An utter refutation of the "fundamental theorem of the HapMap"

Area of Science:

• Genetics
• Population Genetics
• Bioinformatics

Background:

• The International HapMap Project aimed to quantify linkage disequilibrium (LD) in human populations.
• LD is crucial for selecting markers in genome-wide association studies (GWAS).
• A central assumption in GWAS is that markers in high LD with functional variants can detect disease associations.

Purpose of the Study:

• To evaluate the assumptions underlying the central dogma of GWAS.
• To investigate the relationship between LD, functional variants, and disease association detection.
• To theoretically and empirically refute the central dogma of GWAS.

Main Methods:

• Analysis of linkage disequilibrium (LD) relationships among human DNA polymorphisms.
• Application of the r(2) metric to measure LD.
• Theoretical modeling and empirical examples to demonstrate the limitations of the central dogma.

Main Results:

• The "fundamental theorem" of GWAS relies on several non-standard assumptions, including statistical independence.
• Markers in high LD with functional variants may fail to show disease association, even with large sample sizes.
• Direct genotyping of functional variants can detect effects missed by associated markers.

Conclusions:

• The central dogma of GWAS, which assumes LD accurately predicts marker-disease association, is theoretically and empirically flawed.
• The statistical independence assumptions in GWAS are often violated in real-world scenarios.
• Directly genotyping functional variants is essential for robust disease association studies.