Unique roles of rare variants in the genetics of complex diseases in humans

• Published in: Journal of human genetics Vol. 66; no. 1; pp. 11 - 23
• Main Authors: Momozawa, Yukihide, Mizukami, Keijiro
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01-01-2021; Springer Singapore
• Subjects: Disease; Drug development; Gene Frequency; Genetic diversity; Genetic markers; Genetic Predisposition to Disease - genetics; Genetic Variation; Genome, Human - genetics; Genome-wide association studies; Genome-Wide Association Study - methods; Genomes; Genotype; Humans; Phenotypes; Polymorphism, Single Nucleotide; Precision medicine; Precision Medicine - methods; Review; Single-nucleotide polymorphism; Whole genome sequencing; Whole Genome Sequencing - methods
• ISSN: 1434-5161; 1435-232X
• DOI: 10.1038/s10038-020-00845-2

Genome-wide association studies have identified >10,000 genetic variants associated with various phenotypes and diseases. Although the majority are common variants, rare variants with >0.1% of minor allele frequency have been investigated by imputation and using disease-specific custom SNP arrays. Rare variants sequencing analysis mainly revealed have played unique roles in the genetics of complex diseases in humans due to their distinctive features, in contrast to common variants. Unique roles are hypothesis-free evidence for gene causality, a precise target of functional analysis for understanding disease mechanisms, a new favorable target for drug development, and a genetic marker with high disease risk for personalized medicine. As whole-genome sequencing continues to identify more rare variants, the roles associated with rare variants will also increase. However, a better estimation of the functional impact of rare variants across whole genome is needed to enhance their contribution to improvements in human health.