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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, ? = 0.64 cm, P = 8.3E-08), 13q14.2/SPRYD7/rs114089985 (MAF = 0.03, ? = 1.46 cm, P = 4.8E-10) and 17q23.3/GH2/rs2006123 (MAF = 0.30; ? = 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.

SUBMITTER: Du M

PROVIDER: S-EPMC4240196 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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

Du Mengmeng M Auer Paul L PL Jiao Shuo S Haessler Jeffrey J Altshuler David D Boerwinkle Eric E Carlson Christopher S CS Carty Cara L CL Chen Yii-Der Ida YD Curtis Keith K Franceschini Nora N Hsu Li L Jackson Rebecca R Lange Leslie A LA Lettre Guillaume G Monda Keri L KL Nickerson Deborah A DA Reiner Alex P AP Rich Stephen S SS Rosse Stephanie A SA Rotter Jerome I JI Willer Cristen J CJ Wilson James G JG North Kari K Kooperberg Charles C Heard-Costa Nancy N Peters Ulrike U

Human molecular genetics 20140715 24

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 ...[more]

PMID: 25027330

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Project description:Imputation of genome-wide single-nucleotide polymorphism (SNP) arrays to a larger known reference panel of SNPs has become a standard and an essential part of genome-wide association studies. However, little is known about the behavior of imputation in African Americans with respect to the different imputation algorithms, the reference population(s) and the reference SNP panels used. Genome-wide SNP data (Affymetrix 6.0) from 3207 African American samples in the Atherosclerosis Risk in Communities Study (ARIC) was used to systematically evaluate imputation quality and yield. Imputation was performed with the imputation algorithms MACH, IMPUTE and BEAGLE using several combinations of three reference panels of HapMap III (ASW, YRI and CEU) and 1000 Genomes Project (pilot 1 YRI June 2010 release, EUR and AFR August 2010 and June 2011 releases) panels with SNP data on chromosomes 18, 20 and 22. About 10% of the directly genotyped SNPs from each chromosome were masked, and SNPs common between the reference panels were used for evaluating the imputation quality using two statistical metrics-concordance accuracy and Cohen's kappa (?) coefficient. The dependencies of these metrics on the minor allele frequencies (MAF) and specific genotype categories (minor allele homozygotes, heterozygotes and major allele homozygotes) were thoroughly investigated to determine the best panel and method for imputation in African Americans. In addition, the power to detect imputed SNPs associated with simulated phenotypes was studied using the mean genotype of each masked SNP in the imputed data. Our results indicate that the genotype concordances after stratification into each genotype category and Cohen's ? coefficient are considerably better equipped to differentiate imputation performance compared with the traditionally used total concordance statistic, and both statistics improved with increasing MAF irrespective of the imputation method. We also find that both MACH and IMPUTE performed equally well and consistently better than BEAGLE irrespective of the reference panel used. Of the various combinations of reference panels, for both HapMap III and 1000 Genomes Project reference panels, the multi-ethnic panels had better imputation accuracy than those containing only single ethnic samples. The most recent 1000 Genomes Project release June 2011 had substantially higher number of imputed SNPs than HapMap III and performed as well or better than the best combined HapMap III reference panels and previous releases of the 1000 Genomes Project.

Dataset Information

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

Publications

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

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