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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
  • Ruzong Fan, Ph.D., Georgetown University

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(2):588-93. PMID: 23267103. PMCID: PMC3545809
  • Minguzzi S, Molloy AM, Peadar K, Mills J, Scott JM, Troendle J, Parle-McDermott A. Genotyping of a tri-allelic polymorphism by a novel melting curve assay in MTHFD1L: an association study of nonsyndromic cleft in Ireland. BMC Med Genet. 2012;13:29. PMID: 22520921. PMCID: PMC3419639
  • 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. PMCID: PMC3458983
  • Troendle JF and Mills JL. Correction for multiplicity in genetic association studies of triads: the permutational TDT. Ann Hum Genet. 2011;75(2):284-91. PMID: 21108625. PMCID: PMC3117224
  • 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(1):14-21. PMID: 21204206. PMCID: PMC3503244
  • 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(7):610-5. PMID: 21591245. PMCID: PMC3372895
  • 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(2):495-500. PMID: 21653798. PMCID: PMC3142724
  • 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(7):e21851. PMID: 21765920. PMCID: PMC3134459
  • 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(2): 84-93. PMID: 19937600. PMCID: PMC3503531
  • 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(10):677-85. PMID: 20577008. PMCID: PMC4112773
  • Mamasoula C, Prentice RR, Pierscionek T, Pangilinan F, Mills JL, Druschel C, Pass K, Russell MW, Hall D, Töpf A, Brown DL, Zelenika D, Bentham J, Cosgrove C, Bhattacharya S, Riveron JG, Setchfield K, Brook JD, Bu'Lock FA, Thornborough C, Rahman TJ, Doza JP, Tan HL, O'Sullivan J, Stuart AG, Blue G, Winlaw D, Postma AV, Mulder BJ, Zwinderman AH, van Engelen K, Moorman AF, Rauch A, Gewillig M, Breckpot J, Devriendt K, Lathrop GM, Farrall M, Goodship JA, Cordell HJ, Brody LC, Keavney BD. Association between C677T polymorphism of methylene tetrahydrofolate reductase and congenital heart disease: meta-analysis of 7697 cases and 13,125 controls. Circ Cardiovasc Genet. 2013;6(4):347-53. PMID: 23876493. PMCID: PMC3855044
  • Molloy AM, Einri CN, Jain D, Laird E, Fan R, Wang Y, Scott JM, Shane B, Brody LC, Kirke PN, Mills JL. Is low iron status a risk factor for neural tube defects? Birth Defects Res A Clin Mol Teratol. 2014;100(2):100-6. PMID: 24535840. PMCID: PMC4018583
  • Ma Q, Ozel AB, Ramdas S, McGee B, Khoriaty R, Siemieniak D, Li HD, Guan Y, Brody LC, Mills JL, Molloy AM, Ginsburg D, Li JZ, Desch KC. Genetic variants in PLG, LPA, and SIGLEC 14 as well as smoking contribute to plasma plasminogen levels. Blood. 201;124(20):3155-64. PMID: 25208887. PMCID: PMC4231423
  • Mills JL, Fan R, Brody LC, Liu A, Ueland PM, Wang Y, Kirke PN, Shane B, Molloy AM. Maternal choline concentrations during pregnancy and choline-related genetic variants as risk factors for neural tube defects. Am J Clin Nutr. 2014;100(4):1069-74. PMID: 25240073. PMCID: PMC4163794
  • Pangilinan F, Molloy AM, Mills JL, Troendle JF, Parle-McDermott A, Kay DM, Browne ML, McGrath EC, Abaan HO, Sutton M, Kirke PN, Caggana M, Shane B, Scott JM, Brody LC. Replication and exploratory analysis of 24 candidate risk polymorphisms for neural tube defects. BMC Med Genet. 2014;15:102. PMID: 25293959. PMCID: PMC4411759
  • International League Against Epilepsy Consortium on Complex Epilepsies. Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies.  Lancet Neurol. 2014;13(9):893-903. PMID: 25087078. PMCID: PMC4189926
  • Deac OM, Mills JL, Shane B, Midttun Ø, Ueland PM, Brosnan JT, Brosnan ME, Laird E, Gibney ER, Fan R, Wang Y, Brody LC, Molloy AM. Tryptophan catabolism and vitamin B-6 status are affected by gender and lifestyle factors in healthy young adults. J Nutr. 2015;145(4):701-7. PMID: 25833774. PMCID: PMC4381767
  • Carter TC, Pangilinan F, Molloy AM, Fan R, Wang Y, Shane B, Gibney ER, Midttun Ø, Ueland PM, Cropp CD, Kim Y, Wilson AF, Bailey-Wilson JE, Brody LC, Mills JL. Common Variants at Putative Regulatory Sites of the Tissue Nonspecific Alkaline Phosphatase Gene Influence Circulating Pyridoxal 5'-Phosphate Concentration in Healthy Adults. J Nutr. 2015;145(7):1386-93. PMID: 25972531. PMCID: PMC4478949
  • Ozaki M, Molloy AM, Mills JL, Fan R, Wang Y, Gibney ER, Shane B, Brody LC, Parle-McDermott A. The Dihydrofolate Reductase 19 bp Polymorphism Is Not Associated with Biomarkers of Folate Status in Healthy Young Adults, Irrespective of Folic Acid Intake. J Nutr. 2015;14(10):2207-11. PMID: 26269242. PMCID: PMC4580961
  • Boghossian NS, Sicko RJ, Kay DM, Rigler SL, Caggana M, Tsai MY, Yeung EH, Pankratz N, Cole BR, Druschel CM, Romitti PA, Browne ML, Fan R, Liu A, Brody LC, Mills JL. Rare copy number variants implicated in posterior urethral valves. Am J Med Genet A. 2016;170(3):622-33. PMID: 26663319
  • Szymczak S, Holzinger E, Dasgupta A, Malley JD, Molloy AM, Mills JL, Brody LC, Stambolian D, Bailey-Wilson JE. r2VIM: A new variable selection method for random forests in genome-wide association studies. BioData Min. 2016;9:7. PMID: 26839594. PMCID: PMC4736152
  • VanderMeer JE, Carter TC, Pangilinan F, Mitchell A, Kurnat-Thoma E, Kirke PN, Troendle JF, Molloy AM, Munger RG, Feldkamp ML, Mansilla MA, Mills JL, Murray JC, Brody LC. Evaluation of proton-coupled folate transporter (SLC46A1) polymorphisms as risk factors for neural tube defects and oral clefts. Am J Med Genet A. 2016;170A(4):1007-16. PMID: 26789141
  • Molloy AM, Pangilinan F, Mills JL, Shane B, O'Neill MB, McGaughey DM, Velkova A, Abaan HO, Ueland PM, McNulty H, Ward M, Strain JJ, Cunningham C, Casey M, Cropp CD, Kim Y, Bailey-Wilson JE, Wilson AF, Brody LC. A Common Polymorphism in HIBCH Influences Methylmalonic Acid Concentrations in Blood Independently of Cobalamin. Am J Hum Genet. 2016;98(5):869-82. PMID: 27132595. PMCID: PMC4863564
  • Deac OM, Mills JL, Gardiner CM, Shane B, Quinn L, Midttun Ø, McCann A, Meyer K, Ueland PM, Fan R, Lu Z, Brody LC, Molloy AM. Serum Immune System Biomarkers Neopterin and Interleukin-10 Are Strongly Related to Tryptophan Metabolism in Healthy Young Adults. J Nutr. 2016;146(9):1801-6. PMID: 27489009. PMCID: PMC4997280 [Available on 2017-09-01]

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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