1. TCF7L2 overexpression and Type 2
Diabetes:
Dissecting the function of Tcf7l2 as a
regulator of glucose metabolism
Kathleen Bailey, PhD
Department of Human Genetics
The University of Chicago
2. Genome-Wide Association Studies (GWAS) attempt to uncover the
biology behind complex diseases using a case-control study design
G allele found more
often in cases so may
contribute to disease
risk
3. More than 2,000 GWAS have been published identifying over
15,000 SNPs associated with different traits
NHGRI-EBI GWAS Catalog, www.ebi.ac.uk/gwas
published GWAS at
p<5x10-8 through
May 2014
= GWAS locus
4. NHGRI-EBI GWAS Catalog, www.ebi.ac.uk/gwas
published GWAS at
p<5x10-8 through
May 2014
= GWAS locus
Majority of variants associated with complex disease reside
within non-coding regions of the genome making it less clear
how these variants contribute to disease risk
More than 2,000 GWAS have been published identifying over
15,000 SNPs associated with different traits
5. GWAS for Type 2 diabetes (T2D) risk variants identified non-
coding variation in TCF7L2 as the strongest genetic
determinant of T2D risk
Voight et al. Nature Genetics 2010
TCF7L2
6. The diabetes-associated region within the TCF7L2 locus
encompasses an interval of high linkage disequilibrium
TCF7L2
T2D-associated variation is non-coding and perhaps plays a
regulatory role in TCF7L2 expression
*
Savic et al. Genome Research 2011
7. The majority of TCF7L2 enhancer activity is within sequences
spanning the T2D-associated region
Endogenous RP11-139K1RP11-466I19
LacZ
ATG
100kb
TCF7L2
RP11-466I19
RP11-139K1
*
LacZβ
Savic et al. Genome Research 2011
How does regulatory variation contribute to disease risk?
8. Gene XE E E E
Spatial, temporal, and quantitative control of gene expression
Gene X is expressed in
these four tissues driven
by these four enhancers
9. Gene XE E E E
Spatial, temporal, and quantitative control of gene expression
A mutation in one
enhancer can change
expression in one tissue,
in this case,
overexpression
10. Gene XE E E E
Spatial, temporal, and quantitative control of gene expression
However, a mutation can
also cause
underexpression in one
particular tissue
11. TCF7L2
*
Altered TCF7L2
Expression
Type 2 Diabetes
Susceptibility
Global overexpression Global underexpression
Glucose intolerance?
Does altered expression of TCF7L2 lead to T2D susceptibility
and in which direction does a change in expression lead to
glucose intolerance?
13. Beta cells
Hypothalamus
Liver
Adipocytes
Global overexpression
Tcf7l2E E E E
Goal of this study: Isolate the contribution of overexpression in each
tissue to determine in which tissue does overexpression cause
glucose intolerance
Given the modular action of enhancers, it is likely that Tcf7l2 is
overexpressed in a subset of these tissues leading to increased
risk of T2D