Hyperactivity Disorder

Nocturnal Enuresis: A Suggestive Endophenotype Marker for a Subgroup of Inattentive Attention-Deficit/Hyperactivity Disorder Josephine Elia, MD, Toshinobu Takeda, MD, PhD, Rachel Deberardinis, Judy Burke, BA, Jennifer Accardo, MD, Paul J. Ambrosini, MD, Nathan J. Blum, MD, Lawrence W. Brown, MD, Francesca Lantieri, PhD, Wade Berrettini, MD, PhD, Marcella Devoto, PhD, and Hakon Hakonarson, MD, PhD Objective Attention-deficit/hyperactivity disorder (ADHD) and enuresis co-occur at a higher rate than expected; the cause for this is unclear.

Study design Diagnostic and demographic variables were compared in 344 children ages 6 to 12 years, with and without enuresis, recruited in an ADHD genetic study. Sleep variables were investigated in a subgroup of 44 enuretic children with age- and sex-matched nonenuretic controls. The association of enuresis with single nucleotide polymorphisms located in regions reported in linkage with enuresis was explored. Results The prevalence rate of nocturnal enuresis was 16.9% for the entire cohort. There were no differences in sex, age, socioeconomic status, intelligence quotient, medication treatment, or comorbidities. The enuresis group had a higher likelihood of inattentive symptoms than the nonenuretic group. Night wakings and ability of children to wake themselves in the morning were both significantly decreased in children with enuresis compared with control children in the Child Sleep Habits Questionnaire Night Wakings subscale. No significant association was found with chromosomal regions previously reported in linkage with enuresis. Conclusions Deficits in arousal may contribute to both enuresis and inattentive ADHD. Nocturnal enuresis may be a useful clinical marker in identifying a subgroup of the inattentive phenotype in ADHD genetic studies. (J Pediatr 2009;155:239-44).

T

he co-occurrence of Attention-Deficit/Hyperactivity Disorder (ADHD) and enuresis is high in both directions. Enuresis has been reported in 22% to 32% (vs 5% to 14% in control children) of children with ADHD1-3; ADHD has been reported in 30% to 40% (vs 6% to 10% general population rates) of enuretic children.4,5 A strong association between ADHD and enuresis was also reported in a large national representative sample (odds ratio, 2.88).6 Deficits in arousal, hypothesized to play a role in both disorders, could potentially explain this bidirectional co-occurrence. Reduced arousability from sleep in response to sensation of a full bladder and lack of inhibitory cerebral control of reflex voiding during sleep have been proposed as potential causes for enuresis7-9 and impairment in vigilance has been reported in ADHD.10 Specifically, executive dysfunction, of which vigilance is one measure, has been associated primarily with inattentive ADHD,10-12 the predominant subtype reported in the enuretic groups.4 In this study, ADHD symptoms and subtypes are compared in a cohort of children with ADHD, with and without enuresis, with the goal of better defining the association between these two conditions. We hypothesize that inattentive symptoms may be more severe in subjects with ADHD and enuresis, whereas hyperactive-impulsive will be more similar to those in the nonenuretic group. Sleep variables, potential contributors to both conditions, were also assessed in a subgroup. Genetic analyses were limited to single nucleotide polymorphisms (SNPs) of candidate regions previously reported in linkage with enuresis.13-18

Methods This sample of 344 children is the 6- to 12-year-old subset of 500 probands ages 6 to 18 years recruited in an ADHD genetic study. All subjects were Caucasian of European descent because haplotype frequencies can vary substantially across ADHD BPD CD K-SADS-IVR SNP OSA

Attention-deficit/hyperactivity disorder Bipolar disorder Conduct disorder Schedule for Affective Disorders and Schizophrenia for School Age Children Single nucleotide polymorphisms Obstructive sleep apnea

From the Children’s Hospital of Philadelphia (J.E., T.T., J.B., J.A., N.B., L.B., F.L., M.D., H.H.), Philadelphia, PA, the University of Pennsylvania (J.E., R.D., N.B., L.B., W.B., M.D., H.H.), Philadelphia, PA, Drexel University (P.A.), Philadelphia, PA and the University of Rome La Sapienza (M.D.), Rome, Italy Supported by NIMH (K23MH066275-01), UL1-RR024134 from the National Center for Research Resources, and The Center for Applied Genomics at The Children’s Hospital of Philadelphia. The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright Ó 2009 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2009.02.031

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major world populations, lowering power of the study to detect genetic association if all groups were involved.19 The study was approved by the Institutional Review Boards of The Children’s Hospital of Philadelphia and the University of Pennsylvania School of Medicine. Parents provided consent and children assent. Families were recruited from pediatric and behavioral health clinics in the Philadelphia area. Phone screenings were conducted to determine age range of 6 to 18 years, presence of ADHD symptoms, ancestry, and availability and willingness to participate in a genetic study for both biological parents. Exclusionary criteria included gestational age <36 weeks, IQ scores <75, major medical conditions other than asthma, and neurological conditions (eg, seizures, fetal alcohol syndrome, plumbism). Some neuropsychiatric disorders, namely pervasive developmental disorders, bipolar disorder, major depressive disorder with symptoms starting before ADHD, or ADHD symptoms occurring primarily during depressed or psychotic episodes were also grounds for exclusion. Subjects with disruptive behavioral disorders, other mood disorders, and anxiety disorders were not excluded. Blood collected from the families of children with ADHD was sent to the Rutgers University Cell and DNA Repository in New Jersey, where lymphoblastoid cell lines were developed. DNA was extracted and returned to our laboratory, at the Center for Applied Genomics at The Children’s Hospital of Philadelphia where high-throughput, genome-wide SNP genotyping was done using the InfiniumII HumanHap550k BeadChip technology (Illumina, San Diego, California).20,21 ADHD and psychiatric comorbidity were assessed by a semistructured interview, the Schedule for Affective Disorders and Schizophrenia for School Age Children (KSADS-IVR) administered by a child psychiatrist (JE) to the parent(s) and child separately. This instrument provides diagnoses occurring within the last 12 months and for the last week. This K-SADS version rates each symptom on a graded Likert-type severity scale allowing for a composite severity score.22 All ADHD symptoms are scored from 0 (no information) to 4 (severe/extreme). Scores of $3 are considered clinically significant. Intraclass correlations (ICC) between the primary diagnostician and a clinician with extensive experience with this semistructured interview (PJA) for the diagnostic symptoms of the major disorders were assessed through videotape reviews. All ICC values were highly significant with the following ranges: ADHD: 0.82; oppositional defiant disorder: 0.80; affective disorders: 0.74 to 0.85; and anxiety disorders, 0.75 to 0.92. Enuresis status was assessed using a bedwetting question on the Child Behavior Checklist (CBCL)23 and based on questions from a Developmental History questionnaire. These scales did not allow differentiation between primary or secondary enuresis or quantification of the frequency of episodes. Sleep was assessed with the Child’s Sleep Habit Questionnaire (CSHQ)24 and the Sleep Disordered Breathing subscale of the Pediatric Sleep Questionnaire (PSQ).25 These are brief 240

