Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants.
We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.
Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Adrian Building, University Road, Leicester LE1 7RH, UK.
Burton
Paul R
PR
Clayton
David G
DG
Cardon
Lon R
LR
Craddock
Nick
N
Deloukas
Panos
P
Duncanson
Audrey
A
Kwiatkowski
Dominic P
DP
McCarthy
Mark I
MI
Ouwehand
Willem H
WH
Samani
Nilesh J
NJ
Todd
John A
JA
Donnelly
Peter
P
Barrett
Jeffrey C
JC
Davison
Dan
D
Easton
Doug
D
Evans
David M
DM
Leung
Hin-Tak
HT
Marchini
Jonathan L
JL
Morris
Andrew P
AP
Spencer
Chris C A
CC
Tobin
Martin D
MD
Attwood
Antony P
AP
Boorman
James P
JP
Cant
Barbara
B
Everson
Ursula
U
Hussey
Judith M
JM
Jolley
Jennifer D
JD
Knight
Alexandra S
AS
Koch
Kerstin
K
Meech
Elizabeth
E
Nutland
Sarah
S
Prowse
Christopher V
CV
Stevens
Helen E
HE
Taylor
Niall C
NC
Walters
Graham R
GR
Walker
Neil M
NM
Watkins
Nicholas A
NA
Winzer
Thilo
T
Jones
Richard W
RW
McArdle
Wendy L
WL
Ring
Susan M
SM
Strachan
David P
DP
Pembrey
Marcus
M
Breen
Gerome
G
St Clair
David
D
Caesar
Sian
S
Gordon-Smith
Katharine
K
Jones
Lisa
L
Fraser
Christine
C
Green
Elaine K
EK
Grozeva
Detelina
D
Hamshere
Marian L
ML
Holmans
Peter A
PA
Jones
Ian R
IR
Kirov
George
G
Moskivina
Valentina
V
Nikolov
Ivan
I
O'Donovan
Michael C
MC
Owen
Michael J
MJ
Collier
David A
DA
Elkin
Amanda
A
Farmer
Anne
A
Williamson
Richard
R
McGuffin
Peter
P
Young
Allan H
AH
Ferrier
I Nicol
IN
Ball
Stephen G
SG
Balmforth
Anthony J
AJ
Barrett
Jennifer H
JH
Bishop
Timothy D
TD
Iles
Mark M
MM
Maqbool
Azhar
A
Yuldasheva
Nadira
N
Hall
Alistair S
AS
Braund
Peter S
PS
Dixon
Richard J
RJ
Mangino
Massimo
M
Stevens
Suzanne
S
Thompson
John R
JR
Bredin
Francesca
F
Tremelling
Mark
M
Parkes
Miles
M
Drummond
Hazel
H
Lees
Charles W
CW
Nimmo
Elaine R
ER
Satsangi
Jack
J
Fisher
Sheila A
SA
Forbes
Alastair
A
Lewis
Cathryn M
CM
Onnie
Clive M
CM
Prescott
Natalie J
NJ
Sanderson
Jeremy
J
Matthew
Christopher G
CG
Barbour
Jamie
J
Mohiuddin
M Khalid
MK
Todhunter
Catherine E
CE
Mansfield
John C
JC
Ahmad
Tariq
T
Cummings
Fraser R
FR
Jewell
Derek P
DP
Webster
John
J
Brown
Morris J
MJ
Lathrop
Mark G
MG
Connell
John
J
Dominiczak
Anna
A
Marcano
Carolina A Braga
CA
Burke
Beverley
B
Dobson
Richard
R
Gungadoo
Johannie
J
Lee
Kate L
KL
Munroe
Patricia B
PB
Newhouse
Stephen J
SJ
Onipinla
Abiodun
A
Wallace
Chris
C
Xue
Mingzhan
M
Caulfield
Mark
M
Farrall
Martin
M
Barton
Anne
A
Bruce
Ian N
IN
Donovan
Hannah
H
Eyre
Steve
S
Gilbert
Paul D
PD
Hilder
Samantha L
SL
Hinks
Anne M
AM
John
Sally L
SL
Potter
Catherine
C
Silman
Alan J
AJ
Symmons
Deborah P M
DP
Thomson
Wendy
W
Worthington
Jane
J
Dunger
David B
DB
Widmer
Barry
B
Frayling
Timothy M
TM
Freathy
Rachel M
RM
Lango
Hana
