TY - JOUR
T1 - Imputation of exome sequence variants into population-based samples and blood-cell-trait-associated loci in african americans
T2 - NHLBI GO exome sequencing project
AU - Auer, Paul L.
AU - Johnsen, Jill M.
AU - Johnson, Andrew D.
AU - Logsdon, Benjamin A.
AU - Lange, Leslie A.
AU - Nalls, Michael A.
AU - Zhang, Guosheng
AU - Franceschini, Nora
AU - Fox, Keolu
AU - Lange, Ethan M.
AU - Rich, Stephen S.
AU - O'Donnell, Christopher J.
AU - Jackson, Rebecca D.
AU - Wallace, Robert B.
AU - Chen, Zhao
AU - Graubert, Timothy A.
AU - Wilson, James G.
AU - Tang, Hua
AU - Lettre, Guillaume
AU - Reiner, Alex P.
AU - Ganesh, Santhi K.
AU - Li, Yun
N1 - Funding Information:
The authors wish to acknowledge the support of the National Heart, Lung, and Blood Institute (NHLBI) and the contributions of the research institutions, study investigators, field staff, and study participants in creating this resource for biomedical research. Funding for GO ESP was provided by NHLBI grants RC2 HL-103010 (HeartGO), RC2 HL-102923 (LungGO), and RC2 HL-102924 (WHISP). The exome sequencing was performed through NHLBI grants RC2 HL-102925 (BroadGO) and RC2 HL-102926 (SeattleGO). CARe was supported by a contract from NHLBI (HHSN268200960009C) to create a phenotype and genotype database for dissemination to the biomedical research community. Eight parent studies contributed phenotypic data and DNA samples through the Broad Institute (N01-HC-65226): the Atherosclerosis Risk in Communities study (ARIC), the Cleveland Family Study (CFS), the Coronary Artery Risk Development in Young Adults study (CARDIA), the Jackson Heart Study (JHS), the Multi-Ethnic Study of Atherosclerosis (MESA) study, the Cardiovascular Health Study (CHS), the Framingham Heart Study (FHS), and the Sleep Heart Health Study (SHHS). Support for CARe also came from the individual research institutions, investigators, field staff, and study participants. This research was supported in part by grants from the National Human Genome Research Institute to Y.L. (R01HG006292 and R01HG006703). This research was also supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging (Z01-AG000932-04), and this study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health (see Web Resources ).
PY - 2012/11/2
Y1 - 2012/11/2
N2 - 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 thrombpoietin 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.
AB - 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 thrombpoietin 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.
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U2 - 10.1016/j.ajhg.2012.08.031
DO - 10.1016/j.ajhg.2012.08.031
M3 - Article
C2 - 23103231
AN - SCOPUS:84868502906
SN - 0002-9297
VL - 91
SP - 794
EP - 808
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 5
ER -