Vol. 155, No. 2 screening questionnaires completed by parents about their children. The CSHQ screens for a variety of sleep disorders based on International Classification of Sleep Disorders criteria and has 33 items. The Sleep Disordered Breathing subscale of the PSQ screens specifically for obstructive sleep apnea (OSA) based on clusters of questions concerning snoring, daytime sleepiness, and inattentive behaviors. Available reports of IQ assessments for subjects tested before participation in the genetics study were reviewed. The Wechsler Abbreviated Scale of Intelligence (WASI) IQ assessment was administered to a subset of children without previous IQ testing. Other children, included but not formally tested, were able to understand and complete the K-SADS. Socioeconomic status was measured by the Hollingshead 4-Factor Scale.26 Data Analysis Consistent with DSM-IV criteria, subjects with 6 or more clinically significant symptoms of inattention (K-SADS severity scores $3) but fewer than 6 symptoms of hyperactivity and impulsivity were identified as inattentive subtype. Subjects with 6 or more hyperactive-impulsive symptoms (K-SADS severity scores $3) and fewer than 6 symptoms of inattention were categorized as hyperactive-impulsive subtype and subjects with 6 or more symptoms in both dimensions were categorized as combined subtypes. Age of onset was not used in determining ADHD diagnoses because this has questionable validity.27,28 For comorbid mood and anxiety disorders, the K-SADS-IVR diagnostic domain was keyed to the Research Diagnostic Criteria (RDC)29 and the DSM-IVR. Diagnoses were made excluding the DSM hierarchical requirements.30 Statistical Analyses Comparisons of the demographic variables between children with ADHD with and without enuresis were calculated using c2 and 2-tailed Student t tests. In the analyses of symptoms in DSM-IV criteria (inattention and hyperactivity/impulsiveness) for ADHD, because the symptoms within the DSM-IV criteria are generally significantly correlated with one another, multivariate analysis of variances (MANOVAs) were done to determine a between-group difference. A MANOVA yielding a significant difference between groups was followed by multivariate analysis of covariance controlling for age and analysis of variances for comparison of each item between 2 groups. Bonferroni corrections were made to achieve an overall significance level of P < .05 for each group test performed. In this method, the desired overall significance level was divided by the number of comparisons to limit the occurrence of type I errors. Symptom scores in each criterion were highly kurtotic, as would be expected in the sample population. Given the relative robustness of MANOVA to kurtosis, these data were not transformed. Crude odds ratios with 95% confidence intervals were used to evaluate the association between comorbidities (having frequency of at least 10% of participants) and enuresis in children with ADHD. In this analysis, subjects with ADHD Elia et al

ORIGINAL ARTICLES

August 2009

Table I. Characteristics in children with ADHD without and with enuresis ADHD without enuresis (n = 286) Sex Male (%) Female (%) Age, mean (SD) SES,* mean (SD) IQ,† mean (SD) Psychostimulants use

215 (75) 71 (25) 8.6 (1.7) 47.5 (10.8) 109.7 (14.0) 55 (19%)

ADHD with enuresis (n = 58) 48 (83) 10 (17) 8.23(1.6) 48.1 (11.6) 106.5 (15.2) 9 (16%)

Statistics

P

c2 (1) = 1.54

.24

t (342) = 1.43 t (329) = -0.58 t (243) = 1.33 c2 (1) = 0.44

.15 .57 .18 .58

*ADHD without enuresis, n = 276; ADHD with enuresis, n = 55. †ADHD without enuresis, n = 166; ADHD with enuresis, n = 39.

without comorbidities were used as controls. Logistic regression controlling for age was then conducted to determine the relative contribution of comorbidities to the prediction of enuresis. Age was also factored into the equation. This takes into account that the likelihood of enuresis tends to decrease with age and that children with ADHD with comorbidities (ie, dysthymic disorder, generalized anxiety disorder) were significantly older than children with ADHD without them. To evaluate the relationship between enuresis in children with ADHD and sleep disturbance, 44 enuretic children with ADHD for whom sleep questionnaire data were available were compared with 44 age- and sex-matched children with ADHD without enuresis (1 year). In these analyses, children with daytime enuresis only were not included. Paired t tests were used to compare items from the PSQ, which are rated in present or absent fashion, and subscales of the CSHQ. Wilcoxon matched-pair rank sum tests were used to evaluate individual items of the CSHQ, which are rated on a scale of 1 to 3. Items that were repeated elsewhere in the evaluation, such as PSQ items 17 through 22 (which duplicate DSM criteria for inattention and hyperactivity) and PSQ item 9 and CSHQ item 12 (bedwetting) were omitted from analysis.All data were entered and analyzed by using SPSS 16.0 (SPSS, Inc., Chicago, Illinois). Genome-wide genotypes were available for 51 children with ADHD and enuresis and their parents. The transmission disequilibrium test (TDT) was applied in this group to a total of 24 945 SNPs located in the regions already reported in linkage with the enuresis trait, namely, chromosome 13 (3179 SNPs from around 37.9 Mb to around 53 Mb), chromosome 12 (6602 SNPs from around 50.9 Mb to around 89.3 Mb), chromosome 8 (12 817 SNPs from around 60.3 Mb to around 130.4 Mb), and chromosome 22 (2347 SNPs from around 17.8 Mb to around 27.2 Mb). The SNPs chromosome positions were based on NCBI sequence build 35.1 (hg17). The TDT analysis was carried out by means of the software PLINK, version v1.02 (http://pngu.mgh. harvard.edu/purcell/plink/).31 PLINK is a toolset for wholegenome association and population-based linkage analysis. Both nominal and empirical significance, adjusted for the number of tests, were calculated.

Table II. K-SADS symptom severity in DSM-IV criterion A (inattention) for ADHD ADHD without enuresis (n = 286)

ADHD with enuresis (n = 58)

Symptoms*

Mean

SD

Mean

SD

Often careless Often loses things Often fails to finish things Often does not listen Difficulty concentrating Easily distracted Difficulty organizing work Often avoids mental effort Often forgetful

3.04 2.79 2.85

0.54 0.74 0.69

3.09 2.83 3.02

0.68 0.73 0.71

3.24

0.54

3.33

0.60

3.18

0.56

3.12

0.56

3.31 2.91

0.5 0.74

3.50 3.05

0.54 0.60

3.00

0.75

3.17

0.70

2.96

0.78

2.84

0.77

Wilks l for the MANOVA and MANCOVA was 0.95 [F (9, 332) = 2.13, P = 0.03] and 0.95 [F (9.334) = 2.04, 0.04]. *All symptoms were rated on a scale of 1 to 4, 4 being the severest. Significant P level for each item after Bonferroni correction = 0.05/9 = 0.006.

