Abstract
Uterine leiomyomata (UL) are the most common female pelvic tumors and the primary indication for hysterectomy in the United States. We assessed genetic liability for UL by a known embryonic proliferation modulator, HMGA2, in 248 families ascertained through medical record-confirmed affected sister-pairs. Using a (TC)( n ) repeat in the 5' UTR and 17 SNPs spanning HMGA2, permutation-based association tests identified a significant increase in transmission of a single TC repeat allele (TC227) with UL (allele-specific P = 0.00005, multiple testing corrected min-P = 0.0049). The hypothesis that TC227 is a pathogenic variant is supported by a trend towards higher HMGA2 expression in TC227 allele-positive compared with non-TC227 UL tissue as well as by absence of culpable exonic sequence variants. HMGA2 has also been suggested recently by three genome-wide SNP studies to influence human height variation, and our examination of the affected sister-pair families revealed a significant association of TC227 with decreased height (allele-specific P = 0.00033, multiple testing corrected min-P = 0.016). Diminished stature and elevated risk of UL development have both been correlated with an earlier age of menarche, which may be the biological mechanism for TC227 effects as a tendency of women with TC227 to have an earlier onset of menarche was identified in our study population. These results indicate HMGA2 has a role in two growth-related phenotypes, UL predisposition and height, of which the former may affect future medical management decisions for many women.