The investigators propose a unique and powerful collaboration between basic and clinical scientists in Utah to identify genes affecting predisposition to pelvic organ prolapse (POP). The co-PIs both have significant experience, Dr. Norton in Pelvic Floor Disorder (PFD) genetics and Dr. Cannon-Albright in predisposition gene identification. The investigators will access the Utah Population Database, a computerized genealogy of Utah combined with decades of medical data from the two largest healthcare systems in Utah (serving 90% of the state), to identify and recruit surgically treated cases of POP (1,250 cases in 5 years). All POP cases sampled will be genotyped with the Illumina 610Q SNP marker set. The PIs will apply multiple different genetic analyses to this resource of genotyped POP cases to aid in the identification of predisposition genes. The record linkage of medical procedure codes (identifying surgeries performed on each patient) to individual genealogy data allows us to identify all genetic relationships among the POP cases. We will perform genome-wide association analysis, using software we have developed which allows inclusion of both independent and related cases. We will identify all genetic relationships between the sampled POP cases and perform linkage analysis in informative, high-risk POP pedigrees. We will identify chromosomal regions shared Identical by Descent (IBD) in very distantly related cases in these pedigrees, and we will identify IBD sharing within the small subset of POP cases (2%) who are inbred. Initial collaborative analysis of data obtained by Dr. Norton's NIH funded study of affected PFD sib-ships has already provided significant evidence for a predisposition gene localization on chromosome arm 9q, and suggestive evidence for at least one other locus on chromosome 1. In summary, we will create a population-based resource of surgically treated POP cases, we will pursue established and new methods to identify and localize predisposition genes affecting POP, and we will begin a detailed search for the chromosome 9 gene we have localized.
This research has a major potential to affect public health in the prevention of PFDs: we may be able to identify high risk populations who can be identified at a young age, studied and possibly targeted for prevention;and at a later stage in the development of PFDs, special interventions can be studied and possibly implemented in women at risk for recurrence of their condition. Someday, identification of these high risk populations may be as general as familial risk, or as specific as specific gene screening.
|Allen-Brady, Kristina; Cannon-Albright, Lisa A; Farnham, James M et al. (2015) Evidence for pelvic organ prolapse predisposition genes on chromosomes 10 and 17. Am J Obstet Gynecol 212:771.e1-7|
|Allen-Brady, Kristina; Norton, Peggy A; Cannon-Albright, Lisa (2015) Risk of associated conditions in relatives of subjects with interstitial cystitis. Female Pelvic Med Reconstr Surg 21:93-8|
|Norton, Peggy A; Allen-Brady, K; Wu, J et al. (2015) Clinical characteristics of women with familial pelvic floor disorders. Int Urogynecol J 26:401-6|
|Norton, Peggy A; Allen-Brady, Kristina; Cannon-Albright, Lisa A (2013) The familiality of pelvic organ prolapse in the Utah Population Database. Int Urogynecol J 24:413-8|
|Wu, Jennifer M; Ward, Renée M; Allen-Brady, Kristina L et al. (2013) Phenotyping clinical disorders: lessons learned from pelvic organ prolapse. Am J Obstet Gynecol 208:360-5|
|Allen-Brady, Kristina; Cannon-Albright, Lisa; Farnham, James M et al. (2011) Identification of six loci associated with pelvic organ prolapse using genome-wide association analysis. Obstet Gynecol 118:1345-53|