Uterine leiomyomata and decreased height: a common HMGA2 predisposition allele.

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.