Confirming genes influencing risk to cleft lip with/without cleft palate in a case–parent trio study
- 1.2k Downloads
A collection of 1,108 case–parent trios ascertained through an isolated, nonsyndromic cleft lip with or without cleft palate (CL/P) was used to replicate the findings from a genome-wide association study (GWAS) conducted by Beaty et al. (Nat Genet 42:525–529, 2010), where four different genes/regions were identified as influencing risk to CL/P. Tagging SNPs for 33 different genes were genotyped (1,269 SNPs). All four of the genes originally identified as showing genome-wide significance (IRF6, ABCA4 and MAF, plus the 8q24 region) were confirmed in this independent sample of trios (who were primarily of European and Southeast Asian ancestry). In addition, eight genes classified as ‘second tier’ hits in the original study (PAX7, THADA, COL8A1/FILIP1L, DCAF4L2, GADD45G, NTN1, RBFOX3 and FOXE1) showed evidence of linkage and association in this replication sample. Meta-analysis between the original GWAS trios and these replication trios showed PAX7, COL8A1/FILIP1L and NTN1 achieved genome-wide significance. Tests for gene–environment interaction between these 33 genes and maternal smoking found evidence for interaction with two additional genes: GRID2 and ELAVL2 among European mothers (who had a higher rate of smoking than Asian mothers). Formal tests for gene–gene interaction (epistasis) failed to show evidence of statistical interaction in any simple fashion. This study confirms that many different genes influence risk to CL/P.
We sincerely thank all families at each recruitment site for participating in this international replication study, and we gratefully acknowledge the invaluable assistance of clinical, field and laboratory staff who made this work possible. Funding to support data collection, genotyping and analysis came from several sources, some to individual investigators (R01-DE-014581 T.H.B.; R01-DE-016148 M.L.M.; P50-DE016215 J.C.M.) and some to the International Cleft Consortium itself (supported by a supplement to U01-DE-018993; T.H. Beaty PI) which was part of the Gene, Environment Association Studies (GENEVA) Consortium. Recruitment of German trios was supported by the Deutsche Forschungsgemeinschaft (FOR 423 and individual grants MA 2546/3-1, KR 1912/7-1, NO 246/6-1, WI 1555/5-1). Genotyping services were provided by the Center for Inherited Disease Research (CIDR) which is funded through a federal contract from the NIH to Johns Hopkins University (contract number HHSN268200782096C).
- Beaty TH, Murray JC, Marazita ML, Munger RG, Ruczinski I, Hetmanski JB, Liang KY, Wu T, Murray T, Fallin MD, Redett RA, Raymond G, Schwender H, Jin SC, Rose M, Cooper ME, Dunnwald M, Mansilla MA, Leslie E, Bullard S, Lidral A, Moreno LM, Menezes R, Vieira AR, Petrin A, Wilcox A, Lie RT, Jabs EW, Wu-Chou YH, Wang H, Ye X, Huang S, Yeow V, Chong SS, Jee SH, Shi B, Christensen K, Doheny K, Pugh EW, Ling H, Castilla EE, Czeizel AE, Ma L, Field LL, Brody LC, Pangilinan F, Mills JL, Molloy AM, Kirke PN, Scott JM, Arcos-Burgos M, Scott AF (2010) A genome wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4. Nat Genet 42:525–529. doi: 10.38/ng.580 PubMedCrossRefGoogle Scholar
- Birnbaum S, Ludwig KU, Reutter H, Herms S, Steffens M, Rubini M, Baluardo C, Ferrian M, Almeida de Assis N, Alblas MA, Barth S, Freudenberg J, Lauster C, Schmidt G, Scheer M, Braumann B, Bergé SJ, Reich RH, Schiefke F, Hemprich A, Pötzsch S, Steegers-Theunissen RP, Pötzsch B, Moebus S, Horsthemke B, Kramer FJ, Wienker TF, Mossey PA, Propping P, Cichon S, Hoffmann P, Knapp M, Nöthen MM, Mangold E (2009) Key susceptibility locus for nonsyndromic cleft lip with or without cleft palate on chromosome 8q24. Nat Genet 41:473–477. doi: 10.1038/ng.333 PubMedCrossRefGoogle Scholar
