Linkage disequilibrium mapping of the replicated type 2 diabetes linkage signal on chromosome 1q.
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.
Prokopenko
Inga
I
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Zeggini
Eleftheria
E
Hanson
Robert L
RL
Mitchell
Braxton D
BD
Rayner
N William
NW
Akan
Pelin
P
Baier
Leslie
L
Das
Swapan K
SK
Elliott
Katherine S
KS
Fu
Mao
M
Frayling
Timothy M
TM
Groves
Christopher J
CJ
Gwilliam
Rhian
R
Scott
Laura J
LJ
Voight
Benjamin F
BF
Hattersley
Andrew T
AT
Hu
Cheng
C
Morris
Andrew D
AD
Ng
Maggie
M
Palmer
Colin N A
CN
Tello-Ruiz
Marcela
M
Vaxillaire
Martine
M
Wang
Cong-Rong
CR
Stein
Lincoln
L
Chan
Juliana
J
Jia
Weiping
W
Froguel
Philippe
P
Elbein
Steven C
SC
Deloukas
Panos
P
Bogardus
Clifton
C
Shuldiner
Alan R
AR
McCarthy
Mark I
MI
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
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