Uncovering the roles of rare variants in common disease through whole-genome sequencing

• Published in: Nature reviews. Genetics Vol. 11; no. 6; pp. 415 - 425
• Main Authors: Goldstein, David B, Cirulli, Elizabeth T
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2010; Nature Publishing Group
• Subjects: 631/208/2489/144; 631/208/514/2254; 631/208/726/649/2219; Agriculture; Animal Genetics and Genomics; Animals; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Chromosome Mapping - methods; Diabetes; Disease; Disease - genetics; Diseases; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Function; Genetic aspects; Genetic Predisposition to Disease - genetics; Genetic Variation - physiology; Genetics of eukaryotes. Biological and molecular evolution; Genome-Wide Association Study - methods; Genomes; Human Genetics; Humans; Models, Biological; Nucleotide sequencing; Pedigree; review-article; Risk factors; Schizophrenia; Sequence Analysis, DNA - methods; Single nucleotide polymorphisms; United States; United States; Variant; Review; Genome; Sequencing
• ISSN: 1471-0056; 1471-0064
• DOI: 10.1038/nrg2779

Key Points Genome-wide association studies of very common variants have neither identified associations that explain a large portion of the heritability for most traits studied nor identified the causal variants behind the associations seen. Although few common variants that cause a disease have been securely identified, rare variants have been found that have strong influences on common diseases: for example, a SNP in type 1 diabetes and copy-number variants in schizophrenia. It seems likely that rare variants, similar in some ways to those identified in Mendelian diseases, will be found that influence common diseases. It is also likely that these rare variants will often influence the coding regions of genes in a manner that is readily recognizable, and will be of large enough effect size to be identified despite their low frequencies. Whole-genome sequencing will provide the best means of identifying rare causal variants. We propose two strategies for studies: resequencing the genomes of individuals with extreme phenotypes and resequencing the genomes of individuals with a familial disease. We predict that whole-genome sequencing will identify rare variants with large effects on many diseases and traits in the coming years. The knowledge that could potentially be gained about these traits, such as the type of mutation and the gene that influences each trait, could provide information for new drug targets. Genome-wide association studies have explained only a small fraction of the genetic basis of complex diseases. This Review argues that rare variants could have a substantial effect on genetic predisposition to common disease, and the authors outline discovery strategies based on whole-genome sequencing for identifying these genetic risk factors. Although genome-wide association (GWA) studies for common variants have thus far succeeded in explaining only a modest fraction of the genetic components of human common diseases, recent advances in next-generation sequencing technologies could rapidly facilitate substantial progress. This outcome is expected if much of the missing genetic control is due to gene variants that are too rare to be picked up by GWA studies and have relatively large effects on risk. Here, we evaluate the evidence for an important role of rare gene variants of major effect in common diseases and outline discovery strategies for their identification.