In search of low-frequency and rare variants affecting complex traits

The allelic architecture of complex traits is likely to be underpinned by a combination of multiple common frequency and rare variants. Targeted genotyping arrays and next-generation sequencing technologies at the whole-genome sequencing(WGS) andwhole-exome scales (WES) are increasingly employedtoaccesssequence variation across the fullminor allele frequency (MAF) spectrum. Different study design strategies thatmake use of diverse technologies, imputationandsample selectionapproaches are anactive targetofdevelopment andevaluationefforts. Initial insights into thecontributionof rarevariantsincommondiseasesandmedicallyrelevantquantitative 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 rare variants across regionsof thegenome continue toevolve withcurrent efforts focusingonincorporatinginformation 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 experiments constitute important considerations for the powerful analysis and interpretation of rare variant association 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.