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Publication . Article . Other literature type . 2015

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

the negative association between schizophrenia and rheumatoid arthritis
S. Hong Lee; Enda M. Byrne; Christina M. Hultman; Anna K. Kähler; Anna A. E. Vinkhuyzen; Stephan Ripke; Ole A. Andreassen; +137 Authors
Open Access

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. Refereed/Peer-reviewed

Subjects by Vocabulary

Microsoft Academic Graph classification: SNP Genetic correlation Genetics Genotype Genome-wide association study Bipolar disorder medicine.disease medicine Biology Genetic variation Single-nucleotide polymorphism Gene–environment interaction


Adolescent, Adult, Arthritis, Rheumatoid, Cohort Studies, Cross-Sectional Studies, Female, Gene-Environment Interaction, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Schizophrenia, Young Adult, Public, Environmental & Occupational Health, schizophrenia, rheumatoid arthritis, genetic relationship, pleiotropy, genome, General Medicine, Epidemiology, Miscellaneous, Arthritis, Rheumatoid, Polymorphism, Single Nucleotide, SDG 3 - Good Health and Well-being, /dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being, SDG 3 - Good Health and Well-being

Related Organizations
71 references, page 1 of 8

1. Oken RJ, Schulzer M. At issue: schizophrenia and rheumatoid arthritis: the negative association revisited. Schizophr Bull 1999;25:625-38. [OpenAIRE]

2. Sellgren C, Frisell T, Lichtenstein P, Landen M, Askling J. The association between schizophrenia and rheumatoid arthritis: a nationwide population-based Swedish study on intraindividual and familial risks. Schizophr Bull 2014;40:1552-59. [OpenAIRE]

3. de Leon J, Diaz FJ. A meta-analysis of worldwide studies demonstrates an association between schizophrenia and tobacco smoking behaviors. Schizophr Res 2005;76:135-57.

4. Bang SY, Lee KH, Cho SK, Lee HS, Lee KW, Bae SC. Smoking increases rheumatoid arthritis susceptibility in individuals carrying the HLA-DRB1 shared epitope, regardless of rheumatoid factor or anti-cyclic citrullinated peptide antibody status. Arthritis Rheum 2010;62:369-77.

5. Torrey EF, Yolken RH. The schizophrenia-rheumatoid arthritis connection: infectious, immune, or both? Brain Behav Immun 2001;15:401-10.

6. Saha S, Chant D, Welham J, McGrath J. A systematic review of the prevalence of schizophrenia. PLoS Med 2005;2:e141.

7. Benros ME, Pedersen MG, Rasmussen H, Eaton WW, Nordentoft M, Mortensen PB. A nationwide study on the risk of autoimmune diseases in individuals with a personal or a family history of schizophrenia and related psychosis. Am J Psychiatry 2014;171:218-26. [OpenAIRE]

8. Lichtenstein P, Yip BH, Bjork C et al. Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet 2009;373:234-39.

9. Frisell T, Holmqvist M, Kallberg H, Klareskog L, Alfredsson L, Askling J. Familial risks and heritability of rheumatoid arthritis: role of rheumatoid factor/anti-citrullinated protein antibody status, number and type of affected relatives, sex, and age. Arthritis Rheum 2013;65:2773-82. [OpenAIRE]

10. Sullivan PF, Kendler KS, Neale MC. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry 2003;60:1187-92.

Funded byView all
NHMRC| Using New Genomic Technologies, Statistical and Computational Methods to Uncover The Genetic Aetiology of Complex Traits
  • Funder: National Health and Medical Research Council (NHMRC) (NHMRC)
  • Project Code: 1053639
  • Funding stream: Early Career Fellowships
NHMRC| Using genomics to understand psychiatric disorders
  • Funder: National Health and Medical Research Council (NHMRC) (NHMRC)
  • Project Code: 1078901
  • Funding stream: Research Fellowships
NIH| Genetic predictors of response to anti-TNF therapy in rheumatoid arthritis
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5U01GM092691-04
NHMRC| Statistical analyses of whole genome genotype data to better understand psychiatric disorders
  • Funder: National Health and Medical Research Council (NHMRC) (NHMRC)
  • Project Code: 1047956
  • Funding stream: Project Grants
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