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EB Research - Pediatric Epidemiology

Genetic Factors in Birth Defects Study

The Genetic Factors in Birth Defects Study is a multicenter, multidisciplinary study led by NICHD to identify genetic risk factors for a wide range of major birth defects. The collaborating institutions are NICHD, The National Human Genome Research Institute, The New York State Department of Health, and The University of Iowa. The New York State Congenital Malformations Registry has identified approximately 13,000 children who have major birth defects and suitable unaffected controls from among all New York births. This information has been linked to blood spots retained after testing in the newborn period. DNA has been extracted and has been used to test for genetic variants associated with these birth defects.

A variety of defects has been selected and analyzed using a candidate gene approach. To date genetic variants (single nucleotide polymorphisms) have been identified and the results reported in the literature for:

  • Omphalocele
  • Hirschsprung's disease
  • Limb defects
  • Ano-rectal atresia

Additional defects are currently being examined. Because of the very large number of affected children included in this study, it has been possible to examine relatively rare conditions such as non-syndromic omphalocele.

The large number of cases has also enabled the group to make substantial contributions to consortia performing genome wide association studies. The group is currently collaborating in one such study examining craniosynostosis and another examining pyloric stenosis. The group is interested in exploring collaborations with investigators conducting such studies.

The group has recently demonstrated the feasibility of conducting genome wide studies of copy number variants using DNA obtained from blood spots. This has opened a whole new area of investigation. Because of the very large number of subjects available for study, the group has sufficient numbers to look for copy number variants associated with rare defects. Many such birth defects are now being tested for the presence of copy number variants.

Principal Investigator

James Mills, M.D., M.S.

DIPHR Collaborators

Extramural Collaborators

  • Denise Kay, Ph.D., New York State Health Dept.
  • Michele Caggana, Ph.D., New York State Health Dept.
  • Marilyn Browne, Ph.D., New York State Health Dept. and State University N.Y. Albany
  • Charlotte Druschel, M.D., New York State Health Dept. and State University N.Y. Albany
  • Lawrence Brody, Ph.D., NHGRI, NIH
  • Ruzong Fan, Ph.D., Georgetown University
  • Nansi Boghossian, Ph.D., University of South Carolina

