Why One Genetic Variant Isn’t the Smoking Gun for Multiple Sclerosis: What Big Data Reveals About NR1H3 R415Q

In the era of large-scale genome sequencing, single studies claiming that a rare variant “causes” a complex disease are facing an increasingly stringent test: does the claim hold up when compared to massive public datasets? A 2016 commentary by Eric Vallabh Minikel and Daniel MacArthur demonstrates this beautifully. Using data from the Exome Aggregation Consortium (ExAC), they challenge a high-profile assertion that a variant in NR1H3—specifically R415Q—causes a novel familial form of multiple sclerosis (MS).

The conclusion? The numbers simply don’t add up.

The Claim: A Single Variant Behind a Familial Form of MS
Wang et al. (2016) originally reported that rs61731956, a missense variant in NR1H3 causing an R415Q amino acid change, segregated with disease in two MS pedigrees and therefore could represent a causal familial mutation. For a complex, heterogeneous disease like MS, this was a bold and exciting suggestion.

But claims of pathogenicity must be held to a high bar—and that means looking beyond a single family.

ExAC: A Reality Check Using 60,000+ Genomes
Minikel and MacArthur turned to the Exome Aggregation Consortium database, which contains exome sequences from 60,706 individuals of diverse ancestry.

This dataset is indispensable because it lets researchers estimate how common a variant is in the general population, even among people who were not specifically screened for MS.

Their key finding:

NR1H3 R415Q appears in 21 ExAC individuals of non-Finnish European ancestry, corresponding to

an allele frequency of 0.031%.

This might sound extremely rare—but in the context of a severe, inherited familial disease, it’s far too common.

Why Frequency Matters for Causality
If NR1H3 R415Q were truly causing a familial form of MS with meaningful penetrance, we would expect it to be dramatically enriched in MS patients compared to the general population.

But the numbers tell a different story.

In MS cases:

Wang et al. found the variant in 1 out of 2,053 cases (0.024%)—or 2 cases if counting the proband (0.049%).

In ExAC controls:

The allele frequency is essentially identical at 0.031%.

Statistically, there is no significant enrichment (p = 0.39).

For a variant that supposedly causes a Mendelian form of disease—even with incomplete penetrance—this lack of enrichment is a fatal blow.

How Rare Must a Causal Variant Be?
For context, the lifetime risk of MS is low:

0.25% for women,

0.14% for men.

If a variant caused even a modest 50% lifetime risk, its odds ratio relative to baseline would be enormous (~399 for women). This means we would expect NR1H3 R415Q to appear in:

~12–21% of all MS patients,

not < 0.1%, as actually observed.

Put simply, a variant that supposedly causes MS cannot be both rare in MS patients and this common in the general population.

So What Is the Risk for NR1H3 R415Q Carriers?
Using case/control frequencies and established penetrance modeling, the authors estimate:

95% CI upper bound of penetrance:

2.2% for women

1.2% for men

Even if the variant is associated with slight increased susceptibility, the lifetime MS risk for a carrier is only a few percent at most.

This is nowhere near the behavior expected of a causal familial mutation. Why ExAC Is Still Useful
Minikel & MacArthur also address common criticisms of using population databases:

Are ExAC individuals disease-free? Not necessarily, but none were collected based on MS diagnosis.

Could ExAC contain some MS patients? Possibly—but in numbers far too small to affect allele frequency at this scale.

Are rare variants sometimes benign despite being rare? Yes, but this does not undermine cases where a variant is too common to be causal.

Could genotype errors explain this? Unlikely: R415Q calls appear high quality.

In other words, none of the limitations change the main conclusion: this variant is inconsistent with being a high-penetrance cause of familial MS.

Why This Matters for Human Genetics
This paper is more than a critique of one claim—it highlights a principle that is reshaping the field:

Large population datasets must be used to assess pathogenicity claims.

As of 2016, ExAC alone had helped reclassify over 150 previously reported “pathogenic” variants as benign.

Modern allele frequency resources have become essential for:

distinguishing genuine disease-causing variants from noise evaluating candidate gene findings applying rigorous statistical standards to variant interpretation

The authors argue that without considering such datasets, researchers risk drawing incorrect conclusions from small family studies—especially in complex diseases with low baseline incidence.

Conclusion: A Variant Too Common to Cause MS
Minikel & MacArthur deliver a clear message:

NR1H3 R415Q is simply too common—and too evenly distributed between cases and controls—to cause a familial form of multiple sclerosis.

While it’s still technically possible that the variant confers a very small increase in MS risk, the evidence does not support pathogenicity, high penetrance, or familial causation.

Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.

References:
Minikel, E. V., & MacArthur, D. G. (2016). Publicly available data provide evidence against NR1H3 R415Q causing multiple sclerosis. Neuron, 92(2), 336-338.