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EB Research - Pediatric Epidemiology

Birth Defects Research Group

The Birth Defects Research Group is a multi-center, multidisciplinary group led by NICHD to investigate the causes of birth defects. The collaborating institutions are NICHD, The National Human Genome Research Institute, The Health Research Board of Ireland and the Department of Biochemistry, Trinity College, Dublin. This group has made important discoveries related to neural tube defects including finding that mothers carrying affected fetuses have higher homocysteine (a folate-related compound) levels. The group has been the first to identify several genetic risk factors related to folate and vitamin B12. It has also shown that low vitamin B12 status is an independent risk factor in a population where vitamin supplement use is rare.

Current research includes looking at genetic factors related to folate and vitamin B12 status to identify additional risk genes for neural tube defects. The group has also been active in looking for genetic factors related to risk for cleft lip and cleft palate. It recently collaborated in a multi-national genome wide association study that identified two new genetic variants that were strong risk factors for cleft lip with or without cleft palate.

Because low folate status is an important risk factor for neural tube defects, the group has conducted a quantitative traits genome wide association study to look for genetic variants associated with low folate status in 2500 Trinity College students (The Trinity Student Study). The data are currently being analyzed to identify variants that will then be tested for association with neural tube defects.

It should be noted that samples have been collected and stored so that other investigators can assay them and look for genetic factors that affect the concentration of the chemicals they wish to evaluate. This has already been done by collaborators looking for variants in von Willebrand factor. Additional analyses are ongoing. The group is open to other requests to collaborate using these resources.

Principal Investigator

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

DIPHR Collaborators

Extramural Collaborators

  • Anne Molloy, Ph.D. Trinity College Dublin, Ireland
  • Per Ueland, Ph.D. University of Bergen, Norway
  • Barry Shane, Ph.D., University of California
  • Peadar Kirke, M.D. (retired)
  • Lawrence Brody, Ph.D. NHGRI, NIH

Selected Publications

  • Desch KC, Ozel AB, Siemieniak D, Kalish Y, Shavit JA, Thornburg CD, Sharathkumar AA, McHugh CP, Laurie CC, Crenshaw A, Mirel DB, Kim Y, Cropp CD, Molloy AM, Kirke PN, Bailey-Wilson JE, Wilson AF, Mills JL, Scott JM, Brody LC, Li JZ, Ginsburg D. Linkage analysis identifies a locus for plasma von Willebrand factor undetected by genome-wide association. Proc Natl Acad Sci U S A. 2013 ;110:588-93. PMID:23267103
  • Minguzzi S, Molloy AM, Kirke PN, Mills JL, Scott JM, Troendle J, Pangilinan F, Brody LC, Parle-McDermott A. Development of a melting curve assay to genotype a tri-allelic polymorphism of MTHFD1L: An association study of nonsyndromic Cleft in Ireland. BMC Med Genet 2012 ;13:29. PMID:22520921
  • Pangilinan F, Molloy AM, Mills JL, Troendle JF, Parle-McDermott A, Signore C, O'Leary VB, Chines P, Seay JM, Geiler-Samerotte K, Mitchell A, Vandermeer JE, Krebs KM, Sanchez A, Cornman-Homonoff J, Stone N, Conley M, Kirke PN, Shane B, Scott JM, Brody LC. Evaluation of common genetic variants in 82 candidate genes as risk factors for neural tube defects. BMC Med Genet. 2012;13:62. PMID:22856873
  • Troendle JF, Mills JL. Correction for multiplicity in genetic association studies of triads: the permutation TDT. Ann Hum Genet. 2011 75(2):284-91. PMID:21108625
  • Carter TC, Pangilinan F, Troendle JF, Molloy AM, Vandermeer J, Mitchell A, Kirke PN, Conley MR, Shane B, Scott JM, Brody LC, Mills JL. Evaluation of 64 candidate single nucleotide polymorphisms as risk factors for neural tube defects in a large Irish study population. Am J Med Genet A. 2011 ;155:14-21. PMID:21204206
  • Sutton M, Mills JL, Molloy AM, Troendle JF, Brody LC, Conley M, Mc Donnell R, Scott JM, Kirke PN. Maternal folate, vitamin B12 and homocysteine levels in pregnancies affected by congenital malformations other than neural tube defects. Birth Defects Res A Clin Mol Teratol. 2011 ;91:610-5. PMID:21591245
  • Mills JL, Carter TC, Scott JM, Troendle JF, Gibney ER, Shane B, Kirke PN, Ueland PM, Brody LC, Molloy AM. Do high blood folate concentrations exacerbate metabolic abnormalities in people with low vitamin B-12 status? Am J Clin Nutr. 2011 ;94:495-500. PMID:21653798
  • Stone N, Pangilinan F, Molloy AM, Shane B, Scott JM, Ueland PM, Mills JL, Kirke PN, Sethupathy P, Brody LC. Bioinformatic and genetic association analysis of microRNA target sites in one-carbon metabolism genes. PLoS One. 2011;6:e21851. PMID:21765920
  • Carter TC, Molloy AM, Pangilinan F, Troendle JF, Kirke PN, Conley MR, Orr DJ, Earley M, McKiernan E, Lynn EC, Doyle A, Scott JM, Brody LC, Mills JL. Testing reported associations of genetic risk factors for oral clefts in a large Irish study population. Birth Defects Res A Clin Mol Teratol. 2010. 88: 84-93.
  • Pangilinan F, Mitchell A, VanderMeer J, Molloy AM, Troendle J, Conley M, Kirke PN, Sutton M, Sequeira JM, Quadros EV, Scott JM, Mills JL, Brody LC. Transcobalamin II receptor polymorphisms are associated with increased risk for neural tube defects. J Med Genet. 2010;47:677-85. PMID:20577008

Contact Information

Name: Dr Enrique Fabian Schisterman
Chief and Senior Investigator
Epidemiology Branch
Phone: 301-435-6893
Fax: 301-402-2084

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