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.

Fig. 1

The allele frequency spectrum for a genome-wide association study variants (Additional file 1) and b sequenced variants that were associated with a variety of traits (Table 3 and Additional file 1). There is a clear shift to lower allele frequencies for variants discovered in sequencing studies. c The effect size versus allele frequency for sequenced variants; i.e. to detect associations that involve variants with lower allele frequencies, higher effect sizes are needed or large sample sizes. Effect size is usually measured as “beta” for quantitative traits and as “odds ratio” for dichotomous traits