Mutational load analysis of unrelated individuals

摘要

Evolutionary genetic models predict that the cumulative effect of rare deleterious mutations across the genome—known as mutational load burden—increases the susceptibility to complex disease. To test the mutational load burden hypothesis, we adopted a two-tiered approach: assessing the impact of whole-exome minor allele load burden and then conducting individual-gene screening. For our primary analysis, we examined various minor allele frequency (MAF) thresholds and weighting schemes to examine the overall effect of minor allele load on affection status. We found a consistent association between minor allele load and affection status, but this effect did not markedly increase within rare and/or functional single-nucleotide polymorphisms ( SNPs ). Our follow-up analysis considered minor allele load in individual genes to see whether only one or a few genes were driving the overall effect. Examining our most significant result—minor allele load of nonsynonymous SNPs with MAF p