Evidence of linkage with HLA-DR in DRB1*15-negative families with multiple sclerosis

A. Ligers; D. A. Dyment; C. J. Willer; A. D. Sadovnick; G. Ebers; N. Risch; J. Hillert; S. Hashimoto; D. Paty; J. Oger; V. Devonshire; J. Hooge; L. Kastrukoff; G. Rice; L. Metz; S. Warren; W. Hader; T. Auty; C. Power; P. O'Connor; R. Nelson; M. Freedman; D. Brunet; R. Paulseth; Y. Lapierre; P. Duquette; J. Bouchard; T. Murray; V. Bhan; C. Maxner; W. Pryse-Phillips; M. Stefanelli

doi:10.1086/323480

Evidence of linkage with HLA-DR in DRB1*15-negative families with multiple sclerosis

A. Ligers, D. A. Dyment, C. J. Willer, A. D. Sadovnick, G. Ebers, N. Risch, J. Hillert, S. Hashimoto, D. Paty, J. Oger, V. Devonshire, J. Hooge, L. Kastrukoff, G. Rice, L. Metz, S. Warren, W. Hader, T. Auty, C. Power, P. O'ConnorR. Nelson, M. Freedman, D. Brunet, R. Paulseth, Y. Lapierre, P. Duquette, J. Bouchard, T. Murray, V. Bhan, C. Maxner, W. Pryse-Phillips, M. Stefanelli

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Abstract

The importance of the HLA-DR locus to multiple sclerosis (MS) susceptibility was assessed in 542 sib pairs with MS and in their families. By genotyping 1,978 individuals for HLA-DRB1 alleles, we confirmed the well-established association of MS with HLA-DRB1*15 (HLA-DRB1*1501 and HLA-DRB5*0101), by the transmission/disequilibrium test (χ² = 138.3; P < .0001). We obtained significant evidence of linkage throughout the whole data set (mlod = 4.09; 59.9% sharing). Surprisingly, similar sharing was also observed in 58 families in which both parents lacked the DRB1*15 allele (mlod = 1.56; 62.7% sharing; P = .0081). Our findings suggest that the notion that HLA-DRB1*15 is the sole major-histocompatibility-complex determinant of susceptibility in northern-European populations with MS may be incorrect. It remains possible that the association of MS with HLA-DRB1*15 is due to linkage disequilibrium with a nearby locus and/or to the presence of disease-influencing allele(s) in DRB1*15-negative haplotypes.

Original language	English
Pages (from-to)	900-903
Number of pages	4
Journal	American Journal of Human Genetics
Volume	69
Issue number	4
DOIs	https://doi.org/10.1086/323480
Publication status	Published - 2001
Externally published	Yes

Bibliographical note

Funding Information:
This study was supported by Swedish Medical Research Council projects 11023 and 11220, by the Swedish Society for the Neurologically Disabled, by the Bibbi and Nils Jensens Foundation, by the Canadian Genetic Disease Network, by a grant from the Multiple Sclerosis Society of Canada Scientific Research Foundation, and by Multiple Sclerosis Society of Canada Research Studentship awards (to D.A.D. and C.J.W.). Primers and reagents for HLA-DRB1 typing were generously provided by Dr. O. Olerup (Olerup SSP AB).

ASJC Scopus Subject Areas

Genetics
Genetics(clinical)

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10.1086/323480

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Ligers, A., Dyment, D. A., Willer, C. J., Sadovnick, A. D., Ebers, G., Risch, N., Hillert, J., Hashimoto, S., Paty, D., Oger, J., Devonshire, V., Hooge, J., Kastrukoff, L., Rice, G., Metz, L., Warren, S., Hader, W., Auty, T., Power, C., ... Stefanelli, M. (2001). Evidence of linkage with HLA-DR in DRB1*15-negative families with multiple sclerosis. American Journal of Human Genetics, 69(4), 900-903. https://doi.org/10.1086/323480

Ligers, A, Dyment, DA, Willer, CJ, Sadovnick, AD, Ebers, G, Risch, N, Hillert, J, Hashimoto, S, Paty, D, Oger, J, Devonshire, V, Hooge, J, Kastrukoff, L, Rice, G, Metz, L, Warren, S, Hader, W, Auty, T, Power, C, O'Connor, P, Nelson, R, Freedman, M, Brunet, D, Paulseth, R, Lapierre, Y, Duquette, P, Bouchard, J, Murray, T, Bhan, V, Maxner, C, Pryse-Phillips, W & Stefanelli, M 2001, 'Evidence of linkage with HLA-DR in DRB1*15-negative families with multiple sclerosis', American Journal of Human Genetics, vol. 69, no. 4, pp. 900-903. https://doi.org/10.1086/323480

