Nocturnal Enuresis in a Nationwide Twin Cohort

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1 Nocturnal Enuresis in a Nationwide Twin Cohort Christer Hublin, 1,2,5 Jaakko Kaprio, 1,3 Markku Partinen, 1,2,5 and Markku Koskenvuo 1,4 (1) The Finnish Twin Cohort, Department of Public Health, University of Helsinki, Helsinki; (2) Haaga Neurological Research Centre, Helsinki; (3) Department of Mental Health and Alcohol Research, National Public Health Institute; (4) Department of Public Health, University of Turku, Turku; (5) Department of Clinical Neurosciences, Helsinki University Central Hospital, Helsinki, Finland Summary: We studied the occurrence of nocturnal enuresis (bedwetting) after the age of 4 years, using a questionnaire in a well-defined population, the Finnish Twin Cohort, which consists of subjects aged years, including 1298 monozygotic and 2419 dizygotic twin pairs. Structural equation modeling techniques were used to estimate variance components to compare different genetic models. Females reported enuresis in childhood often in 3.4% (males in 4.0%) and in 5.7% (8.0%). As adults, females had experienced enuresis weekly in 0.3% (males in 0.2%) and monthly in 0.07% (0.1%). Those who had experienced enuresis in childhood had had at least enuresis as adults in 5.4% of males and in 5.5% of females. Among those who reported they never had experienced enuresis as adults, 70.8% of males and in 77.9% of females had never experienced enuresis in childhood. For enuresis in childhood, the probandwise concordance rate was 0.43 for monozygotic and 0.19 for dizygotic pairs, and in adults 0.25 and 0, respectively. The proportion of total phenotypic variance attributed to genetic influences (due to dominance) was 67% in males (95% confidence interval 57-76%) and 70% in females (61-78%) in childhood enuresis. In conclusion, nocturnal enuresis is common in childhood and rare in adulthood. Our results confirm the central role of genetic liability in enuresis. Key words: Enuresis; parasomnia; genetics; prevalence; twins NOCTURNAL ENURESIS (bedwetting) is characterized by recurrent involuntary micturation that occurs during sleep. 1 It is often classified into primary and secondary types. In primary enuresis, a full urinary continence has never been achieved by the age of 5 years. In secondary enuresis, the child has had at least 3-6 months of dryness. 1 Persistent bedwetting is considered a primary enuretic disorder in the absence of urologic, medical, or psychiatric pathology. 1 The pathologic basis of primary enuresis is largely unknown, but evidence suggests a neurophysiologic maturational delay. In children enuresis occurs always or often in 5% to 20%, and at least in 10% Accepted for publication June, 1998 Address correspondence and reprint requests to Christer Hublin, MD, PhD, Haaga Neurological Research Centre, Mäkipellontie 15, FIN Helsinki, FINLAND to 50%. 2 In young adults, the respective figures are 0% to 2% and 1% to 3%. 2 In adults or elderly subjects, it is rare. 2 At the age of 5 years, the male-to-female ratio is 3:2. 1 Several studies suggest an important role of genetic factors in enuresis. The familial occurrence is well recognized, and 77% of children suffer from enuresis when both parents have been enuretic as children, and 44% when one parent has a positive enuretic history. 1 Inheritance through a single recessive gene has been suspected in children with primary enuresis. 1 Recently, in 11 multicase, mostly threegeneration families with primary nocturnal enuresis, that trait appeared to follow an autosomal dominant mode of inheritance with penetrance above 90%. 3 That study also presents strong evidence of a locus on chromosome 13q. Even more recently, in another study of 392 families, dominant transmission was observed in 43% and an apparent recessive mode of inheritance in 9% of the families. 4 Moreover, analysis of 16 families suggested linkage to 579

2 chromosome 12q in six families and to chromosome 13q in three families. 4 An autosomal dominant mode of inheritance has also been suggested in a multicase family, in which primary nocturnal enuresis co-occurred with urodynamically proven detrusor instability. 5 To our knowledge, there are four previous twin studies. Hallgren 6 found a higher prevalence of nocturnal enuresis among twins than singletons, and also a higher prevalence among dizygotic (DZ) than monozygotic (MZ) twins. Bakwin, 7 on the other hand, reported no significant difference by zygosity, and pairwise concordance was about twice as high in MZ as in DZ twins. In other studies, concordance for nocturnal enuresis has been about two-and-ahalf 8 and seven 9 times higher in MZ compared to DZ twins. Our aim is to study self-report of childhood enuresis after the age of 4 years, and the role of genetic and environmental factors underlying enuresis. MATERIALS AND METHODS The Finnish Twin Cohort and the Study Population The Finnish Twin Cohort was studied first in It consists of like-sexed twin pairs born before In 1990, a questionnaire was mailed to pairs born , with both co-twins resident in Finland in 1987, and twin individuals could be contacted, with a response rate of 77.3% (n=12 502). 