Neurourology and Urodynamics 29:609–611 (2010) REVIEW ARTICLE Genetics and the Lower Urinary Tract Peggy Norton 1 and Ian Milsom 2 1 UniversityofUtah,SchoolofMedicine,SaltLakeCity,Utah 2 DepartmentofObstetricsandGynaecology,SahlgrenskaUniversityHospital,Goteberg,Sweden Manycomplexdisordershavebeenfoundtohaveaheritablecomponent,includinglowerurinarytractdysfunction.Twin studies have indicated that genetic contributions to urinary incontinence (UI) may be as important as environmental influences. Linkage to chromosome 9 has been demonstrated in families with pelvic organ prolapse and stress UI. An increasing number of incontinence specialists are studying subjects with lower urinary tract dysfunction using single nucleotidepolymorphisms,linkageanalysesofsiblings,andlargeassociationstudies.Thesefindingshaveexcitingimpli- cations for future prevention and treatment of UI. Neurourol. Urodynam. 29:609–611, 2010. © 2010 Wiley-Liss, Inc. Key words: genetics; LUTS; pelvic organ prolapse INTRODUCTION The etiology of lower urinary tract disorders is still largely unknown but likely to be multifactorial. 1 Genetic studies in other complex diseases whose etiologies were unknown have led to important discoveries (Burton, 2003). Similarly, identifi- cationofgeneticcontributionstourinaryincontinence(UI)and related disorders could result in new preventative approaches, earlierintervention,andbettertreatmentsfortheseconditions. Riskfactorsforpelvicfloordisorderstypicallyfocusondefects inpelvicfloormuscles,nerves,andconnectivetissue.Childbirth is the risk factor that has been studied most, but while vagi- nal delivery increases the risk of UI, cesarean delivery is not entirely protective (Rortveit, 2005). Some environmental risk factors have been identified such as occupational lifting, but taken in whole these risk factors fail to fully explain the patho- physiology of lower urinary tract disorders. For example, why might stress urinary incontinence (SUI) develop in nulliparous women, while other highly parous women do not develop SUI? Lackofknowledgeabouttheetiologyoflowerurinarytractdis- orders has limited further development of our understanding and management of these common conditions. While earlier discoveries of genetic-based diseases were Mendelian in nature (single gene autosomal dominant or recessive), genetic epidemiology has found that complex dis- eases such as diabetes mellitus, obesity, ischemic heart disease, asthma, and many cancers have a genetic basis due to interac- tions between multiple genes (Burton, 2003). In common with lower urinary tract disorders, these conditions were known to bemultifactorialandwerenotconsideredtobefamilialinmany cases. We review here the evidence for a genetic basis in lower urinary tract symptoms. FAMILYANDTWINSTUDIES Nocturnal enuresis has been recognized as an autosomal dominant condition with 90% penetrance (Djurhuus, 2002) The earliest studies of familial contributions to UI interviewed affected women about the presence of similar symptoms in female family members, but this technique has considerable ascertainment bias. 2 The EPINCONT study in Norway found that women are more likely to develop UI if their mothers or older sisters have UI. 3 Buchsbaum et al. 4 studied nulliparous Catholic nuns and their parous sisters, and found that while childbirth had no association with the development of UI after menopause, there was high concordance between sisters in their continence status, suggesting that an underlying familial predispositiontowardthedevelopmentofUImaybepresent. It is, however, a common misunderstanding that famil- ial aggregation invariably is a result of genetic factors. Risk estimates derived from family members in most cases cannot distinguish between heritability and non-inherited (environmental) factors in the family environment. Famil- ial environmental influences may have a direct effect on the transmission of risk for UI, and include smoking habits, socio-economicstatus,careseekingbehavior,attitudestowards physical exercise, dietary and drinking habits, and toilet train- ing. By comparing monozygotic twins with identical genotype (share 100% of genes), and dizygotic twins who on average share50%oftheirsegregatinggenes,therelativeproportionsof phenotypic variance resulting from genetic and environmental factorscanbeestimated.Ifmonozygotictwinsaremoreconcor- dant for the condition than dizygotic twins, a genetic influence islikely;discordantmonozygotictwinspointstoenvironmental factors when compared to dizygotic twins. Up to half of urgency incontinence was found to be genetic in a study from the Danish twin registry. 5 In the larger Swedishtwinregistryof3,376monozygoticand5,067dizygotic female twin pairs, there was greater twin similarity among the monozygotictwins,indicatingageneticcomponentforSUIand ConflictofInterest:Dr.Milsom:Consultant,Researchgrant-Astellas,Pfizer,Speaker honorarium-Astellas, Pfizer, Recordati Christopher Chapple led the review process. * Correspondenceto:Dr.PeggyNorton,Room2B200UUMC,50N.MedicalDrive,Salt LakeCity,UT84132.E-mail:peggy.norton@hsc.utah.edu Received10January2010;Accepted5February2010 Published online 15 May 2010 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/nau.20908 © 2010 Wiley-Liss, Inc.