Genetics

This blog post examines how low-frequency and rare protein-coding variants contribute to multiple sclerosis susceptibility beyond the genetic signals detected by conventional genome-wide association studies. Drawing on a large international analysis of more than 68,000 cases and controls, it discusses the estimated contribution of rare variants to disease heritability, the identification of novel risk-associated genes, and the biological implications for regulatory T-cell function, interferon signalling, cytotoxicity, innate immunity and thymic development. It also considers the methodological strengths and limitations of exome-array analysis and explains why larger, ancestry-diverse sequencing studies will be essential for resolving the remaining genetic architecture of multiple sclerosis.