How many genetic variants remain to be discovered?

Area of Science:

• Genetics
• Statistical Genetics
• Computational Biology

Background:

• Most genetic markers from genome-wide association studies (GWAS) have small effect sizes.
• These markers explain a limited portion of the genetic contribution to complex diseases.
• Understanding the number of undiscovered variants and required study sizes is crucial.

Purpose of the Study:

• To derive the relationship between cumulative SNP risk, latent genetic risk models, and disease heritability.
• To determine the sample size needed for case-control studies to achieve a target number of discoveries among significant SNPs.
• To assess the feasibility of discovering numerous variants under different genetic models.

Main Methods:

• Derivation of the connection between cumulative SNP risk and heritability.
• Calculation of required sample sizes for case-control studies based on desired discoveries.
• Modeling of common and rare variant effects with varying penetrance.

Main Results:

• Explaining 40% heritability for complex phenotypes like type-2 diabetes may require approximately 800 variants with similar allele frequencies and effect sizes to validated SNPs.
• Discovering 800 common, low-penetrance variants among the top 5000 SNPs may necessitate studies with up to 50,000 cases and 50,000 controls.
• Large studies for common and rare low-penetrance models approach practical feasibility limits.
• Studies of existing sizes can be adequate for rare-variant, medium- to high-penetrance models (ORs 1.6-4.0) if genotyping technology advances.

Conclusions:

• Discovering common, low-penetrance variants for complex diseases necessitates extremely large sample sizes, potentially exceeding practical limits.
• Rare variants with higher penetrance offer a more feasible alternative for genetic studies with existing resources.
• Advancements in genotyping technology are key to interrogating more and rarer variants for comprehensive genetic discovery.