Causality of Childhood and Adult Body Mass Index on Sick Sinus Syndrome: A Mendelian Randomization Study

Guanzhen Xu; Zhuang Liu; Ping Hou

PMC · DOI:10.7759/cureus.80913·March 20, 2025

Causality of Childhood and Adult Body Mass Index on Sick Sinus Syndrome: A Mendelian Randomization Study

Guanzhen Xu, Zhuang Liu, Ping Hou

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Open Access

TL;DR

This study finds that higher adult BMI increases the risk of sick sinus syndrome, but childhood BMI does not, suggesting adult obesity is a key modifiable risk factor.

Contribution

The study uses Mendelian randomization to clarify the causal relationship between BMI at different life stages and sick sinus syndrome.

Findings

01

Adult BMI is positively correlated with sick sinus syndrome risk (OR = 1.17-1.18).

02

Childhood BMI shows no causal link to sick sinus syndrome (OR = 1.02-1.06).

03

Results remain valid after correcting for telomere length and confirmed through meta-analysis.

Abstract

Background The relationship between body mass index (BMI) and the risk of sick sinus syndrome (SSS) remains unclear. Clarifying the impact of BMI on SSS at different life stages is essential for advancing precision medicine and implementing effective prevention strategies to reduce the burden of SSS. Methods The causalities of childhood and adult BMI with SSS were investigated by univariate and multivariate Mendelian randomization. Reverse causalities were also explored to improve the accuracy of causality findings. Different sources of exposure data were used for replication analysis, and the effects of sample overlap were investigated using MRlap. The stability of the results was further enhanced through meta-analysis. Results There was a positive correlation of adult BMI with the risk of SSS in both the FinnGen (odds ratio (OR) = 1.17, 95% confidence interval (CI) 1.01-1.35, P =…

Linked entities

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Diseases3

sick sinus syndrome obesity SSS

Figures5

Click any figure to enlarge with its caption.

Overview of the Mendelian randomization studyThe extraction of instrumental variables (IVs) adheres to three core assumptions: (1) the IVs are strongly associated with the exposure (relevance assumption), (2) the IVs are independent of confounders (independence assumption), and (3) the IVs have no direct effect on the outcome, influencing the outcome only through the exposure (exclusion restriction assumption).BMI, body mass index; EGG, Early Growth Genetics; FinnGen, Finnish Health Research Environment for Genomic Research; GWAS, Genome-Wide Association Study; IVW, inverse-variance weighted; LD, linkage disequilibrium; MR, Mendelian randomization; MRC-IEU, Medical Research Council Integrated Epidemiology Unit; MR-PRESSO, Mendelian Randomization - Pleiotropy Residual Sum and Outlier; MVMR, multivariate Mendelian randomization; SSS, sick sinus syndrome; WM, weighted median

Forest plot of the MR causal estimates for childhood BMI and SSSBMI, body mass index; CI, confidence interval; EGG, Early Growth Genetics; MR, Mendelian randomization; OR, odds ratio; SSS, sick sinus syndrome

Forest plot of the MR causal estimates for adult BMI and SSSBMI, body mass index; CI, confidence interval; FinnGen, Finnish Health Research Environment for Genomic Research; MR, Mendelian randomization; OR, odds ratio; MRC-IEU, Medical Research Council Integrated Epidemiology Unit; SSS, sick sinus syndrome

Scatter plot depicting causal associations between childhood/adult BMI and SSS(A) Between childhood BMI (EGG2020) and SSS. (B) Between SSS and childhood BMI (EGG2020). (C) Between childhood BMI (EGG2015) and SSS. (D) Between SSS and childhood BMI (EGG2015). (E) Between adult BMI (FinnGen) and SSS. (F) Between SSS and adult BMI (FinnGen). (G) Between adult BMI (IEU OPEN GWAS) and SSS. (H) Between SSS and adult BMI (IEU OPEN GWAS). BMI, body mass index; EGG, Early Growth Genetics; FinnGen, Finnish Health Research Environment for Genomic Research; IEU OPEN GWAS, Integrative Epidemiology Unit Open Genome-Wide Association Study; MR, Mendelian randomization; SNP, single nucleotide polymorphism; SSS, sick sinus syndrome

