A full genome search in multiple sclerosis

G. C. Ebers, K. Kukay, D. E. Bulman, A. D. Sadovnick, G. Rice, C. Anderson, H. Armstrong, K. Cousin, R. B. Bell, W. Hader, D. W. Paty, S. Hashimoto, J. Oger, P. Duquette, S. Warren, T. Gray, P. O'Connor, A. Nath, A. Auty

Research output: Contribution to journalArticle

Abstract

The aetiology of multiple sclerosis (MS) is uncertain. There is strong circumstantial evidence to indicate it is an autoimmune complex trait. Risks for first degree relatives are increased some 20 fold ever the general population. Twin studies have shown monozygotic concordance rates of 25-30% compared to 4% for dizygotic twins and siblings. Studies of adoptees and half sibs show that familial risk is determined by genes, but environmental factors strongly influence observed geographic differences. Studies of candidate genes have been largely unrewarding. We report a genome search using 257 microsatellite markers with average spacing of 15.2 cM in 100 sibling pairs (Table 1, data set 1 - DS1). A locus of λ>3 was excluded from 88% of the genome. Five loci with maximum lod scores (MLS) of >1 were identified on chromosomes 2, 3, 5, 11 and X. Two additional data sets containing 44 (Table 1, DS2) and 78 sib pairs (Table 1, DS3) respectively, were used to further evaluate the HLA region on 6p21 and a locus on chromosome 5 with an MLS of 4.24. Markers within 6p21 gave MLS of 0.65 (nonsignificant, NS). However, D6S461, just outside the HLA region, showed significant evidence for linkage disequilibrium by the transmission disequilibrium test (TDT), in all three data sets (for DS1 χ2 = 10.8, adjusted P <0.01)(DS2 and DS3 χ2 = 10.9, P <0.0005) suggesting a modest susceptibility locus in this region. On chromosome 5p results from all three data sets (222 sib pairs) yielded a multipoint MLS of 1.6. The results support genetic epidemiological evidence that several genes interact epistatically to determine heritable susceptibility.

Original languageEnglish (US)
Pages (from-to)472-476
Number of pages5
JournalNature Genetics
Volume13
Issue number4
DOIs
StatePublished - 1996
Externally publishedYes

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Lod Score
Multiple Sclerosis
Genome
Siblings
Genes
Dizygotic Twins
Chromosomes, Human, Pair 5
Twin Studies
Chromosomes, Human, Pair 3
Chromosomes, Human, Pair 2
Linkage Disequilibrium
Microsatellite Repeats
Chromosomes
Datasets
Population

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Ebers, G. C., Kukay, K., Bulman, D. E., Sadovnick, A. D., Rice, G., Anderson, C., ... Auty, A. (1996). A full genome search in multiple sclerosis. Nature Genetics, 13(4), 472-476. https://doi.org/10.1038/ng0896-472

A full genome search in multiple sclerosis. / Ebers, G. C.; Kukay, K.; Bulman, D. E.; Sadovnick, A. D.; Rice, G.; Anderson, C.; Armstrong, H.; Cousin, K.; Bell, R. B.; Hader, W.; Paty, D. W.; Hashimoto, S.; Oger, J.; Duquette, P.; Warren, S.; Gray, T.; O'Connor, P.; Nath, A.; Auty, A.

In: Nature Genetics, Vol. 13, No. 4, 1996, p. 472-476.

Research output: Contribution to journalArticle

Ebers, GC, Kukay, K, Bulman, DE, Sadovnick, AD, Rice, G, Anderson, C, Armstrong, H, Cousin, K, Bell, RB, Hader, W, Paty, DW, Hashimoto, S, Oger, J, Duquette, P, Warren, S, Gray, T, O'Connor, P, Nath, A & Auty, A 1996, 'A full genome search in multiple sclerosis', Nature Genetics, vol. 13, no. 4, pp. 472-476. https://doi.org/10.1038/ng0896-472
Ebers GC, Kukay K, Bulman DE, Sadovnick AD, Rice G, Anderson C et al. A full genome search in multiple sclerosis. Nature Genetics. 1996;13(4):472-476. https://doi.org/10.1038/ng0896-472
Ebers, G. C. ; Kukay, K. ; Bulman, D. E. ; Sadovnick, A. D. ; Rice, G. ; Anderson, C. ; Armstrong, H. ; Cousin, K. ; Bell, R. B. ; Hader, W. ; Paty, D. W. ; Hashimoto, S. ; Oger, J. ; Duquette, P. ; Warren, S. ; Gray, T. ; O'Connor, P. ; Nath, A. ; Auty, A. / A full genome search in multiple sclerosis. In: Nature Genetics. 1996 ; Vol. 13, No. 4. pp. 472-476.
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abstract = "The aetiology of multiple sclerosis (MS) is uncertain. There is strong circumstantial evidence to indicate it is an autoimmune complex trait. Risks for first degree relatives are increased some 20 fold ever the general population. Twin studies have shown monozygotic concordance rates of 25-30{\%} compared to 4{\%} for dizygotic twins and siblings. Studies of adoptees and half sibs show that familial risk is determined by genes, but environmental factors strongly influence observed geographic differences. Studies of candidate genes have been largely unrewarding. We report a genome search using 257 microsatellite markers with average spacing of 15.2 cM in 100 sibling pairs (Table 1, data set 1 - DS1). A locus of λ>3 was excluded from 88{\%} of the genome. Five loci with maximum lod scores (MLS) of >1 were identified on chromosomes 2, 3, 5, 11 and X. Two additional data sets containing 44 (Table 1, DS2) and 78 sib pairs (Table 1, DS3) respectively, were used to further evaluate the HLA region on 6p21 and a locus on chromosome 5 with an MLS of 4.24. Markers within 6p21 gave MLS of 0.65 (nonsignificant, NS). However, D6S461, just outside the HLA region, showed significant evidence for linkage disequilibrium by the transmission disequilibrium test (TDT), in all three data sets (for DS1 χ2 = 10.8, adjusted P <0.01)(DS2 and DS3 χ2 = 10.9, P <0.0005) suggesting a modest susceptibility locus in this region. On chromosome 5p results from all three data sets (222 sib pairs) yielded a multipoint MLS of 1.6. The results support genetic epidemiological evidence that several genes interact epistatically to determine heritable susceptibility.",
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