Genome-wide association analysis in a 23andMe cohort identifies novel associations with uterine fibroids. A. S. Shmygelska, N. K. Eriksson, J. Y. Tung, J. L. Mountain, U. Francke, A. K. Kiefer, D. A. Hinds 23andMe Inc., Mountain View, CA.

   Uterine leilomyomata, commonly known as uterine fibroids, are benign tumors derived from smooth muscle and fibrous tissue in the uterus, and are the leading cause of hysterectomy in the United States. The lifetime risk for a woman to develop fibroids has been estimated to be as high as 25%. Fibroids tend to grow under the influence of estrogen and shrink when estrogen levels are reduced. The underlying causes of uterine fibroids are not well understood, but twin studies suggest that approximately 55% of the variation in susceptibility to fibroids is genetic. To investigate the genetic factors underlying uterine fibroids, we conducted a genome-wide association study (GWAS) of over 4,000 cases and 12,000 controls of unrelated individuals with European ancestry from the 23andMe cohort. We imputed genotypes against 1000 Genomes reference haplotypes. Participants reported via a web-based survey whether or not they had had uterine fibroids. We report one novel genome-wide association and four suggestive associations. The most significant finding is a variant in the spectrin repeat containing nuclear envelope 1 (SYNE1) gene (rs71575922: odds ratio=1.3, p = 4.8 x 10-10), which is 18 kbp upstream of the ESR1 gene that encodes estrogen receptor alpha. Variants in ESR1 have been previously shown to be associated with breast and endometrial cancer. SYNE1 is expressed in skeletal and smooth muscle, and peripheral blood lymphocytes, and localizes to the nuclear membrane. Other suggestive associations include (1) the lipoprotein(a) (LPA) gene (rs1800769: odds ratio=1.2, p=8.8x 10-7), which has been shown to promote smooth muscle cells proliferation in transgenic rabbits and (2) the rs12789861 variant (odds ratio=0.9, p=6.7x 10-7) 40 kbp downstream of the Wilms tumor protein (WT1), whose product interacts with the estrogen receptor alpha in breast cancer cells, and downstream of the reticulocalbin 1 (RCN1) gene which is involved in muscle development and tumorigenesis. We also detect an association between uterine fibroids and the recoverin (RCVRN) gene (rs6503269: odds ratio=1.2, p=4.4x 10-7) that appears non causal. RCVRN encodes a neuronal calcium sensor that plays role in the phototransduction cascade in the retina and is implicated in endometrial cancer associated retinopathy. In our European cohort we replicate two of the three previously identified associations reported in women of Japanese ancestry, however, not on the genome-wide significance level.

You may contact the first author (during and after the meeting) at