Genetics

This post unpacks a large International Multiple Sclerosis Genetics Consortium study that uses exome-array genotyping in tens of thousands of MS cases and controls to probe low-frequency and rare coding variation—genetic signals largely missed by conventional GWAS. It explains how the authors identify genome-wide significant protein-altering variants (including novel associations in PRF1, HDAC7, PRKRA, and NLRP8) and then quantify how much low-frequency coding variation contributes to MS liability at the population level. Along the way, it connects these statistical findings to immunological mechanisms—Treg biology, interferon and NF-κB signaling, cytotoxic function, and innate immune sensing—and closes with what sequencing and functional follow-up should prioritize to translate coding discoveries into causal, testable disease biology.