Identifying Genes for Type 2 Diabetes: FUSION

Project Summary / Abstract
Type 2 diabetes (T2D) is a major cause of morbidity and mortality, affecting >450M people worldwide and
>34M in the US alone; >26% of Americans aged ≥65 years have T2D. T2D incidence and prevalence are
increasing rapidly. In the US, direct medical costs of diabetes in 2017 were estimated at $237 billion, ~15% of
all US health-care costs. The goals of the Finland-United States Investigation of NIDDM Genetics (FUSION)
study are to identify genetic variants, genes, and mechanisms that influence T2D risk and variability in T2D-
related quantitative traits (QTs), and to foster clinical translation of these findings. Improved understanding of
the genetic bases of T2D and related QTs has the potential to reduce the impact of the T2D epidemic by
supporting identification of novel therapies, enabling better targeting of therapies, providing more accurate risk
prediction, and advising lifestyle changes in at-risk individuals. In this competing renewal, we will
a. discover and fine map genetic loci that influence T2D risk and QT variability using array- and sequence-
based GWAS in our FUSION, METSIM, and MGI cohorts, and through meta-analysis of Finnish, European,
and diverse multi-ancestry samples;
b. select individuals with and without high-interest T2D- and QT-associated variants for genotype-based
callback and targeted phenotyping to test for association and identify physiological mechanisms;
c. use skeletal muscle data (bulk and single-nucleus) to understand how cell-type composition, chromatin
accessibility, DNA methylation, gene expression, and metabolites vary by sex, T2D, QTs, and genetic
variants, and to identify cell-type molecular QTLs that colocalize with T2D and QT GWAS;
d. use iPSC-derived beta cells to understand how chromatin accessibility and gene expression vary by
developmental stage and glucose stimulation, and identify stage-specific, accessible-chromatin enrichment
for T2D and QT GWAS signals; and
e. accelerate advances in T2D genetics through enhanced data sharing and support for easy exploration and
visualization of our study results by any investigator.
Successful completion of these aims will improve our understanding of T2D etiology, point the way to novel
methods of prevention and treatment, and help address the public health crisis posed by T2D. The
longstanding, productive collaboration of our FUSION study team makes achievement of these aims feasible.
Methods developed and lessons learned here will be useful in the study of other human diseases and traits.

Grant Number: 3R01DK062370-22S1
NIH Institute/Center: NIH
Principal Investigator: MICHAEL BOEHNKE