Results Demographic and enuretic characteristics of the sample are summarized in Table I. Of 58 enuresis cases, 56 cases (47 boys, 9 girls) had nocturnal, 2 cases (1 male, 1 female) had only diurnal enuresis, and 6 cases (4 boys, 2 girls) had both nocturnal and diurnal enuresis. Prevalence rates for enuresis in boys and girls were 18.3% and 12.3%, respectively (total sample, 16.9%). There was no significant difference in sex, age, SES, IQ, and psychostimulant treatment between children with ADHD with and without enuresis. There was no significant association (c2 [3] = 2.91, P = .39) between ADHD subtype and enuretic status. Rates of the inattentive, hyperactive-impulsive, and combined subtype were 22.4%, 12%, and 63.7%, respectively, for the enuretic group and 26.3%, 8.7%, and 64.5% for the nonenuretic group. As is summarized in Table II, there was a significant between-group difference in the 9 clinical symptoms of inattention (P = .03) even after controlling for age (P = .04). There was no difference among the 9 clinical scales of hyperactivity/ impulsivity (P = .28). Children with ADHD and enuresis scored significantly higher (P = .02) than children with ADHD without enuresis on the ‘‘easily distracted’’ scale in inattention by ANOVA, which disappeared after Bonferroni correction (significant P < .05/9 = .006). There was no significant association between enuresis and any of the ADHD-associated comorbidities examined in this study (Table III). There was no significant difference in sex, age, SES, IQ, or stimulant use between the subset of 44 enuretic children with ADHD and their 44 nonenuretic counterparts used in analysis of sleep questionnaire data. In the CSHQ, there were several significant differences between the 2 groups: children

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Table III. Association of enuresis with comorbidities in children with ADHD Independent variables

OR

95% CI

Any comorbidities (n = 227) Affective disorders (n = 91) Emotional disorders (n = 114) ODD (n = 151) MDDD (n = 81) GAD (n = 43) OAD (n = 43)

1.18 0.96 0.66 1.46 1.16 0.44 1.12

0.64-2.16 0.51-1.84 0.35-1.25 0.83-2.57 0.61-2.23 0.06-3.47 0.50-2.62

with enuresis were more likely to be reported to need a parent in the room to fall asleep (n = 33; P = .04, r = -0.25) and to be afraid to fall asleep in the dark (n = 33; p = .006, r = -0.34). Children with enuresis were reported to be less likely than their matched peers to awaken once during the night (n = 40; P = 0.007, r = -0.30). Similarly, their night wakings subscale on the CSHQ, which asks about nighttime wakings plus whether children move to others’ beds during the night, was significantly lower (t[39] = 2.20, P = .034). There was also a trend for them to be reported as less likely to wake by themselves than matched peers (P = .051) (Table IV). In the PSQ, there was no significant difference between the 2 groups on any items. When we carried out a family-based association, analysis on 51 trios affected by both ADHD and enuresis for the specific chromosomal regions supposed to play a role in enuresis, several SNPs showed a TDT point-wise P value below (Table V; available at www.jpeds.com). However, no SNP was still significant after correction for multiple tests.

Discussion In our study, the enuresis group had higher K-SADS severity scores in the DSM-IV inattention symptoms (9 symptoms as a whole) than the nonenuresis group. Although modest, these results support the link between enuresis and inattentive ADHD, previously reported by Baeyens et al4 in enuretic cohorts with ADHD. In their sample, subjects with higher scores for inattentive symptoms were older, rendering their link between inattentive ADHD and enuresis inconclusive due to the decreasing hyperactivity and increasing inattention with age noted with ADHD.32 Our cohort, limited to 6- to 12-year-olds, avoided this confounding age effect, providing stronger evidence for the link between inattention and enuresis. Baeyens et al33 explored decreased brainstem inhibition, hypothesized to contribute to problems in early identification of bladder signals, and found impairment in children with enuresis with and without ADHD. However, with the addition of a controlled attentional task, children with ADHD, Inattentive subtype, showed similar deficits regardless of whether they were enuretic or not. These findings suggest that deficits in arousal may be contributing to both enuresis and inattentive ADHD. 242

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Table IV. CSHQ items in enuretic vs nonenuretic group P Need a parent in the room to fall asleep Afraid to fall asleep in the dark Awaken once during the night Wilcoxon matched-paired rank sum test

.04 .006 .007

Sleep data from our cohort also suggest that children with enuresis may have decreased levels of arousal based on their decreased tendency to wake from sleep, both during the night and in the mornings. Night wakings were reported to be decreased in children with enuresis compared with control children, and difficulty waking independently was reported to be increased. Other researchers have reported that children with enuresis are difficult to wake from sleep during the night,9,34,35 which is compatible with our finding that they are perceived to have fewer spontaneous night wakings. The area remains controversial, with polysomnographic studies suggesting that enuretic children in fact have similar total sleep time and movements as evidence of arousal as their nonenuretic peers.7 OSA has been associated with increased likelihood of nocturnal enuresis in children.36,37 OSA has also been associated with symptoms of ADHD.38,39 Symptoms of OSA were screened for in our cohort by use of the Sleep Disordered Breathing subscale of the PSQ.25 According to the criteria for this questionnaire, however, the subjects with enuresis did not have an increased risk of OSA compared with the subjects without enuresis. Enuresis in children has been associated with increased levels of stress surrounding bedtime. This may explain the increased likelihood for parents of subjects with enuresis to report that their children need parents present in order to fall asleep and are afraid to fall asleep in the dark. Moilanen et al40 report an increased prevalence of difficulties falling asleep among children with enuresis. Several authors have highlighted the psychosocial burdens of nocturnal enuresis in children.41,42 In fact, Joinson et al42 suggest that nocturnal enuresis is associated with parent-reported internalizing problems such as sadness and anxiety in children. Genetic factors may also play an important role in both nocturnal enuresis43 and ADHD.44 Several studies reported linkage for enuresis at 4 loci, at chromosomes 8, 12, 13, and 22.13,17,45 The mode of transmission, however, is not yet known for either enuresis or ADHD. The high co-occurrence of these 2 conditions could be explained by risk conferred by similar genes. In a family study, similar rates of primary nocturnal enuresis (PNE) were found in family members of subjects with ADHD and PNE vs subjects with PNE without ADHD, suggesting that these 2 conditions are transmitted independently.46 However, a global ADHD diagnoses that includes all subtypes, such as the one used by Bailey et al,46 is unlikely to detect any potentially shared transmission. Our results, which examine symptoms and Elia et al

