title: Identification of novel risk genes associated with type 1 diabetes mellitus using a genome-wide gene-based association analysis.
abstract: OBJECTIVE
  Type 1 diabetes mellitus is a serious disorder characterized by destruction of pancreatic β-cells, culminating in absolute insulin deficiency. Genetic factors contribute to the susceptibility of type 1 diabetes mellitus. The aim of the present study was to identify more susceptibility genes of type 1 diabetes mellitus.
  
  
  METHODS
  We carried out an initial gene-based genome-wide association study in a total of 4,075 type 1 diabetes mellitus cases and 2,604 controls by using the Gene-based Association Test using Extended Simes procedure. Furthermore, we carried out replication studies, differential expression analysis and functional annotation clustering analysis to support the significance of the identified susceptibility genes.
  
  
  RESULTS
  We identified 452 genes associated with type 1 diabetes mellitus, even after adapting the genome-wide threshold for significance (P < 9.05E-04). Among these genes, 171 were newly identified for type 1 diabetes mellitus, which were ignored in single-nucleotide polymorphism-based association analysis and were not previously reported. We found that 53 genes have supportive evidence from replication studies and/or differential expression studies. In particular, seven genes including four non-human leukocyte antigen (HLA) genes (RASIP1, STRN4, BCAR1 and MYL2) are replicated in at least one independent population and also differentially expressed in peripheral blood mononuclear cells or monocytes. Furthermore, the associated genes tend to enrich in immune-related pathways or Gene Ontology project terms.
  
  
  CONCLUSIONS
  The present results suggest the high power of gene-based association analysis in detecting disease-susceptibility genes. Our findings provide more insights into the genetic basis of type 1 diabetes mellitus.
authors.affiliation: Center for Genetic Epidemiology and Genomics, School of Public Health, Soochow University Suzhou, Jiangsu, China ; Department of Epidemiology, School of Public Health, Soochow University Suzhou, Jiangsu, China.
authors.forename: Ying-Hua
authors.initials: YH
authors.lastname: Qiu
authors.affiliation: Center for Genetic Epidemiology and Genomics, School of Public Health, Soochow University Suzhou, Jiangsu, China ; Department of Epidemiology, School of Public Health, Soochow University Suzhou, Jiangsu, China.
authors.forename: Fei-Yan
authors.initials: FY
authors.lastname: Deng
authors.affiliation: Center for Genetic Epidemiology and Genomics, School of Public Health, Soochow University Suzhou, Jiangsu, China ; Department of Epidemiology, School of Public Health, Soochow University Suzhou, Jiangsu, China.
authors.forename: Min-Jing
authors.initials: MJ
authors.lastname: Li
authors.affiliation: Center for Genetic Epidemiology and Genomics, School of Public Health, Soochow University Suzhou, Jiangsu, China ; Department of Epidemiology, School of Public Health, Soochow University Suzhou, Jiangsu, China.
authors.forename: Shu-Feng
authors.initials: SF
authors.lastname: Lei
keywords: Genome-wide Gene-Based Association Study; Knowledge-based mining system for Genome-wide Genetic studies; Type 1 diabetes mellitus