Genetic determinants of facial clefting: analysis of 357 candidate genes using two national cleft studies from Scandinavia.
BACKGROUND
Facial clefts are common birth defects with a strong genetic component. To identify fetal genetic risk factors for clefting, 1536 SNPs in 357 candidate genes were genotyped in two population-based samples from Scandinavia (Norway: 562 case-parent and 592 control-parent triads; Denmark: 235 case-parent triads).


RESULTS
We used two complementary statistical methods, TRIMM and HAPLIN, to look for associations across these two national samples. TRIMM tests for association in each gene by using multi-SNP genotypes from case-parent triads directly without the need to infer haplotypes. HAPLIN on the other hand estimates the full haplotype distribution over a set of SNPs and estimates relative risks associated with each haplotype. For isolated cleft lip with or without cleft palate (I-CL/P), TRIMM and HAPLIN both identified significant associations with IRF6 and ADH1C in both populations, but only HAPLIN found an association with FGF12. For isolated cleft palate (I-CP), TRIMM found associations with ALX3, MKX, and PDGFC in both populations, but only the association with PDGFC was identified by HAPLIN. In addition, HAPLIN identified an association with ETV5 that was not detected by TRIMM.


CONCLUSIONS
Strong associations with seven genes were replicated in the Scandinavian samples and our approach effectively replicated the strongest previously known association in clefting--with IRF6. Based on two national cleft cohorts of similar ancestry, two robust statistical methods and a large panel of SNPs in the most promising cleft candidate genes to date, this study identified a previously unknown association with clefting for ADH1C and provides additional candidates and analytic approaches to advance the field.
Jugessur
Astanand
A
Craniofacial Development, Musculoskeletal Disorders, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Australia.
Shi
Min
M
Gjessing
Håkon Kristian
HK
Lie
Rolv Terje
RT
Wilcox
Allen James
AJ
Weinberg
Clarice Ring
CR
Christensen
Kaare
K
Boyles
Abee Lowman
AL
Daack-Hirsch
Sandra
S
Trung
Truc Nguyen
TN
Bille
Camilla
C
Lidral
Andrew Carl
AC
Murray
Jeffrey Clark
JC
D000426:Alcohol Dehydrogenase / Q000235:genetics; D016022:Case-Control Studies; D002971:Cleft Lip / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics; D055106:Genome-Wide Association Study; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007231:Infant, Newborn; D050835:Interferon Regulatory Factors / Q000235:genetics; D008222:Lymphokines / Q000235:genetics; D008297:Male; D010982:Platelet-Derived Growth Factor / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012537:Scandinavian and Nordic Countries; D014157:Transcription Factors / Q000235:genetics
C485163:ALX3 protein, human; D004268:DNA-Binding Proteins; C086680:ETV5 protein, human; C486356:FGF12 protein, human; D018398:Homeodomain Proteins; C109803:IRF6 protein, human; D050835:Interferon Regulatory Factors; D008222:Lymphokines; D010982:Platelet-Derived Growth Factor; D014157:Transcription Factors; C411423:platelet-derived growth factor C; D005346:Fibroblast Growth Factors; C420272:ADH1C protein, human; D000426:Alcohol Dehydrogenase