August 2009 ADHD subtypes, suggest that deficits in arousal may be a common trait that links enuresis and inattentive ADHD, which may result from common genetic risk. Our genetic analysis included 24 945 SNPs from the enuresis candidate regions and tested them for association with the enuresis phenotype in a subgroup of children with ADHD by means of the TDT. Results were not significant after correction for multiple tests and therefore we could not confirm the previous findings, probably due to the lack of statistical power from the small sample size. Calculations using the software QUANTO (http://hydra.usc.edu/gxe) show that to detect odds-ratios of the order expected for genetic risk factors affecting common traits (usually assumed to be less then 2) with 80% power at a Bonferroni-corrected significance level for 25 000 tests of 2  10 6, we would need at least 300 trios. However, we cannot exclude that some variants in one or more of these chromosomal regions increase either the risk of enuresis and ADHD or that they are involved in enuresis or ADHD independently. This sample is not representative of the general ADHD population or even clinical ADHD groups because it only included ADHD probands of European descent, in which both biological parents were available and willing to participate in a genetic study. The entire cohort was recruited at a single tertiary pediatric center (The Children’s Hospital of Philadelphia) and may reflect biased referrals. The majority of the K-SADS IVR interviews were completed by one rater (JE), and this could introduce an information collection bias to this data set. However, these may also be potential strengths by minimizing sample heterogeneity. In our ADHD cohort, the prevalence of enuresis is higher than that reported in epidemiological samples but lower than that reported in most other clinical studies. This may be due in part to the fact that the information was obtained only from the parents. Klages et al47 reported poor to fair concordance between parent and child report of enuresis: the diagnosis of enuresis was obtained from parent report in 52.3% of cases and from child report in 25% of cases, with both informants providing the same information in only 22.7% of cases.47 Nocturnal enuresis has also been linked to conduct disorder (CD)48,49 and bipolar disorder (BPD).47 We did not find enuresis to be associated with any comorbid disorders or socioeconomic status, similar to reports by Biederman et al.2 However, our cohort had not passed through the period of risk for CD or BPD. Sleep questionnaires administered relied on parent report. Typically, parent reports have not correlated well with ‘‘objective’’ sleep measures such as polysomnography or actigraphy, but parent report data may also be measuring other constructs not captured by these tests.50,51 Polysomnography is, however, the gold standard for diagnosis of OSA, and clinical history has not been found to be particularly accurate in screening for this condition.52,53 In addition, parent report and child report of sleep disturbances often diverge, particularly in older children and adolescents.24 Parents of children with enuresis may report fewer nighttime awakenings and

ORIGINAL ARTICLES difficulty waking their children due to information gleaned from healthcare providers and their own reading. They may also make more attempts to wake their children during sleep phases from which it is difficult to rouse children in an effort to prevent enuresis. This could lead to overestimation of the magnitude of these associations so that it would be difficult to avoid in a questionnaire-based evaluation such as in the present study. n We want to thank all the families that participated, the referring clinicians, research coordinator, Tamika Scott, and Adam Moffit. Submitted for publication July 31, 2008; last revision received Jan 5, 2009; accepted Feb 13, 2009. Reprint requests: Dr Josephine Elia, The Children’s Hospital of Philadelphia, Science Center Suite 200; 3440 Market Street, Philadelphia, PA. 19104-6209. E-mail: [email protected].

References 1. Biederman J, Faraone SV, Keenan K, Benjamin J, Krifcher B, Moore C, et al. Further evidence for family-genetic risk factors in attention deficit hyperactivity disorder: patterns of comorbidity in probands and relatives psychiatrically and pediatrically referred samples. Arch Gen Psychiatry 1992;49:728-38. 2. Biederman J, Santangelo SL, Faraone SV, Kiely K, Guite J, Mick E, et al. Clinical correlates of enuresis in ADHD and non-ADHD children. J Child Psychol Psychiatry 1995;36:865-77. 3. Robson WL, Jackson HP, Blackhurst D, Leung AK. Enuresis in children with attention-deficit hyperactivity disorder. South Med J 1997;90:503-5. 4. Baeyens D, Roeyers H, D’Haese L, Pieters F, Hoebeke P, Vande Walle J. The prevalence of ADHD in children with enuresis: comparison between a tertiary and non-tertiary care sample. Acta Paediatr 2006;95: 347-52. 5. Baeyens D, Roeyers H, Hoebeke P, Verte S, Van Hoecke E, Walle JV. Attention deficit/hyperactivity disorder in children with nocturnal enuresis. J Urol 2004;171:2576-9. 6. Shreeram S, He JP, Kalaydjian A, Brothers S, Merikangas KR. Prevalence of enuresis and its association with attention-deficit/hyperactivity disorder among US children: results from a nationally representative study. J Am Acad Child Adolesc Psychiatry 2009;48:35-41. 7. Bader G, Neveus T, Kruse S, Sillen U. Sleep of primary enuretic children and controls. Sleep 2002;25:579-83. 8. Kawauchi A, Imada N, Tanaka Y, Minami M, Watanabe H, Shirakawa S. Changes in the structure of sleep spindles and delta waves on electroencephalography in patients with nocturnal enuresis. Br J Urol 1998; 81(Suppl 3):72-5. 9. Wolfish NM, Pivik RT, Busby KA. Elevated sleep arousal thresholds in enuretic boys: clinical implications. Acta Paediatr 1997;86:381-4. 10. Willcutt EG, Doyle AE, Nigg JT, Faraone SV, Pennington BF. Validity of the executive function theory of attention-deficit/hyperactivity disorder: a meta-analytic review. Biol Psychiatry 2005;57:1336-46. 11. Chhabildas N, Pennington BF, Willcutt EG. A comparison of the neuropsychological profiles of the DSM-IV subtypes of ADHD. J Abnorm Child Psychol 2001;29:529-40. 12. Nigg JT, Stavro G, Ettenhofer M, Hambrick DZ, Miller T, Henderson JM. Executive functions and ADHD in adults: evidence for selective effects on ADHD symptom domains. J Abnorm Psychol 2005;114:706-17. 13. Bayoumi RA, Eapen V, Al-Yahyaee S, Al Barwani HS, Hill RS, Al Gazali L. The genetic basis of inherited primary nocturnal enuresis: a UAE study. J Psychosom Res 2006;61:317-20. 14. Eiberg H, Berendt I, Mohr J. Assignment of dominant inherited nocturnal enuresis (ENUR1) to chromosome 13q. Nat Genet 1995;10: 354-6.

