title: Imputation of exome sequence variants into population- based samples and blood-cell-trait-associated loci in African Americans: NHLBI GO Exome Sequencing Project.
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.
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle WA 98109, USA.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Auer
authors.forename: Jill M
authors.initials: JM
authors.lastname: Johnsen
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Johnson
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Logsdon
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Lange
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nalls
authors.forename: Guosheng
authors.initials: G
authors.lastname: Zhang
authors.forename: Nora
authors.initials: N
authors.lastname: Franceschini
authors.forename: Keolu
authors.initials: K
authors.lastname: Fox
authors.forename: Ethan M
authors.initials: EM
authors.lastname: Lange
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rich
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.forename: Rebecca D
authors.initials: RD
authors.lastname: Jackson
authors.forename: Robert B
authors.initials: RB
authors.lastname: Wallace
authors.forename: Zhao
authors.initials: Z
authors.lastname: Chen
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Graubert
authors.forename: James G
authors.initials: JG
authors.lastname: Wilson
authors.forename: Hua
authors.initials: H
authors.lastname: Tang
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lettre
authors.forename: Alex P
authors.initials: AP
authors.lastname: Reiner
authors.forename: Santhi K
authors.initials: SK
authors.lastname: Ganesh
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D001773:Blood Cells / Q000378:metabolism*; D059472:Exome; D005260:Female; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D006400:Hematocrit; D006402:Hematologic Diseases / Q000235:genetics; D006454:Hemoglobins / Q000235:genetics; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010976:Platelet Count; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D019655:Quantitative Trait, Heritable; D014481:United States; D055815:Young Adult
chemical_list: D006454:Hemoglobins