In searchof low-frequencyand rarevariants affecting complex traits

The allelic architecture of complex traits is likely to be underpinned by a combination of multiple common fre-quency and rare variants. Targeted genotyping arrays and next-generation sequencing technologies at the whole-genomesequencing (WGS)andwhole-exomescales (WES)are increasinglyemployed toaccesssequence variationacross the fullminor allele frequency (MAF) spectrum.Different studydesignstrategies thatmakeuseof diverse technologies, imputationandsampleselectionapproachesareanactive targetofdevelopmentandevalu-ationefforts. Initial insights intothecontributionofrarevariants incommondiseasesandmedically relevantquan-titative traits point to low-frequency and rare alleles acting either independently or in aggregate and in several cases alongside common variants. Studies conducted in population isolates have been successful in detecting rare variant associations with complex phenotypes. Statistical methodologies that enable the joint analysis of rarevariantsacross regionsof thegenomecontinue toevolvewithcurrentefforts focusingon incorporating infor-mation such as functional annotation, and on the meta-analysis of these burden tests. In addition, population stratification, defining genome-wide statistical significance thresholds and the design of appropriate replication experimentsconstitute important considerations for thepowerful analysis and interpretationof rare variant asso-ciation studies. Progress in addressing these emerging challenges and the accrual of sufficiently large data sets are poised to help the field of complex trait genetics enter a promising era of discovery. The genetic architecture of complex traits has not been fully elu-cidated yet. Following the advent of genome-wide association studies (GWASs) and large-scale consortial meta-analyses of GWASs, several thousands of variants have been robustly associated with complex phenotypes of medical relevanc