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Publicly Available Data Provide Evidence against NR1H3 R415Q Causing Multiple Sclerosis

2016; Cell Press; Volume: 92; Issue: 2 Linguagem: Inglês

10.1016/j.neuron.2016.09.054

1097-4199

Eric Vallabh Minikel, Daniel G. MacArthur,

RNA regulation and disease

It has recently been reported that an NR1H3 missense variant, R415Q, causes a novel familial form of multiple sclerosis (Wang et al., 2016aWang Z. Sadovnick A.D. Traboulsee A.L. Ross J.P. Bernales C.Q. Encarnacion M. Yee I.M. de Lemos M. Greenwood T. Lee J.D. et al.Nuclear Receptor NR1H3 in Familial Multiple Sclerosis.Neuron. 2016; 90: 948-954Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar). This claim is at odds with publicly available data from the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org). The allele frequency of R415Q is not significantly higher in cases (0.024%–0.049%) than in ExAC population controls (0.031%), whereas if R415Q conferred even 50% lifetime risk of developing MS, it would be hundreds of times more common in cases than in controls. The upper bound of the 95% confidence interval of penetrance for R415Q can be estimated at 2.2% for women and 1.2% for men, indicating that even if this variant is disease associated, individuals harboring the variant would have a lifetime risk of developing MS no higher than a few percent. ExAC data should be considered when evaluating claims of variant pathogenicity. This Matters Arising paper is in response to Wang et al., 2016aWang Z. Sadovnick A.D. Traboulsee A.L. Ross J.P. Bernales C.Q. Encarnacion M. Yee I.M. de Lemos M. Greenwood T. Lee J.D. et al.Nuclear Receptor NR1H3 in Familial Multiple Sclerosis.Neuron. 2016; 90: 948-954Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, published in Neuron. See also the related Matters Arising paper by The International Multiple Sclerosis Genetics Consortium, 2016The International Multiple Sclerosis Genetics ConsortiumNR1H3 p.Arg415Gln is not associated to multiple sclerosis risk.Neuron. 2016; 92 (this issue): 333-335Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar and the response by Wang et al., 2016bWang Z. Sadovnick A.D. Traboulsee A.L. Ross J.P. Bernales C.Q. Encarnacion M. Yee I.M. de Lemos M. Greenwood T. Lee J.D. et al.Case-control studies are not familial studies.Neuron. 2016; 92 (this issue): 339-341Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, published in this issue.