Meta-analysis of genome-wide association studies of adult height in East Asians identifies 17 novel loci

Abstract

Human height is associated with risk of multiple diseases and is profoundly determined by an individual's genetic makeup and shows a high degree of ethnic heterogeneity. Large-scale genome-wide association (GWA) analyses of adult height in Europeans have identified nearly 180 genetic loci. A recent study showed high replicability of results from Europeans-based GWA studies in Asians; however, population-specific loci may exist due to distinct linkage disequilibrium patterns. We carried out a GWA meta-analysis in 93 926 individuals from East Asia. We identified 98 loci, including 17 novel and 81 previously reported loci, associated with height at P < 5 × 10(-8), together explaining 8.89% of phenotypic variance. Among the newly identified variants, 10 are commonly distributed (minor allele frequency, MAF > 5%) in Europeans, with comparable frequencies with in Asians, and 7 single-nucleotide polymorphisms are with low frequency (MAF < 5%) in Europeans. In addition, our data suggest that novel biological pathway such as the protein tyrosine phosphatase family is involved in regulation of height. The findings from this study considerably expand our knowledge of the genetic architecture of human height in Asians.

Figure 1.

The 98 loci associated with adult height in East Asians. The genome location of the 17 novel loci (in red) and 81 previously reported loci (in green) was shown by each chromosome. The chromosome numbers were shown in blue. The figure was created by using Affymation (http://genepipe.ngc.sinica.edu.tw/mkr/menu.do).

Figure 2.

The frequencies of the 10 newly identified SNPs with MAF > 5% in Asians and Europeans.

Figure 3.

Regional association plots for newly identified locus FADS1-FADS2 cluster. SNPs are plotted by their position on the chromosome against their association (−log₁₀ P) with adult height using Stage 1 (GWAS meta-analysis) data. The names are shown for the top SNPs (purple triangle), which were selected on the basis of combined data from all the studies (Table 1). The P-value in Stage 1 for the same SNP is denoted by a purple circle. Estimated recombination rates (from HapMap) are plotted in cyan to reflect the local LD structure. The SNPs surrounding the top SNP are colored to reflect their LD with the top SNP [using pairwise r² values from HapMap Han Chinese in Beijing (CHB) and Japanese in Tokyo (JPT) data]. Blue arrows indicate SNPs that were highly linkage disequilibrium with the top height SNP rs174547 (r² = 1.0) and their association with other biomedical traits or diseases. The positions of genes and exons, as well as the direction of transcription, are shown below the plots (using data from the UCSC Genome Browser). Plots were generated using LocusZoom.