Common Disease Is More Complex Than Implied by the Core Gene Omnigenic Model.

Area of Science:

• Genetics and genomics
• Complex disease biology
• Precision medicine

Background:

• Overwhelming evidence supports a polygenic genetic architecture for most adult-onset common diseases.
• These diseases involve robust biological systems with multiple backup mechanisms.
• The recent "omnigenic" or "core genes" model proposes a small number of core genes per disease.

Purpose of the Study:

• To evaluate the implications of polygenicity in common diseases.
• To critically assess the "omnigenic" or "core genes" model.
• To determine the optimal approach for advancing precision medicine.

Main Methods:

• Review and consideration of existing evidence on polygenic architecture.
• Analysis of the assumptions and limitations of the "omnigenic" model.
• Exploration of the consequences of polygenicity for experimental design and clinical strategy.

Main Results:

• The polygenic nature of common diseases suggests significant biological complexity.
• The "omnigenic" model's assumption of few core genes may underestimate this complexity.
• Focusing on discovering a small set of "core genes" might not be the most effective experimental strategy.

Conclusions:

• The complexity of polygenic diseases necessitates moving beyond simplified models like the "omnigenic" hypothesis.
• Experimental designs should not be solely guided by the search for "core genes".
• Patient stratification is crucial for achieving the objectives of precision medicine in complex diseases.