Genome-Wide Copy Number Variation Association Analyses for Age at Menarche

Context: Menarche is a significant physiological event for women. Age at menarche (AAM) is a heritable trait associated with many common female diseases. The genetic basis and the mechanism for AAM are largely unknown. Copy number variation (CNV) is a common type of genetic variation underlying human complex traits. The importance of CNV to AAM variation is unclear. Objective: The objective of the study was to identify CNV important to AAM variation. Design: We performed the first genome-wide CNV study of AAM in 1654 Caucasian females using Affymetrix human single-nucleotide polymorphism 6.0 array. We also replicated our findings in another Chinese cohort containing 752 women. Results: We identified a CNV, variation_38399, in the 2q14.2 region, for association with AAM(P = 1.03 x 10(-3)). The CNV has two variants (one copy and two copy), with a mean AAM of 14.00 yr and 12.90 yr, respectively. Interestingly, in a Chinese sample containing 752 women, this CNV has been replicated both with a marginally significant P = 0.090 and with a same direction of effect (a lower copy number for a later AAM). The CNV is located approximately 75 kb upstream of the diazepam binding inhibitor (DBI), a gene known to regulate estrogen levels, a key factor for menarche. Conclusion: Our findings for the first time identified a novel CNV and suggested the DBI-mediated endocrinological pathway as a potential mechanism for AAM regulation. (J Clin Endocrinol Metab 97: E2133-E2139, 2012)