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SNPs in the neural cell adhesion molecule 1 gene (NCAM1) may be associated with human neural tube defects

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Abstract

Neural tube defects (NTDs) are common birth defects, occurring in approximately 1/1,000 births; both genetic and environmental factors are implicated. To date, no major genetic risk factors have been identified. Throughout development, cell adhesion molecules are strongly implicated in cell–cell interactions, and may play a role in the formation and closure of the neural tube. To evaluate the role of neural cell adhesion molecule 1 (NCAM1) in risk of human NTDs, we screened for novel single-nucleotide polymorphisms (SNPs) within the gene. Eleven SNPs across NCAM1 were genotyped using TaqMan. We utilized a family-based approach to evaluate evidence for association and/or linkage disequilibrium. We evaluated American Caucasian simplex lumbosacral myelomeningocele families (n=132 families) using the family based association test (FBAT) and the pedigree disequilibrium test (PDT). Association analysis revealed a significant association between risk for NTDs and intronic SNP rs2298526 using both the FBAT test (P=0.0018) and the PDT (P=0.0025). Using the HBAT version of the FBAT to look for haplotype association, all pairwise comparisons with SNP rs2298526 were also significant. A replication study set, consisting of 72 additional families showed no significant association; however, the overall trend for overtransmission of the less common allele of SNP rs2298526 remained significant in the combined sample set. In addition, we analyzed the expression pattern of the NCAM1 protein in human embryos, and while NCAM1 is not expressed within the neural tube at the time of closure, it is expressed in the surrounding and later in differentiated neurons of the CNS. These results suggest variations in NCAM1 may influence risk for human NTDs.

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Acknowledgements

The authors wish to thank the families who participated in this study; without their interest, this work could not be performed. We also thank Silke Schmidt for helpful comment on this manuscript and Pat Hurban and Paradigm Genetics for bioinformatics support. We gratefully acknowledge support from grants HD39948, ES11375, NS39818, ES011961, and NS26630.

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Authors and Affiliations

  1. Center for Human Genetics, Duke University Medical Center, Box 3445, Durham, NC, 27710, USA

    Kristen L. Deak, Abee L. Boyles, Elizabeth C. Melvin, Deborah G. Siegel, Felicia L. Graham, Susan H. Slifer, John R. Gilbert & Marcy C. Speer

  2. Department of Radiology, Duke University Medical Center, Box 3808, Durham, NC, 27710, USA

    David S. Enterline

  3. Department of Surgery, Duke University Medical Center, Box 3272, Durham, NC, 27710, USA

    Timothy M. George

  4. Department of Molecular Genetics and Microbiology, Duke University Medical Center, Box 3020, Durham, NC, 27710, USA

    Elwood Linney

  5. Département de Génétique Médicale and INSERM U393, Hôpital Necker, Paris, France

    Heather C. Etchevers & Michel Vekemans

  6. Department of Biology, Duke University Medical Center, Box 3445, Durham, NC, 27710, USA

    David McClay

  7. Northwestern University’s Feinberg School of Medicine, Chicago, IL, USA

    Alexander G. Bassuk & John A. Kessler

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  1. Kristen L. Deak
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  2. Abee L. Boyles
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  4. Elizabeth C. Melvin
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  5. Deborah G. Siegel
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  11. David McClay
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  16. Marcy C. Speer
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Consortia

NTD Collaborative Group

Corresponding author

Correspondence to Marcy C. Speer.

Additional information

Other members of NTD Collaborative Group involved in this study are listed in the appendix

Appendix

Appendix

NTD Collaborative Group

Joanna Aben, Children’s Rehabilitation Service, Birmingham, Alabama; Arthur Aylsworth, Cynthia Powell, University of North Carolina, Chapel Hill, North Carolina; Joanne Mackey, Gordon Worley, Duke University Medical Center; Timothy Brei, Connie Buran, Indiana University School of Medicine, Indianapolis, Indiana; Joann Bodurtha, Kathleen Sawin, Virginia Commonwealth University, Richmond, Virginia; Mark S. Dias, Children’s Hospital of Buffalo, Buffalo, N.Y.; Philip Mack, Elli Meeropol, Shriner’s Hospital, Springfield, Massachusetts; Nicole Lasarsky, Carolinas Medical Center, Charlotte, NC; David McLone, Joy Ito, Children’s Memorial Hospital, Chicago, Illinois; W. Jerry Oakes, University of Alabama, Birmingham, Alabama; Marion Walker, University of Utah, Salt Lake City, Utah; Bermans Iskandar, University of Wisconsin Hospitals, Madison, Wisconsin.

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Deak, K.L., Boyles, A.L., Etchevers, H.C. et al. SNPs in the neural cell adhesion molecule 1 gene (NCAM1) may be associated with human neural tube defects. Hum Genet 117, 133–142 (2005). https://doi.org/10.1007/s00439-005-1299-7

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  • DOI: https://doi.org/10.1007/s00439-005-1299-7

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