Whole-exome imputation of sequence variants identified two novel alleles associated with adult body height in African Americans

Mengmeng Du; Paul L Auer; Shuo Jiao; Jeffrey Haessler; David Altshuler; Eric Boerwinkle; Christopher S Carlson; Cara L Carty; Yii-Der Ida Chen; Keith Curtis; Nora Franceschini; Li Hsu; Rebecca Jackson; Leslie A Lange; Guillaume Lettre; Keri L Monda; National Heart, Lung, and Blood Institute (NHLBI) GO Exome Sequencing Project; Deborah A Nickerson; Alex P Reiner; Stephen S Rich; Stephanie A Rosse; Jerome I Rotter; Cristen J Willer; James G Wilson; Kari North; Charles Kooperberg; Nancy Heard-Costa; Ulrike Peters

doi:10.1093/hmg/ddu361

Whole-exome imputation of sequence variants identified two novel alleles associated with adult body height in African Americans

Hum Mol Genet. 2014 Dec 15;23(24):6607-15. doi: 10.1093/hmg/ddu361. Epub 2014 Jul 15.

Authors

Mengmeng Du¹, Paul L Auer², Shuo Jiao³, Jeffrey Haessler³, David Altshuler⁴, Eric Boerwinkle⁵, Christopher S Carlson³, Cara L Carty³, Yii-Der Ida Chen⁶, Keith Curtis³, Nora Franceschini⁷, Li Hsu³, Rebecca Jackson⁸, Leslie A Lange⁹, Guillaume Lettre¹⁰, Keri L Monda⁷; National Heart, Lung, and Blood Institute (NHLBI) GO Exome Sequencing Project; Deborah A Nickerson¹¹, Alex P Reiner³, Stephen S Rich¹², Stephanie A Rosse³, Jerome I Rotter⁶, Cristen J Willer¹³, James G Wilson¹⁴, Kari North⁷, Charles Kooperberg³, Nancy Heard-Costa¹⁵, Ulrike Peters¹⁶

Affiliations

¹ 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, [email protected].
² 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.
³ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁴ Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
⁵ Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁶ Los Angeles Biomedical Research Institute, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA.
⁷ Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, Chapel Hill, NC, USA.
⁸ Division of Endocrinology, Diabetes and Metabolism, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
⁹ Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
¹⁰ Medicine, Montreal Heart Institute and Université de Montréal, Montreal, QC, Canada.
¹¹ School of Medicine, University of Washington, Seattle, WA, USA.
¹² Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA, USA.
¹³ Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA.
¹⁴ Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA and.
¹⁵ Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
¹⁶ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA, [email protected].

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Adult
Aged
Alleles*
Black or African American*
Body Height / genetics*
Chromosomes, Human, Pair 13 / chemistry
Chromosomes, Human, Pair 17 / chemistry
Chromosomes, Human, Pair 5 / chemistry
Exome*
Female
Gene Frequency
Genetic Loci*
Genome-Wide Association Study
Humans
Male
Middle Aged
Quantitative Trait, Heritable*
White People

Abstract

Publication types

MeSH terms

Grants and funding