Methods for scoring the collective effect of SNPs: Minor alleles of common SNPs quantitatively affect traits/diseases and are under both positive and negative selection

TL;DR

This study introduces new methods to analyze how the cumulative effect of minor alleles in SNPs influences traits and diseases, revealing their significant role under both positive and negative selection in humans and animals.

Contribution

The paper develops novel approaches to quantify the collective impact of minor alleles on traits and diseases, addressing the missing heritability issue in complex traits.

Findings

MAC correlates with extreme trait values in model organisms.

Enrichment of MAs linked to various human diseases.

High and low MAC associated with stabilizing selection.

Abstract

Most common SNPs are popularly assumed to be neutral. We here developed novel methods to examine in animal models and humans whether extreme amount of minor alleles (MAs) carried by an individual may represent extreme trait values and common diseases. We analyzed panels of genetic reference populations and identified the MAs in each panel and the MA content (MAC) that each strain carried. We also analyzed 21 published GWAS datasets of human diseases and identified the MAC of each case or control. MAC was nearly linearly linked to quantitative variations in numerous traits in model organisms, including life span, tumor susceptibility, learning and memory, sensitivity to alcohol and anti-psychotic drugs, and two correlated traits poor reproductive fitness and strong immunity. Similarly, in Europeans or European Americans, enrichment of MAs of fast but not slow evolutionary rate was linked to autoimmune and numerous other diseases, including type 2 diabetes, Parkinson's disease, psychiatric disorders, alcohol and cocaine addictions, cancer, and less life span. Therefore, both high and low MAC correlated with extreme values in many traits, indicating stabilizing selection on most MAs. The methods here are broadly applicable and may help solve the missing heritability problem in complex traits and diseases.