- Grant SF, Wang K, Zhang H, Glaberson W, Annaiah K, Kim CE, Bradfield JP, Glessner JT, Thomas KA, Garris M, Frackelton EC, Otieno FG, Chiavacci RM, Nah HD, Kirschner RE, Hakonarson H (2009) A genome-wide association study identifies a locus for nonsyndromic cleft lip with or without cleft palate on 8q24. J Pediatr 155:909–913. doi: 10.1016/j.jpeds.2009.06.020 PubMedCrossRefGoogle Scholar
- Laurie CC, Doheny KF, Mirel DB, Pugh EW, Bierut LJ, Bhangale T, Boehm F, Caporaso NE, Cornelis MF, Edenberg HL, Gabriel SB, Harris EL, Hu FB, Jacobs KB, Kraft P, Landi MT, Lumley T, Manolio TA, McHugh C, Painter I, Paschall J, Rice JP, Rice KM, Zheng X, Weir BS for the GENEVA Investigators (2010) Quality control and quality assurance in genotypic data for genome-wide association studies. Genetic Epidemiol 34:591–602 doi: 10.1002/gepi.20516 Google Scholar
- Leslie EJ, Mansilla MA, Biggs LC, Schuette K, Bullard S, Cooper M, Dunnwald M, Lidral AC, Marazita ML, Beaty TH, Murray JC (2012a) Mutation screen and expression analysis implicate ARHGAP29 as the etiologic gene for nonsyndromic cleft lip/palate first localized by GWAS. Birth Defects Res A 94:934–942. doi: 10.1002/bdra.23076 CrossRefGoogle Scholar
- Leslie EJ, Standley J, Compton J, Bale S, Schutte BC, Murray JC (2012b) Comparative analysis of IRF6 variants in families with Van der Woude syndrome and popliteal pterygium syndrome using public whole-exome databases. Genet Med (epub). doi: 10.1038/gim.2012.141
- Ludwig KU, Mangold E, Herms S, Nowak S, Reutter H, Paul A, Becker J, Herberz R, AlChawa T, Nasser E, Boehmer A, Mattheisen M, Alblas MA, Barth S, Kluck N, Lauster C, Braumann B, Reich RH, Hemprich A, Poetzsch S, Blaumeiser B, Daratsianos N, Kreusch T, Murray JC, Marazita ML, Scott AF, Beaty TH, Ruczinski I, Kramer FJ, Wienker TF, Steegers-Theunissen RP, Rubini M, Mossey PA, Hoffmann P, Lange C, Cichon S, Propping P, Knapp M, Noethen MM (2012) First genome wide meta-analyses of nonsyndromic cleft lip with or without cleft palate identify six new risk loci including one subtype specific locus. Nat Genet 44:968–971. doi: 10.1038/ng.2360 PubMedCrossRefGoogle Scholar
- Mangold E, Ludwig KU, Birnbaum S, Baluardo C, Ferrian M, Herms S, Reutter H, de Assis NA, Chawa TA, Mattheisen M, Steffens M, Barth S, Kluck N, Paul A, Becker J, Lauster C, Schmidt G, Braumann B, Scheer M, Reich RH, Hemprich A, Pötzsch S, Blaumeiser B, Moebus S, Krawczak M, Schreiber S, Meitinger T, Wichmann HE, Steegers-Theunissen RP, Kramer FJ, Cichon S, Propping P, Wienker TF, Knapp M, Rubini M, Mossey PA, Hoffmann P, Nöthen MM (2010) Genome-wide association study identifies two susceptibility loci for nonsyndromic cleft lip with or without cleft palate. Nature Genet 42:24–26. doi: 10.1038/ng.506 PubMedCrossRefGoogle Scholar
- Marazita ML, Lidral AC, Murray JC, Field LL, Maher BS, McHenry TG, Cooper ME, Govil M, Daack-Hirsch S, Riley B, Jugessur A, Felix T, Moreno L, Mansilla MA, Vieira AR, Doheny K, Pugh E, Valencia-Ramirez C, Arcos-Burgos M (2009) Genome scan, fine-mapping, and candidate gene analysis of non-syndromic cleft lip with or without cleft palate reveals phenotype specific differences in linkage and association results. Hum Hered 68:151–170. doi: 10.1159/000224636 PubMedCrossRefGoogle Scholar
- Moreno LM, Mansilla MA, Bullard SA, Cooper ME, Busch TD, Machida J, Johnson MK, Brauer D, Krahn K, Daack-Hirsch S, L’heureux J, Valencia-Ramirez C, Rivera D, Lopez AM, Moreno MA, Hing A, Lammer EJ, Jones M, Christensen K, Lie RT, Jugessur A, Wilcox AJ, Chines P, Pugh E, Doheny K, Arcos-Burgos M, Marazita ML, Murray JC, Lidral AC (2009) FOXE1 association with both isolated cleft lip with or without cleft palate and isolated cleft palate. Hum Molec Genet 18:4879–4896. doi: 10.1093/hmg/ddp444 PubMedCrossRefGoogle Scholar
- Murray T, Taub MA, Ruczinski I, Scott AF, Hetmanski JB, Schwender H, Patel P, Zhang TX, Munger RG, Wilcox AJ, Ye X, Wang H, Wu-Chou YH, Shi B, Jee SH, Chong SS, Yeow V, Murray JC, Marazita ML, Beaty TH (2012) Examining 8q24 to explain differences in evidence of association with cleft lip/palate between Asians and Europeans. Genetic Epidemiol 6:392–399. doi: 10.1002/gepi.21633 CrossRefGoogle Scholar