Follow-up analysis of genome-wide association data identifies novel loci for type 1 diabetes.
OBJECTIVE
Two recent genome-wide association (GWA) studies have revealed novel loci for type 1 diabetes, a common multifactorial disease with a strong genetic component. To fully utilize the GWA data that we had obtained by genotyping 563 type 1 diabetes probands and 1,146 control subjects, as well as 483 case subject-parent trios, using the Illumina HumanHap550 BeadChip, we designed a full stage 2 study to capture other possible association signals.


METHODS
From our existing datasets, we selected 982 markers with P < 0.05 in both GWA cohorts. Genotyping these in an independent set of 636 nuclear families with 974 affected offspring revealed 75 markers that also had P < 0.05 in this third cohort. Among these, six single nucleotide polymorphisms in five novel loci also had P < 0.05 in the Wellcome Trust Case-Control Consortium dataset and were further tested in 1,303 type 1 diabetes probands from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) plus 1,673 control subjects.


RESULTS
Two markers (rs9976767 and rs3757247) remained significant after adjusting for the number of tests in this last cohort; they reside in UBASH3A (OR 1.16; combined P = 2.33 x 10(-8)) and BACH2 (1.13; combined P = 1.25 x 10(-6)).


CONCLUSIONS
Evaluation of a large number of statistical GWA candidates in several independent cohorts has revealed additional loci that are associated with type 1 diabetes. The two genes at these respective loci, UBASH3A and BACH2, are both biologically relevant to autoimmunity.
Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Struan F A
SF
Grant
Hui-Qi
HQ
Qu
Jonathan P
JP
Bradfield
Luc
L
Marchand
Cecilia E
CE
Kim
Joseph T
JT
Glessner
Rosemarie
R
Grabs
Shayne P
SP
Taback
Edward C
EC
Frackelton
Andrew W
AW
Eckert
Kiran
K
Annaiah
Margaret L
ML
Lawson
F George
FG
Otieno
Erin
E
Santa
Julie L
JL
Shaner
Ryan M
RM
Smith
Robert
R
Skraban
Marcin
M
Imielinski
Rosetta M
RM
Chiavacci
Robert W
RW
Grundmeier
Charles A
CA
Stanley
Susan E
SE
Kirsch
Daryl
D
Waggott
Andrew D
AD
Paterson
Dimitri S
DS
Monos
Constantin
C
Polychronakos
Hakon
H
Hakonarson
D000293:Adolescent; D000328:Adult; D002170:Canada; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006801:Humans; D007223:Infant; D015201:Meta-Analysis as Topic; D020641:Polymorphism, Single Nucleotide; D014481:United States; D055815:Young Adult