accounting for allele frequencies.

DOI10.1016/j.ajhg.2010.01.025
Alternate JournalAm. J. Hum. Genet.
PubMed ID20152958
PubMed Central IDPMC2833364
Grant ListN01HC55020 / HL / NHLBI NIH HHS / United States
UL1RR025005 / RR / NCRR NIH HHS / United States
HL092550 / HL / NHLBI NIH HHS / United States
N01HC55018 / HL / NHLBI NIH HHS / United States
R01HL59367 / HL / NHLBI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
HL082896 / HL / NHLBI NIH HHS / United States
N01-HC-55022 / HC / NHLBI NIH HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
N01-HC-55016 / HC / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
HHSN268200625226C / / PHS HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
N01HC55022 / HL / NHLBI NIH HHS / United States
N01-HC-55021 / HC / NHLBI NIH HHS / United States
N01HC55015 / HL / NHLBI NIH HHS / United States
U01HG004402 / HG / NHGRI NIH HHS / United States
N01 HC055018 / HC / WHI NIH HHS / United States
RL1 HL092550 / HL / NHLBI NIH HHS / United States
N01 HC055016 / HC / WHI NIH HHS / United States
N01-HC-55019 / HC / NHLBI NIH HHS / United States
R01HL087641 / HL / NHLBI NIH HHS / United States
N01-HC-55015 / HC / NHLBI NIH HHS / United States
UL1RR024982 / RR / NCRR NIH HHS / United States
UL1 RR024982 / RR / NCRR NIH HHS / United States
N01-HC-55020 / HC / NHLBI NIH HHS / United States
N01HC55016 / HL / NHLBI NIH HHS / United States
N01HC55019 / HL / NHLBI NIH HHS / United States
R01 HL082896 / HL / NHLBI NIH HHS / United States
N01-HC-55018 / HC / NHLBI NIH HHS / United States
N01HC55021 / HL / NHLBI NIH HHS / United States
N01 HC055019 / HC / WHI NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
R01HL086694 / HL / NHLBI NIH HHS / United States