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title = "Evidence of linkage with HLA-DR in DRB1*15-negative families with multiple sclerosis",

abstract = "The importance of the HLA-DR locus to multiple sclerosis (MS) susceptibility was assessed in 542 sib pairs with MS and in their families. By genotyping 1,978 individuals for HLA-DRB1 alleles, we confirmed the well-established association of MS with HLA-DRB1*15 (HLA-DRB1*1501 and HLA-DRB5*0101), by the transmission/disequilibrium test (χ2 = 138.3; P < .0001). We obtained significant evidence of linkage throughout the whole data set (mlod = 4.09; 59.9% sharing). Surprisingly, similar sharing was also observed in 58 families in which both parents lacked the DRB1*15 allele (mlod = 1.56; 62.7% sharing; P = .0081). Our findings suggest that the notion that HLA-DRB1*15 is the sole major-histocompatibility-complex determinant of susceptibility in northern-European populations with MS may be incorrect. It remains possible that the association of MS with HLA-DRB1*15 is due to linkage disequilibrium with a nearby locus and/or to the presence of disease-influencing allele(s) in DRB1*15-negative haplotypes.",

author = "A. Ligers and Dyment, {D. A.} and Willer, {C. J.} and Sadovnick, {A. D.} and G. Ebers and N. Risch and J. Hillert and S. Hashimoto and D. Paty and J. Oger and V. Devonshire and J. Hooge and L. Kastrukoff and G. Rice and L. Metz and S. Warren and W. Hader and T. Auty and C. Power and P. O'Connor and R. Nelson and M. Freedman and D. Brunet and R. Paulseth and Y. Lapierre and P. Duquette and J. Bouchard and T. Murray and V. Bhan and C. Maxner and W. Pryse-Phillips and M. Stefanelli",

note = "Funding Information: This study was supported by Swedish Medical Research Council projects 11023 and 11220, by the Swedish Society for the Neurologically Disabled, by the Bibbi and Nils Jensens Foundation, by the Canadian Genetic Disease Network, by a grant from the Multiple Sclerosis Society of Canada Scientific Research Foundation, and by Multiple Sclerosis Society of Canada Research Studentship awards (to D.A.D. and C.J.W.). Primers and reagents for HLA-DRB1 typing were generously provided by Dr. O. Olerup (Olerup SSP AB). ",

year = "2001",

doi = "10.1086/323480",

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volume = "69",

pages = "900--903",

journal = "American Journal of Human Genetics",

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T1 - Evidence of linkage with HLA-DR in DRB1*15-negative families with multiple sclerosis

AU - Ligers, A.

AU - Dyment, D. A.

AU - Willer, C. J.

AU - Sadovnick, A. D.

AU - Ebers, G.

AU - Risch, N.

AU - Hillert, J.

AU - Hashimoto, S.

AU - Paty, D.

AU - Oger, J.

AU - Devonshire, V.

AU - Hooge, J.

AU - Kastrukoff, L.

AU - Rice, G.

AU - Metz, L.

AU - Warren, S.

AU - Hader, W.

AU - Auty, T.

AU - Power, C.

AU - O'Connor, P.

AU - Nelson, R.

AU - Freedman, M.

AU - Brunet, D.

AU - Paulseth, R.

AU - Lapierre, Y.

AU - Duquette, P.

AU - Bouchard, J.

AU - Murray, T.

AU - Bhan, V.

AU - Maxner, C.

AU - Pryse-Phillips, W.

AU - Stefanelli, M.

N1 - Funding Information: This study was supported by Swedish Medical Research Council projects 11023 and 11220, by the Swedish Society for the Neurologically Disabled, by the Bibbi and Nils Jensens Foundation, by the Canadian Genetic Disease Network, by a grant from the Multiple Sclerosis Society of Canada Scientific Research Foundation, and by Multiple Sclerosis Society of Canada Research Studentship awards (to D.A.D. and C.J.W.). Primers and reagents for HLA-DRB1 typing were generously provided by Dr. O. Olerup (Olerup SSP AB).

PY - 2001

Y1 - 2001

N2 - The importance of the HLA-DR locus to multiple sclerosis (MS) susceptibility was assessed in 542 sib pairs with MS and in their families. By genotyping 1,978 individuals for HLA-DRB1 alleles, we confirmed the well-established association of MS with HLA-DRB1*15 (HLA-DRB1*1501 and HLA-DRB5*0101), by the transmission/disequilibrium test (χ2 = 138.3; P < .0001). We obtained significant evidence of linkage throughout the whole data set (mlod = 4.09; 59.9% sharing). Surprisingly, similar sharing was also observed in 58 families in which both parents lacked the DRB1*15 allele (mlod = 1.56; 62.7% sharing; P = .0081). Our findings suggest that the notion that HLA-DRB1*15 is the sole major-histocompatibility-complex determinant of susceptibility in northern-European populations with MS may be incorrect. It remains possible that the association of MS with HLA-DRB1*15 is due to linkage disequilibrium with a nearby locus and/or to the presence of disease-influencing allele(s) in DRB1*15-negative haplotypes.

AB - The importance of the HLA-DR locus to multiple sclerosis (MS) susceptibility was assessed in 542 sib pairs with MS and in their families. By genotyping 1,978 individuals for HLA-DRB1 alleles, we confirmed the well-established association of MS with HLA-DRB1*15 (HLA-DRB1*1501 and HLA-DRB5*0101), by the transmission/disequilibrium test (χ2 = 138.3; P < .0001). We obtained significant evidence of linkage throughout the whole data set (mlod = 4.09; 59.9% sharing). Surprisingly, similar sharing was also observed in 58 families in which both parents lacked the DRB1*15 allele (mlod = 1.56; 62.7% sharing; P = .0081). Our findings suggest that the notion that HLA-DRB1*15 is the sole major-histocompatibility-complex determinant of susceptibility in northern-European populations with MS may be incorrect. It remains possible that the association of MS with HLA-DRB1*15 is due to linkage disequilibrium with a nearby locus and/or to the presence of disease-influencing allele(s) in DRB1*15-negative haplotypes.

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Evidence of linkage with HLA-DR in DRB1*15-negative families with multiple sclerosis

Abstract

Bibliographical note

ASJC Scopus Subject Areas

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