Melissa A Richard1, Pagna Sok1, Stephen Canon2,3, Austin L Brown1, Erin C Peckham-Gregory1, Wendy N Nembhard4, Suzan L Carmichael5, Erik A Ehli6, Noah A Kallsen6, Shanna A Peyton6, Gareth E Davies6, Ashay Patel2,3, Ismael Zamilpa2,3, Richard A Wyatt7, Charlotte A Hobbs8, Michael E Scheurer1, Philip J Lupo1. 1. Department of Pediatrics, Baylor College of Medicine, Houston, Texas. 2. Arkansas Children's Hospital, Little Rock, Arkansas. 3. Department of Urology, University of Arkansas for Medical Sciences, Little Rock, Arkansas. 4. Department of Epidemiology, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences and Arkansas Children's Research Institute, Little Rock, Arkansas. 5. Department of Pediatrics, Stanford University School of Medicine, California. 6. Avera Institute for Human Genetics, Sioux Falls, South Dakota. 7. School of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas. 8. Division of Birth Defects Research, Department of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, Arkansas Children's Research Institute, Little Rock, Arkansas.
Abstract
BACKGROUND: Recent genome-wide association studies of hypospadias have implicated the role of genetic variants in or near the diacylglycerol kinase kappa (DGKK) gene. However, these variants are largely identified among samples of mild and moderate hypospadias cases. Therefore, we evaluated previously identified DGKK variants among second- and third-degree hypospadias cases and controls recruited in Arkansas, a state characterized by a high birth prevalence of hypospadias. METHODS: Second- and third-degree hypospadias non-Hispanic white cases (n = 36 and n = 9, respectively) and controls (n = 45) were recruited at Arkansas Children's Hospital. Preputial tissue was collected on cases and controls between 2013 and 2017. Cases and controls were genotyped using the Illumina Infinium Global Screening Array. We used logistic regression models to assess the association of genotyped and imputed genetic variants mapped to the DGKK region with second- and third-degree hypospadias. RESULTS: All families self-reported as non-Hispanic white and genetic principal component analyses did not demonstrate evidence of population stratification. Five DGKK variants previously reported as associated with hypospadias were identified in the genotype data. None of the variants were associated with second- or third-degree hypospadias (range of odds ratios = 0.7-0.9, all p > .05). CONCLUSIONS: In our analyses, genetic variation in DGKK does not play a role in the development of moderate and severe hypospadias. Our findings provide support to the etiologic heterogeneity of hypospadias by all classifications of severity.
BACKGROUND: Recent genome-wide association studies of hypospadias have implicated the role of genetic variants in or near the diacylglycerol kinase kappa (DGKK) gene. However, these variants are largely identified among samples of mild and moderate hypospadias cases. Therefore, we evaluated previously identified DGKK variants among second- and third-degree hypospadias cases and controls recruited in Arkansas, a state characterized by a high birth prevalence of hypospadias. METHODS: Second- and third-degree hypospadias non-Hispanic white cases (n = 36 and n = 9, respectively) and controls (n = 45) were recruited at Arkansas Children's Hospital. Preputial tissue was collected on cases and controls between 2013 and 2017. Cases and controls were genotyped using the Illumina Infinium Global Screening Array. We used logistic regression models to assess the association of genotyped and imputed genetic variants mapped to the DGKK region with second- and third-degree hypospadias. RESULTS: All families self-reported as non-Hispanic white and genetic principal component analyses did not demonstrate evidence of population stratification. Five DGKK variants previously reported as associated with hypospadias were identified in the genotype data. None of the variants were associated with second- or third-degree hypospadias (range of odds ratios = 0.7-0.9, all p > .05). CONCLUSIONS: In our analyses, genetic variation in DGKK does not play a role in the development of moderate and severe hypospadias. Our findings provide support to the etiologic heterogeneity of hypospadias by all classifications of severity.
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Authors: Melissa A Richard; Pagna Sok; Stephen Canon; Wendy N Nembhard; Austin L Brown; Erin C Peckham-Gregory; Minh Ton; Erik A Ehli; Noah A Kallsen; Shanna A Peyton; Gareth E Davies; Ashay Patel; Ismael Zamilpa; Charlotte A Hobbs; Michael E Scheurer; Philip J Lupo Journal: Sci Rep Date: 2020-07-29 Impact factor: 4.379
Authors: Melissa A Richard; Jenil Patel; Renata H Benjamin; Emine Bircan; Stephen J Canon; Lisa K Marengo; Mark A Canfield; A J Agopian; Philip J Lupo; Wendy N Nembhard Journal: JAMA Netw Open Date: 2022-07-01