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 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; Ingrid Agartz; Farooq Amin; Maria H. Azevedo; Nicholas Bass; Donald W. Black; Douglas H.R. Blackwood; Richard Bruggeman; Nancy G. Buccola; Khalid Choudhury; C. Robert 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; Rene 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; 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; 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

doi:10.1093/ije/dyv136

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 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'DonovanYukinori Okada, Bryan J. Mowry, Soumya Raychaudhuri, Naomi R. Wray, Ingrid Agartz, Farooq Amin, Maria H. Azevedo, Nicholas Bass, Donald W. Black, Douglas H.R. Blackwood, Richard Bruggeman, Nancy G. Buccola, Khalid Choudhury, C. Robert 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, Rene 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, 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, 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

Research output: Contribution to journal › Article › peer-review

49 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	1706-1721
Number of pages	16
Journal	International Journal of Epidemiology
Volume	44
Issue number	5
DOIs	https://doi.org/10.1093/ije/dyv136
State	Published - Oct 1 2015

Keywords

Schizophrenia
genetic relationship
pleiotropy
rheumatoid arthritis

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10.1093/ije/dyv136

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Hong Lee, S., Byrne, E. M., Hultman, C. M., Kähler, A., Vinkhuyzen, A. A. E., Ripke, S., Andreassen, O. A., Frisell, T., Gusev, A., Hu, X., Karlsson, R., Mantzioris, V. X., McGrath, J. J., Mehta, D., Stahl, E. A., Zhao, Q., Kendler, K. S., Sullivan, P. F., Price, A. L., ... Van Riel, P. (2015). New data and an old puzzle: The negative association between schizophrenia and rheumatoid arthritis. International Journal of Epidemiology, 44(5), 1706-1721. https://doi.org/10.1093/ije/dyv136

@article{f14922f29bd84138aa8512927eff67e4,

title = "New data and an old puzzle: The negative association between schizophrenia and rheumatoid arthritis",

abstract = "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.",

keywords = "Schizophrenia, genetic relationship, pleiotropy, rheumatoid arthritis",

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

note = "Funding Information: This work was supported by the Australian Research Council [grant number DE130100614 to S.H.L.], the National Health and Medical Research Council [grant numbers 613602, 1078901 to N.R.W; 1047956 to N.R.W., S.H.L. and B.J.M., 1053639 to E.M.B]; the Arthritis Foundation to S.R., the Doris Duke Foundation to S.R.; the National Institutes of Health [grant numbers 1R01AR063759-01A1, 1U01HG0070033, 5U01GM092691-04 to S.R.; R01 MH077139 for the Sweden SZ Study to P.F.S.]. The Swedish SZ study was also funded by the Karolinska Institutet, Karolinska University Hospital, and the Swedish Research Council. The RA dataset from Vanderbilt University Medical Center''s Bio VU is supported by institutional funding and by the Vanderbilt CTSA grant ULTR000445 from NCATS/NIH. Other funding acknowledgements can be found in the primary publications from each study, as references. Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara, and financially supported by The Netherlands Scientific Organization (NWO 480-05-003) along with a supplement from the Dutch Brain Foundation and the VU University Amsterdam. Publisher Copyright: {\textcopyright} The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.",

year = "2015",

month = oct,

day = "1",

doi = "10.1093/ije/dyv136",

language = "English",

volume = "44",

pages = "1706--1721",

journal = "International Journal of Epidemiology",

issn = "0300-5771",

number = "5",

}

Hong Lee, S, 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, Kendler, KS, Sullivan, PF, Price, AL, O'Donovan, M, Okada, Y, Mowry, BJ, Raychaudhuri, S, Wray, NR, Agartz, I, Amin, F, Azevedo, MH, Bass, N, Black, DW, Blackwood, DHR, Bruggeman, R, Buccola, NG, Choudhury, K, Cloninger, CR, 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, Haan, LD, 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, 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, Scott Stroup, T, Van Os, J, Visscher, PM, Wiersma, D, Zammit, S, 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, Louis Bridges, S, Choi, HK, Coenen, MJH, De Vries, N, Dieud, P, Greenberg, JD, Huizinga, TWJ, Padyukov, L, Siminovitch, KA, Tak, PP, Worthington, J, 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, vol. 44, no. 5, pp. 1706-1721. https://doi.org/10.1093/ije/dyv136

TY - JOUR

T1 - New data and an old puzzle

T2 - The negative association between schizophrenia and rheumatoid arthritis

AU - Hong Lee, S.

AU - Byrne, Enda M.

AU - Hultman, Christina M.

AU - Kähler, Anna

AU - Vinkhuyzen, Anna A.E.

AU - Ripke, Stephan

AU - Andreassen, Ole A.

AU - Frisell, Thomas

AU - Gusev, Alexander

AU - Hu, Xinli

AU - Karlsson, Robert

AU - Mantzioris, Vasilis X.

AU - McGrath, John J.

AU - Mehta, Divya

AU - Stahl, Eli A.

AU - Zhao, Qiongyi

AU - Kendler, Kenneth S.

AU - Sullivan, Patrick F.

AU - Price, Alkes L.

AU - O'Donovan, Michael

AU - Okada, Yukinori

AU - Mowry, Bryan J.

AU - Raychaudhuri, Soumya

AU - Wray, Naomi R.

AU - Agartz, Ingrid

AU - Amin, Farooq

AU - Azevedo, Maria H.

AU - Bass, Nicholas

AU - Black, Donald W.

AU - Blackwood, Douglas H.R.

AU - Bruggeman, Richard

AU - Buccola, Nancy G.

