Confirming genes influencing risk to cleft lip with/without cleft palate in a case–parent trio study
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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.
KeywordsMinor Allele Frequency Single Nucleotide Polymorphic Maternal Smoking Conditional Logistic Regression Model Asian Ancestry
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).
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