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

S Hong Lee, Enda M Byrne, Christina M Hultman, Anna Kähler, Anna AE 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 KE 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 JH Coenen, Niek de Vries, Philippe Dieud, Jeffrey D Greenberg, Tom WJ 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

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. 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. 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). 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.