Common genetic association in autoimmune diseases

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Common genetic association in autoimmune diseases

  1. 1. Converging on a theme: autoimmune genetic architecture across diseases Chris Cotsapas PhD Daly Lab MGH/Broad Institute [email_address] broad.mit.edu/~cotsapas/autoimm.html
  2. 2. Acknowledgements Mark Daly Steve Rich David Hafler Sarah Krause John Todd Jeff Barrett Tim Behrens Rob Graham John Harley Carl Langefeld Pat Gaffney Kathy Moser JT Elder Goncalo Abecasis Peter Gregersen Lars Klareskog Leonid Padyukov Robert Plenge David van Heel Judy Cho Michel Georges John Rioux Chris Amos
  3. 3. Familial aggregation of autoimmunity <ul><li>SLE/T1D/RA/Hashimoto (Criswell et al 05)‏ </li></ul><ul><ul><li>PTPN22 (protective for others?)‏ </li></ul></ul><ul><li>RA/T1D/AITD (Torfs et al 86; Lin et al 98)‏ </li></ul><ul><li>SLE/RA (Alarcon-Segovia et al 05)‏ </li></ul><ul><li>AITD (Marwaha et al 03)‏ </li></ul><ul><li>Autoimmune Disease Db (Karopka et al 06)‏ </li></ul><ul><li>IBD/GD/Psor/AS </li></ul>
  4. 4. Autoimmune associations
  5. 5. Genes common to >1 disease
  6. 6. Motivations <ul><li>Over-arching theme </li></ul><ul><li>Cohort and GWAS availability </li></ul><ul><li>Low power (as yet)‏ </li></ul><ul><li>Potential for signal boosting </li></ul>
  7. 7. Auto-immune GWAS <ul><li>RA </li></ul><ul><ul><li>BRASS </li></ul></ul><ul><ul><li>NARAC/EIRA </li></ul></ul><ul><ul><li>WTCCC </li></ul></ul><ul><li>MS </li></ul><ul><ul><li>IMSGC </li></ul></ul><ul><li>SLE </li></ul><ul><ul><li>SLEGEN </li></ul></ul><ul><ul><li>Genentech </li></ul></ul><ul><ul><li>MNSLE </li></ul></ul><ul><li>Crohn's </li></ul><ul><ul><li>NIDDK </li></ul></ul><ul><ul><li>WTCCC </li></ul></ul><ul><ul><li>Liege </li></ul></ul><ul><li>Type I diabetes </li></ul><ul><ul><li>WTCCC </li></ul></ul><ul><li>Psoriasis </li></ul><ul><ul><li>GAIN </li></ul></ul><ul><ul><li>Bowcock et al </li></ul></ul><ul><li>AS </li></ul><ul><ul><li>AAASC </li></ul></ul>
  8. 8. FOCiS/NOC meta-analysis
  9. 9. Locus selection <ul><li>Replicated GWAS hit </li></ul><ul><ul><li>Combined p < 5 x 10 -7 </li></ul></ul><ul><li>Not in the MHC! </li></ul><ul><ul><li>Extensive LD structure in region </li></ul></ul><ul><li>52 loci </li></ul><ul><ul><li>216 proxy SNPs on common platforms </li></ul></ul>
  10. 10. Data collection <ul><li>Participant studies share genotype counts </li></ul><ul><li>Imputed genotypes (if available)‏ </li></ul><ul><li>No overlapping cases </li></ul><ul><li>Shared controls can be a problem </li></ul><ul><li>Calculate association as (meta) Z score </li></ul><ul><ul><li>directional </li></ul></ul>
  11. 11. Loci ascertained in T1D: Association in RA
  12. 13. Next steps <ul><li>Account for shared controls </li></ul><ul><ul><li>Composite likelihood method </li></ul></ul><ul><li>Incorporate further imputed data </li></ul><ul><li>Validate directionality </li></ul><ul><li>Additional studies and loci </li></ul><ul><li>Within-disease meta-analyses </li></ul><ul><li>Replication </li></ul>
  13. 14. Overlap between diseases

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