Region-Based Tests for Association Analysis of Rare Variants

Despite numerous discoveries based on genome wide association studies of common variants, the heritability of most complex traits remains largely unexplained. Rare variants may play a significant role in disease risk and phenotypic variation. Such variants are known to be associated with mendelian disorders and rare forms of common diseases. They are also known to be associated with complex diseases. Dramatic advances in DNA sequencing technologies have enabled a more comprehensive evaluation of the full spectrum of genetic variation and now enable us to evaluate the role of low frequency and rare variation in complex traits. In this review, I provide an overview of the various methods that are available for testing simultaneous association of multiple rare variants with disease or any other phenotypes in the context of sequencing based association studies. The tests focus on rare variation from a particular genomic region such as a gene and its surrounding regions. I discuss the basic underlying ideas behind many currently available approaches for region-based association testing of rare variants as well as their advantages and limitations.