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

Schizophrenia Working Group of the Psychiatric Genomics Consortium and Rheumatoid Arthritis Consortium International; 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; Benjamin S Pickard; Douglas H R Blackwood; Peter M Visscher

doi:10.1093/ije/dyv136

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

Schizophrenia Working Group of the Psychiatric Genomics Consortium and Rheumatoid Arthritis Consortium International, 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 PriceMichael 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, Benjamin S Pickard, Douglas H R Blackwood, Peter M Visscher

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

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
Journal	International Journal of Epidemiology
DOIs	https://doi.org/10.1093/ije/dyv136
Publication status	Published - 18 Aug 2015

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Schizophrenia Working Group of the Psychiatric Genomics Consortium and Rheumatoid Arthritis Consortium International, Lee, S. H., Byrne, E. M., Hultman, C. M., Kähler, A., Vinkhuyzen, A. A., 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., ... Visscher, P. M. (2015). New data and an old puzzle: the negative association between schizophrenia and rheumatoid arthritis. International Journal of Epidemiology. https://doi.org/10.1093/ije/dyv136

@article{f3ac96ba7dd44d2ca3e187a5aa32651e,

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.",

author = "{Schizophrenia Working Group of the Psychiatric Genomics Consortium and Rheumatoid Arthritis Consortium International} and Lee, {S Hong} and Byrne, {Enda M} and Hultman, {Christina M} and Anna K{\"a}hler and Vinkhuyzen, {Anna Ae} 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 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 Pickard, {Benjamin S} and Blackwood, {Douglas H R} and Visscher, {Peter M}",

year = "2015",

month = aug,

day = "18",

doi = "10.1093/ije/dyv136",

language = "English",

journal = "International Journal of Epidemiology",

issn = "0300-5771",

publisher = "Oxford University Press",

}

Schizophrenia Working Group of the Psychiatric Genomics Consortium and Rheumatoid Arthritis Consortium International, 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, 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, Pickard, BS, Blackwood, DHR & Visscher, PM 2015, 'New data and an old puzzle: the negative association between schizophrenia and rheumatoid arthritis', International Journal of Epidemiology. https://doi.org/10.1093/ije/dyv136

New data and an old puzzle : the negative association between schizophrenia and rheumatoid arthritis. / Schizophrenia Working Group of the Psychiatric Genomics Consortium and Rheumatoid Arthritis Consortium International; Lee, S Hong; Byrne, Enda M et al.

In: International Journal of Epidemiology, 18.08.2015.

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

TY - JOUR

T1 - New data and an old puzzle

T2 - the negative association between schizophrenia and rheumatoid arthritis

AU - Schizophrenia Working Group of the Psychiatric Genomics Consortium and Rheumatoid Arthritis Consortium International

AU - Lee, S Hong

AU - Byrne, Enda M

AU - Hultman, Christina M

AU - Kähler, Anna

AU - Vinkhuyzen, Anna Ae

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 - 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 - Pickard, Benjamin S

AU - Blackwood, Douglas H R

AU - Visscher, Peter M

PY - 2015/8/18

Y1 - 2015/8/18

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.

U2 - 10.1093/ije/dyv136

DO - 10.1093/ije/dyv136

M3 - Article

C2 - 26286434

JO - International Journal of Epidemiology

JF - International Journal of Epidemiology

SN - 0300-5771

ER -

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

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