H
Perry
John R B
JR
Shields
Beverley M
BM
Weedon
Michael N
MN
Hattersley
Andrew T
AT
Hitman
Graham A
GA
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Mark
M
Elliott
Kate S
KS
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Christopher J
CJ
Lindgren
Cecilia M
CM
Rayner
Nigel W
NW
Timpson
Nicolas J
NJ
Zeggini
Eleftheria
E
Newport
Melanie
M
Sirugo
Giorgio
G
Lyons
Emily
E
Vannberg
Fredrik
F
Hill
Adrian V S
AV
Bradbury
Linda A
LA
Farrar
Claire
C
Pointon
Jennifer J
JJ
Wordsworth
Paul
P
Brown
Matthew A
MA
Franklyn
Jayne A
JA
Heward
Joanne M
JM
Simmonds
Matthew J
MJ
Gough
Stephen C L
SC
Seal
Sheila
S
Stratton
Michael R
MR
Rahman
Nazneen
N
Ban
Maria
M
Goris
An
A
Sawcer
Stephen J
SJ
Compston
Alastair
A
Conway
David
D
Jallow
Muminatou
M
Newport
Melanie
M
Sirugo
Giorgio
G
Rockett
Kirk A
KA
Bumpstead
Suzannah J
SJ
Chaney
Amy
A
Downes
Kate
K
Ghori
Mohammed J R
MJ
Gwilliam
Rhian
R
Hunt
Sarah E
SE
Inouye
Michael
M
Keniry
Andrew
A
King
Emma
E
McGinnis
Ralph
R
Potter
Simon
S
Ravindrarajah
Rathi
R
Whittaker
Pamela
P
Widden
Claire
C
Withers
David
D
Cardin
Niall J
NJ
Davison
Dan
D
Ferreira
Teresa
T
Pereira-Gale
Joanne
J
Hallgrimsdo'ttir
Ingeleif B
IB
Howie
Bryan N
BN
Su
Zhan
Z
Teo
Yik Ying
YY
Vukcevic
Damjan
D
Bentley
David
D
Brown
Matthew A
MA
Compston
Alastair
A
Farrall
Martin
M
Hall
Alistair S
AS
Hattersley
Andrew T
AT
Hill
Adrian V S
AV
Parkes
Miles
M
Pembrey
Marcus
M
Stratton
Michael R
MR
Mitchell
Sarah L
SL
Newby
Paul R
PR
Brand
Oliver J
OJ
Carr-Smith
Jackie
J
Pearce
Simon H S
SH
McGinnis
R
R
Keniry
A
A
Deloukas
P
P
Reveille
John D
JD
Zhou
Xiaodong
X
Sims
Anne-Marie
AM
Dowling
Alison
A
Taylor
Jacqueline
J
Doan
Tracy
T
Davis
John C
JC
Savage
Laurie
L
Ward
Michael M
MM
Learch
Thomas L
TL
Weisman
Michael H
MH
Brown
Mathew
M
D000626:Aminopeptidases / Q000235:genetics; D015551:Autoimmunity / Q000235:genetics*; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D002874:Chromosome Mapping; D005828:Genetics, Population; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium; D015778:Minor Histocompatibility Antigens; D009103:Multiple Sclerosis / Q000453:epidemiology / Q000235:genetics*; D009656:North America / Q000453:epidemiology; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011971:Receptors, Immunologic / Q000235:genetics; D018123:Receptors, Interleukin / Q000235:genetics; D013167:Spondylitis, Ankylosing / Q000453:epidemiology / Q000235:genetics*; D013967:Thyroiditis, Autoimmune / Q000453:epidemiology / Q000235:genetics*
C457775:FCRL3 protein, human; C515500:IL23R protein, human; D015778:Minor Histocompatibility Antigens; D011971:Receptors, Immunologic; D018123:Receptors, Interleukin; D000626:Aminopeptidases; C464841:ERAP1 protein, human