Meta-analysis of genome-wide scans for human adult stature identifies novel Loci and associations with measures of skeletal frame size

Abstract

Recent genome-wide (GW) scans have identified several independent loci affecting human stature, but their contribution through the different skeletal components of height is still poorly understood. We carried out a genome-wide scan in 12,611 participants, followed by replication in an additional 7,187 individuals, and identified 17 genomic regions with GW-significant association with height. Of these, two are entirely novel (rs11809207 in CATSPER4, combined P-value = 6.1x10(-8) and rs910316 in TMED10, P-value = 1.4x10(-7)) and two had previously been described with weak statistical support (rs10472828 in NPR3, P-value = 3x10(-7) and rs849141 in JAZF1, P-value = 3.2x10(-11)). One locus (rs1182188 at GNA12) identifies the first height eQTL. We also assessed the contribution of height loci to the upper- (trunk) and lower-body (hip axis and femur) skeletal components of height. We find evidence for several loci associated with trunk length (including rs6570507 in GPR126, P-value = 4x10(-5) and rs6817306 in LCORL, P-value = 4x10(-4)), hip axis length (including rs6830062 at LCORL, P-value = 4.8x10(-4) and rs4911494 at UQCC, P-value = 1.9x10(-4)), and femur length (including rs710841 at PRKG2, P-value = 2.4x10(-5) and rs10946808 at HIST1H1D, P-value = 6.4x10(-6)). Finally, we used conditional analyses to explore a possible differential contribution of the height loci to these different skeletal size measurements. In addition to validating four novel loci controlling adult stature, our study represents the first effort to assess the contribution of genetic loci to three skeletal components of height. Further statistical tests in larger numbers of individuals will be required to verify if the height loci affect height preferentially through these subcomponents of height.

Figure 1. Association with gene expression in the GNA12 region.

(A) P-values, expressed on the −log10 scale, for associations with adult height (red) and gene expression measured at probes specific for GNA12 (blue) and LOC392620 (magenta) within the 370-Kb recombination interval surrounding the lead SNP rs1182188. (B) Association signal with height in the 1 MB interval surrounding the lead SNP. The red dot indicates the association P-value for the lead SNP rs1182188 in the discovery GWAS+EPIC sample (n = 12,611 individuals), the blue dot indicates the meta-analysis P-value after replication. Red diamonds indicate high LD with the lead SNP (r²>0.8), orange diamonds indicate moderate LD with the lead SNP (0.5<r²<0.8), yellow indicates markers in weak LD with the lead SNP (0.2<r²<0.5), white indicates either no LD with the lead SNP (r²<0.2), or loci where such information was not available.