Genome-wide Association of Copy-Number Variation Reveals an Association between Short Stature and the Presence of Low-Frequency Genomic Deletions

• Published in: American journal of human genetics Vol. 89; no. 6; pp. 751 - 759
• Main Authors: Dauber, Andrew, Yu, Yongguo, Turchin, Michael C., Chiang, Charleston W., Meng, Yan A., Demerath, Ellen W., Patel, Sanjay R., Rich, Stephen S., Rotter, Jerome I., Schreiner, Pamela J., Wilson, James G., Shen, Yiping, Wu, Bai-Lin, Hirschhorn, Joel N.
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 09.12.2011; Cell Press; Elsevier
• Subjects: Adolescent; Biological and medical sciences; Biological variation; Body Height - genetics; Child; Child, Preschool; Cohort Studies; DNA Copy Number Variations; Female; Fundamental and applied biological sciences. Psychology; Gene Deletion; Gene Duplication; Gene Frequency; General aspects. Genetic counseling; Genetic disorders; Genetics of eukaryotes. Biological and molecular evolution; Genome-Wide Association Study; Genomics; Humans; Male; Medical genetics; Medical sciences; Molecular and cellular biology; Multifactorial Inheritance; Polymorphism; Young Adult; Chromosomal aberration; Human; Association; Copy number; Deletion; Variations; Genetics; Genome; Low frequency; Growth retardation
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2011.10.014

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.