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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 &lt;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% &lt; MAF &lt; 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  &lt; 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  &lt; 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 &lt;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.

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