Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight.
To identify genetic variants associated with birth weight, we meta-analyzed six genome-wide association (GWA) studies (n = 10,623 Europeans from pregnancy/birth cohorts) and followed up two lead signals in 13 replication studies (n = 27,591). rs900400 near LEKR1 and CCNL1 (P = 2 x 10(-35)) and rs9883204 in ADCY5 (P = 7 x 10(-15)) were robustly associated with birth weight. Correlated SNPs in ADCY5 were recently implicated in regulation of glucose levels and susceptibility to type 2 diabetes, providing evidence that the well-described association between lower birth weight and subsequent type 2 diabetes has a genetic component, distinct from the proposed role of programming by maternal nutrition. Using data from both SNPs, we found that the 9% of Europeans carrying four birth weight-lowering alleles were, on average, 113 g (95% CI 89-137 g) lighter at birth than the 24% with zero or one alleles (P(trend) = 7 x 10(-30)). The impact on birth weight is similar to that of a mother smoking 4-5 cigarettes per day in the third trimester of pregnancy.
Freathy
Rachel M
RM
Genetics of Complex Traits, Peninsula College of Medicine and Dentistry, University of Exeter, Exeter, UK.
Mook-Kanamori
Dennis O
DO
Sovio
Ulla
U
Prokopenko
Inga
I
Timpson
Nicholas J
NJ
Berry
Diane J
DJ
Warrington
Nicole M
NM
Widen
Elisabeth
E
Hottenga
Jouke Jan
JJ
Kaakinen
Marika
M
Lange
Leslie A
LA
Bradfield
Jonathan P
JP
Kerkhof
Marjan
M
Marsh
Julie A
JA
Mägi
Reedik
R
Chen
Chih-Mei
CM
Lyon
Helen N
HN
Kirin
Mirna
M
Adair
Linda S
LS
Aulchenko
Yurii S
YS
Bennett
Amanda J
AJ
Borja
Judith B
JB
Bouatia-Naji
Nabila
N
Charoen
Pimphen
P
Coin
Lachlan J M
LJ
Cousminer
Diana L
DL
de Geus
Eco J C
EJ
Deloukas
Panos
P
Elliott
Paul
P
Evans
David M
DM
Froguel
Philippe
P
Glaser
Beate
B
Groves
Christopher J
CJ
Hartikainen
Anna-Liisa
AL
Hassanali
Neelam
N
Hirschhorn
Joel N
JN
Hofman
Albert
A
Holly
Jeff M P
JM
Hyppönen
Elina
E
Kanoni
Stavroula
S
Knight
Bridget A
BA
Laitinen
Jaana
J
Lindgren
Cecilia M
CM
McArdle
Wendy L
WL
O'Reilly
Paul F
PF
Pennell
Craig E
CE
Postma
Dirkje S
DS
Pouta
Anneli
A
Ramasamy
Adaikalavan
A
Rayner
Nigel W
NW
Ring
Susan M
SM
Rivadeneira
Fernando
F
Shields
Beverley M
BM
Strachan
David P
DP
Surakka
Ida
I
Taanila
Anja
A
Tiesler
Carla
C
Uitterlinden
Andre G
AG
van Duijn
Cornelia M
CM
Wijga
Alet H
AH
Willemsen
Gonneke
G
Zhang
Haitao
H
Zhao
Jianhua
J
Wilson
James F
JF
Steegers
Eric A P
EA
Hattersley
Andrew T
AT
Eriksson
Johan G
JG
Peltonen
Leena
L
Mohlke
Karen L
KL
Grant
Struan F A
SF
Hakonarson
Hakon
H
Koppelman
Gerard H
GH
Dedoussis
George V
GV
Heinrich
Joachim
J
Gillman
Matthew W
MW
Palmer
Lyle J
LJ
Frayling
Timothy M
TM
Boomsma
Dorret I
DI
Davey Smith
George
G
Power
Chris
C
Jaddoe
Vincent W V
VW
Jarvelin
Marjo-Riitta
MR
McCarthy
Mark I
MI
D000262:Adenylyl Cyclases / Q000235:genetics*; D000483:Alleles; D001724:Birth Weight; D015331:Cohort Studies; D016213:Cyclins / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005006:Ethnicity; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D008297:Male; D008957:Models, Genetic; D011247:Pregnancy
C468873:CCNL1 protein, human; D016213:Cyclins; D007527:Isoenzymes; D000262:Adenylyl Cyclases; C419510:adenylyl cyclase type V; D005947:Glucose