WNT16 influences bone mineral density, cortical bone thickness, bone strength, and osteoporotic fracture risk.
We aimed to identify genetic variants associated with cortical bone thickness (CBT) and bone mineral density (BMD) by performing two separate genome-wide association study (GWAS) meta-analyses for CBT in 3 cohorts comprising 5,878 European subjects and for BMD in 5 cohorts comprising 5,672 individuals. We then assessed selected single-nucleotide polymorphisms (SNPs) for osteoporotic fracture in 2,023 cases and 3,740 controls. Association with CBT and forearm BMD was tested for ∼2.5 million SNPs in each cohort separately, and results were meta-analyzed using fixed effect meta-analysis. We identified a missense SNP (Thr>Ile; rs2707466) located in the WNT16 gene (7q31), associated with CBT (effect size of -0.11 standard deviations [SD] per C allele, P = 6.2 × 10(-9)). This SNP, as well as another nonsynonymous SNP rs2908004 (Gly>Arg), also had genome-wide significant association with forearm BMD (-0.14 SD per C allele, P = 2.3 × 10(-12), and -0.16 SD per G allele, P = 1.2 × 10(-15), respectively). Four genome-wide significant SNPs arising from BMD meta-analysis were tested for association with forearm fracture. SNP rs7776725 in FAM3C, a gene adjacent to WNT16, was associated with a genome-wide significant increased risk of forearm fracture (OR = 1.33, P = 7.3 × 10(-9)), with genome-wide suggestive signals from the two missense variants in WNT16 (rs2908004: OR = 1.22, P = 4.9 × 10(-6) and rs2707466: OR = 1.22, P = 7.2 × 10(-6)). We next generated a homozygous mouse with targeted disruption of Wnt16. Female Wnt16(-/-) mice had 27% (P<0.001) thinner cortical bones at the femur midshaft, and bone strength measures were reduced between 43%-61% (6.5 × 10(-13)<P<5.9 × 10(-4)) at both femur and tibia, compared with their wild-type littermates. Natural variation in humans and targeted disruption in mice demonstrate that WNT16 is an important determinant of CBT, BMD, bone strength, and risk of fracture.
Department of Medicine, Human Genetics, McGill University, Montreal, Canada.
Hou-Feng
HF
Zheng
Jon H
JH
Tobias
Emma
E
Duncan
David M
DM
Evans
Joel
J
Eriksson
Lavinia
L
Paternoster
Laura M
LM
Yerges-Armstrong
Terho
T
Lehtimäki
Ulrica
U
Bergström
Mika
M
Kähönen
Paul J
PJ
Leo
Olli
O
Raitakari
Marika
M
Laaksonen
Geoffrey C
GC
Nicholson
Jorma
J
Viikari
Martin
M
Ladouceur
Leo-Pekka
LP
Lyytikäinen
Carolina
C
Medina-Gomez
Fernando
F
Rivadeneira
Richard L
RL
Prince
Harri
H
Sievanen
William D
WD
Leslie
Dan
D
Mellström
John A
JA
Eisman
Sofia
S
Movérare-Skrtic
David
D
Goltzman
David A
DA
Hanley
Graeme
G
Jones
Beate
B
St Pourcain
Yongjun
Y
Xiao
Nicholas J
NJ
Timpson
George Davey
GD
Smith
Ian R
IR
Reid
Susan M
SM
Ring
Philip N
PN
Sambrook
Magnus
M
Karlsson
Elaine M
EM
Dennison
John P
JP
Kemp
Patrick
P
Danoy
Adrian
A
Sayers
Scott G
SG
Wilson
Maria
M
Nethander
Eugene
E
McCloskey
Liesbeth
L
Vandenput
Richard
R
Eastell
Jeff
J
Liu
Tim
T
Spector
Braxton D
BD
Mitchell
Elizabeth A
EA
Streeten
Robert
R
Brommage
Ulrika
U
Pettersson-Kymmer
Matthew A
MA
Brown
Claes
C
Ohlsson
J Brent
JB
Richards
Mattias
M
Lorentzon
D000293:Adolescent; D000328:Adult; D000818:Animals; D015519:Bone Density / Q000235:genetics* / Q000502:physiology; D001842:Bone and Bones / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D005260:Female; D005269:Femur; D005542:Forearm; D050723:Fractures, Bone / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D010024:Osteoporosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D051153:Wnt Proteins / Q000235:genetics*
C417262:WNT16 protein, human; D051153:Wnt Proteins