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. 2022 Oct 6;13:1014947. doi: 10.3389/fgene.2022.1014947

TABLE 1.

Comparison between CV and RV association analysis.

Considerations CV association analysis RV association analysis
Assays Typically captured using inexpensive genotyping microarrays Often requires NGS, especially for detecting extremely rare/novel variants
Number of variants tested Often single variant based (e.g., GWAS) Often multiple variants based due to low power of single-variant methods
Population structure Confounding can be adequately controlled using PCA or mixed models Rare variants are likely more recent and reflect finer subpopulations. May need either more PCs or specifically designed methods
Null distributions of test statistics Ordinary asymptotic distributions work well Null distributions are often complex mixtures and more sophisticated methods may be necessary
Use of annotations Statistical test for each variant is often performed without relying on annotations Due to the large number of rare variants in a region, annotations are often used to filter rare variants
Interpretation Due to potential LD, single-variant associations may be tag-SNPs May be unclear which RVs are “driving” a significant RV association result using aggregative testing, especially those considering both directions