A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4.
Case-parent trios were used in a genome-wide association study of cleft lip with and without cleft palate. SNPs near two genes not previously associated with cleft lip with and without cleft palate (MAFB, most significant SNP rs13041247, with odds ratio (OR) per minor allele = 0.704, 95% CI 0.635-0.778, P = 1.44 x 10(-11); and ABCA4, most significant SNP rs560426, with OR = 1.432, 95% CI 1.292-1.587, P = 5.01 x 10(-12)) and two previously identified regions (at chromosome 8q24 and IRF6) attained genome-wide significance. Stratifying trios into European and Asian ancestry groups revealed differences in statistical significance, although estimated effect sizes remained similar. Replication studies from several populations showed confirming evidence, with families of European ancestry giving stronger evidence for markers in 8q24, whereas Asian families showed stronger evidence for association with MAFB and ABCA4. Expression studies support a role for MAFB in palatal development.
Beaty
Terri H
TH
Johns Hopkins University, School of Public Health, Baltimore, Maryland, USA. tbeaty@jhsph.edu
Murray
Jeffrey C
JC
Marazita
Mary L
ML
Munger
Ronald G
RG
Ruczinski
Ingo
I
Hetmanski
Jacqueline B
JB
Liang
Kung Yee
KY
Wu
Tao
T
Murray
Tanda
T
Fallin
M Daniele
MD
Redett
Richard A
RA
Raymond
Gerald
G
Schwender
Holger
H
Jin
Sheng-Chih
SC
Cooper
Margaret E
ME
Dunnwald
Martine
M
Mansilla
Maria A
MA
Leslie
Elizabeth
E
Bullard
Stephen
S
Lidral
Andrew C
AC
Moreno
Lina M
LM
Menezes
Renato
R
Vieira
Alexandre R
AR
Petrin
Aline
A
Wilcox
Allen J
AJ
Lie
Rolv T
RT
Jabs
Ethylin W
EW
Wu-Chou
Yah Huei
YH
Chen
Philip K
PK
Wang
Hong
H
Ye
Xiaoqian
X
Huang
Shangzhi
S
Yeow
Vincent
V
Chong
Samuel S
SS
Jee
Sun Ha
SH
Shi
Bing
B
Christensen
Kaare
K
Melbye
Mads
M
Doheny
Kimberly F
KF
Pugh
Elizabeth W
EW
Ling
Hua
H
Castilla
Eduardo E
EE
Czeizel
Andrew E
AE
Ma
Lian
L
Field
L Leigh
LL
Brody
Lawrence
L
Pangilinan
Faith
F
Mills
James L
JL
Molloy
Anne M
AM
Kirke
Peadar N
PN
Scott
John M
JM
Scott
James M
JM
Arcos-Burgos
Mauricio
M
Scott
Alan F
AF
D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D044466:Asian People / Q000235:genetics; D002971:Cleft Lip / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D051258:MafB Transcription Factor / Q000235:genetics*; D051379:Mice; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics
C056475:ABCA4 protein, human; D018528:ATP-Binding Cassette Transporters; C490407:MAFB protein, human; D051258:MafB Transcription Factor