title: Genome-wide analyses of non-syndromic cleft lip with palate identify 14 novel loci and genetic heterogeneity.
abstract: Non-syndromic cleft lip with palate (NSCLP) is the most serious sub-phenotype of non-syndromic orofacial clefts (NSOFC), which are the most common craniofacial birth defects in humans. Here we conduct a GWAS of NSCLP with multiple independent replications, totalling 7,404 NSOFC cases and 16,059 controls from several ethnicities, to identify new NSCLP risk loci, and explore the genetic heterogeneity between sub-phenotypes of NSOFC. We identify 41 SNPs within 26 loci that achieve genome-wide significance, 14 of which are novel (RAD54B, TMEM19, KRT18, WNT9B, GSC/DICER1, PTCH1, RPS26, OFCC1/TFAP2A, TAF1B, FGF10, MSX1, LINC00640, FGFR1 and SPRY1). These 26 loci collectively account for 10.94% of the heritability for NSCLP in Chinese population. We find evidence of genetic heterogeneity between the sub-phenotypes of NSOFC and among different populations. This study substantially increases the number of genetic susceptibility loci for NSCLP and provides important insights into the genetic aetiology of this common craniofacial malformation.
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, Hubei 430079, China.
authors.forename: Yanqin
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Institute of Dermatology and Department of Dermatology at No. 1 Hospital, Anhui Medical University, Hefei, Anhui 230032, China.|State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China.|Key Lab of Dermatology, Ministry of Education, Heifei, China.|Key Lab of Gene Resources Utilization for Severe Inherited Disorders, Anhui 230032, China.|Collaborative Innovation Center of Complex and Severe skin Disease, Anhui Medical University, Hefei, Anhui 230032, China.
authors.forename: Xianbo
authors.initials: X
authors.lastname: Zuo
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, Hubei 430079, China.|Department of Pediatric Dentistry, School and Hospital of Stomatology, Wuhan University, Wuhan, Hubei 430079, China.
authors.forename: Miao
authors.initials: M
authors.lastname: He
authors.affiliation: Institute of Dermatology and Department of Dermatology at No. 1 Hospital, Anhui Medical University, Hefei, Anhui 230032, China.|State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China.|Key Lab of Dermatology, Ministry of Education, Heifei, China.|Key Lab of Gene Resources Utilization for Severe Inherited Disorders, Anhui 230032, China.|Collaborative Innovation Center of Complex and Severe skin Disease, Anhui Medical University, Hefei, Anhui 230032, China.
authors.forename: Jinping
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan, Hubei 430079, China.
authors.forename: Yuchuan
authors.initials: Y
authors.lastname: Fu
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, Hubei 430079, China.|Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan, Hubei 430079, China.
authors.forename: Chuanqi
authors.initials: C
authors.lastname: Qin
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, Hubei 430079, China.
authors.forename: Liuyan
authors.initials: L
authors.lastname: Meng
authors.affiliation: Institute of Dermatology and Department of Dermatology at No. 1 Hospital, Anhui Medical University, Hefei, Anhui 230032, China.|State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China.|Key Lab of Dermatology, Ministry of Education, Heifei, China.|Key Lab of Gene Resources Utilization for Severe Inherited Disorders, Anhui 230032, China.|Collaborative Innovation Center of Complex and Severe skin Disease, Anhui Medical University, Hefei, Anhui 230032, China.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Wang
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, Hubei 430079, China.
authors.forename: Yaling
authors.initials: Y
authors.lastname: Song
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, Hubei 430079, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Institute of Dermatology and Department of Dermatology at No. 1 Hospital, Anhui Medical University, Hefei, Anhui 230032, China.|State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China.|Key Lab of Dermatology, Ministry of Education, Heifei, China.|Key Lab of Gene Resources Utilization for Severe Inherited Disorders, Anhui 230032, China.|Collaborative Innovation Center of Complex and Severe skin Disease, Anhui Medical University, Hefei, Anhui 230032, China.
authors.forename: Fusheng
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Institute of Dermatology and Department of Dermatology at No. 1 Hospital, Anhui Medical University, Hefei, Anhui 230032, China.|State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China.|Key Lab of Dermatology, Ministry of Education, Heifei, China.|Key Lab of Gene Resources Utilization for Severe Inherited Disorders, Anhui 230032, China.|Collaborative Innovation Center of Complex and Severe skin Disease, Anhui Medical University, Hefei, Anhui 230032, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Institute of Dermatology and Department of Dermatology at No. 1 Hospital, Anhui Medical University, Hefei, Anhui 230032, China.|State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China.|Key Lab of Dermatology, Ministry of Education, Heifei, China.|Key Lab of Gene Resources Utilization for Severe Inherited Disorders, Anhui 230032, China.|Collaborative Innovation Center of Complex and Severe skin Disease, Anhui Medical University, Hefei, Anhui 230032, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zheng
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, Hubei 430079, China.
