EB Research: 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

  • Boghossian NS, Sicko RJ, Giannakou A, Dimopoulos A, Caggana M, Tsai MY, Yeung EH, Pankratz N, Cole BR, Romitti PA, Browne ML, Fan R, Liu A, Kay DM, Mills JL. Rare copy number variants identified in prune belly syndrome. European Journal of Medical Genetics. 2018; 61(3):145-151. PMID: 29174092. PMCID: PMC5803418
  • Zhang W, Yang L, Tang LL, Liu A, Mills JL, Sun Y, Li Q. GATE: an efficient procedure in study of pleiotropic genetic associations. BioMed Central Genomics. 2017; 18(1):552. PMID: 28732532. PMCID: PMC5521155
  • Giannakou A, Sicko RJ, Zhang W, Romitti P, Browne ML, Caggana M, Brody LC, Jelliffe-Pawlowski L, Shaw GM, Kay DM, Mills JL. Copy number variants in Ebstein anomaly. Public Library of Science One. 2017; 12(12):e0188168. PMID: 29216221. PMCID: PMC5720705
  • Carter TC, Sicko RJ, Kay DM, Browne ML, Romitti PA, Edmunds ZL, Liu A, Fan R, Druschel CM, Caggana M, Brody LC, Mills JL. Copy-number variants and candidate gene mutations in isolated split hand/foot malformation. Journal of Human Genetics. 2017; 62(10):877-884. PMID: 28539665. PMCID: PMC5612852
  • 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. American Journal of Medical Genetics, Part A. 2017; 173(2):352-359. 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. European Journal of Human Genetics. 2017; 25(3):350-359. PMID: 28000696. PMCID: PMC5315507
  • 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 Research. 2017; 109(1):8-15. PMID: 28009100. PMCID: PMC5388571
  • 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. Genetic Epidemiology. 2017; 41(1):18-34. PMID: 27917525. PMCID: PMC5154843
  • Fan R, Chiu CY, Jung J, Weeks DE, Wilson AF, Bailey-Wilson JE, Amos CI, Chen Z, Mills JL, Xiong M. A Comparison Study of Fixed and Mixed Effect Models for Gene Level Association Studies of Complex Traits. Genetic Epidemiology. 2016; 40(8):702-721. PMID: 27374056. PMCID: PMC5567849
  • 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. Human Genetics. 2016; 135(12):1355-1364. PMID: 27637763. PMCID: PMC5065782
  • Mills JL, Dimopoulos A, Bailey RL. What is standing in the way of complete prevention of folate preventable neural tube defects? Birth Defects Research Part A: Clinical and Molecular Teratology. 2016; 106(7):517-519.  PMID: 27418028.  PMCID: PMC4948865
  • 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. Public Library of Science 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. Genetics in Medicine. 2015; 17(5):348-357. PMID: 25232849. PMCID: PMC5901701
  • 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. Genetic Epidemiology. 2015; 39(4):259-275. 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. Genetic Epidemiology. 2014; 38(7):622-637. 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 
  • 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. Journal of the American Medical Association. 2013; 310(7):714-721. 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. Genetic Epidemiology. 2013; 37(7):726-742. 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. BioMed Central Genetics. 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. Annals of Human Genetics. 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. Human Genetics. 2012; 131(5):739-746. 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. Journal of Human Genetics. 2012; 57(8):485-493. 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. American Journal of Medical Genetics, Part A. 2012; 158A(10):2463-2472. 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. Nature Genetics. 2012; 44(12):1360-1364. 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. Nature Genetics. 2010; 42(6):525-529. PMID: 20436469. PMCID: PMC2941216
  • Mills JL, Troendle J, Conley MR, Carter T, Druschel CM. Maternal obesity and congenital heart defects: a population-based study. The American Journal of Clinical Nutrition. 2010; 91(6):1543-1549. PMID: 20375192. PMCID: PMC2869507
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