11 Mean age was 43.9 years (standard deviation 7.8 and range years). The study population consisted of subjects, who answered the items on enuresis in childhood and as adults (see below). Of these, 3409 were monozygotic (MZ), 7001 like-sexed dizygotic (DZ), and 810 of undetermined zygosity; 54.4% of the subjects were women. The respondents were divided into three age groups: 37.2% were years, 38.6% years, and 24.2% years old. The study was approved by the ethical committee of the Department of Public Health, University of Helsinki. An informed consent was obtained from the respondents. The Questionnaire The frequency of nocturnal enuresis was asked in five categories separately for adulthood ( weekly, once monthly, less often, never, or don t know ) and for childhood after the age of 4 years ( often,, a few times, never or don t know ), later referred to as childhood. This covers the period up to about 15 years of age. We used in our questionnaire non-numerical frequency categories such as often or in assessment of childhood enuresis because it would have been difficult to give exact frequencies for events that occurred decades previously. The complete questionnaire, including 103 multiple-choice questions, is available from the authors. Responses from both co-twins to the question on childhood enuresis were given by 902 MZ (338 male and 564 female) and 1643 DZ (723 male and 920 female) twin pairs, and to the question on enuresis as adult by 1249 MZ (485 male and 764 female) and 2302 DZ (1009 male and 1293 female) twin pairs. Diagnosis of Zygosity Twin zygosity was determined by using the responses of both twins of each pair to two questions on the similarity of appearance at school age (similarly to other large twin samples ). A set of decision rules classified the twin pairs as MZ, DZ, or undetermined zygosity. The questionnaire method of zygosity was validated by studying a subsample with 11 blood markers. 16 The roughly 1:2 ratio of MZ:DZ twins found for older twins in the Finnish Cohort reflects the elevated rate of DZ twinning typical in both Finland and Sweden in the first half of this century. 17 Statistical Methods and Modeling Basic statistics were computed using the SAS program. 18 Twin similarity for categorical traits can be summarized using estimates of concordance. Probandwise concordance rate 19 is the proportion of all probands that belong to concordant pairs. When the number of unaffected twin pairs in the population is known, more sophisticated models can be used to estimate the contribution of genetic factors to a trait. For complex traits, the polygenic multifactorial model 19 is most frequently used. It assumes that there is a normally distributed liability to the trait. When a certain level or a threshold of liability is reached, the trait becomes manifest. Both genetic and environmental factors are assumed to contribute to the liability, and they result from the joint effects of many genes with small effects and a multitude of environmental effects. We used structural equation modeling techniques with the Mx software package 20 to estimate variance components and to compare different genetic models by first carrying out standard univariate twin analyses. 21 These included tests of homogeneity of frequencies across twin type. We then performed maximum likelihood analyses based on sample contingency tables to estimate the components of variance to the liability in enuresis using a threshold model. 22 The contingency tables (frequency categories in co-twin 1 vs frequency categories in co-twin 2) are set out for enuresis separately for MZ and DZ pairs. The correlation in trait liability between the two members of each kind of twin pair is obtained as the polychoric correlation; the polychoric correlation is the correlation of a bivariate normal distribution that duplicates the cell probabilities from a contingency table. Polychoric correlations were computed with the Prelis2 program

