Research on Rare Variants for Complex Diseases


Despite the notable success of genome‐wide association studies (GWAS) in revealing numerous new disease‐associated genes and loci, all the identified single nucleotide polymorphisms (SNPs) collectively only account for a small proportion of the heritability of complex diseases. The failure of GWAS‐SNPs to account most heritability of complex diseases has invoked some considerable discussion on the reasons for the missing heritability. One of the factors likely to contribute to the missing heritability is the rare variants, which have not been well examined for disease association in GWAS. However, currently the tools and approaches are readily available to investigate rare variants.

Key Concepts:

  • Despite the notable success of GWAS in revealing numerous new disease‐associated genes and loci, all the GWAS‐SNPs collectively only account for a small proportion of the heritability of complex diseases.

  • Most heritability of complex diseases is still unexplained, even though several diseases are claimed to be well‐studied by GWAS and meta‐analysis of sufficiently large sample sizes.

  • The unexplained heritability is commonly known as ‘missing heritability’ and it has been described as the ‘dark matter’ in the genetics of complex diseases.

  • The failure of GWAS‐SNPs to account most heritability of complex diseases has invoked some considerable discussion on the reasons for the missing heritability and the strategies for finding the remaining disease variants.

  • Meta‐analysis is a promising strategy to detect associations of less common SNPs with larger effect sizes.

  • GWAS have almost reached their limit of discovery for common SNPs using current genotyping arrays, which mainly focus on SNPs with MAF >5%.

  • Expanding the content of genotyping array to cover less common SNPs, indels and CNVs is urgently needed to make new discoveries in future GWAS.

  • The next phase of GWAS will require a much larger sample size than the current standard to ensure that the less common SNPs are observed in sufficient number of cases and controls.

  • Sequencing is a more efficient method to detect less common SNPs or single nucleotide variants (<1%) regardless of population.

  • The various strategies for research on rare variants can be executed at the same time.

Keywords: rare variants; complex diseases; next generation genotyping arrays; 1000 genomes project; targeted sequencing; exome sequencing

Figure 1.

Strategies for finding disease‐associated SNPs or variants.



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Ku, Chee Seng, Magnusson, Patrik KE, Chia, Kee Seng, and Pawitan, Yudi(Sep 2010) Research on Rare Variants for Complex Diseases. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0022658]