Innovate therapeutic targets for autoimmune diseases: insights from proteome-wide mendelian randomization and Bayesian colocalization

Figures & data

Figure 1. The overall flowchart of this study. ADs, autoimmune diseases; pQTL, protein quantitative trait loci; GWAS, genome-wide association studies; MR, Mendelian randomization; PPH4, posterior probability of hypothesis 4.

Figure 2. Forest plot of the primary MR analysis. ADs, autoimmune diseases; AS, ankylosing spondylitis; SLE, systemic lupus erythematosus; UC, ulcerative colitis; CD, Crohn’s disease; RA, rheumatoid arthritis; T1D, type 1 diabetes.

Figure 3. Volcano plots of primary MR analysis. A, B, C, D, E, F, and G show primary MR with Wald ratio method on circulating proteins on the risk of ADs. OR for increased risk of ADs were expressed as per SD increase in circulating protein levels. The black horizontal dashed line represents the filtering threshold for Bonferroni correction. ln = natural logarithm; PVE = proportion of variance explained.

Table 1. Results of primary MR analysis after bonferroni correction.

ADs	Protein	UniProt ID	SNP	OR (95% CI)	p value	F
AS	IL12B	P29460	rs4921484	1.08 (1.05, 1.11)	1.61E − 07	142.08
	IL23R	Q5VWK5	rs11581607	1.26 (1.20, 1.31)	3.32E − 25	73.17
	ERAP1	Q9NZ08	rs17482078	1.07 (1.06, 1.08)	3.18E − 33	1467.41
SLE	PPP3R1	P63098	rs17266357	0.66 (0.57, 0.78)	5.47E − 07	66.9
	ICAM1	P05362	rs5498	0.90 (0.86, 0.95)	4.62E − 05	7769.9
UC	ERAP2	B2R769	rs2927608	1.05 (1.03, 1.08)	1.67E − 05	3923.38
	FCGR3B	O75015	rs10919543	1.17 (1.10, 1.24)	6.91E − 07	300.77
	IL1R2	P27930	rs7561460	1.22 (1.14, 1.30)	7.61E − 10	276.63
	IL12B	P29460	rs4921484	1.44 (1.32, 1.57)	4.56E − 17	142.08
	MAPKAPK2	P49137	rs6669284	1.26 (1.16, 1.37)	4.84E − 08	54.13
	IL23R	Q5VWK5	rs11581607	3.16 (2.76, 3.62)	1.33E − 62	73.17
	TYMP	P19971	rs131798	0.71 (0.62, 0.83)	6.28E − 06	46.24
CD	ERAP2	Q6P179	rs2927608	1.12 (1.09, 1.16)	4.47E − 14	3923.38
	TLR4	O00206	rs4986790	0.86 (0.80, 0.92)	2.78E − 05	313.96
	HP	P00738	rs217184	1.10 (1.06, 1.16)	2.08E − 05	983.74
	PLAU	P00749	rs2227551	0.65 (0.55, 0.76)	3.97E − 08	83.8
	IL12B	P29460	rs4921484	1.68 (1.50, 1.87)	2.89E − 20	142.08
	IL18R1	Q13478	rs1420106	1.15 (1.11, 1.20)	2.37E − 12	1249.64
	IL23R	Q5VWK5	rs11581607	6.61 (5.52, 7.93)	5.88E − 93	73.17
	RSPO3	Q9BXY4	rs2489623	1.34 (1.20, 1.51)	6.52E − 07	121.45
	FLRT3	Q9NZU0	rs11908097	0.80 (0.74, 0.87)	3.42E − 07	255.54
RA	SWAP70	B3KUB9	rs415895	1.37 (1.24, 1.51)	3.26E − 10	107.88
	SIGLEC6	O43699	rs2124910	1.08 (1.04, 1.11)	2.47E − 05	226.77
	FCGR3B	O75015	rs10919543	1.14 (1.07, 1.22)	3.41E − 05	300.77
	ICOSLG	O75144	rs11558819	1.17 (1.11, 1.23)	1.67E − 09	487.38
	ISG15	P05161	rs1891906	1.34 (1.16, 1.53)	3.69E − 05	104.96
	MFAP2	P55001	rs4920605	1.41 (1.25, 1.60)	5.12E − 08	72.78
	FCRL3	Q96P31	rs7528684	1.15 (1.10, 1.20)	1.10E − 10	508.28
T1D	CTSH	P09668	rs34593439	1.25 (1.17, 1.34)	7.36E − 11	1098.94
	B4GALT1	P15291	rs7019909	0.71 (0.60, 0.84)	6.59E − 05	124.08
	IL7R	P16871	rs11957503	1.30 (1.17, 1.44)	4.95E − 07	94.74
	CTRB1	P17538	rs8051363	0.85 (0.79, 0.91)	1.44E − 05	715.01
	SIRPG	Q9P1W8	rs6043409	1.63 (1.37, 1.95)	7.55E − 08	101.38
Narcolepsy	CTSH	P09668	rs34593439	0.76 (0.69, 0.83)	1.58E − 09	1098.94

Table 2. Summary of reverse MR analysis, steiger filting, and Bayesian co-localization analysis.

