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Imputation of exome sequence variants into population- based samples and blood-cell-trait-associated loci in African Americans: NHLBI GO Exome Sequencing Project.

TitleImputation of exome sequence variants into population- based samples and blood-cell-trait-associated loci in African Americans: NHLBI GO Exome Sequencing Project.
Publication TypeJournal Article
Year of Publication2012
AuthorsAuer PL, Johnsen JM, Johnson AD, Logsdon BA, Lange LA, Nalls MA, Zhang G, Franceschini N, Fox K, Lange EM, Rich SS, O'Donnell CJ, Jackson RD, Wallace RB, Chen Z, Graubert TA, Wilson JG, Tang H, Lettre G, Reiner AP, Ganesh SK
Secondary AuthorsLi Y
JournalAm J Hum Genet
Volume91
Issue5
Pagination794-808
Date Published2012 Nov 02
ISSN1537-6605
KeywordsAdult, African Americans, Aged, Blood Cells, Exome, Female, Gene Frequency, Genome-Wide Association Study, Hematocrit, Hematologic Diseases, Hemoglobins, Humans, Leukocytes, Male, Middle Aged, Platelet Count, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Quantitative Trait, Heritable, United States, Young Adult
Abstract

Researchers have successfully applied exome sequencing to discover causal variants in selected individuals with familial, highly penetrant disorders. We demonstrate the utility of exome sequencing followed by imputation for discovering low-frequency variants associated with complex quantitative traits. We performed exome sequencing in a reference panel of 761 African Americans and then imputed newly discovered variants into a larger sample of more than 13,000 African Americans for association testing with the blood cell traits hemoglobin, hematocrit, white blood count, and platelet count. First, we illustrate the feasibility of our approach by demonstrating genome-wide-significant associations for variants that are not covered by conventional genotyping arrays; for example, one such association is that between higher platelet count and an MPL c.117G>T (p.Lys39Asn) variant encoding a p.Lys39Asn amino acid substitution of the thrombopoietin receptor gene (p = 1.5 × 10(-11)). Second, we identified an association between missense variants of LCT and higher white blood count (p = 4 × 10(-13)). Third, we identified low-frequency coding variants that might account for allelic heterogeneity at several known blood cell-associated loci: MPL c.754T>C (p.Tyr252His) was associated with higher platelet count; CD36 c.975T>G (p.Tyr325(∗)) was associated with lower platelet count; and several missense variants at the α-globin gene locus were associated with lower hemoglobin. By identifying low-frequency missense variants associated with blood cell traits not previously reported by genome-wide association studies, we establish that exome sequencing followed by imputation is a powerful approach to dissecting complex, genetically heterogeneous traits in large population-based studies.

DOI10.1016/j.ajhg.2012.08.031
Alternate JournalAm J Hum Genet
PubMed ID23103231
PubMed Central IDPMC3487117
Grant ListRC2 HL102923 / HL / NHLBI NIH HHS / United States
R01 HG006292 / HG / NHGRI NIH HHS / United States
Z01 AG000932 / ImNIH / Intramural NIH HHS / United States
RC2 HL102926 / HL / NHLBI NIH HHS / United States
RC2 HL-102923 / HL / NHLBI NIH HHS / United States
N01HC65226 / HL / NHLBI NIH HHS / United States
RC2 HL-102925 / HL / NHLBI NIH HHS / United States
Z01-AG000932-04 / AG / NIA NIH HHS / United States
RC2 HL103010 / HL / NHLBI NIH HHS / United States
N01-HC-65226 / HC / NHLBI NIH HHS / United States
R01 HG006703 / HG / NHGRI NIH HHS / United States
RC2 HL-102926 / HL / NHLBI NIH HHS / United States
RC2 HL-102924 / HL / NHLBI NIH HHS / United States
RC2 HL102924 / HL / NHLBI NIH HHS / United States
R01HG006292 / HG / NHGRI NIH HHS / United States
R01HG006703 / HG / NHGRI NIH HHS / United States
UC2 HL102924 / HL / NHLBI NIH HHS / United States
RC2 HL-103010 / HL / NHLBI NIH HHS / United States
RC2 HL102925 / HL / NHLBI NIH HHS / United States