Mutational load analysis of unrelated individuals. Journal Article uri icon



  • 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 < 2.4%-we detected no significantly associated genes after Bonferroni correction for multiple testing. After moderately significant genes (p < 0.05) were removed, the overall effect of rare nonsynonymous allele load remained significant. Overall, we did not find clear support for mutational load burden on affection status; however, these results are ultimately dependent on and limited by the nature of the Genetic Analysis Workshop 17 simulation.

publication date

  • January 1, 2011

has restriction

  • gold

Date in CU Experts

  • September 9, 2013 9:28 AM

Full Author List

  • Howrigan DP; Simonson MA; Kamens HM; Stephens SH; Wills AG; Ehringer MA; Keller MC; McQueen MB

author count

  • 8

citation count

  • 2

Other Profiles

Electronic International Standard Serial Number (EISSN)

  • 1753-6561

Additional Document Info

start page

  • S55


  • 5 Suppl 9