What methods are used for rare variant association testing and why are they different from common variant GWAS?

Rare variants (MAF < 1%) require specialized association methods due to statistical challenges: 1) Problem - standard single-variant tests lack power because few individuals carry each variant; multiple testing burden is severe. 2) Aggregation strategies - collapse variants in functional units (genes, pathways, regulatory regions). Methods: burden tests (CAST, CMC) sum variant effects assuming same direction; variance-component tests (SKAT) allow mixed directions using kernel methods; SKAT-O optimally combines both. 3) Weighting - weight variants by MAF (rarer = larger effect) or functional annotation (CADD, PolyPhen, loss-of-function). 4) Whole-genome sequencing requirements - capture all variation, not just tagged. 5) Large sample sizes - UK Biobank, gnomAD enable discovery. 6) Study designs - family-based studies enrich for rare variants; extreme phenotypes. 7) Interpretation challenges - functional validation critical; many rare variants of uncertain significance.