Editing GWAS: experimental approaches to dissect and exploit disease-associated genetic variation

Rao, Shuquan; Yao, Yao; Bauer, Daniel E.

doi:10.1186/s13073-021-00857-3

Table 1 Summary of studies that employ genome editing technologies to investigate the functions of GWAS loci

From: Editing GWAS: experimental approaches to dissect and exploit disease-associated genetic variation

Trait/disease	Index SNP (or causative SNP)	Coding or non-coding	Target gene	Technology	Strategy	Model	Reference (PMID)
Fetal hemogblobin	rs1427407 and rs7606173	Regulatory	BCL11A	TALEN	Genomic deletion	Mouse erythroleukemia cells and pre-B lymphocyte cells	24115442
Breast cancer	rs2981578	Regulatory	FGFR2	ZFN	Allele substitution	MCF7 cells	24265722
Hypertension	rs5603	Coding	Agtrap, Mthfr, Clcn6, Nppa, Nppb, and Plod1	ZFN	Target gene knockout	Rat	24006081
Colorectal cancer	n.a.	Regulatory	MYC31 (possible)	CRISPR/Cas	Genomic deletion	HCT116 cells	25268989
Hypertension	n.a.	n.a.	Nr2f2	ZFN	Target gene knockout	Rat	25687237
Coronary artery disease	rs9349379	Regulatory	PHACTR1	CRISPR/Cas	Genomic deletion	Human embryonic stem cells (hESCs)	25838425
Obesity	rs1421085		IRX3 and IRX5	CRISPR/Cas	Allele substitution	Human primary adipocytes	26287746
Prostate cancer	rs339331	Regulatory	RFX6	TALEN	Allele substitution	22Rv1 cells	26398868
Parkinson	rs356168 and rs3756054	Regulatory	SNCA	CRISPR/Cas	Allele substitution and genomic deletion	hPSCs	27096366
Prostate cancer	rs2742624	Regulatory	UPK3A	CRISPR/Cas	Genomic deletion	LNCaP cells	27409348
Type 2 diabetes	rs7903146	Regulatory	ACSL5	CRISPR/Cas	Genomic deletion	HCT116 cells	27539148
Colorectal cancer	rs6983267	Regulatory	n.a.	CRISPR/Cas	Genomic deletion	HCT116 cells	26743005
Ankylosing spondylitis	rs9283753		PTGER4	CRISPR/Cas	Allele substitution	Lymphoblastoid cell lines (LCLs)	27259153
Type 2 diabetes	N.A.	n.a.	CDKAL1, KCNQ1, and KCNJ11	CRISPR/Cas	Target gene knockout	hESCs	27524441
Renal cancer	rs35252396		MYC and PVT1	CRISPR/Cas	Random indels	786-O renal cancer cells	27774982
Urinary bladder cancer	rs8102137	Regulatory	CCNE1	CRISPR/Cas	Random indels	5637 cells	27514407
Serum acylcarnitine level	rs113569197	Coding	SLC22A1	CRISPR/Cas	Allele substitution	Huh7 cells	28942964
Thrombosis	rs1039084	Coding	STXBP5	CRISPR/Cas	Allele substitution	Mice	28062498
Schizophrenia	rs1198588	Regulatory	MIR137	CRISPR/Cas	Allele substitution	hiPSCs	28803920
Cardiac QT-interval	19bp indel polymorphism	Regulatory	Rffl-lnc1	CRISPR/Cas	Random indels and allele substitution	Rat	28827789
Vascular diseases	rs9349379	Regulatory	EDN1	CRISPR/Cas	Allele substitution and genomic deletion	iPSCs	28753427
Basophil production	rs78744187	Regulatory	CEBPA	CRISPR/Cas	Genomic deletion	HSPCs	28031487
Hypertension	rs16998073	Regulatory	ANTXR2	CRISPR/Cas	Target gene knockout	Rat	28077422
Blood lipid level	rs2277862, rs10889356, rs10889356 and rs10872142	Regulatory	CPNE1 and ERGIC3	CRISPR/Cas	Genomic deletion, CRISPRi and allele substitution	hiPSCs, HepG2 and HEK293T cellls and Mice	28388432
Bicuspid aortic valve	rs6601627 and p.S377G (GATA4)	Regulatory and coding	GATA4	CRISPR/Cas	Target gene knockout	hiPSCs	28541271
