Hypospadias is a common congenital condition in boys in which the urethra opens on the underside of the penis. We performed a genome-wide association study on 1,006 surgery-confirmed hypospadias ...cases and 5,486 controls from Denmark. After replication genotyping of an additional 1,972 cases and 1,812 controls from Denmark, the Netherlands and Sweden, 18 genomic regions showed independent association with P < 5 × 10(-8). Together, these loci explain 9% of the liability to developing this condition. Several of the identified regions harbor genes with key roles in embryonic development (including HOXA4, IRX5, IRX6 and EYA1). Subsequent pathway analysis with GRAIL and DEPICT provided additional insight into possible genetic mechanisms causing hypospadias.
What's known on the subject? and What does the study add?
The various phenotypes of hypospadias may result from disturbances of dissimilar embryonic processes in different time windows, suggesting ...aetiological heterogeneity; however, only a few studies have investigated the risk factors for the different hypospadias phenotypes.
The study confirmed that genetic predisposition possibly plays a role in anterior and middle hypospadias, as shown by the large effect estimates for familial occurrence of these forms of hypospadias. By contrast, the posterior phenotype was more often associated with pregnancy‐related factors, such as primiparity, preterm delivery, and being small for gestational age. New findings were that hormone‐containing contraceptive use after conception increased the risk of middle and posterior hypospadias, while multiple pregnancies were associated with the posterior form in particular.
Objective
To identify specific risk factors for different phenotypes of hypospadias that may arise as a result of dissimilar embryonic processes in different time windows.
Patients and Methods
A total of 405 hypospadias cases and 627 male controls were included in a Dutch case–control study.
Medical records of cases were reviewed to determine the anatomical location of the urethral opening, while demographic, lifestyle and pregnancy‐related risk factor data were obtained from self‐administered questionnaires.
Multivariable and multinomial logistic regression analyses were used to calculate effect estimates for the group containing all cases of hypospadias and for the different hypospadias phenotypes.
Results
Cases were subdivided into anterior (glandular and coronal; 59%), middle (penile; 29%) and posterior (penoscrotal, scrotal and perineal; 12%) hypospadias.
Being a twin/triplet, primiparity, preterm delivery, and being small for gestational age were associated with hypospadias, particularly in posterior cases.
Family history of hypospadias increased the risk of hypospadias, an effect that seemed to be more predominant in anterior and middle forms.
Maternal obesity seemed to increase the risk of hypospadias in general, and hormone‐containing contraceptive use during pregnancy especially increased the risk of middle and posterior hypospadias.
Conclusions
Our study provides some indications for aetiological heterogeneity of hypospadias, separating anterior and middle phenotypes from posterior hypospadias.
Future research should continue to try to establish which specific risk factors and mechanisms may differ according to hypospadias phenotype.
Purpose Hypospadias is a common congenital malformation of the male external genitalia. Association studies for single nucleotide polymorphisms in genes encoding steroid 5alpha-reductase, estrogen ...receptors 1 and 2, and activating transcription factor 3 have been equivocal. We examined whether nonreplication of findings for 4 single nucleotide polymorphisms in these genes could be due to interaction with environmental exposures. Materials and Methods We genotyped 712 Dutch hypospadias case-parent triads for the 4 single nucleotide polymorphisms, used questionnaire information to determine exposures and performed association tests using the log-linear approach. We studied gene-environment interactions for the 4 single nucleotide polymorphisms with exposure to estrogens, cytokines or cigarette smoke, multiple birth, being born small for gestational age, maternal hypertension or preeclampsia, high body mass index or primiparity. In addition, the presence of maternal genetic and parent of origin effects was tested. Results Gene-environment interactions were identified for rs523349 in SRD5A2 with estrogen exposure and maternal hypertension or preeclampsia, as well as for rs11119982 in ATF3 with exposure to cytokines. Both single nucleotide polymorphisms seemed to influence hypospadias risk only in exposed cases. For rs6932902 in ESR1 only maternally derived alleles appeared to increase hypospadias risk in offspring. Conclusions Interactions between genetic and environmental factors may help to explain nonreplication in genetic studies of hypospadias.
Background
Hypospadias is a frequently occurring congenital anomaly in male infants, in which the opening of the urethra is located along the ventral side of the penis. Although various studies ...attempted to identify its causes, the aetiology of the majority of hypospadias cases remains poorly understood. Maternal hypertensive disorders are believed to be associated with hypospadias, but the results of previous studies are not consistent, especially for subtypes of hypospadias.
Objectives
To investigate the associations between maternal hypertensive disorders, stratified by pharmacological treatment, and the occurrence of hypospadias divided into subtypes in a large population‐based case‐control study.
Methods
We included 887 hypospadias cases and 1005 male controls from the AGORA data‐ and biobank. Cases and controls were born in the periods 1975‐2016 and 1990‐2011, respectively. All data were collected in the period 2004‐2018. Maternal questionnaires were used to obtain information on hypertensive disorders during pregnancy, antihypertensive medication treatment, and potential confounders. Adjusted odds ratios (aORs) with 95% confidence intervals (CIs) for the associations between hypertensive disorders and hypospadias were estimated using logistic regression.
Results
Hypertensive disorders were reported by 15.3% of the women in this study. Maternal hypertensive disorders in general, chronic hypertension, and gestational hypertension were not associated with hypospadias or its subtypes. Preeclampsia was associated with posterior hypospadias (aOR 3.09, 95% CI 1.49, 6.43), whether it was untreated (aOR 2.81, 95% CI 1.24, 6.38) or pharmacologically treated preeclampsia (aOR 4.96, 95% CI 1.08, 22.80).