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243

THE JOURNAL OF PEDIATRICS



www.jpeds.com

15. Eiberg H. Total genome scan analysis in a single extended family for primary nocturnal enuresis: evidence for a new locus (ENUR3) for primary nocturnal enuresis on chromosome 22q11. Eur Urol 1998;33(Suppl 3): 34-6. 16. Loeys B, Hoebeke P, Raes A, Messiaen L, De Paepe A, Vande Walle J. Does monosymptomatic enuresis exist? A molecular genetic exploration of 32 families with enuresis/incontinence. BJU Int 2002;90:76-83. 17. Arnell H, Hjalmas K, Jagervall M, Lackgren G, Stenberg A, Bengtsson B, et al. The genetics of primary nocturnal enuresis: inheritance and suggestion of a second major gene on chromosome 12q. J Med Genet 1997;34: 360-5. 18. von Gontard A, Eiberg H, Hollmann E, Rittig S, Lehmkuhl G. Molecular genetics of nocturnal enuresis: clinical and genetic heterogeneity. Acta Paediatr 1998;87:571-8. 19. Chang FM, Kidd JR, Livak KJ, Pakstis AJ, Kidd KK. The world-wide distribution of allele frequencies at the human dopamine D4 receptor locus. Hum Genet 1996;98:91-101. 20. Gunderson KL, Steemers FJ, Lee G, Mendoza LG, Chee MS. A genomewide scalable SNP genotyping assay using microarray technology. Nat Genet 2005;37:549-54. 21. Steemers FJ, Chang W, Lee G, Barker DL, Shen R, Gunderson KL. Whole-genome genotyping with the single-base extension assay. Nat Methods 2006;3:31-3. 22. Ambrosini PJ. Historical development and present status of the schedule for affective disorders and schizophrenia for school-age children (KSADS). J Am Acad Child Adolesc Psychiatry 2000;39:49-58. 23. Achenbach TM, Howell CT, Quay HC, Conners CK. National survey of problems and competencies among four- to sixteen-year-olds: parents’ reports for normative and clinical samples. Monogr Soc Res Child Dev 1991;56:1-131. 24. Owens JA, Maxim R, Nobile C, McGuinn M, Msall M. Parental and selfreport of sleep in children with attention-deficit/hyperactivity disorder. Arch Pediatr Adolesc Med 2000;154:549-55. 25. Chervin RD, Hedger K, Dillon JE, Pituch KJ. Pediatric sleep questionnaire (PSQ): validity and reliability of scales for sleep-disordered breathing, snoring, sleepiness, and behavioral problems. Sleep Med 2000;1: 21-32. 26. Hollingshead A. Four Factor Index of Social Status. New Haven, CT: Yale University; 1975. 27. Reinhardt MC, Benetti L, Victor MM, Grevet EH, Belmonte-de-Abreu P, Faraone SV, et al. Is age-at-onset criterion relevant for the response to methylphenidate in attention-deficit/hyperactivity disorder? J Clin Psychiatry 2007;68:1109-16. 28. Faraone SV, Biederman J, Mick E. The age-dependent decline of attention deficit hyperactivity disorder: a meta-analysis of follow-up studies. Psychol Med 2006;36:159-65. 29. Spitzer RL, Endicott J, Robins E. Research diagnostic criteria: rationale and reliability. Arch Gen Psychiatry 1978;35:773-82. 30. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. DSM-IV-TR (Text Revision). Washington, DC: American Psychiatric Association; 2004. 31. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and populationbased linkage analyses. Am J Hum Genet 2007;81:559-75. 32. Lahey BB, Pelham WE, Loney J, Lee SS, Willcutt E. Instability of the DSM-IV subtypes of ADHD from preschool through elementary school. Arch Gen Psychiatry 2005;62:896-902.

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Vol. 155, No. 2 33. Baeyens D, Roeyers H, Hoebeke P, Antrop I, Mauel R, Walle JV. The impact of attention deficit hyperactivity disorders on brainstem dysfunction in nocturnal enuresis. J Urol 2006;176:744-8. 34. Neveus T, Hetta J, Cnattingius S, Tuvemo T, Lackgren G, Olsson U, et al. Depth of sleep and sleep habits among enuretic and incontinent children. Acta Paediatr 1999;88:748-52. 35. Chandra M, Saharia R, Hill V, Shi Q. Prevalence of diurnal voiding symptoms and difficult arousal from sleep in children with nocturnal enuresis. J Urol 2004;172:311-6. 36. Brooks LJ, Topol HI. Enuresis in children with sleep apnea. J Pediatr 2003;142:515-8. 37. Weider DJ, Sateia MJ, West RP. Nocturnal enuresis in children with upper airway obstruction. Otolaryngol Head Neck Surg 1991;105:427-32. 38. Beebe DW. Neural and neurobehavioral dysfunction in children with obstructive sleep apnea. PLoS Med 2006;3:e323. 39. Chervin RD, Archbold KH, Dillon JE, Panahi P, Pituch KJ, Dahl RE, et al. Inattention, hyperactivity, and symptoms of sleep-disordered breathing. Pediatrics 2002;109:449-56. 40. Moilanen I, Tirkkonen T, Jarvelin MR, Linna SL, Almqvist F, Piha J, et al. A follow-up of enuresis from childhood to adolescence. Br J Urol 1998; 81(Suppl 3):94-7. 41. Schulpen TW. The burden of nocturnal enuresis. Acta Paediatr 1997;86: 981-4. 42. Joinson C, Heron J, Emond A, Butler R. Psychological problems in children with bedwetting and combined (day and night) wetting: a UK population-based study. J Pediatr Psychol 2007;32:605-16. 43. Hublin C, Kaprio J, Partinen M, Koskenvuo M. Nocturnal enuresis in a nationwide twin cohort. Sleep 1998;21:579-85. 44. Faraone SV, Perlis RH, Doyle AE, Smoller JW, Goralnick JJ, Holmgren MA, et al. Molecular genetics of attention-deficit/hyperactivity disorder. Biol Psychiatry 2005;57:1313-23. 45. von Gontard A, Eiberg H, Hollmann E, Rittig S, Lehmkuhl G. Molecular genetics of nocturnal enuresis: linkage to a locus on chromosome 22. Scand J Urol Nephrol Suppl 1999;202:76-80. 46. Bailey JN, Ornitz EM, Gehricke JG, Gabikian P, Russell AT, Smalley SL. Transmission of primary nocturnal enuresis and attention deficit hyperactivity disorder. Acta Paediatr 1999;88:1364-8. 47. Klages T, Geller B, Tillman R, Bolhofner K, Zimerman B. Controlled study of encopresis and enuresis in children with a prepubertal and early adolescent bipolar-I disorder phenotype. J Am Acad Child Adolesc Psychiatry 2005;44:1050-7. 48. Feehan M, McGee R, Stanton W, Silva PA. A 6 year follow-up of childhood enuresis: prevalence in adolescence and consequences for mental health. J Paediatr Child Health 1990;26:75-9. 49. Fergusson DM, Horwood LJ. Nocturnal enuresis and behavioral problems in adolescence: a 15-year longitudinal study. Pediatrics 1994;94:662-8. 50. Wiggs L, Montgomery P, Stores G. Actigraphic and parent reports of sleep patterns and sleep disorders in children with subtypes of attention-deficit hyperactivity disorder. Sleep 2005;28:1437-45. 51. Sadeh A, Pergamin L, Bar-Haim Y. Sleep in children with attention-deficit hyperactivity disorder: a meta-analysis of polysomnographic studies. Sleep Med Rev 2006;10:381-98. 52. Carroll JL, McColley SA, Marcus CL, Curtis S, Loughlin GM. Inability of clinical history to distinguish primary snoring from obstructive sleep apnea syndrome in children. Chest 1995;108:610-8. 53. Rowley JA, Aboussouan LS, Badr MS. The use of clinical prediction formulas in the evaluation of obstructive sleep apnea. Sleep 2000;23:929-38.

