Abstract
Current genome-wide association studies (GWAS) have high power to detect intermediate frequency SNPs making modest contributions to complex disease, but they are underpowered to detect rare alleles of large effect (RALE). This has led to speculation that the bulk of variation for most complex diseases is due to RALE. One concern with existing models of RALE is that they do not make explicit assumptions about the evolution of a phenotype and its molecular basis. Rather, much of the existing literature relies on arbitrary mapping of phenotypes onto genotypes obtained either from standard population-genetic simulation tools or from non-genetic models. We introduce a novel simulation of a 100-kilobase gene region, based on the standard definition of a gene, in which mutations are unconditionally deleterious, are continuously arising, have partially recessive and non-complementing effects on phenotype (analogous to what is widely observed for most Mendelian disorders), and are interspersed with neutral markers that can be genotyped. Genes evolving according to this model exhibit a characteristic GWAS signature consisting of an excess of marginally significant markers. Existing tests for an excess burden of rare alleles in cases have low power while a simple new statistic has high power to identify disease genes evolving under our model. The structure of linkage disequilibrium between causative mutations and significantly associated markers under our model differs fundamentally from that seen when rare causative markers are assumed to be neutral. Rather than tagging single haplotypes bearing a large number of rare causative alleles, we find that significant SNPs in a GWAS tend to tag single causative mutations of small effect relative to other mutations in the same gene. Our results emphasize the importance of evaluating the power to detect associations under models that are genetically and evolutionarily motivated.
Highlights
Genome-wide association studies (GWAS) genotype upwards of 500,000 common SNPs and test for allele frequency differences in case/control panels consisting of several thousand individuals
The potential importance of rare alleles of large effect (RALE) is supported empirically by studies that have carried out deep resequencing of candidate gene exons and observed an excess of rare radical amino acid polymorphisms in cases relative to controls for a variety of diseases
Under our gene-based model, the effect size of a causative mutation is exponentially-distributed with mean l (l = 0 implies a mutation that does not contribute to a complex disease phenotype), and the effect of a maternal or paternal haplotype is additive over causative mutations
Summary
Genome-wide association studies (GWAS) genotype upwards of 500,000 common SNPs and test for allele frequency differences in case/control panels consisting of several thousand individuals Such studies have identified highly significant and replicable associations, and as a result have uncovered entirely new pathways contributing to complex disease risk (http://www.genome.gov/ gwastudies/). The potential importance of rare alleles of large effect (RALE) is supported empirically by studies that have carried out deep resequencing of candidate gene exons and observed an excess of rare radical amino acid polymorphisms in cases relative to controls for a variety of diseases These studies suggest the possibility that the same sort of genetic heterogeneity commonly observed for Mendelian disorders [9,10]) may characterize complex disease
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