title: Joint testing of genotypic and gene-environment interaction identified novel association for BMP4 with non-syndromic CL/P in an Asian population using data from an International Cleft Consortium.
abstract: BACKGROUND
  Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common disorder with complex etiology. The Bone Morphogenetic Protein 4 gene (BMP4) has been considered a prime candidate gene with evidence accumulated from animal experimental studies, human linkage studies, as well as candidate gene association studies. The aim of the current study is to test for linkage and association between BMP4 and NSCL/P that could be missed in genome-wide association studies (GWAS) when genotypic (G) main effects alone were considered.
  
  
  RESULTS
  We performed the analysis considering G and interactions with multiple maternal environmental exposures using additive conditional logistic regression models in 895 Asian and 681 European complete NSCL/P trios. Single nucleotide polymorphisms (SNPs) that passed the quality control criteria among 122 genotyped and 25 imputed single nucleotide variants in and around the gene were used in analysis. Selected maternal environmental exposures during 3 months prior to and through the first trimester of pregnancy included any personal tobacco smoking, any environmental tobacco smoke in home, work place or any nearby places, any alcohol consumption and any use of multivitamin supplements. A novel significant association held for rs7156227 among Asian NSCL/P and non-syndromic cleft lip and palate (NSCLP) trios after Bonferroni correction which was not seen when G main effects alone were considered in either allelic or genotypic transmission disequilibrium tests. Odds ratios for carrying one copy of the minor allele without maternal exposure to any of the four environmental exposures were 0.58 (95%CI = 0.44, 0.75) and 0.54 (95%CI = 0.40, 0.73) for Asian NSCL/P and NSCLP trios, respectively. The Bonferroni P values corrected for the total number of 117 tested SNPs were 0.0051 (asymptotic P = 4.39*10(-5)) and 0.0065 (asymptotic P = 5.54*10(-5)), accordingly. In European trios, no significant association was seen for any SNPs after Bonferroni corrections for the total number of 120 tested SNPs.
  
  
  CONCLUSIONS
  Our findings add evidence from GWAS to support the role of BMP4 in susceptibility to NSCL/P originally identified in linkage and candidate gene association studies.
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China; Ministry of Health Key Laboratory of Reproductive Health, Beijing, China.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China; Ministry of Health Key Laboratory of Reproductive Health, Beijing, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Mathematical Institute, Heinrich Heine University Duesseldorf, Duesseldorf, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Schwender
authors.affiliation: Division of Biology and Biomedical Sciences, Washington University, St. Louis, Missouri, United States of America.
authors.forename: Tianxiao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
authors.forename: Jacqueline B
authors.initials: JB
authors.lastname: Hetmanski
authors.affiliation: Department of Medical Research, Chang Gung Memorial Hospital, Taipei, Taiwan.
authors.forename: Yah-Huei Wu
authors.initials: YH
authors.lastname: Chou
authors.affiliation: Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York City, New York, United States of America.
authors.forename: Xiaoqian
authors.initials: X
authors.lastname: Ye
authors.affiliation: Department of Plastic Surgery, K K Women's and Children's Hospital, Singapore, Singapore.
authors.forename: Vincent
authors.initials: V
authors.lastname: Yeow
authors.affiliation: Department of Pediatrics, National University of Singapore, Singapore, Singapore.
authors.forename: Samuel S
authors.initials: SS
authors.lastname: Chong
authors.affiliation: Department of Engineering, Xi'an JiaoTong University, Xi'an, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America; Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York City, New York, United States of America.
authors.forename: Ethylin Wang
authors.initials: EW
authors.lastname: Jabs
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Parker
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Alan F
authors.initials: AF
authors.lastname: Scott
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
authors.forename: Terri H
authors.initials: TH
authors.lastname: Beaty
mesh_terms: D044466:Asian People / Q000235:genetics; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics*; D002971:Cleft Lip / Q000150:complications / Q000209:etiology / Q000235:genetics*; D002972:Cleft Palate / Q000150:complications / Q000209:etiology / Q000235:genetics*; D005260:Female; D059647:Gene-Environment Interaction; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D018811:Maternal Exposure / Q000009:adverse effects; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects; D014028:Tobacco Smoke Pollution / Q000009:adverse effects
chemical_list: C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D014028:Tobacco Smoke Pollution