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 | |
State | Published - Oct 1 2015 |
Keywords
- Schizophrenia
- genetic relationship
- pleiotropy
- rheumatoid arthritis
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New data and an old puzzle : The negative association between schizophrenia and rheumatoid arthritis. / Hong Lee, S.; Byrne, Enda M.; Hultman, Christina M.; Kähler, Anna; Vinkhuyzen, Anna A.E.; Ripke, Stephan; Andreassen, Ole A.; Frisell, Thomas; Gusev, Alexander; Hu, Xinli; Karlsson, Robert; Mantzioris, Vasilis X.; McGrath, John J.; Mehta, Divya; Stahl, Eli A.; Zhao, Qiongyi; Kendler, Kenneth S.; Sullivan, Patrick F.; Price, Alkes L.; O'Donovan, Michael; Okada, Yukinori; Mowry, Bryan J.; Raychaudhuri, Soumya; Wray, Naomi R.; Agartz, Ingrid; Amin, Farooq; Azevedo, Maria H.; Bass, Nicholas; Black, Donald W.; Blackwood, Douglas H.R.; Bruggeman, Richard; Buccola, Nancy G.; Choudhury, Khalid; Cloninger, C. Robert; Corvin, Aiden; Craddock, Nicholas; Daly, Mark J.; Datta, Susmita; Donohoe, Gary J.; Duan, Jubao; Dudbridge, Frank; Fanous, Ayman; Freedman, Robert; Freimer, Nelson B.; Friedl, Marion; Gill, Michael; Gurling, Hugh; Haan, Lieuwe De; Hamshere, Marian L.; Hartmann, Annette M.; Holmans, Peter A.; Kahn, Rene S.; Keller, Matthew C.; Kenny, Elaine; Kirov, George K.; Krabbendam, Lydia; Krasucki, Robert; Lawrence, Jacob; Lencz, Todd; Levinson, Douglas F.; Lieberman, Jeffrey A.; Lin, Dan Yu; Linszen, Don H.; Magnusson, Patrik K.E.; Maier, Wolfgang; Malhotra, Anil K.; Mattheisen, Manuel; Mattingsdal, Morten; McCarroll, Steven A.; Medeiros, Helena; Melle, Ingrid; Milanova, Vihra; Myin-Germeys, Inez; Neale, Benjamin M.; Ophoff, Roel A.; Owen, Michael J.; Pimm, Jonathan; Purcell, Shaun M.; Puri, Vinay; Quested, Digby J.; Rossin, Lizzy; Ruderfer, Douglas; Sanders, Alan R.; Shi, Jianxin; Sklar, Pamela; St Clair, David; Scott Stroup, T.; Van Os, Jim; Visscher, Peter M.; Wiersma, Durk; Zammit, Stanley; Byerley, William; Cahn, Wiepke; Cantor, Rita M.; Cichon, Sven; Cormican, Paul; Curtis, David; Djurovic, Srdjan; Escott-Price, Valentina; Gejman, Pablo V.; Georgieva, Lyudmila; Giegling, Ina; Hansen, Thomas F.; Ingason, Andrés; Kim, Yunjung; Konte, Bettina; Lee, Phil H.; McIntosh, Andrew; McQuillin, Andrew; Morris, Derek W.; Nöthen, Markus M.; O'Dushlaine, Colm; Olincy, Ann; Olsen, Line; Pato, Carlos N.; Pato, Michele T.; Pickard, Benjamin S.; Posthuma, Danielle; Rasmussen, Henrik B.; Rietschel, Marcella; Rujescu, Dan; Schulze, Thomas G.; Silverman, Jeremy M.; Thirumalai, Srinivasa; Werge, Thomas; Louis Bridges, S.; Choi, Hyon K.; Coenen, Marieke J.H.; De Vries, Niek; Dieud, Philippe; Greenberg, Jeffrey D.; Huizinga, Tom W.J.; Padyukov, Leonid; Siminovitch, Katherine A.; Tak, Paul P.; Worthington, Jane; De Jager, Philip L.; Denny, Joshua C.; Gregersen, Peter K.; Klareskog, Lars; Mariette, Xavier; Plenge, Robert M.; Van Laar, Mart; Van Riel, Piet.
In: International Journal of Epidemiology, Vol. 44, No. 5, 01.10.2015, p. 1706-1721.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 - 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
VL - 44
SP - 1706
EP - 1721
JO - International Journal of Epidemiology
JF - International Journal of Epidemiology
SN - 0300-5771
IS - 5
ER -