NR1H3 p.Arg415Gln is not associated to multiple sclerosis risk

Abstract

A recent study by Wang et al claims the low-frequency variant NR1H3 p.Arg415Gln is pathological for multiple sclerosis and determines a patients likelihood of primary progressive disease. We sought to replicate this finding in the International MS Genetics Consortium (IMSGC) patient collection, which is 13-fold larger than the collection of Wang et al, but we find no evidence that this variant is associated either with MS or disease subtype. Wang et al also report a common variant association in the region, which we show captures the association the IMSGC reported in 2013. Therefore, we conclude that the reported low-frequency association is a false positive, likely generated by insufficient sample size. The claim of NR1H3 mutations describing a Mendelian form of MS - of which no examples exist - can therefore not be substantiated by data.