The impact of rare and low-frequency genetic variants in common disease

Abstract

Despite thousands of genetic loci identified to date, a large proportion of genetic variation predisposing to complex disease and traits remains unaccounted for. Advances in sequencing technology enable focused explorations on the contribution of low-frequency and rare variants to human traits. Here we review experimental approaches and current knowledge on the contribution of these genetic variants in complex disease and discuss challenges and opportunities for personalised medicine.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-017-1212-4) contains supplementary material, which is available to authorized users.

Human leucocyte antigen but not KIR alleles and haplotypes associated with chronic HCV infection in a Chinese Han population

“…Individuals carrying rare alleles may show survival advantage against severe infection disease, for virus may adapt to the most frequent alleles in certain population (Trachtenberg et al, ). Moreover, genome‐wide association studies indicated that not only common variants were associated with complex traits (MAF > 5%), but some mutations with low frequency (MAF 1%–5%) or even rare genetic variants (typically defined to occur in less than 1% of the population) were also associated with complex diseases (Bomba, Walter, & Soranzo, ). So, we deduced that different HLA alleles may either associate with protection or susceptibility to CHC progression.…”

The genetics of obstructive sleep apnoea

“…Such technologies are promising, and have accelerated the understanding of other diseases . Rare variants may play an important role in chronic disease . Indeed, discovery of rare, protective variants for CVD has already resulted in successful development of cholesterol‐lowering drugs that mimic human mutations .…”

Causative and common PHOX2B variants define a broad phenotypic spectrum

“…Common variants are believed either to have small effect sizes or to be neutral. However, increasing evidence suggest that a modifier role of apparently neutral variants cannot be excluded …”