TCF7L2 overexpression and Type 2 Diabetes:

Dissecting the function of Tcf7l2 as a regulator of glucose metabolism

Kathleen Bailey, PhD

Department of Human GeneticsThe University of Chicago

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

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

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

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

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

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?

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

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

Gene XE E E E

Spatial, temporal, and quantitative control of gene expression

However, a mutation can also cause underexpression in one particular tissue

TCF7L2 *

Altered TCF7L2Expression

Type 2 DiabetesSusceptibility

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?

Tcf7l2 over- and under-expression mouse

Tcf7l2 exp

Tcf7l2 exp

Minutes

Glu

cose

(m

g/dL

)

***

*

WT n=11Underexpression n=12

Minutes

Glu

cose

(m

g/dL

)Overexpression n=6WT n=8** *

Global overexpression

Glucose intolerance?

Global underexpression

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