New data and an old puzzle: the negative association between schizophrenia and rheumatoid arthritis.
Lee SH., Byrne EM., Hultman CM., Kähler A., Vinkhuyzen AAE., Ripke S., Andreassen OA., Frisell T., Gusev A., Hu X., Karlsson R., Mantzioris VX., McGrath JJ., Mehta D., Stahl EA., Zhao Q., 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 Consortium and Rheumatoid Arthritis Consortium International None., Schizophrenia Working Group of the Psychiatric Genomics Consortium Authors None., 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 Consortium Collaborators None., Agartz I., Amin F., Azevedo MH., Bass N., Black DW., Blackwood DHR., 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 D-Y., Linszen DH., Magnusson PKE., 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., Stroup TS., Van Os J., Visscher PM., Wiersma D., Zammit S., Rheumatoid Arthritis Consortium International Authors None., Bridges SL., Choi HK., Coenen MJH., de Vries N., Dieud P., Greenberg JD., Huizinga TWJ., Padyukov L., Siminovitch KA., Tak PP., Worthington J., Rheumatoid Arthritis Consortium International Collaborators None., De Jager PL., Denny JC., Gregersen PK., Klareskog L., Mariette X., Plenge RM., van Laar M., van Riel P.
BackgroundA 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.MethodsWe 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.ResultsWe 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).ConclusionsOur 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.