title: Whole-exome imputation of sequence variants identified two novel alleles associated with adult body height in African Americans.
abstract: Adult body height is a quantitative trait for which genome-wide association studies (GWAS) have identified numerous loci, primarily in European populations. These loci, comprising common variants, explain <10% of the phenotypic variance in height. We searched for novel associations between height and common (minor allele frequency, MAF ≥5%) or infrequent (0.5% < MAF < 5%) variants across the exome in African Americans. Using a reference panel of 1692 African Americans and 471 Europeans from the National Heart, Lung, and Blood Institute's (NHLBI) Exome Sequencing Project (ESP), we imputed whole-exome sequence data into 13 719 African Americans with existing array-based GWAS data (discovery). Variants achieving a height-association threshold of P < 5E-06 in the imputed dataset were followed up in an independent sample of 1989 African Americans with whole-exome sequence data (replication). We used P < 2.5E-07 (=0.05/196 779 variants) to define statistically significant associations in meta-analyses combining the discovery and replication sets (N = 15 708). We discovered and replicated three independent loci for association: 5p13.3/C5orf22/rs17410035 (MAF = 0.10, β = 0.64 cm, P = 8.3E-08), 13q14.2/SPRYD7/rs114089985 (MAF = 0.03, β = 1.46 cm, P = 4.8E-10) and 17q23.3/GH2/rs2006123 (MAF = 0.30; β = 0.47 cm; P = 4.7E-09). Conditional analyses suggested 5p13.3 (C5orf22/rs17410035) and 13q14.2 (SPRYD7/rs114089985) may harbor novel height alleles independent of previous GWAS-identified variants (r(2) with GWAS loci <0.01); whereas 17q23.3/GH2/rs2006123 was correlated with GWAS-identified variants in European and African populations. Notably, 13q14.2/rs114089985 is infrequent in African Americans (MAF = 3%), extremely rare in European Americans (MAF = 0.03%), and monomorphic in Asian populations, suggesting it may be an African-American-specific height allele. Our findings demonstrate that whole-exome imputation of sequence variants can identify low-frequency variants and discover novel variants in non-European populations.
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA, School of Public Health and Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA, mdu@fhcrc.org.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Du
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA, University of Wisconsin-Milwaukee Joseph J. Zilber School of Public Health, Biostatistics, Milwaukee, WI, USA.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Auer
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Shuo
authors.initials: S
authors.lastname: Jiao
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Haessler
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
authors.affiliation: Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Carlson
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Cara L
authors.initials: CL
authors.lastname: Carty
authors.affiliation: Los Angeles Biomedical Research Institute, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA.
authors.forename: Yii-Der Ida
authors.initials: YD
authors.lastname: Chen
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Curtis
authors.affiliation: Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, Chapel Hill, NC, USA.
authors.forename: Nora
authors.initials: N
authors.lastname: Franceschini
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Hsu
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Jackson
authors.affiliation: Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Lange
authors.affiliation: Medicine, Montreal Heart Institute and Université de Montréal, Montreal, QC, Canada.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lettre
authors.affiliation: Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, Chapel Hill, NC, USA.
authors.forename: Keri L
authors.initials: KL
authors.lastname: Monda
authors.affiliation: School of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Alex P
authors.initials: AP
authors.lastname: Reiner
authors.affiliation: Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA, USA.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rich
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Rosse
authors.affiliation: Los Angeles Biomedical Research Institute, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA.
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.affiliation: Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Cristen J
authors.initials: CJ
authors.lastname: Willer
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA and.
authors.forename: James G
authors.initials: JG
authors.lastname: Wilson
authors.affiliation: Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, Chapel Hill, NC, USA.
authors.forename: Kari
authors.initials: K
authors.lastname: North
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Kooperberg
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Heard-Costa
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA, mdu@fhcrc.org.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Peters
mesh_terms: D000328:Adult; D001741:Black or African American; D000368:Aged; D000483:Alleles; D001827:Body Height / Q000235:genetics*; D002882:Chromosomes, Human, Pair 13 / Q000737:chemistry; D002886:Chromosomes, Human, Pair 17 / Q000737:chemistry; D002895:Chromosomes, Human, Pair 5 / Q000737:chemistry; D059472:Exome; D005260:Female; D005787:Gene Frequency; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D019655:Quantitative Trait, Heritable; D044465:White People