title: Identification of novel candidate genes for type 2 diabetes from a genome-wide association scan in the Old Order Amish: evidence for replication from diabetes-related quantitative traits and from independent populations.
abstract: OBJECTIVE
  We sought to identify type 2 diabetes susceptibility genes through a genome-wide association scan (GWAS) in the Amish.
  
  
  METHODS
  DNA from 124 type 2 diabetic case subjects and 295 control subjects with normal glucose tolerance were genotyped on the Affymetrix 100K single nucleotide polymorphism (SNP) array. A total of 82,485 SNPs were tested for association with type 2 diabetes. Type 2 diabetes-associated SNPs were further prioritized by the following: 1) associations with 5 oral glucose tolerance test (OGTT) traits in 427 nondiabetic Amish subjects, and 2) in silico replication from three independent 100L SNP GWASs (Framingham Heart Study Caucasians, Pima Indians, and Mexican Americans) and a 500K GWAS in Scandinavians.
  
  
  RESULTS
  The strongest association (P = 1.07 x 10(-5)) was for rs2237457, which is located in growth factor receptor-bound protein 10 (Grb10), an adaptor protein that regulate insulin receptor signaling. rs2237457 was also strongly associated with OGTT glucose area under the curve in nondiabetic subjects (P = 0.001). Of the 1,093 SNPs associated with type 2 diabetes at P < 0.01, 67 SNPs demonstrated associations with at least one OGTT trait in nondiabetic individuals; 80 SNPs were nominally associated with type 2 diabetes in one of the three independent 100K GWASs, 3 SNPs (rs2540317 in MFSD9, rs10515353 on chromosome 5, and rs2242400 in BCAT1 were associated with type 2 diabetes in more than one population), and 11 SNPs were nominally associated with type 2 diabetes in Scandinavians. One type 2 diabetes-associated SNP (rs3845971, located in FHIT) showed replication with OGTT traits and also in another population.
  
  
  CONCLUSIONS
  Our GWAS of type 2 diabetes identified several gene variants associated with type 2 diabetes, some of which are worthy of further study.
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, 660 West Redwood St., Room 494, Baltimore, MD 21201, USA.
authors.forename: Evadnie
authors.initials: E
authors.lastname: Rampersaud
authors.forename: Coleen M
authors.initials: CM
authors.lastname: Damcott
authors.forename: Mao
authors.initials: M
authors.lastname: Fu
authors.forename: Haiqing
authors.initials: H
authors.lastname: Shen
authors.forename: Patrick
authors.initials: P
authors.lastname: McArdle
authors.forename: Xiaolian
authors.initials: X
authors.lastname: Shi
authors.forename: John
authors.initials: J
authors.lastname: Shelton
authors.forename: Jing
authors.initials: J
authors.lastname: Yin
authors.forename: Yen-Pei C
authors.initials: YP
authors.lastname: Chang
authors.forename: Sandra H
authors.initials: SH
authors.lastname: Ott
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Yiju
authors.initials: Y
authors.lastname: Zhao
authors.forename: Braxton D
authors.initials: BD
authors.lastname: Mitchell
authors.forename: Jeffery
authors.initials: J
authors.lastname: O'Connell
authors.forename: Alan R
authors.initials: AR
authors.lastname: Shuldiner
mesh_terms: D000328:Adult; D000368:Aged; D015992:Body Mass Index; D002874:Chromosome Mapping; D004247:DNA / Q000097:blood / Q000235:genetics / Q000302:isolation & purification; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005006:Ethnicity / Q000235:genetics*; D005260:Female; D051383:GRB10 Adaptor Protein / Q000235:genetics; D015894:Genome, Human; D006801:Humans; D008297:Male; D008396:Maryland; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D050177:Overweight / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci
chemical_list: D051383:GRB10 Adaptor Protein; D004247:DNA