title: A genome-wide association study identifies GRK5 and RASGRP1 as type 2 diabetes loci in Chinese Hans.
abstract: Substantial progress has been made in identification of type 2 diabetes (T2D) risk loci in the past few years, but our understanding of the genetic basis of T2D in ethnically diverse populations remains limited. We performed a genome-wide association study and a replication study in Chinese Hans comprising 8,569 T2D case subjects and 8,923 control subjects in total, from which 10 single nucleotide polymorphisms were selected for further follow-up in a de novo replication sample of 3,410 T2D case and 3,412 control subjects and an in silico replication sample of 6,952 T2D case and 11,865 control subjects. Besides confirming seven established T2D loci (CDKAL1, CDKN2A/B, KCNQ1, CDC123, GLIS3, HNF1B, and DUSP9) at genome-wide significance, we identified two novel T2D loci, including G-protein-coupled receptor kinase 5 (GRK5) (rs10886471: P = 7.1 × 10(-9)) and RASGRP1 (rs7403531: P = 3.9 × 10(-9)), of which the association signal at GRK5 seems to be specific to East Asians. In nondiabetic individuals, the T2D risk-increasing allele of RASGRP1-rs7403531 was also associated with higher HbA(1c) and lower homeostasis model assessment of β-cell function (P = 0.03 and 0.0209, respectively), whereas the T2D risk-increasing allele of GRK5-rs10886471 was also associated with higher fasting insulin (P = 0.0169) but not with fasting glucose. Our findings not only provide new insights into the pathophysiology of T2D, but may also shed light on the ethnic differences in T2D susceptibility.
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Graduate School of the Chinese Academy of Sciences, Shanghai, China.
authors.forename: Huaixing
authors.initials: H
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Gan
authors.forename: Ling
authors.initials: L
authors.lastname: Lu
authors.forename: Xiao
authors.initials: X
authors.lastname: Dong
authors.forename: Xueyao
authors.initials: X
authors.lastname: Han
authors.forename: Cheng
authors.initials: C
authors.lastname: Hu
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yang
authors.forename: Liang
authors.initials: L
authors.lastname: Sun
authors.forename: Wei
authors.initials: W
authors.lastname: Bao
authors.forename: Pengtao
authors.initials: P
authors.lastname: Li
authors.forename: Meian
authors.initials: M
authors.lastname: He
authors.forename: Liangdan
authors.initials: L
authors.lastname: Sun
authors.forename: Yiqin
authors.initials: Y
authors.lastname: Wang
authors.forename: Jingwen
authors.initials: J
authors.lastname: Zhu
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Ning
authors.forename: Yong
authors.initials: Y
authors.lastname: Tang
authors.forename: Rong
authors.initials: R
authors.lastname: Zhang
authors.forename: Jie
authors.initials: J
authors.lastname: Wen
authors.forename: Di
authors.initials: D
authors.lastname: Wang
authors.forename: Xilin
authors.initials: X
authors.lastname: Zhu
authors.forename: Kunquan
authors.initials: K
authors.lastname: Guo
authors.forename: Xianbo
authors.initials: X
authors.lastname: Zuo
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Guo
authors.forename: Handong
authors.initials: H
authors.lastname: Yang
authors.forename: Xianghai
authors.initials: X
authors.lastname: Zhou
authors.forename: Xuejun
authors.initials: X
authors.lastname: Zhang
authors.forename: Lu
authors.initials: L
authors.lastname: Qi
authors.forename: Ruth J F
authors.initials: RJ
authors.lastname: Loos
authors.forename: Frank B
authors.initials: FB
authors.lastname: Hu
authors.forename: Tangchun
authors.initials: T
authors.lastname: Wu
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Liegang
authors.initials: L
authors.lastname: Liu
authors.forename: Ze
authors.initials: Z
authors.lastname: Yang
authors.forename: Renming
authors.initials: R
authors.lastname: Hu
authors.forename: Weiping
authors.initials: W
authors.lastname: Jia
authors.forename: Linong
authors.initials: L
authors.lastname: Ji
authors.forename: Yixue
authors.initials: Y
authors.lastname: Li
authors.forename: Xu
authors.initials: X
authors.lastname: Lin
mesh_terms: D050154:Adiposity; D001786:Blood Glucose / Q000032:analysis; D002681:China / Q000208:ethnology; D004268:DNA-Binding Proteins / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000235:genetics*; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci
chemical_list: D001786:Blood Glucose; D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; C491790:RASGRP1 protein, human; D054774:G-Protein-Coupled Receptor Kinase 5; C517898:GRK5 protein, human