PT  - JOURNAL ARTICLE
AU  - Gosia Trynka
AU  - Harm-Jan Westra
AU  - Kamil Slowikowski
AU  - Xinli Hu
AU  - Han Xu
AU  - Barbara E Stranger
AU  - Buhm Han
AU  - Soumya Raychaudhuri
TI  - Disentangling effects of colocalizing genomic annotations to functionally prioritize non-coding variants within complex trait loci
AID  - 10.1101/009258
DP  - 2014 Jan 01
TA  - bioRxiv
PG  - 009258
4099  - http://biorxiv.org/content/early/2014/09/18/009258.short
4100  - http://biorxiv.org/content/early/2014/09/18/009258.full
AB  - Identifying genomic annotations that differentiate causal from associated variants is critical to fine-map disease loci. While many studies have identified non-coding annotations overlapping disease variants, these annotations colocalize, complicating fine-mapping efforts. We demonstrate that conventional enrichment tests are inflated and cannot distinguish causal effects from colocalizing annotations. We developed a sensitive and specific statistical approach that is able to identify independent effects from colocalizing annotations. We first confirm that gene regulatory variants map to DNase-I hypersensitive sites (DHS) near transcription start sites. We then show that (1) 15-35% of causal variants within disease loci map to DHS independent of other annotations; (2) breast cancer and rheumatoid arthritis loci harbor potentially causal variants near the summits of histone marks rather than full peak bodies; and (3) variants associated with height are highly enriched for embryonic stem cell DHS sites. We highlight specific loci where we can most effectively prioritize causal variation.