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Evidence for CRHR1 in multiple sclerosis using supervised machine learning and meta-analysis in 12,566 individuals.

Publication ,  Journal Article
Briggs, FBS; Bartlett, SE; Goldstein, BA; Wang, J; McCauley, JL; Zuvich, RL; De Jager, PL; Rioux, JD; Ivinson, AJ; Compston, A; Hafler, DA ...
Published in: Hum Mol Genet
November 1, 2010

The primary genetic risk factor in multiple sclerosis (MS) is the HLA-DRB1*1501 allele; however, much of the remaining genetic contribution to MS has yet to be elucidated. Several lines of evidence support a role for neuroendocrine system involvement in autoimmunity which may, in part, be genetically determined. Here, we comprehensively investigated variation within eight candidate hypothalamic-pituitary-adrenal (HPA) axis genes and susceptibility to MS. A total of 326 SNPs were investigated in a discovery dataset of 1343 MS cases and 1379 healthy controls of European ancestry using a multi-analytical strategy. Random Forests, a supervised machine-learning algorithm, identified eight intronic SNPs within the corticotrophin-releasing hormone receptor 1 or CRHR1 locus on 17q21.31 as important predictors of MS. On the basis of univariate analyses, six CRHR1 variants were associated with decreased risk for disease following a conservative correction for multiple tests. Independent replication was observed for CRHR1 in a large meta-analysis comprising 2624 MS cases and 7220 healthy controls of European ancestry. Results from a combined meta-analysis of all 3967 MS cases and 8599 controls provide strong evidence for the involvement of CRHR1 in MS. The strongest association was observed for rs242936 (OR = 0.82, 95% CI = 0.74-0.90, P = 9.7 × 10(-5)). Replicated CRHR1 variants appear to exist on a single associated haplotype. Further investigation of mechanisms involved in HPA axis regulation and response to stress in MS pathogenesis is warranted.

Duke Scholars

Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

November 1, 2010

Volume

19

Issue

21

Start / End Page

4286 / 4295

Location

England

Related Subject Headings

  • Receptors, Corticotropin-Releasing Hormone
  • Polymorphism, Single Nucleotide
  • Multiple Sclerosis
  • Mass Spectrometry
  • Humans
  • Genetics & Heredity
  • Case-Control Studies
  • 3105 Genetics
  • 11 Medical and Health Sciences
  • 06 Biological Sciences
 

Citation

APA
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MLA
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Briggs, F. B. S., Bartlett, S. E., Goldstein, B. A., Wang, J., McCauley, J. L., Zuvich, R. L., … Barcellos, L. F. (2010). Evidence for CRHR1 in multiple sclerosis using supervised machine learning and meta-analysis in 12,566 individuals. Hum Mol Genet, 19(21), 4286–4295. https://doi.org/10.1093/hmg/ddq328
Briggs, Farren B. S., Selena E. Bartlett, Benjamin A. Goldstein, Joanne Wang, Jacob L. McCauley, Rebecca L. Zuvich, Philip L. De Jager, et al. “Evidence for CRHR1 in multiple sclerosis using supervised machine learning and meta-analysis in 12,566 individuals.Hum Mol Genet 19, no. 21 (November 1, 2010): 4286–95. https://doi.org/10.1093/hmg/ddq328.
Briggs FBS, Bartlett SE, Goldstein BA, Wang J, McCauley JL, Zuvich RL, et al. Evidence for CRHR1 in multiple sclerosis using supervised machine learning and meta-analysis in 12,566 individuals. Hum Mol Genet. 2010 Nov 1;19(21):4286–95.
Briggs, Farren B. S., et al. “Evidence for CRHR1 in multiple sclerosis using supervised machine learning and meta-analysis in 12,566 individuals.Hum Mol Genet, vol. 19, no. 21, Nov. 2010, pp. 4286–95. Pubmed, doi:10.1093/hmg/ddq328.
Briggs FBS, Bartlett SE, Goldstein BA, Wang J, McCauley JL, Zuvich RL, De Jager PL, Rioux JD, Ivinson AJ, Compston A, Hafler DA, Hauser SL, Oksenberg JR, Sawcer SJ, Pericak-Vance MA, Haines JL, International Multiple Sclerosis Genetics Consortium, Barcellos LF. Evidence for CRHR1 in multiple sclerosis using supervised machine learning and meta-analysis in 12,566 individuals. Hum Mol Genet. 2010 Nov 1;19(21):4286–4295.
Journal cover image

Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

November 1, 2010

Volume

19

Issue

21

Start / End Page

4286 / 4295

Location

England

Related Subject Headings

  • Receptors, Corticotropin-Releasing Hormone
  • Polymorphism, Single Nucleotide
  • Multiple Sclerosis
  • Mass Spectrometry
  • Humans
  • Genetics & Heredity
  • Case-Control Studies
  • 3105 Genetics
  • 11 Medical and Health Sciences
  • 06 Biological Sciences