Height is a model polygenic trait that is highly heritable. Genome-wide association studies have identified hundreds of single-nucleotide polymorphisms associated with stature, but the role of structural variation in determining height is largely unknown. We performed a genome-wide association study of copy-number variation and stature in a clinical cohort of children who had undergone comparative genomic hybridization (CGH) microarray analysis for clinical indications. We found that subjects with short stature had a greater global burden of copy-number variants (CNVs) and a greater average CNV length than did controls (p < 0.002). These associations were present for lower-frequency (<5%) and rare (<1%) deletions, but there were no significant associations seen for duplications. Known gene-deletion syndromes did not account for our findings, and we saw no significant associations with tall stature. We then extended our findings into a population-based cohort and found that, in agreement with the clinical cohort study, an increased burden of lower-frequency deletions was associated with shorter stature (p = 0.015). Our results suggest that in individuals undergoing copy-number analysis for clinical indications, short stature increases the odds that a low-frequency deletion will be found. Additionally, copy-number variation might contribute to genetic variation in stature in the general population.
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We would like to thank Guillaume Lettre and the CARe anthropometric working group for generating the height Z scores for the CARe cohort. We would like to thank Steve McCaroll, Joshua Korn, and James Nemesh for their assistance in calling the CNVs in the CARe cohorts. Funding for the work with the clinical cohort was supported by the March of Dimes 6-FY09-507 (J.N.H.), by the National Basic Research Program of China (973 Program) (2010CB529601) (B.L.W.), and by the Science and Technology Council of Shanghai (09JC1402400 and 09ZR1404500) (B.L.W.).