bio-population-genetics-rare-variant-association

Gene and region-based rare-variant aggregation - burden/collapsing, SKAT, SKAT-O, ACAT-V/ACAT-O, annotation-weighted STAAR - with regenie (--vc-tests), SAIGE-GENE+, and the SKAT R package. Single-variant tests are powerless at low minor allele count, so rare variants are aggregated across a gene or region under an explicit mask (functional class plus a MAF cutoff). A burden test collapses variants into one score assuming a single effect direction (powerful when true, near-zero power when risk and protective variants cancel); SKAT is a variance-component test robust to mixed directions; SKAT-O blends the two; ACAT/STAAR are dependence-robust and annotation-weighted. The mask is the hypothesis, imbalance needs SPA or Firth, and testing burden is per-gene-per-mask. Use when aggregating rare coding or regulatory variants into gene or region tests, choosing burden vs SKAT vs SKAT-O, or building masks. For single-variant GWAS see association-testing; for mask annotations see variant-calling/variant-annotation.