Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls.
Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed approximately 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated approximately 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
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Nick
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Hurles
Matthew E
ME
Cardin
Niall
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Pearson
Richard D
RD
Plagnol
Vincent
V
Robson
Samuel
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Vukcevic
Damjan
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Barnes
Chris
C
Conrad
Donald F
DF
Giannoulatou
Eleni
E
Holmes
Chris
C
Marchini
Jonathan L
JL
Stirrups
Kathy
K
Tobin
Martin D
MD
Wain
Louise V
LV
Yau
Chris
C
Aerts
Jan
J
Ahmad
Tariq
T
Andrews
T Daniel
TD
Arbury
Hazel
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Attwood
Anthony
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Adam
A
Ball
Stephen G
SG
Balmforth
Anthony J
AJ
Barrett
Jeffrey C
JC
Barroso
Inês
I
Barton
Anne
A
Bennett
Amanda J
AJ
Bhaskar
Sanjeev
S
Blaszczyk
Katarzyna
K
Bowes
John
J
Brand
Oliver J
OJ
Braund
Peter S
PS
Bredin
Francesca
F
Breen
Gerome
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Brown
Morris J
MJ
Bruce
Ian N
IN
Bull
Jaswinder
J
Burren
Oliver S
OS
Burton
John
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Byrnes
Jake
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Caesar
Sian
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Clee
Chris M
CM
Coffey
Alison J
AJ
Connell
John M C
JM
Cooper
Jason D
JD
Dominiczak
Anna F
AF
Downes
Kate
K
Drummond
Hazel E
HE
Dudakia
Darshna
D
Dunham
Andrew
A
Ebbs
Bernadette
B
Eccles
Diana
D
Edkins
Sarah
S
Edwards
Cathryn
C
Elliot
Anna
A
Emery
Paul
P
Evans
David M
DM
Evans
Gareth
G
Eyre
Steve
S
Farmer
Anne
A
Ferrier
I Nicol
IN
Feuk
Lars
L
Fitzgerald
Tomas
T
Flynn
Edward
E
Forbes
Alistair
A
Forty
Liz
L
Franklyn
Jayne A
JA
Freathy
Rachel M
RM
Gibbs
Polly
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Gilbert
Paul
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Gokumen
Omer
O
Gordon-Smith
Katherine
K
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Emma
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Elaine
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Chris J
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Detelina
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Gwilliam
Rhian
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Hall
Anita
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Hammond
Naomi
N
Hardy
Matt
M
Harrison
Pile
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Hassanali
Neelam
N
Hebaishi
Husam
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Hines
Sarah
S
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Anne
A
Hitman
Graham A
GA
Hocking
Lynne
L
Howard
Eleanor
E
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Philip
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Joanna M M
JM
Hughes
Debbie
D
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Sarah
S
Isaacs
John D
JD
Jain
Mahim
M
Jewell
Derek P
DP
Johnson
Toby
T
Jolley
Jennifer D
JD
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Ian R
IR
Jones
Lisa A
LA
Kirov
George
G
Langford
Cordelia F
CF
Lango-Allen
Hana
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Dunecan C O
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McArdle
Wendy L
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McGuffin
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P
McLay
Kirsten E
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Mentzer
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Mimmack
Michael L
ML
Morgan
Ann E
AE
Morris
Andrew P
AP
Mowat
Craig
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Myers
Simon
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Newman
William
W
Nimmo
Elaine R
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O'Donovan
Michael C
MC
Onipinla
Abiodun
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Onyiah
Ifejinelo
I
Ovington
Nigel R
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Michael J
MJ
Palin
Kimmo
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Pernet
David
D
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John R B
JR
Phillips
Anne
A
Pinto
Dalila
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Natalie J
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Prokopenko
Inga
I
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Michael A
MA
Rafelt
Suzanne
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Nigel W
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Redon
Richard
R
Reid
David M
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Renwick
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Susan M
SM
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Neil
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Russell
Ellie
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St Clair
David
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Jennifer G
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Sanderson
Jeremy D
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Schuilenburg
Helen
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Richard
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Sheila
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Shaw-Hawkins
Sue
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Beverley M
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Debbie J
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Elilan
E
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Katarina
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Sophia
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Helen E
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Millicent A
MA
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Symmons
Deborah P M
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John R
JR
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Wendy
W
Travers
Mary E
ME
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Clare
C
Valsesia
Armand
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Mark
M
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Neil M
NM
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Chris
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Margaret
M
Watkins
Nicholas A
NA
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John
J
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Michael N
MN
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Anthony G
AG
Woodburn
Matthew
M
Wordsworth
B Paul
BP
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Allan H
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Zeggini
Eleftheria
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Nigel P
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Frayling
Timothy M
TM
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Charles
C
McVean
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Patricia B
PB
Palotie
Aarno
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Stephen W
SW
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David P
DP
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PR
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Stephen C L
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Adrian V S
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Mathew
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Marcus
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Jack
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Michael R
MR
Worthington
Jane
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Panos
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Audrey
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DP
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Mark I
MI
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Willem
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Miles
M
Rahman
Nazneen
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Todd
John A
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D001172:Arthritis, Rheumatoid / Q000235:genetics; D016022:Case-Control Studies; D003424:Crohn Disease / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics*; D003920:Diabetes Mellitus / Q000235:genetics; D004194:Disease; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011786:Quality Control