AU - Choudhury, Khalid

AU - Cloninger, C. Robert

AU - Corvin, Aiden

AU - Craddock, Nicholas

AU - Daly, Mark J.

AU - Datta, Susmita

AU - Donohoe, Gary J.

AU - Duan, Jubao

AU - Dudbridge, Frank

AU - Fanous, Ayman

AU - Freedman, Robert

AU - Freimer, Nelson B.

AU - Friedl, Marion

AU - Gill, Michael

AU - Gurling, Hugh

AU - Haan, Lieuwe De

AU - Hamshere, Marian L.

AU - Hartmann, Annette M.

AU - Holmans, Peter A.

AU - Kahn, Rene S.

AU - Keller, Matthew C.

AU - Kenny, Elaine

AU - Kirov, George K.

AU - Krabbendam, Lydia

AU - Krasucki, Robert

AU - Lawrence, Jacob

AU - Lencz, Todd

AU - Levinson, Douglas F.

AU - Lieberman, Jeffrey A.

AU - Lin, Dan Yu

AU - Linszen, Don H.

AU - Magnusson, Patrik K.E.

AU - Maier, Wolfgang

AU - Malhotra, Anil K.

AU - Mattheisen, Manuel

AU - Mattingsdal, Morten

AU - McCarroll, Steven A.

AU - Medeiros, Helena

AU - Melle, Ingrid

AU - Milanova, Vihra

AU - Myin-Germeys, Inez

AU - Neale, Benjamin M.

AU - Ophoff, Roel A.

AU - Owen, Michael J.

AU - Pimm, Jonathan

AU - Purcell, Shaun M.

AU - Puri, Vinay

AU - Quested, Digby J.

AU - Rossin, Lizzy

AU - Ruderfer, Douglas

AU - Sanders, Alan R.

AU - Shi, Jianxin

AU - Sklar, Pamela

AU - St Clair, David

AU - Scott Stroup, T.

AU - Van Os, Jim

AU - Visscher, Peter M.

AU - Wiersma, Durk

AU - Zammit, Stanley

AU - Byerley, William

AU - Cahn, Wiepke

AU - Cantor, Rita M.

AU - Cichon, Sven

AU - Cormican, Paul

AU - Curtis, David

AU - Djurovic, Srdjan

AU - Escott-Price, Valentina

AU - Gejman, Pablo V.

AU - Georgieva, Lyudmila

AU - Giegling, Ina

AU - Hansen, Thomas F.

AU - Ingason, Andrés

AU - Kim, Yunjung

AU - Konte, Bettina

AU - Lee, Phil H.

AU - McIntosh, Andrew

AU - McQuillin, Andrew

AU - Morris, Derek W.

AU - Nöthen, Markus M.

AU - O'Dushlaine, Colm

AU - Olincy, Ann

AU - Olsen, Line

AU - Pato, Carlos N.

AU - Pato, Michele T.

AU - Pickard, Benjamin S.

AU - Posthuma, Danielle

AU - Rasmussen, Henrik B.

AU - Rietschel, Marcella

AU - Rujescu, Dan

AU - Schulze, Thomas G.

AU - Silverman, Jeremy M.

AU - Thirumalai, Srinivasa

AU - Werge, Thomas

AU - Louis Bridges, S.

AU - Choi, Hyon K.

AU - Coenen, Marieke J.H.

AU - De Vries, Niek

AU - Dieud, Philippe

AU - Greenberg, Jeffrey D.

AU - Huizinga, Tom W.J.

AU - Padyukov, Leonid

AU - Siminovitch, Katherine A.

AU - Tak, Paul P.

AU - Worthington, Jane

AU - De Jager, Philip L.

AU - Denny, Joshua C.

AU - Gregersen, Peter K.

AU - Klareskog, Lars

AU - Mariette, Xavier

AU - Plenge, Robert M.

AU - Van Laar, Mart

AU - Van Riel, Piet

N1 - Funding Information: This work was supported by the Australian Research Council [grant number DE130100614 to S.H.L.], the National Health and Medical Research Council [grant numbers 613602, 1078901 to N.R.W; 1047956 to N.R.W., S.H.L. and B.J.M., 1053639 to E.M.B]; the Arthritis Foundation to S.R., the Doris Duke Foundation to S.R.; the National Institutes of Health [grant numbers 1R01AR063759-01A1, 1U01HG0070033, 5U01GM092691-04 to S.R.; R01 MH077139 for the Sweden SZ Study to P.F.S.]. The Swedish SZ study was also funded by the Karolinska Institutet, Karolinska University Hospital, and the Swedish Research Council. The RA dataset from Vanderbilt University Medical Center''s Bio VU is supported by institutional funding and by the Vanderbilt CTSA grant ULTR000445 from NCATS/NIH. Other funding acknowledgements can be found in the primary publications from each study, as references. Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara, and financially supported by The Netherlands Scientific Organization (NWO 480-05-003) along with a supplement from the Dutch Brain Foundation and the VU University Amsterdam. Publisher Copyright: © The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.

PY - 2015/10/1

Y1 - 2015/10/1

N2 - 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.

AB - 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.

KW - Schizophrenia

KW - genetic relationship

KW - pleiotropy

KW - rheumatoid arthritis

UR - http://www.scopus.com/inward/record.url?scp=84952907851&partnerID=8YFLogxK

U2 - 10.1093/ije/dyv136

DO - 10.1093/ije/dyv136

M3 - Article

C2 - 26286434

AN - SCOPUS:84952907851

SN - 0300-5771

VL - 44

SP - 1706

EP - 1721

JO - International Journal of Epidemiology

JF - International Journal of Epidemiology

IS - 5

ER -

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

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