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

Lee, SH; Byrne, EM; Hultman, CM; Kähler, A; Vinkhuyzen, AA; Ripke, S; Andreassen, OA; Frisell, T; Gusev, A; Hu, X; Karlsson, R; Mantzioris, VX; McGrath, JJ; Mehta, D; Stahl, EA; Zhao, Q; Kendler, KS; Sullivan, PF; Price, AL; O'Donovan, M; Okada, Y; Mowry, BJ; Raychaudhuri, S; Wray, NR; Schizophrenia Working Group of the Psychiatric Genomics Consorti, ; Schizophrenia Working Group of the Psychiatric Genomics Consorti, ; Byerley, W; Cahn, W; Cantor, RM; Cichon, S; Cormican, P; Curtis, D; Djurovic, S; Escott-Price, V; Gejman, PV; Georgieva, L; Giegling, I; Hansen, TF; Ingason, A; Kim, Y; Konte, B; Lee, PH; McIntosh, A; McQuillin, A; Morris, DW; Nöthen, MM; O'Dushlaine, C; Olincy, A; Olsen, L; Pato, CN; Pato, MT; Pickard, BS; Posthuma, D; Rasmussen, HB; Rietschel, M; Rujescu, D; Schulze, TG; Silverman, JM; Thirumalai, S; Werge, T; Schizophrenia Working Group of the Psychiatric Genomics Consorti, ; Agartz, I; Amin, F; Azevedo, MH; Bass, N; Black, DW; Blackwood, DH; Bruggeman, R; Buccola, NG; Choudhury, K; Cloninger, RC; Corvin, A; Craddock, N; Daly, MJ; Datta, S; Donohoe, GJ; Duan, J; Dudbridge, F; Fanous, A; Freedman, R; Freimer, NB; Friedl, M; Gill, M; Gurling, H; De Haan, L; Hamshere, ML; Hartmann, AM; Holmans, PA; Kahn, RS; Keller, MC; Kenny, E; Kirov, GK; Krabbendam, L; Krasucki, R; Lawrence, J; Lencz, T; Levinson, DF; Lieberman, JA; Lin, DY; Linszen, DH; Magnusson, PK; Maier, W; Malhotra, AK; Mattheisen, M; Mattingsdal, M; McCarroll, SA; Medeiros, H; Melle, I; Milanova, V; Myin-Germeys, I; Neale, BM; Ophoff, RA; Owen, MJ; Pimm, J; Purcell, SM; Puri, V; Quested, DJ; Rossin, L; Ruderfer, D; Sanders, AR; Shi, J; Sklar, P; St Clair, D; Scott Stroup, T; Van Os, J; Visscher, PM; Wiersma, D; Zammit, S; Rheumatoid Arthritis Consortium International authors, ; Louis Bridges, SJr; Choi, HK; Coenen, MJ; de Vries, N; Dieud, P; Greenberg, JD; Huizinga, TW; Padyukov, L; Siminovitch, KA; Tak, PP; Worthington, J; Rheumatoid Arthritis Consortium International collaborators, ; De Jager, PL; Denny, JC; Gregersen, PK; Klareskog, L; Mariette, X; Plenge, RM; van Laar, M; van Riel, P; (2015) New data and an old puzzle: the negative association between schizophrenia and rheumatoid arthritis. International journal of epidemiology. ISSN 0300-5771 DOI:

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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.

Item Type: Article
Faculty and Department: Faculty of Epidemiology and Population Health > Dept of Non-Communicable Disease Epidemiology
PubMed ID: 26286434
Web of Science ID: 367178000038


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