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Genome-wide association studies have been successful in identifying common variants that impact complex human traits and diseases. However, despite this success, the joint effects of these variants explain only a small proportion of the genetic variance in these phenotypes, leading to speculation that rare genetic variation might account for much of the 'missing heritability'. Consequently, there has been an exciting period of research and development into the methodology for the analysis of rare genetic variants, typically by considering their joint effects on complex traits within the same functional unit or genomic region. In this review, we describe a general framework for modelling the joint effects of rare genetic variants on complex traits in association studies of unrelated individuals. We summarise a range of widely used association tests that have been developed from this model and provide an overview of the relative performance of these approaches from published simulation studies.

Original publication




Journal article


Brief Funct Genomics

Publication Date





362 - 370


burden test, dispersion test, genome-wide association, rare variant, statistical methodology, whole-genome and whole-exome re-sequencing, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Models, Theoretical, Phenotype