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SNP

rs10105068 rs2049131 rs10109510 rs2356370 rs13273490 rs3110289 rs7827287 rs10099098 rs7841951 rs4366112 rs4737715 rs7017178 rs4339683 rs4448317 rs1877829 rs13270922 rs4737209 rs16932321 rs578611 rs2028444 rs896381 rs17671921 rs12679412 rs4439163 rs970505 rs1035665 rs4738150 rs6983656 rs11995376 rs7812753 rs7842758 rs2383926 rs17437854 rs16939567 rs1554347 rs7016252 rs2448962 rs1896216 rs1559905 rs4237100 rs6473389 rs12543966 rs4446742 rs10109906 rs7829511 rs4601315 rs10958161

Chr

8q

60922574 64879828 65044623 65128913 65157632 65509490 65768273 66297357 66301103 66306182 66306772 66314483 66314690 66315057 66350817 66363095 66390972 66815041 70153310 70689576 70990827 71027171 72405159 72496335 72766034 72766586 72770461 73197825 75648423 75853815 75870217 76017080 77886211 78859328 78865143 79024311 79163162 82259466 82309140 83965673 83969563 83976503 83990099 84027993 84033179 84040813 84710007

Position in bp

intron

intron intron intron

intron

PDE7A SULF1 EYA1

ZFHX4

Gene position

CYP7B1

Gene A G T C G G T G G C G G G G A G C C G T T C C T G T A T A G A A T A T C G C G A A C G G A C G

Major allele G A C T A A G A A A A A T A G A T T T C C T T C A C G C C A G C G C C T A T T G G T A A G T A

Minor allele 0.094 0.292 0.352 0.481 0.472 0.113 0.495 0.302 0.118 0.305 0.467 0.137 0.314 0.316 0.224 0.448 0.286 0.057 0.182 0.264 0.208 0.123 0.382 0.271 0.104 0.481 0.380 0.038 0.142 0.114 0.156 0.205 0.090 0.033 0.033 0.033 0.033 0.146 0.146 0.371 0.371 0.371 0.443 0.462 0.466 0.452 0.127

MAF 2 11 13 12 13 3 32 11 4 11 42 6 12 12 9 36 13 11 4 24 6 4 17 27 18 16 15 0 5 18 22 8 14 0 0 0 0 18 18 14 13 13 16 16 17 17 20

T* 12 27 30 29 30 15 14 34 17 35 15 19 33 33 26 14 30 1 17 9 22 16 39 11 4 35 34 8 18 5 7 25 3 7 7 7 7 5 5 34 35 35 37 38 36 37 3

U* 0.167 0.407 0.433 0.414 0.433 0.2 2.286 0.324 0.235 0.314 2.8 0.316 0.364 0.364 0.346 2.571 0.433 11 0.235 2.667 0.273 0.25 0.436 2.455 4.5 0.457 0.441 0 0.278 3.6 3.143 0.32 4.667 0 0 0 0 3.6 3.6 0.412 0.371 0.371 0.432 0.421 0.472 0.460 6.667

OR 7.143 6.737 6.721 7.049 6.721 8 7.043 11.76 8.048 12.52 12.79 6.76 9.8 9.8 8.257 9.68 6.721 8.333 8.048 6.818 9.143 7.2 8.643 6.737 8.909 7.078 7.367 8 7.348 7.348 7.759 8.758 7.118 7 7 7 7 7.348 7.348 8.333 10.08 10.08 8.321 8.963 6.811 7.407 12.57

c2 .007526 .009444 .009529 .007932 .009529 .004678 .007955 .000607 .004556 .000402 .000349 .009322 .001745 .001745 .004059 .001863 .009529 .003892 .004556 .009023 .002497 .007290 .003283 .009444 .002838 .007802 .006642 .004678 .006714 .006714 .005346 .003083 .007633 .008151 .008151 .008151 .008151 .006714 .006714 .003892 .001496 .001496 .003919 .002755 .009058 .006496 .000393

P value

1 1 1 1 1 1 1 .9567 1 .8667 .8143 1 .9997 .9997 1 .9999 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 .9996 .9996 1 1 1 1 .856 (continued )

Empirical P value

Table V. Results of TDT analysis for SNPs located in regions reported in linkage with enuresis with nominal P values <.01 in trios affected by both ADHD and enuresis

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244.e2

rs2977874 rs7006944 rs2339149 rs2339151 rs7013893 rs10504908 rs17668660 rs843094 rs1480895 rs2318878 rs12155746 rs7819896 rs2959644 rs7001509 rs17460250 rs1026228 rs2053931 rs4734506 rs4734508 rs2514616 rs166995 rs9642972 rs6468782 rs2226399 rs3018437 rs6996424 rs7821869 rs627350 rs16872638 rs10464844 rs1383592 rs1954732 rs281712 rs281713 rs11777363 rs1955031 rs9969501 rs11992820 rs2349200 rs10111798 rs1353645 rs12677646 rs4236795 rs17520 rs12546383 rs4374960 rs6981930 rs6988997 rs4236799 rs7817222

Table V. Continued

87029998 89437710 91485181 91485361 91632313 92554048 92600330 92616012 93426796 96652727 96706088 96820979 99157427 101694512 101890196 102076877 102082773 102085020 102125133 102161849 102178213 102673482 102681696 102723358 105577567 105617757 105792483 106178193 106362114 106488930 106499852 108317089 108612603 108614231 109480239 109495231 109509927 109560981 109680923 109715777 109726901 110042208 110060813 110071256 110079897 110093080 110101114 110106246 110145208 110151113 intron intron

intron intron intron intron intron

intron intron

intron intron intron intron

C8orf47† SNX31

GRHL2 GRHL2 GRHL2 LRP12 LRP12

ZFPM2 ZFPM2

LOC100128549† LOC100128549† LOC100128549† TTC35

A T C A G C A A T A G T C A T T G C A G C T T G C T G A G A G C T G C C G G C T G C G C C G C G A A

C C T G A T G G C C A C T G C C A T C A T C C A T C A G T G A T G T T T A A T C T A A T T A T A G G

0.405 0.286 0.337 0.343 0.357 0.057 0.052 0.205 0.194 0.212 0.255 0.269 0.467 0.085 0.038 0.495 0.500 0.419 0.363 0.448 0.458 0.458 0.429 0.495 0.113 0.203 0.236 0.363 0.052 0.241 0.222 0.088 0.250 0.297 0.274 0.283 0.341 0.264 0.114 0.101 0.113 0.222 0.476 0.462 0.190 0.189 0.437 0.288 0.392 0.392

15 12 12 12 11 1 10 25 5 24 11 27 38 2 0 15 39 35 16 15 18 13 13 12 19 25 27 13 11 9 9 2 30 35 31 32 35 31 3 3 4 26 18 18 25 25 11 27 13 13

34 29 32 31 29 11 1 9 20 8 27 11 15 12 8 38 15 16 35 41 39 33 30 30 3 8 11 30 0 29 27 13 13 12 13 14 16 13 14 14 17 10 41 38 7 7 33 11 35 35

0.441 0.414 0.375 0.387 0.379 0.091 10 2.778 0.25 3 0.407 2.455 2.533 0.167 0 0.395 2.6 2.188 0.457 0.366 0.462 0.394 0.433 0.4 6.333 3.125 2.455 0.433 NA 0.310 0.333 0.154 2.308 2.917 2.385 2.286 2.188 2.385 0.214 0.214 0.235 2.6 0.439 0.474 3.571 3.571 0.333 2.455 0.371 0.371

