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.
Grant
Struan F A
SF
Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Qu
Hui-Qi
HQ
Bradfield
Jonathan P
JP
Marchand
Luc
L
Kim
Cecilia E
CE
Glessner
Joseph T
JT
Grabs
Rosemarie
R
Taback
Shayne P
SP
Frackelton
Edward C
EC
Eckert
Andrew W
AW
Annaiah
Kiran
K
Lawson
Margaret L
ML
Otieno
F George
FG
Santa
Erin
E
Shaner
Julie L
JL
Smith
Ryan M
RM
Skraban
Robert
R
Imielinski
Marcin
M
Chiavacci
Rosetta M
RM
Grundmeier
Robert W
RW
Stanley
Charles A
CA
Kirsch
Susan E
SE
Waggott
Daryl
D
Paterson
Andrew D
AD
Monos
Dimitri S
DS
Polychronakos
Constantin
C
Hakonarson
Hakon
H
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