Colorectal cancer	rs6983267	Regulatory	n.a.	CRISPR/Cas	Allele substitution	HCT-116 cells	29118424
Type 2 diabetes	rs780094, rs780095 and rs780096	Regulatory	GCKR	CRISPR/Cas	CRISPRa	HepG2 cells	28683826
Breast cancer prevention	rs9940645	Regulatory	ZNF423	CRISPR/Cas	Allele substitution	ZR75-1 cells and xenograft model	28821270
Red blood cell hydration and malaria susceptibility	rs10751452	Regulatory	ATP2B4	CRISPR/Cas	Genomic deletion	HUDEP-2 and HEK293T cells	28714864
Breast cancer and leukemia	rs11055880 and rs12142375	Regulatory	ATF7IP, PDE4B	CRISPR/Cas	CRISPRi	HEK293T cells	29061142
Prostate cancer	n.a.	Regulatory	HOXA13, HOTTIP	CRISPR/Cas	Genomic deletion	RWPE-1 cells	29117547
Pediatric chronic kidney disease	n.a.	Coding	GREB1L	CRISPR/Cas	Target gene knockout	Zebrafish	29100090
Height	rs9920291	Regulatory	CHSY1	CRISPR/Cas	Genomic deletion	T/C-28a2 cells	29205154
CKD	rs17319721	Regulatory	SHROOM3	CRISPR/Cas	Allele substitution	HEK293T cells	29476007
Osteoporosis	rs6426749	Regulatory	LINC00339	CRISPR/Cas	Genomic deletion and CRISPRi	HEK293T and hFOB1.19 cells	29706346
Prostate cancer	rs11672691	Regulatory	PCAT19 and CEACAM21	CRISPR/Cas	Allele substitution and CRISPRi/a	22Rv1 cells	30033361
Osteoporosis	rs9533090	Regulatory	RANKL	CRISPR/Cas	Genomic deletion	U2-OS cell line	29528523
Eyebrow thickness	rs1345417 and rs12651896	Regulatory	SOX2 and FOXD1	CRISPR/Cas	Allele substitution and genomic deletion	A375 cells	30248107
Idiopathic pulmonary fibrosis	rs2076295	Regulatory	DSP	CRISPR/Cas	CRISPRi/a	A549 cells	29924937
Prostate cancer	rs12144978 and rs4919742	Regulatory	KCNN3 and KRT78	CRISPR/Cas	Genomic deletion	22Rv1 cells	30296942
Bladder cancer	rs710521	Regulatory	ΔNTP63 and p63	CRISPR/Cas	Genomic deletion	5637 cells	29956121
Coronary artery disease and ischemic stroke	rs17114036	Regulatory	PLPP3	CRISPR/Cas	Genomic deletion and CRISPRi	HAECs cells	30429326
Primary biliary bholangitis	rs17032850 and rs227361	Regulatory	NFKB1 and MANBA	CRISPR/Cas	Allele substitution	Jurkat cell lines	30528300
Hirschsprung disease, or congenital aganglionosis	p.G446R (BACE2)	Coding	BACE2	CRISPR/Cas	Target gene knockout and allele substitution	hiPSCs	30217742
Chronic obstructive pulmonary disease	rs2013701	Regulatory	FAM13A	CRISPR/Cas	Allele substitution	16HBE cells	30079747
Multiple autoimmune diseases	rs558245864	Regulatory	BLK	CRISPR/Cas	Random indels	LCL HG00146 cells	30478436
Biliary atresia	n.a.	n.a.	GPC1 or ADD3	CRISPR/Cas	Target gene knockout	iPSCs	30358741
Pulmonary arterial hypertension	rs10958403 and rs765727	Regulatory	SOX17	CRISPR/Cas	CRISPRi	hPAECs cells	30527956
Alzheimer's disease	n.a.	n.a.	FERMT2	CRISPR/Cas	Target gene knockout	fAD and fAD^corr iPSCs	30371777
Colon cancer	rs6854845	Regulatory	CXCLs (CXCL2, 3, 5, 6 and 8), EREG and EPGN	CRISPR/Cas	Allele substitution	HC, HCT-116 and SW-480 cells	31078271
Total cholesterol and low-density lipoprotein cholesterol	rs3780181	Regulatory	VLDLR and SMARCA2	CRISPR/Cas	Genomic deletion	HEK293T cells	30445632
coronary artery disease	rs8042271	Regulatory	MFGE8 and HAPLN3	CRISPR/Cas	Genomic deletion	Cell model (HuH-7, relevant to CAD)	30861420
