Phenome-Wide Association Study Suggests Common Genetic Etiology between Rheumatoid Arthritis and Multiple Diseases

Ellen Arndt
University of Wisconsin
La Crosse

Ellen R. Arndt¹, Jamie C. Fox¹, Zhan (Harold) Ye², John G. Mayer2, Jixia Liu1, Brian A. Hoch2, Scott J. Hebbring1
¹Center for Human Genetics, ²Biomedical Informatics Research Center

Research area: Genetics 

Background: The genetic component of rheumatoid arthritis is known to be complex. Genome-wide association studies (GWASs) have identified single nucleotide polymorphisms (SNPs) associated with rheumatoid arthritis using a phenotype-to-genotype approach. This study utilized a paired approach, a phenome-wide association study (PheWAS), to comprehensively assess whether the genes of rheumatoid arthritis possess significant pleiotropic properties. 

Methods: Previously completed GWASs identified 257 SNPs associated with rheumatoid arthritis. All 257 SNPs were sorted and condensed to 57 independent loci/SNPs. PheWAS data from selected SNPs was compiled from 3,940 patients genotyped on Illumina 660W-Quad SNP chip and 7,061 patients genotyped on Illumina’s Expanded Human Core Exome SNP chip from the Personalized Medicine Research Project bio-bank. PheWAS data was used to select a mixture of SNPs to best represent rheumatoid arthritis for a combined meta-analysis.

Results: Of the 57 representative loci, 53 were assessed in patients genotyped on the Illumina 660W-Quad SNP chip and 47 SNPs in patients genotyped on the Illumina Expanded Human Core Exome SNP chip. PheWAS results showed a statistically significant relationship (P=2.18x10-8) between hypothyroidism and rheumatoid arthritis. In addition, suggestive yet strong associations surfaced between rheumatoid arthritis and other diseases such as intrinsic asthma and type I diabetes.

Conclusion: This comprehensive PheWAS identified SNP-disease associations suggesting rheumatoid arthritis shares a common genetic etiology with multiple diseases including hypothyroidism, intrinsic asthma, and type I diabetes. Better understanding the genetic causes of rheumatoid arthritis, and of the diseases that may share a common genetic etiology, will potentially lead to new paradigms in how these diseases are predicted, diagnosed, and treated.