Mutations Causing Complex Disease May under Certain Circumstances Be Protective in an Epidemiological Sense

Area of Science:

• Population Genetics
• Genetic Epidemiology
• Complex Disease Etiology

Background:

• Classical epidemiology assumes disease-causing mutations are over-represented in affected individuals.
• This assumption is fundamental to identifying genetic risk factors for complex diseases.

Purpose of the Study:

• To investigate whether mutations contributing to complex disease etiology can be depleted among patients.
• To evaluate the relationship between mutation frequency, odds ratios (ORs), and disease prevalence.

Main Methods:

• Simulated populations with defined disease prevalence using a Wright-Fisher model.
• Analyzed genotype-phenotype relationships under various population histories.
• Evaluated mutation-specific population frequencies and ORs.
• Examined real-world data from the NIH GWAS Catalogue for single-nucleotide polymorphisms (SNPs).

Main Results:

• Rare diseases (<1% prevalence) consistently showed rare causative mutations with ORs > 1.
• For pandemic diseases (10-20% prevalence), up to 20% of causative mutations had ORs < 1.
• Mutation frequency ranged from 0% to 100% for pandemic disease mutations.
• A significant negative correlation was observed between the OR of genetic variants and disease prevalence in GWAS data.

Conclusions:

• A substantial proportion of mutations causing common complex diseases may appear protective.
• These 'protective' mutations are erroneously excluded from further study in genetic epidemiological research.
• This phenomenon is explained by confounding of genotype-phenotype relationships due to negative correlations between causal mutations.