New data and an old puzzle: the negative   association between schizophrenia and   rheumatoid arthritis.
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.
S Hong
SH
Lee
Enda M
EM
Byrne
Christina M
CM
Hultman
Anna
A
Kähler
Anna A E
AA
Vinkhuyzen
Stephan
S
Ripke
Ole A
OA
Andreassen
Thomas
T
Frisell
Alexander
A
Gusev
Xinli
X
Hu
Robert
R
Karlsson
Vasilis X
VX
Mantzioris
John J
JJ
McGrath
Divya
D
Mehta
Eli A
EA
Stahl
Qiongyi
Q
Zhao
Kenneth S
KS
Kendler
Patrick F
PF
Sullivan
Alkes L
AL
Price
Michael
M
O'Donovan
Yukinori
Y
Okada
Bryan J
BJ
Mowry
Soumya
S
Raychaudhuri
Naomi R
NR
Wray
William
W
Byerley
Wiepke
W
Cahn
Rita M
RM
Cantor
Sven
S
Cichon
Paul
P
Cormican
David
D
Curtis
Srdjan
S
Djurovic
Valentina
V
Escott-Price
Pablo V
PV
Gejman
Lyudmila
L
Georgieva
Ina
I
Giegling
Thomas F
TF
Hansen
Andrés
A
Ingason
Yunjung
Y
Kim
Bettina
B
Konte
Phil H
PH
Lee
Andrew
A
McIntosh
Andrew
A
McQuillin
Derek W
DW
Morris
Markus M
MM
Nöthen
Colm
C
O'Dushlaine
Ann
A
Olincy
Line
L
Olsen
Carlos N
CN
Pato
Michele T
MT
Pato
Benjamin S
BS
Pickard
Danielle
D
Posthuma
Henrik B
HB
Rasmussen
Marcella
M
Rietschel
Dan
D
Rujescu
Thomas G
TG
Schulze
Jeremy M
JM
Silverman
Srinivasa
S
Thirumalai
Thomas
T
Werge
Ingrid
I
Agartz
Farooq
F
Amin
Maria H
MH
Azevedo
Nicholas
N
Bass
Donald W
DW
Black
Douglas H R
DH
Blackwood
Richard
R
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Nancy G
NG
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Khalid
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Choudhury
Robert C
RC
Cloninger
Aiden
A
Corvin
Nicholas
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Craddock
Mark J
MJ
Daly
Susmita
S
Datta
Gary J
GJ
Donohoe
Jubao
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Duan
Frank
F
Dudbridge
Ayman
A
Fanous
Robert
R
Freedman
Nelson B
NB
Freimer
Marion
M
Friedl
Michael
M
Gill
Hugh
H
Gurling
Lieuwe
L
De Haan
Marian L
ML
Hamshere
Annette M
AM
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Peter A
PA
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René S
RS
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Matthew C
MC
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Elaine
E
Kenny
George K
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Lydia
L
Krabbendam
Robert
R
Krasucki
Jacob
J
Lawrence
Todd
T
Lencz
Douglas F
DF
Levinson
Jeffrey A
JA
Lieberman
Dan-Yu
DY
Lin
Don H
DH
Linszen
Patrik K E
PK
Magnusson
Wolfgang
W
Maier
Anil K
AK
Malhotra
Manuel
M
Mattheisen
Morten
M
Mattingsdal
Steven A
SA
McCarroll
Helena
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Medeiros
Ingrid
I
Melle
Vihra
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Milanova
Inez
I
Myin-Germeys
Benjamin M
BM
Neale
Roel A
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Michael J
MJ
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Jonathan
J
Pimm
Shaun M
SM
Purcell
Vinay
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Digby J
DJ
Quested
Lizzy
L
Rossin
Douglas
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Ruderfer
Alan R
AR
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Jianxin
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Shi
Pamela
P
Sklar
David
D
St Clair
T Scott
TS
Stroup
Jim
J
Van Os
Peter M
PM
Visscher
Durk
D
Wiersma
Stanley
S
Zammit
S Louis
SL
Bridges
Hyon K
HK
Choi
Marieke J H
MJ
Coenen
Niek
N
de Vries
Philippe
P
Dieud
Jeffrey D
JD
Greenberg
Tom W J
TW
Huizinga
Leonid
L
Padyukov
Katherine A
KA
Siminovitch
Paul P
PP
Tak
Jane
J
Worthington
Philip L
PL
De Jager
Joshua C
JC
Denny
Peter K
PK
Gregersen
Lars
L
Klareskog
Xavier
X
Mariette
Robert M
RM
Plenge
Mart
M
van Laar
Piet
P
van Riel
D000293:Adolescent; D000328:Adult; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D005260:Female; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000235:genetics*; D055815:Young Adult