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

作者：Leslie Elizabeth J^*; Carlson Jenna C; Shaffer John R; Buxo Carmen J; Castilla Eduardo E; Christensen Kaare; Deleyiannis Frederic W B; Field Leigh L; Hecht Jacqueline T; Moreno Lina; Orioli Ieda M; Padilla Carmencita; Vieira Alexandre R; Wehby George L; Feingold Eleanor; Weinberg Seth M; Murray Jeffrey C; Marazita Mary L

来源：American Journal of Medical Genetics, Part A, 2017, 173(6): 1531-1538.

DOI：10.1002/ajmg.a.38210

• association
• burden test
• orofacial cleft
• rare variant

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, weinvestigated 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%). Wefound 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.

• 出版日期2017-6