Common genetic determinants of vitamin D insufficiency: a genome-wide association study.
BACKGROUND
Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency.


METHODS
We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z-score-weighted meta-analysis. Genotype scores were constructed for confirmed variants.


RESULTS
Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1.9x10(-109) for rs2282679, in GC); 11q12 (p=2.1x10(-27) for rs12785878, near DHCR7); and 11p15 (p=3.3x10(-20) for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6.0x10(-10) for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2.47, 95% CI 2.20-2.78, p=2.3x10(-48)) or lower than 50 nmol/L (1.92, 1.70-2.16, p=1.0x10(-26)) compared with those in the lowest quartile.


CONCLUSIONS
Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status. Genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency.


BACKGROUND
Full funding sources listed at end of paper (see Acknowledgments).
Wang
Thomas J
TJ
Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. tjwang@partners.org
Zhang
Feng
F
Richards
J Brent
JB
Kestenbaum
Bryan
B
van Meurs
Joyce B
JB
Berry
Diane
D
Kiel
Douglas P
DP
Streeten
Elizabeth A
EA
Ohlsson
Claes
C
Koller
Daniel L
DL
Peltonen
Leena
L
Cooper
Jason D
JD
O'Reilly
Paul F
PF
Houston
Denise K
DK
Glazer
Nicole L
NL
Vandenput
Liesbeth
L
Peacock
Munro
M
Shi
Julia
J
Rivadeneira
Fernando
F
McCarthy
Mark I
MI
Anneli
Pouta
P
de Boer
Ian H
IH
Mangino
Massimo
M
Kato
Bernet
B
Smyth
Deborah J
DJ
Booth
Sarah L
SL
Jacques
Paul F
PF
Burke
Greg L
GL
Goodarzi
Mark
M
Cheung
Ching-Lung
CL
Wolf
Myles
M
Rice
Kenneth
K
Goltzman
David
D
Hidiroglou
Nick
N
Ladouceur
Martin
M
Wareham
Nicholas J
NJ
Hocking
Lynne J
LJ
Hart
Deborah
D
Arden
Nigel K
NK
Cooper
Cyrus
C
Malik
Suneil
S
Fraser
William D
WD
Hartikainen
Anna-Liisa
AL
Zhai
Guangju
G
Macdonald
Helen M
HM
Forouhi
Nita G
NG
Loos
Ruth J F
RJ
Reid
David M
DM
Hakim
Alan
A
Dennison
Elaine
E
Liu
Yongmei
Y
Power
Chris
C
Stevens
Helen E
HE
Jaana
Laitinen
L
Vasan
Ramachandran S
RS
Soranzo
Nicole
N
Bojunga
Jörg
J
Psaty
Bruce M
BM
Lorentzon
Mattias
M
Foroud
Tatiana
T
Harris
Tamara B
TB
Hofman
Albert
A
Jansson
John-Olov
JO
Cauley
Jane A
JA
Uitterlinden
Andre G
AG
Gibson
Quince
Q
Järvelin
Marjo-Riitta
MR
Karasik
David
D
Siscovick
David S
DS
Econs
Michael J
MJ
Kritchevsky
Stephen B
SB
Florez
Jose C
JC
Todd
John A
JA
Dupuis
Josee
J
Hyppönen
Elina
E
Spector
Timothy D
TD
D002170:Canada; D002880:Chromosomes, Human, Pair 11; D002894:Chromosomes, Human, Pair 4; D015331:Cohort Studies; D019587:Dietary Supplements; D005060:Europe; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007118:Immunoassay; D007391:International Cooperation; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D012621:Seasons; D014481:United States; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000097:blood / Q000235:genetics; D014808:Vitamin D Deficiency / Q000097:blood / Q000235:genetics* / Q000517:prevention & control; D044465:White People / Q000235:genetics*
D014807:Vitamin D; C104450:25-hydroxyvitamin D