Advancing risk gene discovery across the allele frequency spectrum

Area of Science:

• Human Genetics
• Genomic Medicine

Background:

• Genetic risk factor discovery has revolutionized human genetics.
• Current methods excel at identifying rare, high-penetrance variants and common, low-effect variants.
• A gap exists for variants of intermediate frequency and effect size, hindering gene discovery.

Purpose of the Study:

• To review strategies for identifying genetic risk factors across the allele frequency spectrum.
• To highlight limitations in current approaches, particularly for intermediate variants.
• To propose innovative methods for enhancing gene discovery in the "missing middle".

Main Methods:

• Organizing strategies for risk gene identification by variant frequency class.
• Analyzing methodological strengths and constraints at different frequency scales.
• Drawing on cross-disciplinary innovations in variant annotation, joint modeling, phenotype refinement, and network inference.

Main Results:

• Current methods are optimized for extreme allele frequencies, leaving a gap for intermediate variants.
• The "missing middle" poses challenges in statistical power and pathogenicity classification.
• Innovations offer potential to extend discovery into the intermediate frequency range.

Conclusions:

• A comprehensive understanding of genetic risk requires addressing the "missing middle" of variants.
• Integrating diverse methodological advancements can improve gene discovery across the frequency spectrum.
• Framing the frequency spectrum provides a roadmap for future research in human genetics.