How physiology solves the gene-centric impasse.

Area of Science:

• Genetics and Systems Physiology
• Genomics and Disease Pathophysiology

Background:

• Genomic association studies have not yielded expected cures for common diseases.
• The Human Genome Project's promise of genetic cures has been largely unfulfilled for complex conditions.

Purpose of the Study:

• To clarify criteria for distinguishing genetic association from causation.
• To propose a framework for achieving causal understanding of gene function and disease.

Main Methods:

• Detailed experimental data collection at relevant organismal levels.
• Quantitative physiological modeling to measure causal processes.
• Comparison of physiological models with genomic association scores.

Main Results:

• Genomic association scores alone are insufficient for establishing causation.
• A framework integrating experimental data and modeling enables accurate causal measurement.
• This approach successfully identified a useful cardiac medication.

Conclusions:

• Causal understanding of gene function and disease necessitates experimental and physiological data, not just association scores.
• This integrated approach is crucial for developing effective treatments for multifactorial diseases like those affecting the nervous system.