Meta-Analysis of Genome-Wide Scans for Human Adult Stature Identifies Novel Loci and Associations with Measures of Skeletal Frame Size

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 = 6.1×10−8 and rs910316 in TMED10, P-value = 1.4×10−7) and two had previously been described with weak statistical support (rs10472828 in NPR3, P-value = 3×10−7 and rs849141 in JAZF1, P-value = 3.2×10−11). 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 = 4×10−5 and rs6817306 in LCORL, P-value = 4×10−4), hip axis length (including rs6830062 at LCORL, P-value = 4.8×10−4 and rs4911494 at UQCC, P-value = 1.9×10−4), and femur length (including rs710841 at PRKG2, P-value = 2.4×10−5 and rs10946808 at HIST1H1D, P-value = 6.4×10−6). 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.Author Summary: The first genetic association studies of adult height have confirmed a role of many common variants in influencing human height, but to date, the genetic basis of differences between different skeletal components of height have not been addressed. Here, we take advantage of recent technical and methodological advances to examine the role of common genetic variants on both height and skeletal components of height. By examining nearly 20,000 individuals from the UK and the Netherlands, we provide statistically significant evidence that 17 genomic regions are associated with height, including four novel regions. We also examine, for the first time, the association of these 17 regions with skeletal size measurements of spine, femur, and hip axis length, a measurement of hip geometry known to influence the risk of osteoporotic fractures. We find that some height loci are also associated with these skeletal components, although further statistical tests will be required to verify if these genetic variants act differentially on the individual skeletal measurements. The knowledge generated by this and other studies will not only inform the genetics of human quantitative variation, but will also lead to the potential discovery of many medically important polymorphisms.