The aim of this work was to fine-map the region 6q23.1, which obtained suggestive linkage signal (logarithm of the odds [LOD] score = 2.22 under a recessive model) to cleft lip with or without cleft palate (CL±P) in our previous genome-wide linkage scan to identify possible genetic variants that may contribute to CL±P.
Design
We used densely spaced markers spanning the entire 6q23.1 region to test for association with CL±P in a family cohort sample.
Setting
Clinical information and DNA samples were obtained from families in the Philippines at their homes or primary health care clinics.
Participants
The study sample consisted of 477 subjects (224 females and 253 males), segregating isolated CL±P, from 72 living in the same area in the Philippines.
Main Outcome Measure
Overtransmission of alleles to persons born with CL±P.
Results
We found statistical evidence of association between a marker of TULP4 (rs651333) with CL±P (P = .00007).
Conclusions
Our results further support the linkage results for the chromosome 6q region and reveal a novel candidate gene for CL±P.
AertsS.LambrechtsD.MaityS.Van LooP.CoessensB.De SmetF.TrancheventL.C.De MoorB.MarynenP.HassanB.. Gene prioritization through genomic data fusion. Nat Biotechnol.2006; 24: 537–544.
2.
BeatyT.H.MurrayJ.C.MarazitaM.L.MungerR.G.RuczinskiI.HetmanskiJ.B.LiangK.Y.WuT.MurrayT.FallinM.D.. A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4. Nat Genet.2010; 42: 525–529.
3.
BeatyT.H.RuczinskiI.MurrayJ.C.MarazitaM.L.MungerR.G.HetmanskiJ.B.MurrayT.RedettR.J.FallinM.D.LiangK.Y.. Evidence for gene-environment interaction in a genome wide study of nonsyndromic cleft palate. Genet Epidemiol.2011; 35: 469–478.
4.
CarlsonC.S.EberleM.A.RiederM.J.YiQ.KruglyakL.NickersonD.A.Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium. Am J Hum Genet.2004; 74: 106–120.
5.
DeRooL.A.WilcoxA.J.DrevonC.A.LieR.T.First-trimester maternal alcohol consumption and the risk of infant oral clefts in Norway: a population-based case-control study. Am J Epidemiol.2008; 168: 638–646.
6.
GilissenC.ArtsH.H.HoischenA.SpruijtL.MansD.A.ArtsP.van LierB.SteehouwerM.van ReewijkJ.KantS.G.. Exome syndrome identifies WDR35 variants involved in Sensenbrenner syndrome. Am J Hum Genet.2010; 87: 418–423.
7.
GrantS.F.WangK.ZhangH.GlabersonW.AnnaiahK.KimC.E.BradfieldJ.P.GlessnerJ.T.ThomasK.A.GarrisM.. A genome-wide association study identifies a locus for nonsyndromic cleft lip with or without cleft palate on 8q24. J Pediatr.2009; 155: 909–913.
8.
GrewalJ.CarmichaelS.L.MaC.LammerE.J.ShawG.M.Maternal periconceptional smoking and alcohol consumption and risk for select congenital anomalies. Birth Defects Res A Clin Mol Teratol.2008; 82: 519–526.
9.
HardM.L.AbdolellM.RobinsonB.H.KoreanG.Gene-expression analysis after alcohol exposure in the developing mouse. J Lab Clin Med.2005; 145: 47–54.
10.
HopkinR.J.SchorryE.BofingerM.MilatovichA.SternH.J.JayneC.SaalH.M.New insights into the phenotypes of 6q deletions. Am J Med Genet.1997; 70: 377–386.
11.
HorvathS.XuX.LairdN.M.The family based association test method: strategies for studying general genotype–phenotype associations. Eur J Hum Genet.2001; 9: 301–306.
12.
International HapMap Consortium.The International HapMap Project. Nature.2003; 426: 789–796.
13.
LeiteI.C.KoifmanS.Oral clefts, consanguinity, parental tobacco and alcohol use: a case-control study in Rio de Janeiro, Brazil. Braz Oral Res.2009; 23: 31–37.
LidralA.C.MorenoL.M.Progress toward discerning the genetics of cleft lip. Curr Opin Pediatr.2005; 17: 731–739.
16.
MangoldE.LudwigK.U.BirnbaumS.BaluardoC.FerrianM.HermsS.ReutterH.de AssisN.A.ChawaT.A.MattheisenM.. Genome-wide association study identifies two susceptibility loci for nonsyndromic cleft lip with or without cleft palate. Nat Genet.2010; 42: 24–26.
17.
MarazitaM.L.MooneyM.P.Current concepts in the embryology and genetics of cleft lip and palate. Clin Plast Surg.2004; 31: 125–140.
18.
MarazitaM.L.MurrayJ.C.LidralA.C.Arcos-BurgosM.CooperM.E.GoldsteinT.MaherN.S.Daack-HirschS.SchultzR.MansillaM.A.. Meta-analysis of 13 genome scans reveals multiple cleft lip/palate genes with novel loci on 9q21 and 2q32-35. Am J Hum Genet.2004; 75: 161–173.
19.
MukhopadhyayS.JacksonP.K.The tubby family proteins. Genome Biol.2011; 12: 225.
20.
MurrayJ.C.Daack-HirschS.BuetowK.H.MungerR.EspinaL.PaflinawanN.VillanuevaE.RaryJ.MageeK.MageeW.Clinical and epidemiologic studies of cleft lip and palate in the Philippines. Cleft Palate Craniofac J.1997; 34: 7–10.
21.
O'ConnellJ.R.WeeksD.E.PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet.1998; 63: 259–266.
RanadeK.ChangM.S.TingC.T.PeiD.HsiaoC.F.OlivierM.PesichR.HebertJ.ChenY.D.DzauV.J.. High-throughput genotyping with single nucleotide polymorphisms. Genome Res.2001; 11: 1262–1268.
24.
TrancheventL.C.BarriotR.YuS.Van VoorenS.Van LooP.CoessensB.De MoorB.AertsS.MoreauY.ENDEAVOUR update: a web resource for gene prioritization in multiple species. Nucleic Acids Res.2008; 36(Web Server issue): W377–W384.
25.
VieiraA.R.McHenryT.G.Daack-HirschS.MurrayJ.C.MarazitaM.L.A genome wide linkage scan for cleft lip and palate and dental anomalies. Am J Med Genet A.2008; 146: 1406–1413.