3 Table 1. Nocturnal enuresis (bedwetting) in childhood after the age of 4. Numbers of subjects in each category are given in parentheses, including also those subjects whose co-twin did not respond. Often Sometimes A few times Total Male 4.0% (164) 8.0% (326) 18.6% (763) 69.4% (2846) (4099) Female 3.4% (166) 5.7% (282) 14.1% (696) 76.9% (3807) 4951 Monozygotic 3.0% (85) 6.1% (169) 15.8% (442) 75.1% (2094) (2790) Dizygotic 3.9% (222) Under the current study design of twins reared together, it is possible to model four separate parameters an additive genetic component (parameter A), effects of genetic dominance (non-additive) (parameter D), shared environmental (family) components (parameter C), and nonshared environmental components (parameter E) in the variation of the underlying liability to the trait (in this study, enuresis). One can fit models based on the different combinations of these parameters E, AE, ACE and ADE but effects due to dominance and shared environmental effect cannot be simultaneously modeled with data limited to that from twins reared together. 22 These models are estimated under the usual assumptions of twin analyses, expecting no gene-environment interaction or correlation, no assortative mating, and that environments relevant to enuresis etiology will be similar in MZ and DZ twins. 22 Chi-square goodness-of-fit statistics were used to assess how well the models fit the data. The superiority of alternative, hierarchically nested models was assessed by the difference in chi-square values of the models. The difference itself is chi-square-distributed with degrees of freedom equal to the difference in degrees of freedom of the models to be compared. This was done to compare models, where different components of variance have been specified. A small goodness-of-fit chi-square value and a high p value indicate good correspondence between the model and the data. Akaike s information criterion is a statistic which combines information on the goodness-of-fit and the simplicity of the model. 22 The best model is thus generally the one with the lowest Akaike value. Approximate standard errors for the heritability estimates were based on the MZ and DZ correlations. 24 Causes of Adult Enuresis We had access to the hospital discharge records of our study population 25 from the years We checked them in order to find diagnoses explaining the occurrence 7.0% (395) For gender difference c 2 3=65.5, p=0.001, and for difference by zygosity c 2 3=8.0, p= of nocturnal enuresis in adulthood (ie, to identify those with probable secondary enuresis). RESULTS 16.3% (919) Prevalence of Nocturnal Enuresis 72.8% (4108) (5644) The percentages and numbers of subjects in each frequency category for the occurrence of enuresis in childhood are given in Table 1. Enuresis occurred significantly more often in males. Males (compared with females) reported enuresis in childhood often in 4.0% of cases (females in 3.4%), in 8.0% (5.7%), and a few times in 18.6% (14.1%). Enuresis was very infrequent in adults, without a gender difference (c 2 3=2.07, p=0.56). Weekly occurrence was reported by 17 females (0.3%) and 12 males (0.2%), monthly by 4 females (0.07%) and 7 males (0.1%), and less than monthly by 76 females (1.3%) and 70 males (1.4%). Thus, 98.4% of females and 98.2% of males had never experienced enuresis as adults. By checking the hospital discharge records, we found six (3.2%) subjects having a condition that may have contributed to enuresis among the 186 subjects with adult enuresis. These included one subject with cerebral infarction and epilepsy, one with multiple sclerosis, one with mental retardation and cerebral palsy, one with uterovaginal prolapse, one with mental retardation and prostatic hyperplasia, and one with psychosis, alcoholism, and enuresis. In childhood, enuresis was significantly more frequent in DZ (27.2%) than in MZ (24.9%) twin individuals (ie, all with frequency response other than never see Table 1). In adulthood, there was no significant difference by zygosity. The percentage of subjects that did not know whether they had ever had enuresis in childhood was 19.3%. There was a no significant difference between males (20.0%, 95% 581

4 Table 2. Nocturnal enuresis as adults by nocturnal enuresis in childhood after the age of 4 years. Numbers of subjects (twin individuals) in each cell given in parenthesis. Male (n=4051) Childhood Monthly or weekly Less than monthly 2.5% (12) 5.0% (24) 92.5% (442) (478) A few times 0.3% (2) 3.7% (28) 96.0% (719) (749) 0.001% (2) 0.3% (9) 99.6% (2813) (2824) Adult Total Female (n=4916) Childhood Monthly or weekly Less than monthly 3.0% (13) 4.8% (21) 92.2% (405) (439) A few times 0.3% (2) 3.8% (26) 95.9% (663) (691) 0.1% (4) 0.3% (12) 99.6% (3770) (3786) Table 3. Contingency tables for pairwise status for nocturnal enuresis in childhood after the age of 4 years. Males and females pooled together. Numbers of twin pairs concordant for enuresis given in bold, and numbers of discordant twin pairs in italics. Monozygotic twin pairs Twin 2 Twin 1 A few times A few times Twin 2 Dizygotic twin pairs A few times Adult confidence interval %) and females (18.8%, %). Overall, 2.5% of subjects could not say if enuresis had occurred during