Genetics of Skeletal Proportions in Two Different Populations

Abstract

Human height can be divided into sitting height and leg length, reflecting growth of different parts of the skeleton whose relative proportions are captured by the ratio of sitting to total height (as 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 SHR in ~450,000 individuals with European ancestry and ~100,000 individuals with East Asian ancestry from the UK and China Kadoorie Biobanks. We identified 565 loci independently associated with SHR, including all genomic regions implicated in prior GWAS in these ancestries. While SHR loci largely overlap height-associated loci (P < 0.001), the fine-mapped SHR signals were often distinct from height. We additionally used fine-mapped signals to identify 36 credible sets with heterogeneous effects across ancestries. Lastly, we used SHR, sitting height, and leg length to identify genetic variation acting on specific body regions rather than on overall human height.

Note:

Funding Information: This work was funded in part by NIH awards T32 HG002295 and R01DK075787. The CKB baseline survey and the first re-survey were supported by the Kadoorie Charitable Foundation in Hong Kong. Long-term follow-up was supported by the Wellcome Trust (212946/Z/18/Z, 202922/Z/16/Z, 104085/Z/14/Z, 088158/Z/09/Z), the National Natural Science Foundation of China (82192901, 82192904, 82192900), and the National Key Research and Development Program of China (2016YFC0900500). DNA extraction and genotyping was funded by GlaxoSmithKline and the UK Medical Research Council (MC-PC-13049, MC-PC-14135). The project is supported by core funding from the UK Medical Research Council (MC_UU_00017/1,MC_UU_12026/2, MC_U137686851), Cancer Research UK (C16077/A29186; C500/A16896), and the British Heart Foundation (CH/1996001/9454) to the Clinical Trial Service Unit and Epidemiological Studies Unit and to the MRC Population Health Research Unit at Oxford University.

Declaration of Interests: Joel Hirschhorn holds equity for Camp4Therapeutics. Wei Gan is an employee and share holder at NovoNordisk. Other authors declare no competing interests.

Keywords: sitting height ratio, height, growth, body proportion, GWAS, genome-wide association study, fine-mapping, gene set enrichment analysis, gene prioritization, trans-ancestry, PRS