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

Farren B.S. Briggs, Selena E. Bartlett, Benjamin A. Goldstein, Joanne Wang, Jacob L. McCauley, Rebecca L. Zuvich, Philip L. de jager, John D. Rioux, Adrian J. Ivinson, Alastair Compston, David A. Hafler, Stephen L. Hauser, Jorge R. Oksenberg, Stephen J. Sawcer, Margaret A. Pericak-Vance, Jonathan L. Haines, Lisa F. Barcellos

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4286-4295
Number of pages10
JournalHuman molecular genetics
Volume19
Issue number21
DOIs
StatePublished - Aug 10 2010

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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