Table 1 ∣.

Limitations of CRISPR-Cas editing systems

Application	Genomic editing technique	Advantages	Disadvantages
Identifying and investigating autoimmune-associated loci and genes	CRISPR–Cas-mediated genome wide screening30-34	All annotated genes can be targeted	Limited to cell lines
		Can discover cell type-specific effects	Requires a functional outcome (for example, proliferation)
	CRISPR–Cas-mediated knockout of individual genes37,38	Function can be assessed	Low throughput
		Amenable to primary immune cells
	CRISPR–Cas-mediated activation (CRISPRa) or interference (CRISPRi) of gene expression61,64	Easily multiplexable	Currently limited to cell lines
Identifying autoimmune regulatory regions	CRISPR–Cas-mediated activation (CRISPRa) or interference (CRISPRi) of regulatory region60,62,63,65	Can test any region of the genome	Effects might be context-dependent and require multiple cell lines for verification
	CRISPR–Cas-mediated deletion or mutagenesis of regulatory regions55
Identifying causal variants	CRISPR–Cas-mediated mutagenesis of causal variants58	Amenable to primary immune cells	Induced deletions, insertions and substitutions are random and do not recapitulate variant changes
			Some variants cannot be directly targeted
	CRISPR–Cas-mediated homology directed repair80,83	Can directly change reference allele to an alternative allele	Bystander mutations
	CRISPR–Cas-mediated base editing85-90		Not all mutations are possible
	CRISPR–Cas-mediated prime editing91		Low efficiency
Linking variants to causal immune cell types	CRISPR–Cas-mediated editing paired with single-cell technologies101-105	Can be used to directly identify cell populations of interest in rheumatic disorders	Expensive and prone to drop-out in gene expression
		Can assess the function of a particular variant in a broad range of cell populations simultaneously