Genetics

A advances in population-scale genomics are transforming how we evaluate genetic disease risk, and the story of the NR1H3 R415Q variant is a perfect example. Though initially reported to “cause” a familial form of multiple sclerosis, broader evidence from over 60,000 publicly available exomes shows that this variant is far too common—and not enriched in MS patients—to play such a major role. In this human-centered analysis, we walk through how big-data resources like ExAC overturn premature pathogenicity claims and why careful interpretation is essential in the era of complex genetic diseases.