authors.forename: Xinhuan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Institute of Dermatology and Department of Dermatology at No. 1 Hospital, Anhui Medical University, Hefei, Anhui 230032, China.|State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China.|Key Lab of Dermatology, Ministry of Education, Heifei, China.|Key Lab of Gene Resources Utilization for Severe Inherited Disorders, Anhui 230032, China.|Collaborative Innovation Center of Complex and Severe skin Disease, Anhui Medical University, Hefei, Anhui 230032, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Liang
authors.affiliation: Institute of Dermatology and Department of Dermatology at No. 1 Hospital, Anhui Medical University, Hefei, Anhui 230032, China.|State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China.|Key Lab of Dermatology, Ministry of Education, Heifei, China.|Key Lab of Gene Resources Utilization for Severe Inherited Disorders, Anhui 230032, China.|Collaborative Innovation Center of Complex and Severe skin Disease, Anhui Medical University, Hefei, Anhui 230032, China.
authors.forename: Zhengwei
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Department of Genetics and Centre for Developmental Biology, College of Life Science, Wuhan University, Wuhan, Hubei 430072, China.
authors.forename: Xiazhou
authors.initials: X
authors.lastname: Fu
authors.affiliation: Institute of Dermatology and Department of Dermatology at No. 1 Hospital, Anhui Medical University, Hefei, Anhui 230032, China.|State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China.|Key Lab of Dermatology, Ministry of Education, Heifei, China.|Key Lab of Gene Resources Utilization for Severe Inherited Disorders, Anhui 230032, China.|Collaborative Innovation Center of Complex and Severe skin Disease, Anhui Medical University, Hefei, Anhui 230032, China.
authors.forename: Yujun
authors.initials: Y
authors.lastname: Sheng
authors.affiliation: The Second Charity Hospital of Henan Province, Jiaozuo, Henan 454000, China.
authors.forename: Jiebing
authors.initials: J
authors.lastname: Hao
authors.affiliation: Stomatological Hospital of Nanyang, Nanyang, Henan 473013, China.
authors.forename: Zhongyin
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Stomatological Hospital of Xiangyang, Xiangyang, Hubei 441011, China.
authors.forename: Hansong
authors.initials: H
authors.lastname: Yan
authors.affiliation: Institute of Human Genetics, Life and Brain Center, University of Bonn, 53127 Bonn, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Mangold
authors.affiliation: Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205, USA.
authors.forename: Ingo
authors.initials: I
authors.lastname: Ruczinski
authors.affiliation: Institute of Dermatology and Department of Dermatology at No. 1 Hospital, Anhui Medical University, Hefei, Anhui 230032, China.|State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China.|Key Lab of Dermatology, Ministry of Education, Heifei, China.|Key Lab of Gene Resources Utilization for Severe Inherited Disorders, Anhui 230032, China.|Collaborative Innovation Center of Complex and Severe skin Disease, Anhui Medical University, Hefei, Anhui 230032, China.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Oral Biology and Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.|Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.|Clinical and Translational Science, Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Mary L
authors.initials: ML
authors.lastname: Marazita
authors.affiliation: Institute of Human Genetics, Life and Brain Center, University of Bonn, 53127 Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, 53127 Bonn, Germany.
authors.forename: Kerstin U
authors.initials: KU
authors.lastname: Ludwig
authors.affiliation: Department of Epidemiology, School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205, USA.
authors.forename: Terri H
authors.initials: TH
authors.lastname: Beaty
authors.affiliation: Institute of Dermatology and Department of Dermatology at No. 1 Hospital, Anhui Medical University, Hefei, Anhui 230032, China.|State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China.|Key Lab of Dermatology, Ministry of Education, Heifei, China.|Key Lab of Gene Resources Utilization for Severe Inherited Disorders, Anhui 230032, China.|Collaborative Innovation Center of Complex and Severe skin Disease, Anhui Medical University, Hefei, Anhui 230032, China.|Department of Dermatology at No. 2 Hospital, Anhui Medical University, Hefei, Anhui 230022, China.|Institute of Dermatology and Department of Dermatology, Huashan Hospital of Fudan University, Shanghai 200040, China.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Institute of Dermatology and Department of Dermatology at No. 1 Hospital, Anhui Medical University, Hefei, Anhui 230032, China.|State Key Lab Incubation of Dermatology, Ministry of Science and Technology, Hefei, China.|Key Lab of Dermatology, Ministry of Education, Heifei, China.|Key Lab of Gene Resources Utilization for Severe Inherited Disorders, Anhui 230032, China.|Collaborative Innovation Center of Complex and Severe skin Disease, Anhui Medical University, Hefei, Anhui 230032, China.|The Key Laboratory of Major Autoimmune Diseases, Anhui Province, Anhui 230032, China.
authors.forename: Liangdan
authors.initials: L
authors.lastname: Sun
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, Hubei 430079, China.
authors.forename: Zhuan
authors.initials: Z
authors.lastname: Bian
mesh_terms: D000328:Adult; D000367:Age Factors; D044466:Asian People / Q000208:ethnology / Q000235:genetics; D016022:Case-Control Studies; D002971:Cleft Lip / Q000208:ethnology / Q000235:genetics*; D002972:Cleft Palate / Q000208:ethnology / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D060005:Genotyping Techniques; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012737:Sex Factors