Forest plot of the MVMR causal estimates for adult BMI and SSSBMI, body mass index; CI, confidence interval; FinnGen, Finnish Health Research Environment for Genomic Research; IVW, inverse-variance weighted; MRC-IEU, Medical Research Council Integrated Epidemiology Unit; MVMR,multivariate Mendelian randomization; OR, odds ratio; SSS, sick sinus syndrome

Tables12

Table 1. Sources of GWAS data used in the MR studyBMI, body mass index; CHB-CVS, Copenhagen Hospital Biobank Cardiovascular Study; DBDS, Danish Blood Donor Study; EGG, Early Growth Genetics; FinnGen, Finnish Health Research Environment for Genomic Research; GWAS, genome-wide association studies; HUNT, Norwegian Nord-Trøndelag Health Study; MR, Mendelian randomization; MRC-IEU, Medical Research Council Integrated Epidemiology Unit; NA, not applicable; SSS, sick sinus syndrome; TL, telomere length; UKB, UK Biobank

Phenotypes	Consortium	Ancestry	PMID	Sample size	Web source
Adult BMI	FinnGen	European	NA	321,672	https://r11.finngen.fi/
Adult BMI	MRC-IEU	European	NA	461,460	https://gwas.mrcieu.ac.uk/datasets/ukb-b-19953/
Childhood BMI	EGG	European	33045005	39,620	http://egg-consortium.org/
Childhood BMI	EGG	European	26604143	35,668	http://egg-consortium.org/
SSS	The deCODE Genetics,UKB, the CHB-CVS/DBDS, the HUNT cohort	European	33580673	1,006,656 (6469 cases and 1,000,187 controls)	https://www.decode.com
TL	NA	European	NA	472,174	https://gwas.mrcieu.ac.uk/datasets/ieu-b-4879/

Table 2. The Reverse MR analysis does not support a causal relationship between SSS and BMIBMI, body mass index; CI, confidence interval; EGG, Early Growth Genetics; FinnGen, Finnish Health Research Environment for Genomic Research; IEU OPEN GWAS, Integrative Epidemiology Unit Open Genome-Wide Association Study; IVW, inverse-variance weighted; MR, Mendelian randomization; OR, odds ratio; SSS, sick sinus syndrome; WM, weighted median

Exposure	Outcome	IVW		WM		MR-Egger		Power
Exposure	Outcome	OR (95 % CI)	p	OR (95 % CI)	p	OR (95 % CI)	p	Power
SSS	Childhood BMI (EGG2020)	1.05 (0.97, 1.13)	0.266	1.03 (0.95, 1.11)	0.492	1.04 (0.81, 1.33)	0.762	3.3%
	Childhood BMI (EGG2015)	1.05 (0.96, 1.16)	0.294	1.03 (0.94, 1.14)	0.537	1.19 (0.88, 1.62)	0.340	3.2%
	Adult BMI (FinnGen)	1.01 (0.99, 1.03)	0.397	1.02 (1.00, 1.04)	0.080	1.02 (0.96, 1.07)	0.586	3.2%
	Adult BMI (IEU OPEN GWAS)	0.99 (0.98, 1.01)	0.373	1.00 (0.98, 1.01)	0.827	0.99 (0.96, 1.01)	0.434	3.4%

Table 3. Sensitivity analysis of the Mendelian randomizationBMI, body mass index; EGG, Early Growth Genetics; FinnGen, Finnish Health Research Environment for Genomic Research; IEU OPEN GWAS, Integrative Epidemiology Unit Open Genome-Wide Association Study; MR-PRESSO, Mendelian randomization pleiotropy residual sum and outlier; NA, not applicable; SSS, sick sinus syndrome

Exposure	Outcome	Heterogeneity		Pleiotropy		MR-PRESSO
Exposure	Outcome	Cochran Q	P	Intercept	P	Outlier-corrected	P
Childhood BMI (EGG2020)	SSS	16.58	0.34	-0.03	0.27	NA	0.33
Childhood BMI (EGG2015)		16.45	0.49	0.001	0.90	NA	0.627
Adult BMI (FinnGen)		311.48	0.13	-0.004	0.30	rs914187	0.048
Adult BMI (FinnGen)		311.48	0.13	-0.004	0.30	NA	0.12
Adult BMI (IEU OPEN GWAS)		416.15	0.07	-0.001	0.74	NA	0.06
SSS	Childhood BMI (EGG2020)	8.38	0.14	0.001	0.98	NA	0.16
	Childhood BMI (EGG2015)	8.07	0.09	-0.02	0.46	NA	0.17
	Adult BMI (FinnGen)	10.61	0.10	-0.001	0.78	NA	0.14
	Adult BMI (IEU OPEN GWAS)	5.07	0.54	0.001	0.65	NA	0.52

