Association studies of low-frequency coding variants in nonsyndromic cleft lip with or without cleft palate

LESLIE, ELIZABETH J.; BUXÓ, CARMEN J.; DELEYIANNIS, FREDERIC W. B.; MORENO, LINA; VIEIRA, ALEXANDRE R.; WEINBERG, SETH M.; CARLSON, JENNA C.; SHAFFER, JOHN R.; CASTILLA, EDUARDO E.; CHRISTENSEN, KAARE; FIELD, LEIGH L.; HECHT, JACQUELINE T.; ORIOLI, IEDA M.; PADILLA, CARMENCITA; WEHBY, GEORGE L.; FEINGOLD, ELEANOR; MURRAY, JEFFREY C.; MARAZITA, MARY L.

AMERICAN JOURNAL OF MEDICAL GENETICS PART A

WILEY-LISS, DIV JOHN WILEY & SONS INC

Año: 2017 vol. 173 p. 1531 - 1538

1552-4825

Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a group of common human birth defects with complex etiology. Although genome-wide association studies have successfully identified a number of risk loci, these loci only account for about 20% of the heritability of orofacial clefts. The ?missing? heritability may be found in rare variants, copy number variants, or interactions. In this study, we investigated the role of low-frequency variants genotyped in 1995 cases and 1626 controls on the Illumina HumanCore + Exome chip. We performed two statistical tests, Sequence Kernel Association Test (SKAT) and Combined Multivariate and Collapsing (CMC) method using two minor allele frequency cutoffs (1% and 5%). We found that a burden of low-frequency coding variants in N4BP2, CDSN, PRTG, and AHRR were associated with increased risk of NSCL/P. Low-frequency variants in other genes were associated with decreased risk of NSCL/P. These results demonstrate that low-frequency variants contribute to the genetic etiology of NSCL/P.