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

被引：16

作者：

Briggs, Farren B. S. ^{[1
]}

Bartlett, Selena E. ^{[2
]}

Goldstein, Benjamin A. ^{[1
,3
]}

Wang, Joanne ^{[4
,5
]}

McCauley, Jacob L. ^{[6
]}

Zuvich, Rebecca L. ^{[7
]}

De Jager, Philip L. ^{[8
,9
,10
]}

Rioux, John D. ^{[11
]}

Ivinson, Adrian J. ^{[12
]}

Compston, Alastair ^{[13
]}

Hafler, David A. ^{[9
,10
,14
]}

Hauser, Stephen L. ^{[4
,5
]}

Oksenberg, Jorge R. ^{[4
,5
]}

Sawcer, Stephen J. ^{[13
]}

Pericak-Vance, Margaret A. ^{[6
]}

Haines, Jonathan L. ^{[7
]}

Barcellos, Lisa F. ^{[1
]}

机构：

[1] Univ Calif Berkeley, Sch Publ Hlth, Div Epidemiol, Genet Epidemiol & Genom Lab, Berkeley, CA 94720 USA

[2] Univ Calif San Francisco, Ernest Gallo Clin & Res Ctr, San Francisco, CA 94143 USA

[3] Univ Calif San Francisco, Sch Med, Dept Neurol, San Francisco, CA 94143 USA

[4] Univ Calif San Francisco, Sch Med, Inst Human Genet, San Francisco, CA 94143 USA

[5] Univ Calif Berkeley, Sch Publ Hlth, Div Biostat, Berkeley, CA 94720 USA

[6] Univ Miami, Miller Sch Med, John P Hussman Inst Human Genom, Miami, FL 33136 USA

[7] Vanderbilt Univ, Med Ctr, Ctr Human Genet Res, Nashville, TN 37232 USA

[8] Brigham & Womens Hosp, Ctr Neurol Dis, Dept Neurol, Program NeuroPsychiat Genom, Boston, MA 02115 USA

[9] Harvard Univ, Broad Inst, Program Med & Populat Genet, Cambridge, MA 02139 USA

[10] MIT, Cambridge, MA 02139 USA

[11] Univ Montreal, Montreal Heart Inst, Lab Genet & Genom Med Inflammat, Montreal, PQ H1T 1C8, Canada

[12] Harvard Univ, Sch Med, Harvard NeuroDiscovery Ctr, Medford, MA 02155 USA

[13] Univ Cambridge, Addenbrookes Hosp, Dept Clin Neurosci, Cambridge CB2 2QQ, England

[14] Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06520 USA

来源：

HUMAN MOLECULAR GENETICS | 2010年 / 19卷 / 21期

基金：

英国医学研究理事会;

关键词：

CORTICOTROPIN-RELEASING HORMONE; STRESSFUL LIFE EVENTS; WHOLE-GENOME ASSOCIATION; PSYCHOLOGICAL STRESS; DIAGNOSTIC-CRITERIA; WIDE ASSOCIATION; MAST-CELLS; SUSCEPTIBILITY; HAPLOTYPE; RISK;

D O I：

10.1093/hmg/ddq328

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 x 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.

引用

页码：4286 / 4295

页数：10

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