Abstract
Genetic factors contribute to risk for many common traits and diseases affecting reproduction and fertility. We have used genome-wide association (GWA) studies to understand the genetic architecture and discover genomic regions associated with risk for endometriosis, dizygotic twinning, age at menarche and age at menopause. The next steps are to determine how DNA sequence variation alters regulation and/or function of specific genes and pathways to increase disease risk. Multiple approaches are required to interpret the genetic association results, identify the specific genes likely to be responsible, and obtain the necessary genomic evidence connecting the genetic results to the target genes. Strategies include fine mapping, functional annotation, genomics, and target gene identification through gene expression, epigenetics, and cell-based studies to define direct interactions between causal single nucleotide polymorphisms (SNPs) and target genes. GWA and replication studies have identified seven genomic regions with strong evidence for association with endometriosis risk. The target tissue for functional effects is not known, but current theories suggest changes in the endometrium. We are conducting studies of gene expression and epigenetic regulation in samples of endometrium in carriers of the risk alleles. Development of applications to use GWA data for risk prediction and studies of comorbidity also provide valuable insights into the genetic architecture of endometriosis and overlap in risk with other conditions such as ovarian cancer. Multidisciplinary studies combining genetics, genomics, functional biology, and clinical research will be essential better understand disease biology and translate the new knowledge into better outcomes for patients.