ADs	Protein	SNP	p of Reverse MR (IVW)	Steiger Filtering	Direction of Steiger	Co-localization PPH4
AS	IL12B	rs4921484	0.024	6.84391E − 15	TRUE	9.81E − 01
	IL23R	rs11581607	0.164	0.01629079	TRUE	4.48E − 02
	ERAP1	rs17482078	0.058	7.6818E − 144	TRUE	1.26E − 16
SLE	PPP3R1	rs17266357	0.678	6.14507E − 11	TRUE	5.84E − 01
	ICAM1	rs5498	0.623	0.00E + 00	TRUE	3.42E − 02
UC	ERAP2	rs2927608	0.022	0.00E + 00	TRUE	2.03E − 01
	FCGR3B	rs10919543	0.009	1.33179E − 52	TRUE	1.09E − 31
	TYMP	rs131798	0.424	5.48206E − 08	TRUE	9.89E − 01
	IL1R2	rs7561460	0.402	2.09678E − 46	TRUE	6.16E − 03
	IL12B	rs4921484	0.270	1.26299E − 20	TRUE	2.54E − 07
	MAPKAPK2	rs6669284	0.066	1.23451E − 10	TRUE	7.41E − 33
	IL23R	rs11581607	0.356	6.31263E − 05	TRUE	3.79E − 02
CD	ERAP2	rs2927608	0.117	0.00E + 00	TRUE	8.04E − 01
	TLR4	rs4986790	0.032	5.2987E − 55	TRUE	1.34E − 02
	HP	rs217184	0.887	2.691E − 168	TRUE	9.45E − 01
	PLAU	rs2227551	0.014	4.11828E − 13	TRUE	1.93E − 01
	IL12B	rs4921484	0.022	9.52676E − 19	TRUE	9.23E − 07
	IL18R1	rs1420106	0.272	1.945E − 200	TRUE	5.19E − 01
	IL23R	rs11581607	0.614	0.01002336	TRUE	3.95E − 03
	RSPO3	rs2489623	0.848	5.15448E − 20	TRUE	7.60E − 01
	FLRT3	rs11908097	0.422	3.77541E − 43	TRUE	9.65E − 01
RA	SWAP70	rs415895	0.399	8.36598E − 18	TRUE	9.89E − 01
	SIGLEC6	rs2124910	0.073	1.06878E − 43	TRUE	7.87E − 01
	FCGR3B	rs10919543	0.365	2.66664E − 55	TRUE	3.27E − 01
	ICOSLG	rs11558819	0.398	2.16064E − 85	TRUE	1.27E − 02
	ISG15	rs1891906	0.593	3.29317E − 19	TRUE	9.41E − 01
	MFAP2	rs4920605	0.098	2.42849E − 12	TRUE	3.73E − 16
	FCRL3	rs7528684	0.322	3.37432E − 88	TRUE	9.94E − 01
T1D	B4GALT1	rs7019909	0.175	9.49853E − 18	TRUE	9.64E − 01
	IL7R	rs11957503	3.68E-05	3.27539E − 16	TRUE	9.80E − 01
	CTRB1	rs8051363	0.699	2.074E − 107	TRUE	4.65E − 04
	SIRPG	rs6043409	0.025	1.61602E − 12	TRUE	9.93E − 01
	CTSH	rs34593439	0.270	2.9979E − 153	TRUE	9.99E − 01
Narcolepsy	CTSH	rs34593439	0.576	2.9979E − 153	TRUE	9.99E − 01

Figure 4. Forest plot of the external validation. ADs, autoimmune diseases; CD, Crohn’s disease; RA, rheumatoid arthritis; T1D, type 1 diabetes. ‘primary_’ means replacing only the data of ADs, while ‘decode_’ means replacing the data of both plasma proteome and ADs.

Data availability statement

Summary statistics of ADs can be downloaded from IEU consortium (https://gwas.mrcieu.ac.uk/) and the GWAS ID was presented in Supplementary Table 1. The pQTL statistics of plasma proteome are publicly available on the Decode database (https://download.decode.is/form/folder/proteomics).

Further inquiries can be directed to the corresponding author.