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

Kristen L. Deak; Abee L. Boyles; Heather C. Etchevers; Elizabeth C. Melvin; Deborah G. Siegel; Felicia L. Graham; Susan H. Slifer; David S. Enterline; Timothy M. George; Michel Vekemans; David McClay; Alexander G. Bassuk; John A. Kessler; Elwood Linney; John R. Gilbert; Marcy C. Speer; Joanna Aben; Arthur Aylsworth; Cynthia Powell; Joanne Mackey; Gordon Worley; Timothy Brei; Connie Buran; Joann Bodurtha; Kathleen Sawin; Mark S. Dias; Philip Mack; Elli Meeropol; Nicole Lasarsky; David McLone; Joy Ito; Jerry Oakes; Marion Walker; Bermans Iskandar

doi:10.1007/s00439-005-1299-7

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

Kristen L. Deak, Abee L. Boyles, Heather C. Etchevers, Elizabeth C. Melvin, Deborah G. Siegel, Felicia L. Graham, Susan H. Slifer, David S. Enterline, Timothy M. George, Michel Vekemans, David McClay, Alexander G. Bassuk, John A. Kessler, Elwood Linney, John R. Gilbert, Marcy C. Speer, Joanna Aben, Arthur Aylsworth, Cynthia Powell, Joanne MackeyGordon Worley, Timothy Brei, Connie Buran, Joann Bodurtha, Kathleen Sawin, Mark S. Dias, Philip Mack, Elli Meeropol, Nicole Lasarsky, David McLone, Joy Ito, Jerry Oakes, Marion Walker, Bermans Iskandar

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

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). sing 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.

Original language	English (US)
Pages (from-to)	133-142
Number of pages	10
Journal	Human genetics
Volume	117
Issue number	2-3
DOIs	https://doi.org/10.1007/s00439-005-1299-7
State	Published - Jul 2005

All Science Journal Classification (ASJC) codes

Genetics
Genetics(clinical)

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Deak, K. L., Boyles, A. L., Etchevers, H. C., Melvin, E. C., Siegel, D. G., Graham, F. L., Slifer, S. H., Enterline, D. S., George, T. M., Vekemans, M., McClay, D., Bassuk, A. G., Kessler, J. A., Linney, E., Gilbert, J. R., Speer, M. C., Aben, J., Aylsworth, A., Powell, C., ... Iskandar, B. (2005). SNPs in the neural cell adhesion molecule 1 gene (NCAM1) may be associated with human neural tube defects. Human genetics, 117(2-3), 133-142. https://doi.org/10.1007/s00439-005-1299-7

@article{c90c00e451df48f9bd26c0e222a1b4ee,

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

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). sing 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.",

author = "Deak, {Kristen L.} and Boyles, {Abee L.} and Etchevers, {Heather C.} and Melvin, {Elizabeth C.} and Siegel, {Deborah G.} and Graham, {Felicia L.} and Slifer, {Susan H.} and Enterline, {David S.} and George, {Timothy M.} and Michel Vekemans and David McClay and Bassuk, {Alexander G.} and Kessler, {John A.} and Elwood Linney and Gilbert, {John R.} and Speer, {Marcy C.} and Joanna Aben and Arthur Aylsworth and Cynthia Powell and Joanne Mackey and Gordon Worley and Timothy Brei and Connie Buran and Joann Bodurtha and Kathleen Sawin and Dias, {Mark S.} and Philip Mack and Elli Meeropol and Nicole Lasarsky and David McLone and Joy Ito and Jerry Oakes and Marion Walker and Bermans Iskandar",

note = "Funding Information: 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.",

year = "2005",

month = jul,

doi = "10.1007/s00439-005-1299-7",

language = "English (US)",

volume = "117",

pages = "133--142",

journal = "Human genetics",

issn = "0340-6717",

publisher = "Springer Verlag",

number = "2-3",

}

Deak, KL, Boyles, AL, Etchevers, HC, Melvin, EC, Siegel, DG, Graham, FL, Slifer, SH, Enterline, DS, George, TM, Vekemans, M, McClay, D, Bassuk, AG, Kessler, JA, Linney, E, Gilbert, JR, Speer, MC, Aben, J, Aylsworth, A, Powell, C, Mackey, J, Worley, G, Brei, T, Buran, C, Bodurtha, J, Sawin, K, Dias, MS, Mack, P, Meeropol, E, Lasarsky, N, McLone, D, Ito, J, Oakes, J, Walker, M & Iskandar, B 2005, 'SNPs in the neural cell adhesion molecule 1 gene (NCAM1) may be associated with human neural tube defects', Human genetics, vol. 117, no. 2-3, pp. 133-142. https://doi.org/10.1007/s00439-005-1299-7

TY - JOUR

T1 - SNPs in the neural cell adhesion molecule 1 gene (NCAM1) may be associated with human neural tube defects

AU - Deak, Kristen L.

AU - Boyles, Abee L.

AU - Etchevers, Heather C.

AU - Melvin, Elizabeth C.

AU - Siegel, Deborah G.

AU - Graham, Felicia L.

AU - Slifer, Susan H.

AU - Enterline, David S.

AU - George, Timothy M.

AU - Vekemans, Michel

AU - McClay, David

AU - Bassuk, Alexander G.

AU - Kessler, John A.

AU - Linney, Elwood

AU - Gilbert, John R.

AU - Speer, Marcy C.

AU - Aben, Joanna

AU - Aylsworth, Arthur

AU - Powell, Cynthia

AU - Mackey, Joanne

AU - Worley, Gordon

AU - Brei, Timothy

AU - Buran, Connie

AU - Bodurtha, Joann

AU - Sawin, Kathleen

AU - Dias, Mark S.

AU - Mack, Philip

AU - Meeropol, Elli

AU - Lasarsky, Nicole

AU - McLone, David

AU - Ito, Joy

AU - Oakes, Jerry

AU - Walker, Marion

AU - Iskandar, Bermans

N1 - Funding Information: 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.

PY - 2005/7

Y1 - 2005/7

N2 - 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). sing 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.

AB - 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). sing 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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UR - http://www.scopus.com/inward/citedby.url?scp=26944449327&partnerID=8YFLogxK

U2 - 10.1007/s00439-005-1299-7

DO - 10.1007/s00439-005-1299-7

M3 - Article

C2 - 15883837

AN - SCOPUS:26944449327

SN - 0340-6717

VL - 117

SP - 133

EP - 142

JO - Human genetics

JF - Human genetics

IS - 2-3

ER -

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

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