Evidence for CRHR1 in multiple sclerosis using supervised machine learning and meta-analysis in 12,566 individuals.
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.
Briggs
Farren B S
FB
Genetic Epidemiology and Genomics Laboratory, Division of Epidemiology, School of Public Health, CA 94720-7356, USA.
Bartlett
Selena E
SE
Goldstein
Benjamin A
BA
Wang
Joanne
J
McCauley
Jacob L
JL
Zuvich
Rebecca L
RL
De Jager
Philip L
PL
Rioux
John D
JD
Ivinson
Adrian J
AJ
Compston
Alastair
A
Hafler
David A
DA
Hauser
Stephen L
SL
Oksenberg
Jorge R
JR
Sawcer
Stephen J
SJ
Pericak-Vance
Margaret A
MA
Haines
Jonathan L
JL
Barcellos
Lisa F
LF
D016022:Case-Control Studies; D006801:Humans; D013058:Mass Spectrometry; D009103:Multiple Sclerosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics*; D000099052:CRF Receptor, Type 1
D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1