Journal article
Imputation of Exome Sequence Variants into Population-Based Samples and Blood-Cell-Trait-Associated Loci in African Americans: NHLBI GO Exome Sequencing Project
American journal of human genetics, Vol.91(5), pp.794-808
11/02/2012
DOI: 10.1016/j.ajhg.2012.08.031
PMCID: PMC3487117
PMID: 23103231
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 thrombpoietin receptor gene (p = 1.5 x 10(-11)). Second, we identified an association between missense variants of LCT and higher white blood count (p = 4 x 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 alpha-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.
Details
- Title: Subtitle
- Imputation of Exome Sequence Variants into Population-Based Samples and Blood-Cell-Trait-Associated Loci in African Americans: NHLBI GO Exome Sequencing Project
- Creators
- Paul L. Auer - Fred Hutch Cancer CenterJill M. Johnsen - University of WashingtonBenjamin A. Logsdon - Fred Hutch Cancer CenterLeslie A. Lange - University of North CarolinaMichael A. Nalls - NIA, Mol Genet Sect, Neurogenet Lab, Bethesda, MD 20892 USAGuosheng Zhang - University of North CarolinaNora Franceschini - University of North CarolinaKeolu Fox - University of WashingtonEthan M. Lange - University of North CarolinaStephen S. Rich - University of VirginiaChristopher J. O'Donnell - National Institutes of HealthRebecca D. Jackson - The Ohio State UniversityRobert B. Wallace - University of IowaZhao Chen - University of ArizonaTimothy A. Graubert - Washington University in St. LouisJames G. Wilson - University of MississippiHua Tang - Stanford UniversityGuillaume Lettre - Université de MontréalAlex P. Reiner - Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USASanthi K. Ganesh - University of MichiganYun Li - University of North CarolinaNHLBI GO Exome Sequencing Project
- Resource Type
- Journal article
- Publication Details
- American journal of human genetics, Vol.91(5), pp.794-808
- DOI
- 10.1016/j.ajhg.2012.08.031
- PMID
- 23103231
- PMCID
- PMC3487117
- NLM abbreviation
- Am J Hum Genet
- ISSN
- 0002-9297
- eISSN
- 1537-6605
- Publisher
- Elsevier
- Number of pages
- 15
- Grant note
- National Heart, Lung, and Blood Institute (NHLBI); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) Z01-AG000932-04 / Intramural Research Program of the National Institutes of Health, National Institute on Aging; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA) R01HG006292; R01HG006703 / National Human Genome Research Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI) R01HG006703 / NATIONAL HUMAN GENOME RESEARCH INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI) RC2HL102924 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) RC2 HL-103010; RC2 HL-102923; RC2 HL-102924; RC2 HL-102925; RC2 HL-102926; HHSN268200960009C / NHLBI; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) Z01AG000932 / NATIONAL INSTITUTE ON AGING; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA)
- Language
- English
- Date published
- 11/02/2012
- Academic Unit
- Epidemiology; Injury Prevention Research Center; Internal Medicine
- Record Identifier
- 9984364446102771
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