Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose: Rheumatoid arthritis (RA) is a common autoimmune disease and schizophrenia (SZ) is a common psychotic disorder. There is an established negative association between RA and SZ, with some evidence for a similar relationship in bipolar disorder (BPD) (Oken and Schulzer, Schiz Bull 25:625, 1999). We hypothesize that the negative relationship is determined by disease-specific mutually-exclusive (genetic and environmental) factors that provide input into a common pathway, driving disease progression in both the brain and immune system. An allele conferring susceptibility to RA will stimulate the hypothetical disease-causing pathway in the immune system, but will protect from SZ by preventing activation of the pathway in the brain, and vice versa. Our hypothesis predicts a molecular pathway(s) containing shared genetic risk variant(s) driving the pathogenesis of both diseases.
Methods: We exploited genome-wide association scan (GWAS) data by comparing the top 1000 associations from the Genetic Association Information Network (GAIN) SZ dataset and the Wellcome Trust Case Control Consortium (WTCCC) RA dataset for candidate SNPs associated with both RA and SZ in the same direction of association. Replication in RA was done over Australasian, UK, Dutch and Norwegian Caucasian case-control sample sets (3755 cases and 3084 controls) using TaqManÒ technology. For psychotic disorder, replication was done in silico from publicly-available non-GAIN SZ and BPD datasets (3770 cases and 5269 controls).
Results: SNP rs900865 from the chromosome 11 INSC-SOX6 region fitted the selection criteria of consistent direction of association (OR=1.14, P=0.002 in WTCCC RA and OR=1.22, P=5×10-4 in GAIN SZ). In replication there was evidence for association in both the meta-analyzed RA replication dataset (OR=1.09, P=0.009) and in the combined SZ/BPD replication dataset (OR=1.09, P=0.004). Meta-analysis of all datasets (psychotic disease datasets GAIN Sz, non-GAIN Sz and BPD; and RA datasets Australasian, UK, Dutch, Norwegian and WTCCC) provided evidence of association with rs900865 at the genome-wide level of significance (OR=1.11, P=1.8×10-8).
Conclusion: We conclude that the minor allele (C) of SNP rs900865 confers susceptibility to both RA and psychotic disease. The SNP maps between the INSC (inscuteable homolog) and SOX6 (sex-determining region Y box 6) genes. INSC is not well characterized, but is known to be involved in retinal development. SOX6 encodes a transcriptional factor that plays a role in a number of cell developmental processes including development of the central nervous system and human skeletal development (chondrogenesis), and is expressed in both the immune and central nervous systems. Whilst the mechanism is unclear, our data do suggest a genetic relationship between RA and psychosis, perhaps in a common signaling pathway.
Disclosure:
T. R. Merriman,
None;
N. Dalbeth,
None;
A. Harrison,
None;
J. Highton,
None;
L. K. Stamp,
None;
M. D. Smith,
None;
B. A. Lie,
None;
T. K. Kvien,
Abbott Immunology Pharmaceuticals,
8,
AstraZeneca,
8,
Merck Pharmaceuticals,
8,
NiCox, S.A.,
8,
Pfizer Inc,
8,
Roche Pharmaceuticals,
8,
UCB,
8,
BMS,
5,
Abbott Immunology Pharmaceuticals,
5,
Merck Pharmaceuticals,
5,
NiCox, S.A.,
5,
Pfizer Inc,
5,
Roche Pharmaceuticals,
5,
UCB,
5;
T. Radstake,
None;
M. J. H. Coenen,
None;
B. Franke,
None;
J. Broen,
None;
P. Van Riel,
None;
P. Barrera,
None;
S. Steer,
None;
M. E. Merriman,
None;
A. Phipps-Green,
None;
R. Topless,
None;
M. Zamanpoor,
None;
W. R. Wan Tain,
None.
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