Genetics of skeletal proportions across two different populations

Human height can be divided into sitting height and leg length. These measures reflect the growth of different parts of the skeleton whose relative proportions are captured by the ratio of sitting to total height (the sitting height ratio [SHR]). Height is a highly heritable trait, and its genetic basis has been well studied. However, the genetic determinants of skeletal proportion are much less well characterized. Expanding substantially on past work, we performed a genome-wide association study (GWAS) of the SHR in ∼450,000 individuals with European ancestry and ∼100,000 individuals with East Asian ancestry from the UK and China Kadoorie Biobanks, respectively. We identified 565 loci independently associated with the SHR, including all genomic regions implicated in prior GWASs in these ancestries. While SHR loci significantly overlap height-associated loci (p < 0.001), the fine-mapped SHR signals are often distinct from height signals. We also used fine-mapped signals to identify 36 credible sets with heterogeneous effects across ancestries. Lastly, we used the SHR, sitting height, and leg length to identify genetic variation acting on specific body regions rather than on overall human height.