Detecting Clustered Independent Rare Variant Associations Using Genetic Algorithms

The availability of an increasing collection of sequencing data provides the opportunity to study genetic variation with an unprecedented level of detail. There is much interest in uncovering the role of rare variants and their contribution to disease. However, detecting associations of rare variants with small minor allele frequencies (MAF) and modest effects remains a challenge for rare variant association methods. Due to this low signal-to-noise ratio, most methods are underpowered to detect associations even when conducting rare variant association tests at the gene level. We present a new method for detecting rare variant associations. The algorithm consists of two steps. In the first step, a genetic algorithm searches for a promising genomic region containing a collection of genes with causal rare variants. In the second step, a genetic algorithm aims at removing false positives from the located genomic region. We tested the proposed method with a collection of datasets obtained from real exome data. The proposed method possesses sufficient power for detecting associations of rare variants with complex phenotypes. This method can be used for studying the contribution of rare variants with complex disease, particularly in cases where single-variant or gene-based tests are underpowered.

Automated summary

The article presents a new method for detecting rare variant associations through a two-step genetic algorithm, showing sufficient power for detection.