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

Authors:
S Hong Lee Enda M Byrne Christina M Hultman Anna Kähler Anna A E Vinkhuyzen Stephan Ripke Ole A Andreassen Thomas Frisell Alexander Gusev Xinli Hu Robert Karlsson Vasilis X Mantzioris John J McGrath Divya Mehta Eli A Stahl Qiongyi Zhao Kenneth S Kendler Patrick F Sullivan Alkes L Price Michael O'Donovan Yukinori Okada Bryan J Mowry Soumya Raychaudhuri Naomi R Wray William Byerley Wiepke Cahn Rita M Cantor Sven Cichon Paul Cormican David Curtis Srdjan Djurovic Valentina Escott-Price Pablo V Gejman Lyudmila Georgieva Ina Giegling Thomas F Hansen Andrés Ingason Yunjung Kim Bettina Konte Phil H Lee Andrew McIntosh Andrew McQuillin Derek W Morris Markus M Nöthen Colm O'Dushlaine Ann Olincy Line Olsen Carlos N Pato Michele T Pato Benjamin S Pickard Danielle Posthuma Henrik B Rasmussen Marcella Rietschel Dan Rujescu Thomas G Schulze Jeremy M Silverman Srinivasa Thirumalai Thomas Werge Ingrid Agartz Farooq Amin Maria H Azevedo Nicholas Bass Donald W Black Douglas H R Blackwood Richard Bruggeman Nancy G Buccola Khalid Choudhury Robert C Cloninger Aiden Corvin Nicholas Craddock Mark J Daly Susmita Datta Gary J Donohoe Jubao Duan Frank Dudbridge Ayman Fanous Robert Freedman Nelson B Freimer Marion Friedl Michael Gill Hugh Gurling Lieuwe De Haan Marian L Hamshere Annette M Hartmann Peter A Holmans René S Kahn Matthew C Keller Elaine Kenny George K Kirov Lydia Krabbendam Robert Krasucki Jacob Lawrence Todd Lencz Douglas F Levinson Jeffrey A Lieberman Dan-Yu Lin Don H Linszen Patrik K E Magnusson Wolfgang Maier Anil K Malhotra Manuel Mattheisen Morten Mattingsdal Steven A McCarroll Helena Medeiros Ingrid Melle Vihra Milanova Inez Myin-Germeys Benjamin M Neale Roel A Ophoff Michael J Owen Jonathan Pimm Shaun M Purcell Vinay Puri Digby J Quested Lizzy Rossin Douglas Ruderfer Alan R Sanders Jianxin Shi Pamela Sklar David St Clair T Scott Stroup Jim Van Os Peter M Visscher Durk Wiersma Stanley Zammit S Louis Bridges Hyon K Choi Marieke J H Coenen Niek de Vries Philippe Dieud Jeffrey D Greenberg Tom W J Huizinga Leonid Padyukov Katherine A Siminovitch Paul P Tak Jane Worthington Philip L De Jager Joshua C Denny Peter K Gregersen Lars Klareskog Xavier Mariette Robert M Plenge Mart van Laar Piet van Riel

Int J Epidemiol 2015 Oct;44(5):1706-21

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.

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Source
http://dx.doi.org/10.1093/ije/dyv136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881824PMC
October 2015
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References

(Supplied by CrossRef)
Smoking increases rheumatoid arthritis susceptibility in individuals carrying the HLA-DRB1 shared epitope, regardless of rheumatoid factor or anti-cyclic citrullinated peptide antibody status
Bang et al.
Arthritis Rheum 2010

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