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Source: Wikimedia Commons, Bernd Brägelmann, and National Institutes of Health

Inverse Relationship Between Schizophrenia and RA?

Elizabeth Hofheinz, M.P.H., M.Ed. • Wed, March 8th, 2017

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New research from the University of Pittsburgh has pinpointed eight genes that could explain why individuals susceptible to schizophrenia may be at lower risk for rheumatoid arthritis (RA)…and vice versa. The results were published online February 24, 2017 in the journal npj Schizophrenia. The work is entitled, “Generating testable hypotheses for schizophrenia and rheumatoid arthritis pathogenesis by integrating epidemiological, genomic, and protein interaction data.”

"There is a wealth of genomic data on both schizophrenia and rheumatoid arthritis. Analyzing it jointly with known protein interaction information could provide invaluable clues to the relationship between the diseases and also shed light on their shared roots," said Madhavi Ganapathiraju, Ph.D., associate professor of biomedical informatics at the University of Pittsburgh School of Medicine and senior author of the study, in the news release.

"Several previous research studies have hinted at a potential inverse relationship in the prevalence and risk for the two disorders, so we wondered if individual genetic variants may exist that could have opposing effects on the risk of schizophrenia and rheumatoid arthritis," said co-senior author Vishwajit Nimgaonkar M.D., Ph.D., professor of psychiatry at Pitt's School of Medicine and human genetics at Pitt's Graduate School of Public Health.

As indicated in the news release, “The researchers first analyzed two large databases of genetic variants significantly associated with either schizophrenia or rheumatoid arthritis. They identified 18 unique variants, also known as single nucleotide polymorphisms (SNPs) that were located in the HLA [human leukocyte antigen] region of the genome that harbors genes associated with immune function. The variants appeared to confer different risk for schizophrenia or rheumatoid arthritis. As the SNPs were located near eight known genes in this region, the authors suggested those genes might lead to dysfunction in both schizophrenia and rheumatoid arthritis. Proteins encoded by two of these eight genes, HLA-B and HLA-C, are present in both brain and immune cells.”

“Analysis of proteins that interact with these eight genes using a computational model developed last year by Ganapathiraju's team called High-Precision Protein Interaction Prediction found more than 25 signaling pathways with proteins common to both rheumatoid arthritis and schizophrenia signaling. Moreover, several of these pathways were associated with immune system function and inflammation.”

Drs. Madhavi Ganapathiraju and Dr. Vishwajit Nimgaonkar told OTW, “There is evidence in the scientific literature that the two disorders have inverse prevalence. In particular, persons with schizophrenia have a reduced prevalence of rheumatoid arthritis. With the results from genome-wide association studies becoming available for each of the disorders, it was a good time to look for evidence at a genetic level.”

“We identified that the genetic variants that confer opposing risk to the two disorders are localized to 8 genes in the HLA region. Upon carrying out an analysis of the protein interactions of the genes associated with each of the two disorders separately, we found that they exhibit a large overlap in underlying biological processes.”

“It was surprising to find that the genetic variants associated with both the disorders are intricately connected to the same cellular signaling pathways (e.g., interleukin-8 signaling, axon guidance signaling).”

“Similar approaches could be useful for orthopedic diseases that offer analogous epidemiological clues and for which genome wide association data are available.”

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