adulthood, with a significant difference between males (3.1%, 95% confidence interval %) and females (2.1%, %). There was a significant difference in reporting enuresis in the three age groups of the respondents (30-39, 40-49, and years), both in childhood (c 2 8=25.58, p=0.001) and in adulthood (c 2 8=18.21, p=0.020). However, the differences were small in the category of most frequent occurrence of enuresis (in childhood 2.8%, 2.5% and 3.2%). The proportion of never was smallest in the oldest group of the respondents, both in childhood (in respective agegroups 59.6%, 60.0%, and 57.7%) and in adulthood (96.3%, 96.1%, and 94.6%). The frequency of do not know increased with the age of the respondent (in childhood 17.8%, 19.2%, and 21.9%). Co-occurrence of Enuresis in Childhood and in Adulthood Proportions of different enuresis frequencies in adult males and females grouped according to the frequency category in childhood are given in Table 2. Those who reported enuresis often or in childhood also reported it occurring in adulthood weekly or monthly in 2.5% of males and in 3.0% of females. Of adult males who had had enuresis, 85.7% also reported enuresis in childhood at least a few times, vs 79.5% of females. Concordance in Twin pairs Twin 1 A few times Total Pairs in which either twin reported don't know have been excluded, thus in childhood n=902 for monozygotic twin pairs and n=1643 for dizygotic twin pairs. Table 3 shows the pairwise distribution of enuresis in childhood for MZ and DZ pairs pooled over sex. Pairs in 582

5 Table 4. Pairwise similarity of nocturnal enuresis in childhood after the age of 4 years: polychoric correlations (r) and their standard errors (se) of occurrence within the twin pairs, calculated using three frequency categories (see Table 2). which either twin could not specify the occurrence of enuresis frequency were excluded (396 MZ and 776 DZ pairs). The probandwise concordance rate for the MZ pairs was 0.46, based on 38 concordant and 90 discordant pairs. For the DZ pairs, the corresponding probandwise concordance rate was As adults, the number of pairs with enuresis was very low. Among MZ pairs, there was one concordant pair and six discordant pairs, giving a probandwise concordance rate of Among DZ pairs, 20 discordant pairs, but no concordant pairs, were observed. Based on the contingency tables for the two traits in MZ and DZ pairs (Table 3), polychoric correlations (r) were computed (Table 4) for childhood enuresis. In MZ pairs, r=0.69, and in DZ, r=0.16. Models of Genetic and Environmental ffctors Alternative models fitting genetic and environmental sources of variation to the twin data of enuresis in childhood from Table 3 were tested (Table 5). The best fitting model in both genders was that specifying genetic effect due to dominance and unique environmental effects (DE model). In this model, the estimated proportion of total phenotypic variance attributable to the genetic component was 67% (95% confidence interval 57%-76%) in males and 70% (61%-78%) in females. Modeling of the adult data could not be reliably performed because of the small number of affected pairs. DISCUSSION Group All monozygotic pairs All dizygotic pairs Male monozygotic pairs Female monozygotic pairs Male dizygotic pairs Female dizygotic pairs r _+ se _ _ _ _ _ _0.058 This is the first study in which the proportion of genetic effects in the occurrence of nocturnal enuresis has been assessed. We found that in both males and females, about two thirds of the variance is due to nonadditive (dominant) genetic effects in a large, nationwide and population-based twin cohort. This result is well in accordance with results Table 5. Model-fitting results for analysis of liability to enuresis in childhood among Finnish twin pairs from monozygotic and like-sexed dizygotic pairs. Analysis for additive genetic (A) effects, genetic effects due to dominance (D), and shared (C) and nonshared (E) environmental effects. Calculated using three frequency-categories for occurence (see Table 3). Gender Male Female Model Chisquare value p value Akaike s information criterion E < AE CE 48.5 < DE ACE ADE E < AE 38.7 < CE 78.7 < DE ACE 38.7 < ADE from recent multicase family studies. 3-5 Thus, our results show that there are substantial genetic factors involved in the occurrence of enuresis. However, the proportions of genetic effects are population-specific estimates which may vary between populations due to differences in genetic make-up. Also, environmental influences vary between populations, and it is not known which environmental factors have effects on the expression of the genetic components. In our study population, 30.6% of males and 23.1% of females reported nocturnal enuresis at least a few times (ie, all with other frequency response than never see Table 1) in childhood after the age of 4 years. These figures are somewhat higher than in other studies (see below), but this is mostly explained by the cumulative effect of the long observation period, and by the age at the lower cut point, and probably by the fact that the sample consists of twins, as also noted by Hallgren. 6 We also used a frequency scale, and therefore also those with only a few bedwetting episodes have been identified as enuretics. The incidence of enuresis is highest between the ages 4 and 5 years. 26 In 4-year-old children Klackenberg 27 reports bedwetting in 26.3% of boys and 21.2% of girls, and Devlin 28 in 22% of 583