Selected Publications

  • Zhang W, Yang L, Tang LL, Liu A, Mills JL, Sun Y, Li Q. GATE: an efficient procedure in study of pleiotropic genetic associations. BMC Genomics. 2017;18(1):552. PMID: 28732532. PMCID: PMC5521155
  • Dimopoulos A, Sicko RJ, Kay DM, Rigler SL, Fan R, Romitti PA, Browne ML, Druschel CM, Caggana M, Brody LC, Mills JL. Copy number variants in a population-based investigation of Klippel-Trenaunay syndrome. Am J Med Genet A. 2017;173(2):352-9. PMID: 27901321
  • Chiu CY, Jung J, Chen W, Weeks DE, Ren H, Boehnke M, Amos CI, Liu A, Mills JL, Ting Lee ML, Xiong M, Fan R. Meta-analysis of quantitative pleiotropic traits for next-generation sequencing with multivariate functional linear models. Eur J Hum Genet. 2017;25(3):350-9. PMID: 28000696. PMCID: PMC5315507 [Available on 2018-03-01]
  • Dimopoulos A, Sicko RJ, Kay DM, Rigler SL, Druschel CM, Caggana M, Browne ML, Fan R, Romitti PA, Brody LC, Mills JL. Rare copy number variants in a population-based investigation of hypoplastic right heart syndrome. Birth Defects Res. 2017;109(1):8-15. PMID: 28009100. PMCID: PMC5388571 [Available on 2018-01-20]
  • Chiu CY, Jung J, Wang Y, Weeks DE, Wilson AF, Bailey-Wilson JE, Amos CI, Mills JL, Boehnke M, Xiong M, Fan R. A comparison study of multivariate fixed models and Gene Association with Multiple Traits (GAMuT) for next-generation sequencing. Genet Epidemiol. 2017;41(1):18-34. PMID: 27917525. PMCID: PMC5154843 [Available on 2018-01-01]
  • Fan R, Chiu CY, Jung J, Weeks DE, Wilson AF, Bailey-Wilson JE, Amos CI, Chen Z, Mills ML, Xiong M. A Comparison Study of Fixed and Mixed Effect Models for Gene Level Association Studies of Complex Traits. Genet Epidemiol. 2016;40(8):702-21. PMID: 27374056
  • Hagen EM, Sicko RJ, Kay DM, Rigler SL, Dimopoulos A, Ahmad S, Doleman MH, Fan R, Romitti PA, Browne ML, Caggana M, Brody LC, Shaw GM, Jelliffe-Pawlowski LL, Mills JL. Copy-number variant analysis of classic heterotaxy highlights the importance of body patterning pathways. Hum Genet. 2016;135(12):1355-64. PMID: 27637763. PMCID: PMC5065782 [Available on 2017-12-01]
  • Sicko RJ, Browne ML, Rigler SL, Druschel CM, Liu G, Fan R, Romitti PA, Caggana M, Kay DM, Brody LC, Mills JL. Genetic Variants in Isolated Ebstein Anomaly Implicated in Myocardial Development Pathways. PLoS One. 2016;11(10):e0165174. PMID: 27788187. PMCID: PMC5082909
  • Rigler SL, Kay DM, Sicko RJ, Fan R, Liu A, Caggana M, Browne ML, Druschel CM, Romitti PA, Brody LC, Mills JL. Novel copy-number variants in a population-based investigation of classic heterotaxy. Genet Med. 2015;17(5):348-57. PMID: 25232849
  • Wang Y, Liu A, Mills JL, Boehnke M, Wilson AF, Bailey-Wilson JE, Xiong M, Wu CO, Fan R. Pleiotropy analysis of quantitative traits at gene level by multivariate functional linear models. Genet Epidemiol. 2015;39(4):259-75. PMID: 25809955. PMCID: PMC4443751
  • Fan R, Wang Y, Mills JL, Carter TC, Lobach I, Wilson AF, Bailey-Wilson JE, Weeks DE, Xiong M. Generalized functional linear models for gene-based case-control association studies. Genet Epidemiol. 2014;38(7):622-37. PMID: 25203683. PMCID: PMC4189986
  • Li Q, Xiong W, Chen J, Zheng G, Li Z, Mills JL, Liu A. A robust test for quantitative trait analysis with model uncertainty in genetic association studies. Statistics and Its Interface. 2014;7(1):61-68. http://dx.doi.org/10.4310/SII.2014.v7.n1.a7 External Web Site Policy
  • Feenstra B, Geller F, Carstensen L, Romitti PA, Körberg IB, Bedell B, Krogh C, Fan R, Svenningsson A, Caggana M, Nordenskjöld A, Mills JL, Murray JC, Melbye M. Plasma lipids, genetic variants near APOA1, and the risk of infantile hypertrophic pyloric stenosis. JAMA. 2013;310(7):714-21. PMID: 23989729. PMCID: PMC4031654
  • Fan R, Wang Y, Mills JL, Wilson AF, Bailey-Wilson JE, Xiong M. Functional linear models for association analysis of quantitative traits. Genet Epidemiol. 2013;37(7):726-42. PMID: 24130119. PMCID: PMC4163942
  • Fan R, Lee A, Lu Z, Liu A, Troendle JF, Mills JL. Association analysis of complex diseases using triads, parent-child dyads and singleton monads. BMC Genet. 2013;14:78. PMID: 24007308. PMCID: PMC3844511
  • Carter TC, Kay DM, Browne ML, Liu A, Romitti PA, Kuehn D, Conley MR, Caggana M, Druschel CM, Brody LC, Mills JL. Anorectal atresia and variants at predicted regulatory sites in candidate genes. Ann Hum Genet. 2013;77(1):31-46. PMID: 23127126. PMCID: PMC3535506
  • Mills JL, Carter TC, Kay DM, Browne ML, Brody LC, Liu A, Romitti PA, Caggana M, Druschel CM. Folate and vitamin B12-related genes and risk for omphalocele. Hum Genet. 2012;131(5):739-46. PMID: 22116453. PMCID: PMC3374579
  • Carter TC, Kay DM, Browne ML, Liu A, Romitti PA, Kuehn D, Conley MR, Caggana M, Druschel CM, Brody LC, Mills JL. Hirschsprung’s disease and variants in genes that regulate enteric neural crest cell proliferation, migration and differentiation. J Hum Genet. 2012;57(8):485-93. PMID: 22648184. PMCID: PMC3503526
  • Browne ML, Carter TC, Kay DM, Kuehn D, Brody LC, Romitti PA, Liu A, Caggana M, Druschel CM, Mills JL. Evaluation of genes involved in limb development, angiogenesis, and coagulation as risk factors for congenital limb deficiencies. Am J Med Genet A. 2012;158A(10):2463-72. PMID: 22965740. PMCID: PMC3448837
  • Justice CM, Yagnik G, Kim Y, Peter I, Jabs EW, Erazo M, Ye X, Ainehsazan E, Shi L, Cunningham ML, Kimonis V, Roscioli T, Wall SA, Wilkie AO, Stoler J, Richtsmeier JT, Heuzé Y, Sanchez-Lara PA, Buckley MF, Druschel CM, Mills JL, Caggana M, Romitti PA, Kay DM, Senders C, Taub PJ, Klein OD, Boggan J, Zwienenberg-Lee M, Naydenov C, Kim J, Wilson AF, Boyadjiev SA. A genome-wide association study identifies susceptibility loci for nonsyndromic sagittal craniosynostosis near BMP2 and within BBS9. Nat Genet. 2012;44(12):1360-4. PMID: 23160099. PMCID: PMC3736322
  • Beaty TH, Murray JC, Marazita ML, Munger RG, Ruczinski I, Hetmanski JB, Liang KY, Wu T, Murray T, Fallin MD, Redett RA, Raymond G, Schwender H, Jin SC, Cooper ME, Dunnwald M, Mansilla MA, Leslie E, Bullard S, Lidral AC, Moreno LM, Menezes R, Vieira AR, Petrin A, Wilcox AJ, Lie RT, Jabs EW, Wu-Chou YH, Chen PK, Wang H, Ye X, Huang S, Yeow V, Chong SS, Jee SH, Shi B, Christensen K, Melbye M, Doheny KF, Pugh EW, Ling H, Castilla EE, Czeizel AE, Ma L, Field LL, Brody L, Pangilinan F, Mills JL, Molloy AM, Kirke PN, Scott JM, Arcos-Burgos M, Scott AF. A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4. Nat Genet. 2010;42(6):525-9. PMID: 20436469. PMCID: PMC2941216
  • Mills JL, Troendle J, Conley MR, Carter T, Druschel CM. Maternal obesity and congenital heart defects: a population-based study. Am J Clin Nutr. 2010;91(6):1543-9. PMID: 20375192. PMCID: PMC2869507

Contact Information

Name: Dr Enrique Fabian Schisterman
Chief and Senior Investigator
Epidemiology Branch
Phone: 301-435-6893
Fax: 301-402-2084
E-mail: schistee@mail.nih.gov

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