7.367 7.049 9.091 8.395 8.1 8.333 7.364 7.529 9 8 6.737 6.737 9.981 7.143 8 9.981 10.67 7.078 7.078 12.07 7.737 8.696 6.721 7.714 11.64 8.758 6.737 6.721 11 10.53 9 8.067 6.721 11.26 7.364 7.043 7.078 7.364 7.118 7.118 8.048 7.111 8.966 7.143 10.13 10.13 11 6.737 10.08 10.08

.006642 .007932 .002569 .003762 .004427 .003892 .006656 .006070 .002700 .004678 .009444 .009444 .001582 .007526 .004678 .001582 .001091 .007802 .007802 .000512 .005411 .003190 .009529 .005479 .0006467 .003083 .009444 .009529 .0009111 .001177 .002700 .004509 .009529 .000794 .006656 .007955 .007802 .006656 .007633 .007633 .004556 .007661 .002750 .007526 .001463 .001463 .0009111 .009444 .001496 .001496

1 1 1 1 1 1 1 1 1 1 1 1 .9996 1 1 .9996 .998 1 1 .9204 1 1 1 1 .9644 1 1 1 .9919 .9985 1 1 1 .9863 1 1 1 1 1 1 1 1 1 1 .9996 .9996 .9919 1 .9996 .9996 (continued )

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Elia et al

12q

110154994 110159634 110164809 110170859 110173379 110174322 110177001 110264383 110268792 110282723 110283693 110288911 110318905 110337280 110369755 110371174 110371223 115087798 115341476 115363037 116164991 118375544 118390032 118971109 119625666 120186415 121662368 122210873 122251523 122261243 123479292 124576109 126018079 126024582 126037840 126333533 126663920 127297319 128020911 128642480 50998762 51085568

51213665 52741396 54650588 59149958 59232968

rs4506180 rs3110052 rs3110040 rs3134105 rs3134108 rs3134113 rs12544197 rs7819201 rs10091155 rs4236804 rs4291240 rs10087444 rs2980635 rs1458924 rs2980614 rs2980618 rs2980619 rs10086932 rs7819086 rs16885695 rs7013769 rs1472487 rs4876717 rs13280053 rs7834992 rs16892035 rs4871072 rs2163920 rs1604898 rs1354506 rs10217064 rs10505434 rs2077670 rs2590665 rs3909714 rs10091027 rs7016867 rs1386796 rs2129546 rs12543106 rs13377620 rs1395342

rs669379 rs2067554 rs2069408 rs10877434 rs4758868

Table V. Continued

intron intron intron intron

intron

EXT1 SAMD12 COLEC10 SNTB1

NSMCE2

CDK2

intron

intron intron 5’UTR

intron intron exon exon

NUDCD1 NUDCD1 NUDCD1 NUDCD1

KRT83 KRT82 LOC100128683†

intron intron intron intron

TRHR TRHR TRHR TRHR

A C A G A

T C A G G T G G C C T T T C A T T T C G T G T G G T A A T C T A G C G A G C G A G G G T G A G

G T G A T C A T T A C C G T G C G C T A C A C T A C G G C T C G T T A G A T A G A T 0.324 0.387 0.310 0.452 0.490

0.481 0.167 0.392 0.380 0.392 0.392 0.439 0.486 0.340 0.348 0.354 0.486 0.390 0.356 0.377 0.337 0.480 0.382 0.419 0.074 0.071 0.114 0.179 0.457 0.283 0.033 0.238 0.377 0.495 0.420 0.448 0.062 0.306 0.274 0.214 0.255 0.179 0.348 0.420 0.316 0.167 0.076 14 13 33 33 32

13 22 13 13 12 12 35 38 31 30 32 38 33 31 15 30 35 41 15 11 2 17 24 12 13 0 23 36 17 34 38 10 8 30 23 24 6 32 37 11 8 1 32 32 14 14 12

35 7 38 37 39 39 15 16 13 12 13 16 12 12 37 11 13 17 37 1 13 4 7 29 31 7 7 15 36 13 18 1 24 9 8 9 20 14 15 29 25 12 0.438 0.406 2.357 2.357 2.667

0.371 3.143 0.342 0.351 0.308 0.308 2.333 2.375 2.385 2.5 2.462 2.375 2.75 2.583 0.405 2.727 2.692 2.412 0.405 11 0.154 4.25 3.429 0.414 0.419 0 3.286 2.4 0.472 2.615 2.111 10 0.333 3.333 2.875 2.667 0.3 2.286 2.467 0.379 0.32 0.083 7.043 8.022 7.681 7.681 9.091

10.08 7.759 12.25 11.52 14.29 14.29 8 8.963 7.364 7.714 8.022 8.963 9.8 8.395 9.308 8.805 10.08 9.931 9.308 8.333 8.067 8.048 9.323 7.049 7.364 7 8.533 8.647 6.811 9.383 7.143 7.364 8 11.31 7.258 6.818 7.538 7.043 9.308 8.1 8.758 9.308 .007955 .004621 .005581 .005581 .002569

.001496 .005346 .000464 .0006885 .0001564 .0001564 .004678 .002755 .006656 .005479 .004621 .002755 .001745 .003762 .002282 .003004 .001496 .001625 .002282 .003892 .004509 .004556 .002263 .007932 .006656 .008151 .003487 .003276 .009058 .002190 .007526 .006656 .004678 .0007719 .007058 .009023 .00604 .007955 .002282 .004427 .003083 .002282 .9999 .9971

.9817

.9996 .9997

.9997

.9035 .9773 .4881 .4881

.9996

.9984 (continued )

1 1 1 1

1 1 1 1 1 1

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

1 1 1

1 1 1 1 1 1

1

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244.e4

59271311 59273630 60557800 61894165 62602704 62605000 62627372 62669937 64176415 64219990 66662916 66664693 66837082 67724841 67728323 67983633 67990238 68112360 70943649 71398730 71398735 71432163 71473567 73955902

73977054

73981709 73982697 73985339 73993663 74014152

74027150 74027150 74339685 74344078 74573506 74576953 74578155 75032838 75761976 75762235 77703541 81693585 82045414

rs1995471 rs1393988 rs10877757 rs6581474 rs11175208 rs9668434 rs10878096 rs3741607 rs2014427 rs1389800 rs10878720 rs10878721 rs2069716 rs12812855 rs11836417 rs11177587 rs317666 rs10878983 rs4254109 rs12099668 rs1433255 rs1968459 rs11179361 rs7301561

rs6582285

rs11180455 rs7975661 rs11831200 rs11837697 rs3087687

rs7298343 rs7298343 rs17115456 rs10879956 rs7958938 rs7306547 rs7314267 rs1517722 rs762786 rs762785 rs4842407 rs4565970 rs4882436

