# Master regulators of unexplained variation in disease risk

> **NIH NIH R01** · VAN ANDEL RESEARCH INSTITUTE · 2021 · $1,913,232

## Abstract

PROJECT SUMMARY
Precision medicine requires an understanding of the origins and molecular control over complex traits and
disease. The field is largely driven by human genetics, which adheres to a 1918 dogma that phenotype is
determined solely by genetics and the environment. Yet, evidence from monozygotic twins and isogenic animal
models indicate that up to 50% of phenotypic variation across diverse physiological traits and diseases cannot
be explained by genetics or environment – there is something `more' that is unique to each individual, and that
cannot be determined by analyzing population-level mean effects. These findings also indicate that even if we
did have `complete' genetic and environmental knowledge, a substantial portion of disease heterogeneity would
remain unaccounted for. The operating hypothesis for this project is that a substantial fraction of unexplained
disease heterogeneity reflects inherently probabilistic properties of the biological system that lead to fixed,
deterministic, real biological variation. There is compelling evidence for an evolved molecular circuitry that
controls phenotypic variability as a quantitative trait. Thus, understanding variability as a quantitative trait is
essential to understanding the etiology of phenotypic diversity (in general) and an individual's disease potential
(in particular). Here, we will begin to finally answer the precision medicine questions of: what is the normal or
expected disease potential for me? And, what are the origins and regulatory controls of non-genetic, non-
environmental phenotypic and disease variability in humans? The first steps towards addressing these questions
and identifying mechanisms through which probabilistic processes lead to disease heterogeneity is to create a
catalogue of putative variance regulators and genes; a phenotypic, epigenetic, and cellular variance atlas
charting the landscape of probabilistic variation in an isogenic model system (mice); and, to demonstrate that
the regulatory architecture of variance control is conserved between mouse and humans. If it is true that a
significant portion of unexplained disease heterogeneity is due to the molecular control of variability itself, then
we will have uncovered an entirely new area of disease etiology that can be harnessed by the community to
develop fundamentally new predictive, diagnostic, and therapeutic interventions, irrespective of the disease of
interest.

## Key facts

- **NIH application ID:** 10273583
- **Project number:** 1R01HG012444-01
- **Recipient organization:** VAN ANDEL RESEARCH INSTITUTE
- **Principal Investigator:** JOSEPH H. NADEAU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,913,232
- **Award type:** 1
- **Project period:** 2021-09-22 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10273583

## Citation

> US National Institutes of Health, RePORTER application 10273583, Master regulators of unexplained variation in disease risk (1R01HG012444-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10273583. Licensed CC0.

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