Publicly Available Data Provide Evidence against NR1H3 R415Q Causing Multiple Sclerosis

Area of Science:

• Genetics
• Neurology
• Population Genetics

Background:

• A recent study proposed the NR1H3 R415Q missense variant as a cause of familial multiple sclerosis (MS).
• This claim requires careful evaluation against existing population genetic data.

Purpose of the Study:

• To assess the association between the NR1H3 R415Q variant and multiple sclerosis using population control data.
• To re-evaluate the pathogenicity and penetrance of the R415Q variant in the context of MS.

Main Methods:

• Analysis of allele frequency data from the Exome Aggregation Consortium (ExAC).
• Comparison of R415Q allele frequency in MS cases versus ExAC population controls.
• Estimation of the upper bound of penetrance for the R415Q variant.

Main Results:

• The allele frequency of R415Q was not significantly higher in MS cases (0.024%-0.049%) compared to ExAC controls (0.031%).
• The estimated upper bound of 95% confidence interval for R415Q penetrance is 2.2% for women and 1.2% for men.
• These findings indicate a low lifetime risk of MS associated with the R415Q variant.

Conclusions:

• Publicly available population data, such as ExAC, are crucial for evaluating claims of variant pathogenicity.
• The NR1H3 R415Q variant's low frequency in controls and estimated low penetrance challenge its role as a primary cause of familial multiple sclerosis.