While schizophrenia is a psychiatric disorder of unknown origin and
rheumatoid arthritis is an autoimmune disease of the joints that occurs
as a result of the body's immune system attacking its own cells, both
disorders are thought to be influenced by multiple genetic risk factors
modified by the environment.
An in-depth computational analysis of genetic variants implicated in
both schizophrenia and rheumatoid arthritis by researchers at the
University of Pittsburgh points to eight genes that may explain why
susceptibility to one of the disorders could place individuals at lower
risk for the other, revealed the results of a study published in the journal npj Schizophrenia
‘Newly identified eight genes may explain why susceptibility to schizophrenia or rheumatoid arthritis could place individuals at lower risk for the other.’
"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, associate professor of
biomedical informatics at the University of Pittsburgh School of
Medicine and senior author of the study.
"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, professor of
psychiatry at Pitt's School of Medicine and human genetics at Pitt's
Graduate School of Public Health.
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
region of the genome that harbors genes associated with immune function.
The variants appeared to confer different risk for schizophrenia or
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.
The findings are encouraging because they support associations of
the HLA gene region and immune function with schizophrenia and
rheumatoid arthritis that were known over four decades ago, said
Ganapathiraju. Increasing evidence also suggests that a dysfunctional
immune system could play a role in the development of schizophrenia.
"We believe that the research community studying these two disorders will find our results extremely helpful," Nimgaonkar said.
The authors note that the study only focused on SNPs in known gene
regions, and other mechanisms apart from the ones they described may
also contribute to the diseases. However, the study has significantly
narrowed the list of potential genes for examining the
schizophrenia/rheumatoid arthritis relationship. Studying the functional
relevance of the gene candidates in cells and tissues will provide
insights into the two disorders, according to the researchers.