Abstract
Genome-wide association studies have uncovered hundreds of common genetic variants involved in complex diseases. However, for most complex diseases, these common genetic variants only marginally contribute to disease susceptibility. It is now argued that rare variants located in different genes could in fact play a more important role in disease susceptibility than common variants. These rare genetic variants were not captured by genome-wide association studies using single nucleotide polymorphism-chips but with the advent of next-generation sequencing technologies, they have become detectable. It is now possible to study their contribution to common disease by resequencing samples of cases and controls or by using new genotyping exome arrays that cover rare alleles. In this review, we address the question of the contribution of rare variants in common disease by taking the examples of different diseases for which some resequencing studies have already been performed, and by summarizing the results of simulation studies conducted so far to investigate the genetic architecture of complex traits in human. So far, empirical data have not allowed the exclusion of many models except the most extreme ones involving only a small number of rare variants with large effects contributing to complex disease. To unravel the genetic architecture of complex disease, case-control data will not be sufficient, and alternative study designs need to be proposed together with methodological developments.
Highlights
The genetic basis of common human diseases has been the subject of many studies
The paradigm that prevailed in complex disease genetic studies was the so-called ‘common disease-common variants’ (CDCV) paradigm, and it was believed that the genetic susceptibility to common disease was because of the genetic variants that are relatively frequent in general populations and have low penetrances [1]
To identify these common variants, genomewide association studies have been conducted, where single nucleotide polymorphism (SNP)-chips containing probes to genotype hundred thousands of SNPs were used on very large samples of cases and Corresponding author
Summary
The genetic basis of common human diseases has been the subject of many studies. Genetic factors have been identified in most of the common diseases, but how many more genetic factors are to be found is still an open question. It is possible that a polygenic burden of rare coding variants located in different genes is involved, and effects are not detectable at the individual gene level as recently found in schizophrenia exomes [39] Another relevant study is a whole-exome sequencing study of 1000 cases affected by type 2 diabetes and 1000 controls from Denmark, where the authors tested for association using a wide-range of strategies from single-marker tests to gene set analysis with different allele frequency thresholds to include variants in these tests [40]. This is really a pity, as they contain important information useful to gain insights into the importance of rare and common variants in complex diseases, allowing modeling of their respective contribution rather than just detection of effects difficult to link to phenotypes [45]
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