Conclusions
Our findings indicate that preeclampsia is associated with posterior hypospadias, irrespective of pharmacological treatment. This result supports the hypothesis of aetiological heterogeneity among the subtypes of hypospadias, with pregnancy‐related risk factors being associated with the more severe types of hypospadias.
Hypospadias is a common congenital malformation of the male external genitalia. We performed a genome-wide association study using pooled DNA from 436 individuals with hypospadias (cases) and 494 ...controls of European descent and selected the highest ranked SNPs for individual genotyping in the discovery sample, an additional Dutch sample of 133 cases and their parents, and a Swedish series of 266 cases and 402 controls. Individual genotyping of two SNPs (rs1934179 and rs7063116) in DGKK, encoding diacylglycerol kinase κ, produced compelling evidence for association with hypospadias in the discovery sample (allele-specific odds ratio (OR) = 2.5, P = 2.5 × 10−11 and OR = 2.3, P = 2.9 × 10−9, respectively) and in the Dutch (OR = 3.9, P = 2.4 × 10−5 and OR = 3.8, P = 3.4 × 10−5) and Swedish (OR = 2.5, P = 2.6 × 10−8 and OR = 2.2, P = 2.7 × 10−6) replication samples. Expression studies showed expression of DGKK in preputial tissue of cases and controls, which was lower in carriers of the risk allele of rs1934179 (P = 0.047). We propose DGKK as a major risk gene for hypospadias.
Congenital solitary functioning kidney (CSFK) is a birth defect that occurs in 1:1500 children and predisposes them to kidney injury. Its aetiology is likely multifactorial. In addition to known ...monogenic causes and environmental risk factors, common genetic variation may contribute to susceptibility to CSFK. We performed a genome-wide association study among 452 patients with CSFK and two control groups of 669 healthy children and 5363 unaffected adults. Variants in two loci reached the genome-wide significance threshold of 5 × 10
, and variants in 30 loci reached the suggestive significance threshold of 1 × 10
. Of these, an identified locus with lead single nucleotide variant (SNV) rs140804918 (odds ratio 3.1,
-value = 1.4 × 10
) on chromosome 7 was most promising due to its close proximity to
, a gene known to be involved in kidney development. Based on their known molecular functions, both
and
could explain the suggestive significant association with lead SNV rs148413365 on chromosome 6. Our findings need replication in an independent cohort of CSFK patients before they can be established definitively. However, our analysis suggests that common variants play a role in CSFK aetiology. Future research could enhance our understanding of the molecular mechanisms involved.
The leading cause of end-stage renal disease in children is attributed to congenital anomalies of the kidney and urinary tract (CAKUT). Familial clustering and mouse models support the presence of ...monogenic causes. Genetic testing is insufficient as it mainly focuses on HNF1B and PAX2 mutations that are thought to explain CAKUT in 5–15% of patients. To identify novel, potentially pathogenic variants in additional genes, we designed a panel of genes identified from studies on familial forms of isolated or syndromic CAKUT and genes suggested by in vitro and in vivo CAKUT models. The coding exons of 208 genes were analyzed in 453 patients with CAKUT using next-generation sequencing. Rare truncating, splice-site variants, and non-synonymous variants, predicted to be deleterious and conserved, were prioritized as the most promising variants to have an effect on CAKUT. Previously reported disease-causing mutations were detected, but only five were fully penetrant causal mutations that improved diagnosis. We prioritized 148 candidate variants in 151 patients, found in 82 genes, for follow-up studies. Using a burden test, no significant excess of rare variants in any of the genes in our cohort compared with controls was found. Thus, in a study representing the largest set of genes analyzed in CAKUT patients to date, the contribution of previously implicated genes to CAKUT risk was significantly smaller than expected, and the disease may be more complex than previously assumed.
ABSTRACT
Background
Congenital solitary functioning kidney (CSFK) is an anomaly predisposing to hypertension, albuminuria and chronic kidney disease. Its aetiology is complex and includes genetic and ...environmental factors. The role of gene–environment interactions (G×E), although relevant for other congenital anomalies, has not yet been investigated. Therefore, we performed a genome-wide G×E analysis with six preselected environmental factors to explore the role of these interactions in the aetiology of CSFK.
Methods
In the AGORA (Aetiologic research into Genetic and Occupational/environmental Risk factors for Anomalies in children) data- and biobank, genome-wide single-nucleotide variant (SNV) data and questionnaire data on prenatal exposure to environmental risk factors were available for 381 CSFK patients and 598 healthy controls. Using a two-step strategy, we first selected independent significant SNVs associated with one of the six environmental risk factors. These SNVs were subsequently tested in G×E analyses using logistic regression models, with Bonferroni-corrected P-value thresholds based on the number of SNVs selected in step one.
Results
In step one, 7–40 SNVs were selected per environmental factor, of which only rs3098698 reached statistical significance (P = .0016, Bonferroni-corrected threshold 0.0045) for interaction in step two. The interaction between maternal overweight and this SNV, which results in lower expression of the Arylsulfatase B (ARSB) gene, could be explained by lower insulin receptor activity in children heterozygous for rs3098698. Eight other G×E interactions had a P-value <.05, of which two were biologically plausible and warrant further study.
Conclusions
Interactions between genetic and environmental factors may contribute to the aetiology of CSFK. To better determine their role, large studies combining data on genetic and environmental risk factors are warranted.
Graphical Abstract
Graphical Abstract
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