title: Functional interpretation of non-coding sequence variation: concepts and challenges.
abstract: Understanding the functional mechanisms underlying genetic signals associated with complex traits and common diseases, such as cancer, diabetes and Alzheimer's disease, is a formidable challenge. Many genetic signals discovered through genome-wide association studies map to non-protein coding sequences, where their molecular consequences are difficult to evaluate. This article summarizes concepts for the systematic interpretation of non-coding genetic signals using genome annotation data sets in different cellular systems. We outline strategies for the global analysis of multiple association intervals and the in-depth molecular investigation of individual intervals. We highlight experimental techniques to validate candidate (potential causal) regulatory variants, with a focus on novel genome-editing techniques including CRISPR/Cas9. These approaches are also applicable to low-frequency and rare variants, which have become increasingly important in genomic studies of complex traits and diseases. There is a pressing need to translate genetic signals into biological mechanisms, leading to prognostic, diagnostic and therapeutic advances.
authors: UCL Cancer Institute, University College London, London, United Kingdom.
authors: Dirk S
authors: DS
authors: Paul
authors: Nicole
authors: N
authors: Soranzo
authors: Stephan
authors: S
authors: Beck
mesh_terms: D019295:Computational Biology; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans
keywords: GWAS; chromatin; complex traits; gene regulation; genome editing; regulatory variants