Defining the role of common variation in the genomic and biological architecture of adult human height

Abstract

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

Figure 1. Regional association plots for loci with multiple association signals

Panels a to d highlight examples of multiple signals after approximate conditional joint multiple-SNP analysis GCTA-COJO analysis. SNPs are shaded and shaped based on the index SNP with which they are in strongest LD (r²>0.4). Panels a–c show the majority of signals clustering in and around a single gene (ACAN, ADAMTS17, PTCH1, respectively) whereas panel d shows the multiple signals clustering through proximity.

Figure 2. Quantifying the variance explained by height associated SNPs at different levels of significance

The SNPs were selected from the approximate conditional and joint multiple SNPs association analysis using GCTA-COJO analysis with the target cohort being excluded from the meta-analysis. a, b, c, Partitioning the variance in the SNP-derived genetic predictor using a within-family analysis. The SNP-based predictor was adjusted by the first 20 PCs. The four variance-covariance components V_g, V_e, C_g and C_e are defined in Online Methods. d, Accuracy of predicting phenotype by the genetic predictor in unrelated individuals. The prediction R² shown on the y-axis is the squared correlation between phenotype and predictor. The SNP-based predictor was adjusted by the first 20 PCs. The solid line is the average prediction R² weighted by sample size over the five cohorts. The dashed line is the prediction accuracy inferred from the within-family prediction analysis (Equation 19 in Online Methods). e, The variance explained by the SNPs was estimated by the whole-genome estimation method in GCTA. The phenotype was adjusted by the first 20 PCs. Each error bar represents the standard error of the estimate. The estimates from all the five cohorts (B-PROOF, FRAM, QIMR, TwinGene and WTCCC-T2D) were averaged by the inverse-variance approach. The dashed line is the variance explained inferred from the within-family prediction analysis. In panels d and e, the number shown in each column is the number of SNPs used in the analysis.

Figure 3. Tissue enrichment combined with pruned gene set network

Genes within genome-wide significant height associated loci enriched for several relevant tissue annotations as well as gene sets. a, Genes in associated loci tended to be highly expressed in tissues related to chondrocytes and osteoblasts (cartilage, joints, and spine), and other musculoskeletal, cardiovascular and endocrine tissue-types. The analysis was conducted based on the DEPICT method and 37,427 human microarray samples. Tissue annotations are sorted by physiological system and significance. Significantly enriched (FDR<0.05) tissues are color-coded in black. b, Significantly enriched reconstituted gene sets (P-value<1×10⁻¹¹, FDR<1×10⁻⁵) identified by DEPICT. Nodes represent reconstituted gene sets and are color-coded by statistical significance. Edge thickness between nodes is proportional to degree of gene overlap as measured by the Jaccard index. Nodes with gene overlap greater than 25% were collapsed into single meta nodes and marked by blue borders. c, reconstituted gene sets comprised by the Chordate Embryonic Development meta node, which represented several gene sets relevant to human height (e.g. ossification, embryonic skeletal system development, and limb development).