Mendelian Randomization Study Implies Causal Linkage Between Telomere Length and Juvenile Idiopathic Arthritis in a European Population

Figures & data

Figure 1 Mendelian randomization model of leukocyte TL and risk of JIA and JIA-associated iridocyclitis. The study design is under the assumption that genetic variants are directly associated with TL, but not indirectly with TL and not directly with confounders, that is, the instrumental variables influence JIA and JIA-associated iridocyclitis only directly through TL.

Abbreviations: SNP, single-nucleotide polymorphism; TL, telomere length; JIA, juvenile idiopathic arthritis.

Table 1 Characteristics of SNPs Selected as the IV and Association with Leukocyte TL

No.	SNP	Chr.	Position	Proximal	EA	OA	EAF	Beta	SE	P-Value	R^2	F-Statistic	Remove
1	rs2695242	1	226,594,038	PARP1	C	A	0.830	0.042	0.006	9.6E-11	0.0021	41.9610
proxy of rs3219104 (r2=1)
2	rs10936600	3	169,514,585	TERC	T	A	0.243	−0.086	0.006	7.18E-51	0.0019	225.2677	Palindromic
3	rs4683917	3	101,186,025	SENP7	A	C	0.579	−0.037	0.007	2.45E-08	0.0030	31.1529
proxy of rs55749605 (r2=1)
4	rs13137667	4	71,774,347	MOB1B	C	T	0.959	0.077	0.014	2.43E-08	0.0011	31.1630
5	rs4691895	4	164,048,199	NAF1	C	G	0.783	0.058	0.006	1.58E-21	0.0024	90.9546	Palindromic
6	rs7705526	5	1,285,974	TERT	A	C	0.328	0.082	0.006	5.34E-45	0.0026	198.3350
7	rs2853677	5	1,287,194	TERT	A	G	0.592	−0.064	0.005	3.35E-31	0.0021	135.1105
8	rs2736176	6	31,587,561	PRRC2A	C	G	0.313	0.034	0.005	3.53E-10	0.0026	39.4232	Palindromic
9	rs34991172	6	25,480,328	CARMIL1	G	T	0.068	−0.061	0.010	6.19E-09	0.0011	33.8236
10	rs59294613	7	124,554,267	POT1	A	C	0.293	−0.041	0.005	1.17E-13	0.0021	55.1500
11	rs9419958	10	105,675,946	STN1(OBFC1)	C	T	0.862	−0.064	0.007	5.05E-19	0.0016	79.5213
12	rs228595	11	108,105,593	ATM	A	G	0.417	−0.028	0.005	1.43E-08	0.0024	32.1985
13	rs2302588	14	73,404,752	DCAF4	C	G	0.100	0.048	0.008	1.68E-08	0.0017	31.8763	Palindromic
14	rs3785074	16	69,406,986	TERF2	G	A	0.263	0.035	0.006	4.64E-10	0.0024	38.8811
15	rs62053580	16	74,680,074	RFWD3	G	A	0.169	−0.039	0.007	4.06E-08	0.0017	30.1692
16	rs7194734	16	82,199,980	MPHOSPH6	T	C	0.782	−0.037	0.006	6.94E-10	0.0020	38.0989
17	rs8105767	19	22,215,441	ZNF208	G	A	0.289	0.039	0.005	5.42E-13	0.0025	52.1238
18	rs75691080	20	62,269,750	RTEL1/STMN3	T	C	0.091	−0.067	0.009	5.99E-14	0.0013	56.4560
19	rs73624724	20	62,436,398	RTEL1/ZBTB46	C	T	0.129	0.051	0.007	6.33E-12	0.0019	47.3029
20	rs34978822	20	62,291,599	RTEL1	G	C	0.015	−0.140	0.023	7.26E-10	0.0004	38.0094	Palindromic

Abbreviations: SNP, single-nucleotide polymorphism; IV, instrumental variable; TL, telomere length; EA, effect allele; OA, other allele; EAF, effect allele frequency; SE, standard error.

Table 2 MR Results of the Association Between Leukocyte TL and the Risk of JIA

	N	OR (95% CI)	P-Value	P-Value for Heterogeneity	P-Value for Intercept	P-Value for Distortion	N	OR (95% CI)	P-Value	P-Value for Heterogeneity	P-Value for Intercept	P-Value for Distortion
	Full Set						Proxy SNPs Not Identified in Outcome
IVW	13	1.68 (1.13–2.48)	0.009	0.577	–	–	15	1.59 (1.09–2.30)	0.015	0.664	–
Maximum likelihood	13	1.69 (1.14–2.51)	0.008	0.583	–	–	15	1.60 (1.10–2.32)	0.014	0.669	–	–
MR-PRESSO	13	1.68 (1.16–2.41)	0.017	–	–	0.549	15	1.59 (1.14–2.21)	0.017	–	–	0.648
MR-RAPS	13	1.69 (1.13–2.51)	0.010	–	–	–	15	1.59 (1.09–2.33)	0.016	–	–	–
MR-Egger intercept	13	–	–	–	0.175	–	15	–	–	–	0.314	–

Abbreviations: MR, Mendelian randomization; TL, telomere length; JIA, juvenile idiopathic arthritis; N, number of SNPs used in MR analysis; OR, odds ratio; CI, confidence interval; IVW, inverse variance weighted; PRESSO, pleiotropy residual sum and outlier; RAPS, robust adjusted profile score.

Figure 2 Scatter plot of the effect size and 95% CIs of each SNP on leukocyte TL and JIA risk. The horizontal axis represents genetic associations of each variant on leukocyte TL. The vertical axis indicates the genetic association of each SNP with risk of JIA.

Abbreviations: SNP, single-nucleotide polymorphism; TL, telomere length; JIA, juvenile idiopathic arthritis.

Figure 3 Radial plots to visualize individual outlier SNPs in the MR estimates for the effect of leukocyte TL and risk of JIA. The radial curve displays the ratio estimate for each SNP, as well as the overall IVW estimate (in blue). Black dots show valid SNPs.

Abbreviation: IVW, inverse variance weighted method; SNP, single-nucleotide polymorphism; MR, Mendelian randomization; TL, telomere length; JIA, juvenile idiopathic arthritis..