Figure 2. Candidate variant fine-mapping based on functional annotations.
Different types of functional annotations, such as missense variants (a,b) or regulatory marks (c), can lead to prioritization of candidate risk variants. a | Human leukocyte antigen (HLA) locus in chromosome 6, where genes pertaining to major histocompatibility complex (MHC) class I, II and III are found. b | By testing for associations between amino acid residues and rheumatoid arthritis (RA), investigators were able to fine-map independent risk variants that cause changes in amino acids found in the binding pocket of the MHC class II molecule DRβ1. Specifically, ~90% of the MHC risk in RA is attributable to a specific amino acid residue in position 13 at the bottom of the DRβ1 antigen-binding groove, and amino acids 71 and 74 (whose side chains point into the antigen-binding groove) independently modulate RA susceptibility c | Other functional annotations, such as histone modifications, can be used to prioritize non-coding candidate risk variants38,103. In the hypothetical example shown, four non-coding variants in linkage disequilibrium in a disease susceptibility locus have equal posterior probability of being causative for the disease. However, if one uses information on cell-type-specific regulatory annotation (in this case histone H3 trimethylation on Lys4 (H3K4me3)), and knowledge of the most relevant cell type as the genetic mediator of the disease in question (in this case, B cells), one can assign a higher posterior probability to a variant overlapping a B cell H3K4me3 peak. Part a adapted from REF. 199, Nature Publishing Group. Part b adapted from REF. 48, Nature Publishing Group.