Common genetic association in autoimmune diseases - Update

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

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

Familial aggregation of autoimmunity
SLE/T1D/RA/Hashimoto (Criswell et al 05)‏
PTPN22 (protective for others?)‏
RA/T1D/AITD (Torfs et al 86; Lin et al 98)‏
SLE/RA (Alarcon-Segovia et al 05)‏
AITD (Marwaha et al 03)‏
Autoimmune Disease Db (Karopka et al 06)‏
IBD/GD/Psor/AS

Autoimmune associations

Genes common to >1 disease

Motivations
Over-arching theme
Cohort and GWAS availability
Low power (as yet)‏
Potential for signal boosting

Auto-immune GWAS
RA
BRASS
NARAC/EIRA
WTCCC
MS
IMSGC
SLE
SLEGEN
Genentech
(MNSLE)‏
Crohn's
NIDDK
WTCCC
Liege
Type I diabetes
WTCCC
Psoriasis
GAIN
(Bowcock et al )‏
AS
(AAASC)‏

FOCiS/NOC meta-analysis

Locus selection
Replicated GWAS hit
Combined p < 5 x 10 -7
Not in the MHC!
Extensive LD structure in region
52 loci
216 proxy SNPs on common platforms

Data collection
Participant studies share genotype counts
Imputed genotypes (if available)‏
No overlapping cases
Shared controls can be a problem
Calculate association as (meta) Z score
directional

Loci ascertained in T1D: Association in RA

T1D loci

CD loci

AS loci

MS loci

RA loci

SLE loci

Celiac loci

Next steps
Account for shared controls
Composite likelihood method
Incorporate further imputed data
Validate directionality
Additional studies and loci
Within-disease meta-analyses
Replication

Overlap between diseases

http://www.polygenicpathways.co.uk	449
http://www.broad.mit.edu	32
http://www.broadinstitute.org	15
http://broad.mit.edu	4
http://webcache.googleusercontent.com	4
http://www.slideshare.net	2

Common genetic association in autoimmune diseases - Update

by Chris Cotsapas on Jul 07, 2008

Accessibility

Categories

Tags

Upload Details

Usage Rights

6 Embeds 506

Statistics

Common genetic association in autoimmune diseases - Update — Presentation Transcript