title: Genome-wide association of copy-number variation reveals an association between short stature and the presence of low-frequency genomic deletions.
abstract: 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.
authors: Division of Endocrinology, Children's Hospital Boston, Boston, MA 02115, USA.
authors: Andrew
authors: A
authors: Dauber
authors: Yongguo
authors: Y
authors: Yu
authors: Michael C
authors: MC
authors: Turchin
authors: Charleston W
authors: CW
authors: Chiang
authors: Yan A
authors: YA
authors: Meng
authors: Ellen W
authors: EW
authors: Demerath
authors: Sanjay R
authors: SR
authors: Patel
authors: Stephen S
authors: SS
authors: Rich
authors: Jerome I
authors: JI
authors: Rotter
authors: Pamela J
authors: PJ
authors: Schreiner
authors: James G
authors: JG
authors: Wilson
authors: Yiping
authors: Y
authors: Shen
authors: Bai-Lin
authors: BL
authors: Wu
authors: Joel N
authors: JN
authors: Hirschhorn
mesh_terms: D000293:Adolescent; D001827:Body Height / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D056915:DNA Copy Number Variations; D005260:Female; D017353:Gene Deletion; D020440:Gene Duplication; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D020412:Multifactorial Inheritance; D055815:Young Adult