Table V. Continued

intron intron intron intron intron

intron

intron intron intron 3’ intron intron intron intron intron intron intron intron

intron intron intron

FAM19A2 SRGAP1 SRGAP1 SRGAP1 SRGAP1

IFNG

CAPS2 LOC100130268† CAPS2 LOC100130268† CAPS2 CAPS2 CAPS2 CAPS2 GLIPR1L1 CAPS2 GLIPR1L1 CAPS2

CSRP2 CSRP2 TMTC2

G A A A T A T C C G T C

G G C C G G T T A C T

C A T G G

A

T G G A A

C

G C G C C T G C G C C T G G G T T A G A G A T A

0.176 0.392 0.170 0.142 0.094 0.033 0.409 0.405 0.253 0.146 0.466

0.349

0.269 0.281 0.330 0.338 0.344

0.297

0.439 0.429 0.152 0.038 0.429 0.250 0.330 0.443 0.452 0.042 0.203 0.203 0.052 0.333 0.343 0.118 0.113 0.414 0.330 0.167 0.038 0.100 0.033 0.297

23 27 6 6 3 7 29 27 4 15 16

14

10 11 15 15 15

13

33 33 21 0 14 9 15 19 13 0 8 8 10 11 10 17 13 10 32 5 7 3 7 13

6 11 24 19 16 0 12 9 19 3 36

35

32 31 34 33 35

31

13 13 5 7 33 28 35 41 30 8 23 23 1 32 31 2 1 34 14 26 0 15 0 31

3.833 2.455 0.25 0.316 0.188 NA 2.417 3 0.211 5 0.444

0.4

0.313 0.355 0.441 0.455 0.429

0.419

2.538 2.538 4.2 0 0.424 0.321 0.429 0.463 0.433 0 0.348 0.348 10 0.344 0.323 8.5 13 0.294 2.286 0.192 NA 0.2 NA 0.419

9.966 6.737 10.8 6.76 8.895 7 7.049 9 9.783 8 7.692

9

11.52 9.524 7.367 6.75 8

7.364

8.696 8.696 9.846 7 7.681 9.757 8 8.067 6.721 8 7.258 7.258 7.364 10.26 10.76 11.84 10.29 13.09 7.043 14.23 7 8 7 7.364

.001595 .009444 .001015 .009322 .002860 .008151 .007932 .002700 .001762 .004678 .005546

.002700

.0006871 .002028 .006642 .009375 .004678

.006656

.00319 .00319 .001702 .008151 .005581 .001787 .004678 .004509 .009529 .004678 .007058 .007058 .006656 .001363 .001039 .0005791 .001341 .0002967 .007955 .0001621 .008151 .004678 .008151 .006656

.9873 1 .9307 1 .9998 1 1 .9993 .9942 1 1 (continued )

.9993

.8429 .9959 1 1 1

1

.9999 .9999 .991 1 1 .9949 1 1 1 1 1 1 1 .9761 .9421 .7701 .9735 .5172 1 .329 1 1 1 1



T

A T T T T G A T A A T C A T A C C G A G A G C G

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Elia et al

rs7296849 rs12020645 rs1414932 rs9549055 rs9549056 rs7984035 rs4943731 rs7986407 rs9549244 rs7328594 rs4943804 rs4943805 rs4942023 rs9594738 rs12428023 rs9533433 rs9594916 rs9316004 rs1228262 rs17326362 rs17326461 rs7338889 rs1536002 rs2740517 rs12871645 rs3095159 rs9596772 rs10507576 rs8141815 rs140500 rs17540103 rs9612921 rs134717 rs3788395 rs655581 rs5761606 rs17404243 rs16983066 rs114559 rs134926 rs134931 rs713812 rs5752486 rs5752638

82048539 38239638 39556787 39566093 39572419 39593770 39610941 40077798 40116685 40151764 40167994 40168080 40573611 41850145 42452697 42696077 42726170 42735284 45786586 46796030 46797666 46882572 47324955 49660561 49829566 49850299 52734959 52751727 20516139 21921584 21962579 23986279 24832199 25063286 25074784 25288297 25295456 25615798 25744667 25745690 25749716 25768138 25815597 26512757 intron intron intron intron

intron

SEZ6L SEZ6L TPST2 TPST2

MN1

intron intron intron intron

EPSTI1 ENOX1 ENOX1 ENOX1

intron intron intron

intron intron

FOXO1A FOXO1A

MAPK1 BCR BCR

intron

FREM2

MAF, minor allele frequency; OR, odds ratio. *Number of times the minor allele is transmitted (T) and untransmitted (U). †Hypothetical or predicted genes.

22q

13q

Table V. Continued C C T A A G G A G T A A G C C A T A T C C C G C G T G G G G A G C G C G G G C G T T A T

T A C G G T A G A C G G A T T C C G C A A T A T T C A A A A G A T A T T T A T T G C G C

0.418 0.368 0.423 0.392 0.405 0.352 0.500 0.305 0.307 0.290 0.295 0.288 0.189 0.438 0.127 0.274 0.236 0.229 0.142 0.357 0.382 0.453 0.119 0.086 0.042 0.094 0.081 0.052 0.057 0.189 0.165 0.442 0.118 0.212 0.467 0.057 0.080 0.042 0.283 0.283 0.210 0.245 0.495 0.224

17 29 11 12 33 34 16 11 11 9 10 10 7 14 6 27 25 24 20 17 19 39 20 2 9 3 14 10 1 8 7 12 6 26 13 11 12 9 10 11 7 11 32 26

37 12 33 31 10 13 36 27 28 25 26 27 22 41 19 10 8 8 6 39 39 19 3 13 0 15 3 1 10 23 21 37 19 10 31 0 2 0 32 33 22 27 14 10

0.460 2.417 0.333 0.387 3.3 2.615 0.444 0.407 0.393 0.36 0.385 0.370 0.318 0.342 0.316 2.7 3.125 3 3.333 0.436 0.487 2.053 6.667 0.154 NA 0.2 4.667 10 0.1 0.348 0.333 0.324 0.316 2.6 0.419 NA 6 NA 0.313 0.333 0.318 0.407 2.286 2.6

7.407 7.049 11 8.395 12.3 9.383 7.692 6.737 7.41 7.529 7.111 7.811 7.759 13.25 6.76 7.811 8.758 8 7.538 8.643 6.897 6.897 12.57 8.067 9 8 7.118 7.364 7.364 7.258 7 12.76 6.76 7.111 7.364 11 7.143 9 11.52 11 7.759 6.737 7.043 7.111

.006496 .007932 .000911 .003762 .000452 .002190 .005546 .009444 .006485 .006070 .007661 .005193 .005346 .0002719 .009322 .005193 .003083 .004678 .00604 .003283 .008636 .008636 .000393 .004509 .002700 .004678 .007633 .006656 .006656 .007058 .008151 .000355 .009322 .007661 .006656 .000911 .007526 .002700 .000687 .000911 .005346 .009444 .007955 .007661

.6923 .9909 .4336 .9397 .9998 1 .9999 .9999 1 .9997 .9997 .2741 1 .9997 .9854 .9996 .9999 .9883 1 1 .3708 .9968 .9781 .9996 1 1 .9996 .9996 1 .2963 1 .9999 .9996 .627 .9998 .9662 .5384 .627 .9979 1 1 .9999

1 1

August 2009

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