Identification, replication, and fine-mapping of Loci associated with adult height in individuals of african ancestry

Abstract

Adult height is a classic polygenic trait of high heritability (h(2) approximately 0.8). More than 180 single nucleotide polymorphisms (SNPs), identified mostly in populations of European descent, are associated with height. These variants convey modest effects and explain approximately10% of the variance in height. Discovery efforts in other populations, while limited, have revealed loci for height not previously implicated in individuals of European ancestry. Here, we performed a meta-analysis of genome-wide association (GWA) results for adult height in 20,427 individuals of African ancestry with replication in up to 16,436 African Americans. We found two novel height loci (Xp22-rs12393627, P = 3.4×10(-12) and 2p14-rs4315565, P = 1.2×10(-8)). As a group, height associations discovered in European-ancestry samples replicate in individuals of African ancestry (P = 1.7×10(-4) for overall replication). Fine-mapping of the European height loci in African-ancestry individuals showed an enrichment of SNPs that are associated with expression of nearby genes when compared to the index European height SNPs (P<0.01). Our results highlight the utility of genetic studies in non-European populations to understand the etiology of complex human diseases and traits.

Figure 1. Quantile–quantile (QQ) plot of the meta-analysis with up to 3.3 M SNPs across 9 studies (N = 20,427).

Each black circle represents an observed statistic for genotyped SNPs only (defined as the −log₁₀ P) against the corresponding expected statistic. The grey area corresponds to the 90% confidence intervals calculated empirically using permutations. The individual studies' inflation factors, as well as the inflation factor of the meta-analysis, were corrected using genomic control. The inflation factor of the meta-analysis is λ_GC = 1.064.

Figure 2. SNPs are plotted using LocusZoom by position on the chromosome against association with adult height (−log₁₀ P).

The SNP name shown on the plot was the most significant SNP after the discovery meta-analysis. Estimated recombination rates (from HapMap) are plotted in cyan to reflect the local LD structure. The SNPs surrounding the most significant SNP are color coded to reflect their LD with this SNP (taken from pairwise r ² values from the ARIC African Americans Affymetrix6.0 dataset for rs1239627 (A) and from the HapMap YRI data for rs4315565 (B)). The size of the points on the plots is proportional to the number of individuals with available genotype for any given SNP. Genes, the position of exons and the direction of transcription from the UCSC genome browser are noted. Hashmarks represent SNP positions available in the meta-analysis.

Figure 3. Height association results.

In Europeans from the GIANT Consortium (A) and in individuals of African ancestry (B) (this study) at the LCORL locus on chromosome 4. The GIANT Consortium originally reported SNP rs6449353, whereas rs7663818 was fine-mapped in the African height meta-analysis. For each panel, the light blue box corresponds to the chromosomal interval flanked by the leftmost and rightmost SNPs with a r ²≥0.8 with rs7663818 in HapMap CEU (A) and YRI (B) participants: these intervals are 250 kb and 80 kb wide in CEU and YRI, respectively.