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

被引：31

作者：

Leslie, Elizabeth J. ^{[1
]}

Carlson, Jenna C. ^{[1
,2
]}

Shaffer, John R. ^{[1
,3
]}

Buxo, Carmen J. ^{[4
]}

Castilla, Eduardo E. ^{[5
,6
,7
]}

Christensen, Kaare ^{[8
]}

Deleyiannis, Frederic W. B. ^{[9
]}

Field, Leigh L. ^{[10
]}

Hecht, Jacqueline T. ^{[11
,12
]}

Moreno, Lina ^{[13
]}

Orioli, Ieda M. ^{[6
,14
]}

Padilla, Carmencita ^{[15
,16
,17
]}

Vieira, Alexandre R. ^{[1
,3
]}

Wehby, George L. ^{[18
]}

Feingold, Eleanor ^{[1
,2
,3
]}

Weinberg, Seth M. ^{[1
]}

Murray, Jeffrey C. ^{[19
]}

Marazita, Mary L. ^{[1
,3
,20
]}

机构：

[1] Univ Pittsburgh, Sch Dent Med, Dept Oral Biol, Ctr Craniofacial & Dent Genet, Pittsburgh, PA USA

[2] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA

[3] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA

[4] Univ Puerto Rico, Sch Dent Med, San Juan, PR 00936 USA

[5] CEMIC Ctr Med Educ & Clin Res, Buenos Aires, DF, Argentina

[6] Natl Inst Populat Med Genet, INAGEMP, Latin Amer Collaborat Study Congenital Malformat, ECLAMC, Rio De Janeiro, Brazil

[7] Fiocruz MS, Oswaldo Cruz Inst, Lab Congenital Malformat Epidemiol, Rio De Janeiro, Brazil

[8] Univ Southern Denmark, Inst Publ Hlth, Dept Epidemiol, Odense, Denmark

[9] Univ Colorado, Sch Med, Dept Surg Plast & Reconstruct Surg, Denver, CO 80202 USA

[10] Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada

[11] UT Hlth Houston, McGovern Med Sch, Dept Pediat, Houston, TX USA

[12] UT Hlth Houston, Sch Dent, Houston, TX USA

[13] Univ Iowa, Coll Dent, Dept Orthodont, Iowa City, IA 52242 USA

[14] Univ Fed Rio de Janeiro, Inst Biol, Dept Genet, Rio De Janeiro, Brazil

[15] Univ Philippines Manila, Coll Med, Dept Pediat, Manila, Philippines

[16] Univ Philippines Manila, Inst Human Genet, Natl Inst Hlth, Manila, Philippines

[17] Univ Philippines Syst, Philippine Genome Ctr, Manila, Philippines

[18] Univ Iowa, Coll Publ Hlth, Dept Hlth Management & Policy, Iowa City, IA USA

[19] Univ Iowa, Dept Pediat, Carver Coll Med, Iowa City, IA 52242 USA

[20] Univ Pittsburgh, Sch Med, Clin & Translat Sci, Pittsburgh, PA USA

来源：

AMERICAN JOURNAL OF MEDICAL GENETICS PART A | 2017年 / 173卷 / 06期

基金：

美国国家卫生研究院;

关键词：

association; burden test; orofacial cleft; rare variant; GENOME-WIDE ASSOCIATION; RARE VARIANTS; SUSCEPTIBILITY LOCUS; KIAA0586; CAUSE; SEQUENCE DATA; HUMAN-DISEASE; GENE; MUTATIONS; CORNEODESMOSIN; DISRUPTION;

D O I：

10.1002/ajmg.a.38210

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：1531 / 1538

页数：8

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