title: Exome-chip association analysis reveals an Asian-specific missense variant in PAX4 associated with type 2 diabetes in Chinese individuals.
abstract: Genome-wide association studies (GWASs) have identified many common type 2 diabetes-associated variants, mostly at the intronic or intergenic regions. Recent advancements of exome-array genotyping platforms have opened up a novel means for detecting the associations of low-frequency or rare coding variants with type 2 diabetes. We conducted an exomechip association analysis to identify additional type 2 diabetes susceptibility variants in the Chinese population.
  
  
  
  An exome-chip association study was conducted by genotyping 5640 Chinese individuals from Hong Kong, using a custom designed exome array, the Asian Exomechip. Single variant association analysis was conducted on 77,468 single nucleotide polymorphisms (SNPs). Fifteen SNPs were subsequently genotyped for replication analysis in an independent Chinese cohort comprising 12,362 individuals from Guangzhou. A combined analysis involving 7189 cases and 10,813 controls was performed.
  
  
  
  In the discovery stage, an Asian-specific coding variant rs2233580 (p.Arg192His) in PAX4, and two variants at the known loci, CDKN2B-AS1 and KCNQ1, were significantly associated with type 2 diabetes with exome-wide significance (pdiscovery< 6.45 × 10-7). The risk allele (T) of PAX4 rs2233580 was associated with a younger age at diabetes diagnosis. This variant was replicated in an independent cohort and demonstrated a stronger association that reached genome-wide significance (pmeta-analysis[pmeta] = 3.74 × 10-15) in the combined analysis.
  
  
  
  We identified the association of a PAX4 Asian-specific missense variant rs2233580 with type 2 diabetes in an exome-chip association analysis, supporting the involvement of PAX4 in the pathogenesis of type 2 diabetes. Our findings suggest PAX4 is a possible effector gene of the 7q32 locus, previously identified from GWAS in Asians.
authors.affiliation: Department of Medicine, University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, People's Republic of China.
authors.forename: Chloe Y Y
authors.initials: CY
authors.lastname: Cheung
authors.affiliation: Department of Surgery, University of Hong Kong, Hong Kong, People's Republic of China.
authors.forename: Clara S
authors.initials: CS
authors.lastname: Tang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, Hong Kong, People's Republic of China.|Research Centre of Heart, Brain, Hormone and Healthy Ageing, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, People's Republic of China.|Department of Pharmacology & Pharmacy, University of Hong Kong, Hong Kong, People's Republic of China.
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
authors.affiliation: Department of Medicine, University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, People's Republic of China.
authors.forename: Chi-Ho
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Department of Medicine, University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, People's Republic of China.
authors.forename: Ka-Wing
authors.initials: KW
authors.lastname: Au
authors.affiliation: School of Public Health, Room 505, Faculty of Medicine Building, William M.W. Mong Block, University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong, People's Republic of China.
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Medicine, University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, People's Republic of China.
authors.forename: Carol H Y
authors.initials: CH
authors.lastname: Fong
authors.affiliation: Department of Medicine, University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, People's Republic of China.
authors.forename: Kelvin H M
authors.initials: KH
authors.lastname: Kwok
authors.affiliation: Department of Medicine, University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, People's Republic of China.
authors.forename: Wing-Sun
authors.initials: WS
authors.lastname: Chow
authors.affiliation: Department of Medicine, University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, People's Republic of China.
authors.forename: Yu-Cho
authors.initials: YC
authors.lastname: Woo
authors.affiliation: Department of Medicine, University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, People's Republic of China.
authors.forename: Michele M A
authors.initials: MM
authors.lastname: Yuen
authors.affiliation: Department of Medicine, University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, People's Republic of China.
authors.forename: JoJo S H
authors.initials: JS
authors.lastname: Hai
authors.affiliation: Molecular Epidemiological Research Centre, Guangzhou Number 12 Hospital, Guangzhou, Guangdong, People's Republic of China.
authors.forename: Ya-Li
authors.initials: YL
authors.lastname: Jin
authors.affiliation: Department of Medicine, University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, People's Republic of China.
authors.forename: Bernard M Y
authors.initials: BM
authors.lastname: Cheung
authors.affiliation: Department of Medicine, University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, People's Republic of China.
authors.forename: Kathryn C B
authors.initials: KC
authors.lastname: Tan
authors.affiliation: Department of Psychiatry, University of Hong Kong, Hong Kong, People's Republic of China.
authors.forename: Stacey S
authors.initials: SS
authors.lastname: Cherny
authors.affiliation: Molecular Epidemiological Research Centre, Guangzhou Number 12 Hospital, Guangzhou, Guangdong, People's Republic of China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhu
authors.affiliation: Molecular Epidemiological Research Centre, Guangzhou Number 12 Hospital, Guangzhou, Guangdong, People's Republic of China.
authors.forename: Tong
authors.initials: T
authors.lastname: Zhu
authors.affiliation: Institute of Applied Health Research, University of Birmingham, Birmingham, UK.
authors.forename: G Neil
authors.initials: GN
authors.lastname: Thomas
authors.affiliation: Institute of Applied Health Research, University of Birmingham, Birmingham, UK.
authors.forename: Kar-Keung
authors.initials: KK
authors.lastname: Cheng
authors.affiliation: Molecular Epidemiological Research Centre, Guangzhou Number 12 Hospital, Guangzhou, Guangdong, People's Republic of China.
authors.forename: Chao-Qiang
authors.initials: CQ
authors.lastname: Jiang
authors.affiliation: School of Public Health, Room 505, Faculty of Medicine Building, William M.W. Mong Block, University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong, People's Republic of China. hrmrlth@hku.hk.|Molecular Epidemiological Research Centre, Guangzhou Number 12 Hospital, Guangzhou, Guangdong, People's Republic of China. hrmrlth@hku.hk.
authors.forename: Tai-Hing
authors.initials: TH
authors.lastname: Lam
authors.affiliation: Department of Medicine, University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, People's Republic of China. hftse@hkucc.hku.hk.|Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine, University of Hong Kong, Hong Kong, People's Republic of China. hftse@hkucc.hku.hk.
authors.forename: Hung-Fat
authors.initials: HF
authors.lastname: Tse
authors.affiliation: Department of Psychiatry, University of Hong Kong, Hong Kong, People's Republic of China. pcsham@hku.hk.|Centre for Genomic Sciences, Centre for Genomic Sciences, University of Hong Kong, 6/F, HKJC Building for Interdisciplinary Research, 5 Sassoon Road, Pokfulam, Hong Kong, People's Republic of China. pcsham@hku.hk.|State Key Laboratory in Brain and Cognitive Sciences, University of Hong Kong, Hong Kong, People's Republic of China. pcsham@hku.hk.
authors.forename: Pak-Chung
authors.initials: PC
authors.lastname: Sham
authors.affiliation: Department of Medicine, University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, People's Republic of China. ksllam@hku.hk.|State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, Hong Kong, People's Republic of China. ksllam@hku.hk.|Research Centre of Heart, Brain, Hormone and Healthy Ageing, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, People's Republic of China. ksllam@hku.hk.
authors.forename: Karen S L
authors.initials: KS
authors.lastname: Lam
mesh_terms: D000368:Aged; D044466:Asian People; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D051761:Paired Box Transcription Factors / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D018398:Homeodomain Proteins; C491709:PAX4 protein, human; D051761:Paired Box Transcription Factors
keywords: Asian-specific; Exome-chip association analysis; PAX4; Type 2 diabetes