Genome-wide association study identifies five loci associated with lung function.
Pulmonary function measures are heritable traits that predict morbidity and mortality and define chronic obstructive pulmonary disease (COPD). We tested genome-wide association with forced expiratory volume in 1 s (FEV(1)) and the ratio of FEV(1) to forced vital capacity (FVC) in the SpiroMeta consortium (n = 20,288 individuals of European ancestry). We conducted a meta-analysis of top signals with data from direct genotyping (n < or = 32,184 additional individuals) and in silico summary association data from the CHARGE Consortium (n = 21,209) and the Health 2000 survey (n < or = 883). We confirmed the reported locus at 4q31 and identified associations with FEV(1) or FEV(1)/FVC and common variants at five additional loci: 2q35 in TNS1 (P = 1.11 x 10(-12)), 4q24 in GSTCD (2.18 x 10(-23)), 5q33 in HTR4 (P = 4.29 x 10(-9)), 6p21 in AGER (P = 3.07 x 10(-15)) and 15q23 in THSD4 (P = 7.24 x 10(-15)). mRNA analyses showed expression of TNS1, GSTCD, AGER, HTR4 and THSD4 in human lung tissue. These associations offer mechanistic insight into pulmonary function regulation and indicate potential targets for interventions to alleviate respiratory disease.
Repapi
Emmanouela
E
Departments of Health Sciences and Genetics, Adrian Building, University of Leicester, Leicester, UK.
Sayers
Ian
I
Wain
Louise V
LV
Burton
Paul R
PR
Johnson
Toby
T
Obeidat
Ma'en
M
Zhao
Jing Hua
JH
Ramasamy
Adaikalavan
A
Zhai
Guangju
G
Vitart
Veronique
V
Huffman
Jennifer E
JE
Igl
Wilmar
W
Albrecht
Eva
E
Deloukas
Panos
P
Henderson
John
J
Granell
Raquel
R
McArdle
Wendy L
WL
Rudnicka
Alicja R
AR
Barroso
Inês
I
Loos
Ruth J F
RJ
Wareham
Nicholas J
NJ
Mustelin
Linda
L
Rantanen
Taina
T
Surakka
Ida
I
Imboden
Medea
M
Wichmann
H Erich
HE
Grkovic
Ivica
I
Jankovic
Stipan
S
Zgaga
Lina
L
Hartikainen
Anna-Liisa
AL
Peltonen
Leena
L
Gyllensten
Ulf
U
Johansson
Asa
A
Zaboli
Ghazal
G
Campbell
Harry
H
Wild
Sarah H
SH
Wilson
James F
JF
Gläser
Sven
S
Homuth
Georg
G
Völzke
Henry
H
Mangino
Massimo
M
Soranzo
Nicole
N
Spector
Tim D
TD
Polasek
Ozren
O
Rudan
Igor
I
Wright
Alan F
AF
Heliövaara
Markku
M
Ripatti
Samuli
S
Pouta
Anneli
A
Naluai
Asa Torinsson
AT
Olin
Anna-Carin
AC
Torén
Kjell
K
Cooper
Matthew N
MN
James
Alan L
AL
Palmer
Lyle J
LJ
Hingorani
Aroon D
AD
Wannamethee
S Goya
SG
Whincup
Peter H
PH
Smith
George Davey
GD
Ebrahim
Shah
S
McKeever
Tricia M
TM
Pavord
Ian D
ID
MacLeod
Andrew K
AK
Morris
Andrew D
AD
Porteous
David J
DJ
Cooper
Cyrus
C
Dennison
Elaine
E
Shaheen
Seif
S
Karrasch
Stefan
S
Schnabel
Eva
E
Schulz
Holger
H
Grallert
Harald
H
Bouatia-Naji
Nabila
N
Delplanque
Jérôme
J
Froguel
Philippe
P
Blakey
John D
JD
Britton
John R
JR
Morris
Richard W
RW
Holloway
John W
JW
Lawlor
Debbie A
DA
Hui
Jennie
J
Nyberg
Fredrik
F
Jarvelin
Marjo-Riitta
MR
Jackson
Cathy
C
Kähönen
Mika
M
Kaprio
Jaakko
J
Probst-Hensch
Nicole M
NM
Koch
Beate
B
Hayward
Caroline
C
Evans
David M
DM
Elliott
Paul
P
Strachan
David P
DP
Hall
Ian P
IP
Tobin
Martin D
MD
D005260:Female; D005541:Forced Expiratory Volume; D020869:Gene Expression Profiling; D015894:Genome, Human / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000502:physiology* / Q000503:physiopathology; D008297:Male; D015201:Meta-Analysis as Topic; D008840:Microfilament Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics / Q000503:physiopathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics; D044422:Receptors, Serotonin, 5-HT4 / Q000235:genetics; D012129:Respiratory Function Tests; D013147:Spirometry; D000070876:Tensins; D019699:Thrombospondins / Q000235:genetics; D014797:Vital Capacity
D008840:Microfilament Proteins; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C000603369:TNS1 protein, human; D000070876:Tensins; D019699:Thrombospondins; D044422:Receptors, Serotonin, 5-HT4; D005982:Glutathione Transferase