New data and an old puzzle: the negative association between schizophrenia and rheumatoid arthritis.

Int J Epidemiol
Authors
Keywords
Abstract

BACKGROUND: A long-standing epidemiological puzzle is the reduced rate of rheumatoid arthritis (RA) in those with schizophrenia (SZ) and vice versa. Traditional epidemiological approaches to determine if this negative association is underpinned by genetic factors would test for reduced rates of one disorder in relatives of the other, but sufficiently powered data sets are difficult to achieve. The genomics era presents an alternative paradigm for investigating the genetic relationship between two uncommon disorders.

METHODS: We use genome-wide common single nucleotide polymorphism (SNP) data from independently collected SZ and RA case-control cohorts to estimate the SNP correlation between the disorders. We test a genotype X environment (GxE) hypothesis for SZ with environment defined as winter- vs summer-born.

RESULTS: We estimate a small but significant negative SNP-genetic correlation between SZ and RA (-0.046, s.e. 0.026, P = 0.036). The negative correlation was stronger for the SNP set attributed to coding or regulatory regions (-0.174, s.e. 0.071, P = 0.0075). Our analyses led us to hypothesize a gene-environment interaction for SZ in the form of immune challenge. We used month of birth as a proxy for environmental immune challenge and estimated the genetic correlation between winter-born and non-winter born SZ to be significantly less than 1 for coding/regulatory region SNPs (0.56, s.e. 0.14, P = 0.00090).

CONCLUSIONS: Our results are consistent with epidemiological observations of a negative relationship between SZ and RA reflecting, at least in part, genetic factors. Results of the month of birth analysis are consistent with pleiotropic effects of genetic variants dependent on environmental context.

Year of Publication
2015
Journal
Int J Epidemiol
Volume
44
Issue
5
Pages
1706-21
Date Published
2015 Oct
ISSN
1464-3685
URL
DOI
10.1093/ije/dyv136
PubMed ID
26286434
PubMed Central ID
PMC4881824
Links
Grant list
R01 MH077139 / MH / NIMH NIH HHS / United States
MR/K006215/1 / Medical Research Council / United Kingdom
104036 / Wellcome Trust / United Kingdom
ULTR000445 / PHS HHS / United States
1R01AR063759-01A1 / AR / NIAMS NIH HHS / United States
1U01HG0070033 / HG / NHGRI NIH HHS / United States
5U01GM092691-04 / GM / NIGMS NIH HHS / United States
R01 AR063759 / AR / NIAMS NIH HHS / United States
MR/L010305/1 / Medical Research Council / United Kingdom
G0800509 / Medical Research Council / United Kingdom