Genome-wide Analysis of Body Proportion Classifies Height-Associated Variants by Mechanism of Action and Implicates Genes Important for Skeletal Development
Genome-wide Analysis of Body Proportion Classifies Height-Associated Variants by Mechanism of Action and Implicates Genes Important for Skeletal Development
复制标题
DOI：
10.1016/j.ajhg.2015.02.018
复制
发表时间：
2015-05-07
影响因子：
9.8
通讯作者：
Hirschhorn, Joel N.
中科院分区：
文献类型：
--
作者：
Chan, Yingleong;Salem, Rany M.;Hirschhorn, Joel N.
人类身高是一种复合测量指标，反映了腿长、脊柱长度和头长的总和。许多常见的变异会影响总体身高，但这些或其他变异对身高各组成部分（身体比例）的影响在很大程度上仍然未知。我们研究了坐高比（SHR），即坐高与总身高的比值，以在3545名非裔美国人和21590名欧洲血统个体中确定此类影响。我们发现SHR是可遗传的：在欧洲裔美国人和非裔美国人中，分别有26%和39%的SHR总方差可由常见变异来解释，并且全球欧洲血统混合比例在非裔美国人中与SHR呈负相关（r²约为0.03）。六个区域在与SHR的关联上达到了全基因组显著水平（p < 5×10⁻⁸），并且与生物学候选基因重叠，包括TBX2和IGFBP3。我们发现670个与身高相关的变异中有130个与SHR名义上相关（p < 0.05），这比偶然预期的要多（p = 5×10⁻⁴⁰）。在这130个基因座上，增加身高的等位基因与SHR的降低（71个基因座）或升高（59个基因座）相关，这表明不同的身高基因座对腿长或脊柱/头长的影响不成比例。通过DEPICT进行的通路分析显示，影响SHR的身高基因座，尤其是那些影响腿长的基因座，与对SHR无影响的基因座（例如胚胎发育）相比，呈现出不同生物学通路（例如骨/软骨/生长板通路）的富集。这些结果凸显了使用一对相关但正交的表型（在此情况下为SHR和身高）作为棱镜来剖析多基因性状和疾病中遗传关联背后生物学机制的价值。
Human height is a composite measurement, reflecting the sum of leg, spine, and head lengths. Many common variants influence total height, but the effects of these or other variants on the components of height (body proportion) remain largely unknown. We studied sitting height ratio (SHR), the ratio of sitting height to total height, to identify such effects in 3,545 African Americans and 21,590 individuals of European ancestry. We found that SHR is heritable: 26% and 39% of the total variance of SHR can be explained by common variants in European and African Americans, respectively, and global European admixture is negatively correlated with SHR in African Americans (r(2) approximate to 0.03). Six regions reached genome-wide significance (p < 5 x 10(-8)) for association with SHR and overlapped biological candidate genes, including TBX2 and IGFBP3. We found that 130 of 670 height-associated variants are nominally associated (p < 0.05) with SHR, more than expected by chance (p = 5 x 10(-40)). At these 130 loci, the height-increasing alleles are associated with either a decrease (71 loci) or increase (59 loci) in SHR, suggesting that different height loci disproportionally affect either leg length or spine/head length. Pathway analyses via DEPICT revealed that height loci affecting SHR, and especially those affecting leg length, show enrichment of different biological pathways (e.g., bone/cartilage/growth plate pathways) than do loci with no effect on SHR (e.g., embryonic development). These results highlight the value of using a pair of related but orthogonal phenotypes, in this case SHR with height, as a prism to dissect the biology underlying genetic associations in polygenic traits and diseases.