6 Table 6. Twin studies of childhood enuresis. Concordance rates are given as pairwise concordance. Authors Study population Age (years) Number of pairs Prevalence of enuresis (%) Concordance Total MZ Boys Girls MZ DZ MZ DZ Hallgren School children a Higher in DZ?? Bakwin Selected twin sample b Badalian et al Selected twin sample Total 12.5 (more frequent in males) Abe et al Selected twin sample 3 79 b 56?? The present study Population sample 5 to about 15 a) including 308 non-same-sexed pairs b) all same-sexed pairs 2545 b boys and in 27% of girls. In 5- to 18-year-old American schoolchildren, nocturnal enuresis had been a problem at one time or another in 18%. 29 In large Finnish random samples, enuresis has been found in 8.0% of 7-year-old children during the preceding 6 months, 30 and in 10.9% of boys and 6.2% of girls aged 8 years. 31. Interestingly, Hallgren 6 reported about 1.5 times higher frequencies of enuresis in twins than in singletons of the same age. As earlier reported, enuresis as adult is infrequent, and in our sample 1.8% of males and 1.6% of females had experienced it. The respective figures in another Finnish study were 1.7% of males and 0.5% of females aged In two other studies, enuresis was found in 0.07% of the general population after the age of 14, 33 and in 0.6% (mean age of affected subjects 29 years) of an inpatient population, of which about 93% were 20 years or older. 34 We estimated that 3.2% of our subjects suffering from enuresis as adults had a possible primary cause for enuresis. Although the hospital discharge records cover practically all institutional care in Finland, it is possible that the actual proportion of secondary enuresis is higher, because cases treated in the primary health care system or as hospital outpatients are not included. Twin studies of enuresis are summarized in Table 6. Hallgren s (1960) 6 large twin population, recruited from a population of about schoolchildren, included a considerable proportion (about one third) non-same-sexed twins, thus differing from the other studies. Nocturnal enuresis was defined as repeated involuntary micturition during sleep after the fourth year of life, and the data were obtained by sending a questionnaire to the children s parents. Unfortunately, more detailed data on this extensive twin population has never been published, and concordance rates, for example, cannot be calculated. However, of those 119 same-sexed twin pairs in which one or both partners were enuretic, 42 were MZ. 6 Bakwin s (1971) 7 data on bedwetting after the fourth birthday were obtained through the cooperation of organizations of [twin] mothers, within driving distance of New York City. Badalian et al (1971) 9 have included in their study only twin pairs with at least one enuretic co-twin. The study of Abe et al (1984) 8 differs from others in covering twins examined at the age of 3 years when enuresis is to a large extent a physiologic phenomenon. The probandwise concordance rates differ from study to study. Although the prevalence rates in our study are among the highest, the concordance rates are among the lowest. The studies 7-9 for which concordances can be calculated are purely based on twin samples, and the risk of bias is considerable. Compared to these studies, ours differs primarily with respect to sampling and the number of subjects. However, the main results are similar: the concordance is significantly higher among MZ than DZ twins. In conclusion, nocturnal enuresis is common in childhood and quite rare in adulthood, as could be expected from results of earlier studies. In childhood, enuresis genetic factors due to dominance accounted for about two thirds of the variance in occurrence of this trait. Thus, our results also suggest that genetic liability is important in the occurrence of enuresis. ACKNOWLEDGMENTS This study has been supported by a grant from Finska Läkaresällskapet and the Academy of Finland. REFERENCES 1. ICSD - International classification of sleep disorders. Diagnostic and coding manual. Diagnostic Classification Steering Committee, 584

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