Colocalization methods are designed to disentangle shared and distinct casual variants in regions where two diseases show association. We extended existing methods to allow for the shared control design common in GWAS. 126 ImmunoChip regions assigned to at least one of the 4 diseases studies - Multiple Sclerosis (MS), Celiac Disease (CEL), Rheumatoid Arthritis (RA) & Type 1 Diabetes (T1D) - were analysed for all six pariwise comparisons. Ninety of the 126 regions (71%) showed association with at least one disease, with 33 regions (26%) showing association shared between at least 2 diseases.
Two colocolaization methods were applied to each of the 126 regions, a Bayesian Approach and a Proportional Approach. 21 regions were found most likely to be disease-specific under the analyses, 14 regions showed evidence for seperate SNP effects (P(H3) > 0.5) and finally 12 regions showed strong evidence of novel association (P(H3H4) > 0.5)
All samples included in this study were gathered in the UK and are reported, or self-declared, as European ancestry.
Sample exclusions were applied as described in each of the ImmunoChip papers for CEL (GDXHsS00009 - Trynka et al.), RA (GDXHsS00019 - Eyre et al.), MS (GDXHsS00030 - IMSGC et al.) and T1D (GDXHsS00025 - Onengut et al.)
Markers were excluded due to...
- Call rate <99%
- MAF <1%
- HardyWeinberg Z-score > 5
- Lying in the MHC region (defiend as hg18 chr6:29,797,978-33,606,563)
Regions were excluded due to...
- Containing fewer than 10 SNPs
- SNP density < 1 SNP/kb
High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis.
Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers.
Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.
|Region||Location||Gene(s)||Marker||Allele||MAF||P Value||Odds Ratio|
|1q24.3||chr1:172681545-172896352||FASLG||rs12068671||T > C||0.187||1.27e-05D||1.14D|
|2p14||chr2:65170461-65489960||SPRED2||rs1858037||T > A||0.344||7.26e-04D||1.06 (1.02-1.1)D|
|2q11.2||chr2:99928492-100425222||AFF3||rs9653442||T > C||1.37e-05D||1.08D|
|2q37.1||chr2:230185270-230371171||SP140||rs10201872||C > T||2.02e-04D||1.09D|
|5q11.2||chr5:56122309-56161300||ANKRD55||rs71624119||G > A||0.246||5.53e-05D||1.11D|
|6q15||chr6:90097116-90319078||BACH2||rs72928038||G > A||0.176||8.23e-07D||1.13D|
|6q23.3||chr6:137568592-137806067||TNFAIP3||rs6920220||G > A||0.220||7.26e-06D||1.12D|
|7p12.2||chr7:50212219-50325817||IKZF1||rs201847125||C > T||0.301||8.59e-02D||1.04D|
|7p14.1||chr7:37323977-37400850||ELMO1||rs79758729||A > G||0.105||9.15e-07D||1.15D|
|13q32.3||chr13:99240634-99534324||GPR183||rs9585056||T > C||6.17e-01D||1.01D|
|15q25.1||chr15:78728401-78968794||CTSH||rs34593439||G > A||6.50e-07D||1.16D|
|19p13.2||chr19:10280033-10517872||ICAM1 ICAM3 TYK2||rs34536443||G > C||1.69e-05D||1.23D|