title: Linkage disequilibrium mapping of the replicated type 2 diabetes linkage signal on chromosome 1q.
abstract: OBJECTIVE
  Linkage of the chromosome 1q21-25 region to type 2 diabetes has been demonstrated in multiple ethnic groups. We performed common variant fine-mapping across a 23-Mb interval in a multiethnic sample to search for variants responsible for this linkage signal.
  
  
  METHODS
  In all, 5,290 single nucleotide polymorphisms (SNPs) were successfully genotyped in 3,179 type 2 diabetes case and control subjects from eight populations with evidence of 1q linkage. Samples were ascertained using strategies designed to enhance power to detect variants causal for 1q linkage. After imputation, we estimate approximately 80% coverage of common variation across the region (r (2) > 0.8, Europeans). Association signals of interest were evaluated through in silico replication and de novo genotyping in approximately 8,500 case subjects and 12,400 control subjects.
  
  
  RESULTS
  Association mapping of the 23-Mb region identified two strong signals, both of which were restricted to the subset of European-descent samples. The first mapped to the NOS1AP (CAPON) gene region (lead SNP: rs7538490, odds ratio 1.38 [95% CI 1.21-1.57], P = 1.4 x 10(-6), in 999 case subjects and 1,190 control subjects); the second mapped within an extensive region of linkage disequilibrium that includes the ASH1L and PKLR genes (lead SNP: rs11264371, odds ratio 1.48 [1.18-1.76], P = 1.0 x 10(-5), under a dominant model). However, there was no evidence for association at either signal on replication, and, across all data (>24,000 subjects), there was no indication that these variants were causally related to type 2 diabetes status.
  
  
  CONCLUSIONS
  Detailed fine-mapping of the 23-Mb region of replicated linkage has failed to identify common variant signals contributing to the observed signal. Future studies should focus on identification of causal alleles of lower frequency and higher penetrance.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Inga
authors.initials: I
authors.lastname: Prokopenko
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Zeggini
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hanson
authors.forename: Braxton D
authors.initials: BD
authors.lastname: Mitchell
authors.forename: N William
authors.initials: NW
authors.lastname: Rayner
authors.forename: Pelin
authors.initials: P
authors.lastname: Akan
authors.forename: Leslie
authors.initials: L
authors.lastname: Baier
authors.forename: Swapan K
authors.initials: SK
authors.lastname: Das
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Elliott
authors.forename: Mao
authors.initials: M
authors.lastname: Fu
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Frayling
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Groves
authors.forename: Rhian
authors.initials: R
authors.lastname: Gwilliam
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Scott
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Voight
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
authors.forename: Cheng
authors.initials: C
authors.lastname: Hu
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Morris
authors.forename: Maggie
authors.initials: M
authors.lastname: Ng
authors.forename: Colin N A
authors.initials: CN
authors.lastname: Palmer
authors.forename: Marcela
authors.initials: M
authors.lastname: Tello-Ruiz
authors.forename: Martine
authors.initials: M
authors.lastname: Vaxillaire
authors.forename: Cong-Rong
authors.initials: CR
authors.lastname: Wang
authors.forename: Lincoln
authors.initials: L
authors.lastname: Stein
authors.forename: Juliana
authors.initials: J
authors.lastname: Chan
authors.forename: Weiping
authors.initials: W
authors.lastname: Jia
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.forename: Steven C
authors.initials: SC
authors.lastname: Elbein
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.forename: Clifton
authors.initials: C
authors.lastname: Bogardus
authors.forename: Alan R
authors.initials: AR
authors.lastname: Shuldiner
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1; D004268:DNA-Binding Proteins / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005006:Ethnicity / Q000235:genetics; D005787:Gene Frequency; D014644:Genetic Variation; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D012016:Reference Values; D018570:Risk Assessment; D014157:Transcription Factors / Q000235:genetics; D044465:White People / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C488081:NOS1AP protein, human; D014157:Transcription Factors; C490911:ASH1L protein, human; D011495:Histone-Lysine N-Methyltransferase