Bone mineral density	n.a.	Regulatory	LHFP	CRISPR/Cas	Target gene knockout	Mice	31042701
Osteoarthritis	rs4730222	Regulatory	HBP1	CRISPR/Cas	Allele substitution	Saos-2 cells	31164647
Cardiovascular disease	rs2366739 and rs1194196	Regulatory	CD36	CRISPR/Cas	Genomic deletion	K562 and Meg-01 cells	31344026
Chronic obstructive pulmonary disease	rs1690789	Regulatory	TGFB2	CRISPR/Cas	Genomic deletion	Primary human lung fibroblasts	31343404
Coronary artery disease, blood pressure, and hypertension	rs17163363	Regulatory	AIDA	CRISPR/Cas	Genomic deletion	TeloHAEC cells	31287004
Ventricular conduction system function	rs13165478 and rs13185595	Regulatory	HAND1	CRISPR/Cas	Allele substitution and genomic deletion	Mice	31366290
Neuropsychiatric disorder	n.a.	Regulatory	CDK5RAP3, STRAP and DRD2	CRISPR/Cas	Genomic deletion and CRISPRi	i3N iPSCs (Excitatory neurons induced from i3N iPSCs)	31367015
Primary open-angle glaucoma	n.a.	n.a.	CAV1	CRISPR/Cas	Target gene knockout	Trabecular meshwork cells	30916825
Type 2 diabetes	n.a.	n.a.	ABCC5	CRISPR/Cas	Target gene knockout	Mice	31338999
Schizophrenia	Multiple	Regulatory	FURIN, SNAP91, TSNARE1 and CLCN3	CRISPR/Cas	Multiplexing, allele substitution and CRISPRi/a	iPSC	31548722
Atrial fibrillation	rs2595104	Regulatory	PITX2	CRISPR/Cas	Genomic deletion	Mice	31636200
Age-related hearing loss	c.539G > A, p.R180Q (SLC9A3R1)	Coding	slc9a3r1	CRISPR/Cas	Allele substitution	Zebrafish	30863428
Crohn's disease	rs6651252	Regulatory	MYC	CRISPR/Cas	Genomic deletion and CRISPRi	HCT116 and DLD-1 cells	30794691
Autoimmune diseases	rs2476601 and rs1893217	Coding and regulatory	PTPN22, PTPN2	CRISPR/Cas	Target gene knockout	Primary human CD4+ T cells.	31722988
Type 2 diabetes	rs534870	Regulatory	SPRY2	CRISPR/Cas	Target gene knockout	HepG2 cells	31664995
Pubertal timing	n.a.	n.a.	LIN28B	CRISPR/Cas	Target gene knockout	Zebrafish	31792362
Multiple diseases	n.a.	Regulatory	TNFAIP3	CRISPR/Cas	CRISPRi/a	Multiple cell lines	2144282
Colon and rectal adenocarcinoma	rs11064124	Regulatory	CD9 and PLEKHG6	CRISPR/Cas	Genomic deletion	HCT116 and LoVo cells	31988071
Prostate Cancer	rs10993994	Regulatory	MSMB and SNHG11	CRISPR/Cas	Genomic deletion	LNCaP cells	32065238
Polyunsaturated fatty acid metabolism	rs953413	Regulatory	ELOVL2	CRISPR/Cas	Genomic deletion	HepG2 cells	31928966
Major depressive disorder	rs3101339 and rs2050033	Regulatory	NEGR1, MEI1, NHP2L1, CSDC2, and POLR3H	CRISPR/Cas	Genomic deletion	HEK293T cells	32214206
Breast cancer	rs1024176	Regulatory	XCL1	CRISPR/Cas	Genomic deletion, CRISPRi and CRISPRa	BT-474 and MDA-MB-231 cells	31904872
Nonsyndromic cleft lip with or without cleft palate	rs4791774	Regulatory	NTN1	CRISPR/Cas	Target gene knockout	Zebrafish	31780810
Erythroid Regeneration	rs10892563	Regulatory	ARHGEF12	CRISPR/Cas	Target gene knockout	Zebrafish	31467124
Psoriasis	rs10979182	Regulatory	KLF4	CRISPR/Cas	CRISPRa	HaCaT cells	32366252
Major depressive disorder	rs70959274	Regulatory	LINC01360	CRISPR/Cas	Genomic deletion	HEK293T cells	32193514

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