Table 4. Independent IVs in the causal analysis of childhood BMI (EGG2020) and SSSBMI, body mass index; EGG, early growth genetics; IVs, instrumental variables; NA, not applicable; SNP: single nucleotide polymorphism; SSS, sick sinus syndrome

SNP	effect_allele.exposure	other_allele.exposure	effect_allele.outcome	other_allele.outcome	beta.exposure	beta.outcome	eaf.exposure	eaf.outcome	pval.outcome	se.outcome	samplesize.outcome	chr.exposure	pos.exposure	se.exposure	pval.exposure	samplesize.exposure	R2	F
rs114670539	T	C	T	C	0.0991	0.09019713	0.0487	NA	0.0411	0.0441	1006656	2	207064335	0.0179	3.16E-08	39618	0.000773059	30.64921265
rs11676272	A	G	A	G	-0.075	0.02550244	0.5358	NA	0.184	0.0192	1006656	2	25141538	0.0079	2.37E-21	36714	0.002448904	90.12487706
rs12042908	A	G	A	G	0.0586	-0.007699566	0.4523	NA	0.694	0.0197	1006656	1	74997762	0.0077	2.77E-14	38693	0.001494623	57.9150363
rs12641981	T	C	T	C	0.044	-0.027104018	0.4185	NA	0.162	0.0194	1006656	4	45179883	0.008	4.19E-08	34819	0.000868024	30.24826244
rs13107325	T	C	T	C	0.0953	0.048199514	0.0795	NA	0.383	0.0553	1006656	4	103188709	0.0173	3.51E-08	36677	0.000826686	30.34379616
rs17817449	T	G	T	G	-0.0683	-0.040796394	0.5855	NA	0.0399	0.0199	1006656	16	53813367	0.008	1.69E-17	36963	0.001968061	72.88496237
rs41279738	T	G	T	G	-0.1199	-0.059503994	0.9692	NA	0.266	0.0535	1006656	1	110082551	0.0211	1.30E-08	39618	0.00081438	32.28877219
rs4477562	T	C	T	C	0.0802	-0.007095111	0.1103	NA	0.81	0.0293	1006656	13	54104968	0.0112	8.29E-13	39618	0.001292583	51.27324057
rs543874	A	G	A	G	-0.0793	0.007598798	0.8131	NA	0.752	0.0241	1006656	1	177889480	0.0099	1.62E-15	36963	0.001732828	64.15824652
rs56133711	A	G	A	G	0.0566	-0.006400439	0.2296	NA	0.77	0.022	1006656	11	27723334	0.0089	2.00E-10	38160	0.001058728	40.44176365
rs571312	A	C	A	C	0.059	0.028801234	0.2396	NA	0.198	0.0223	1006656	18	57839769	0.0093	2.00E-10	37068	0.001084595	40.2452559
rs61765651	T	C	T	C	-0.0584	-0.019998647	0.174	NA	0.416	0.0245	1006656	1	72754314	0.0102	9.50E-09	38693	0.000846496	32.77954356
rs62500888	A	G	A	G	0.0472	-0.002097798	0.5408	NA	0.916	0.0197	1006656	8	28061823	0.0076	6.91E-10	39618	0.000972617	38.56868999
rs7138803	A	G	A	G	0.0729	-0.008596847	0.338	NA	0.669	0.0201	1006656	12	50247468	0.008	7.12E-20	37067	0.002235197	83.03317584
rs7199285	T	C	T	C	-0.0647	-0.004299228	0.171	NA	0.874	0.0272	1006656	16	19980931	0.0101	1.34E-10	37743	0.001086069	41.03390039
rs939584	T	C	T	C	0.1066	0.002102208	0.83	NA	0.937	0.0266	1006656	2	621558	0.0102	8.85E-26	38668	0.002816679	109.2173419
Summary	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	0.022319532	845.2060775

Table 5. Independent IVs in the causal analysis of childhood BMI (EGG2015) and SSSBMI, body mass index; EGG, Early Growth Genetics; IVs, instrumental variables; NA, not applicable; SNP: single nucleotide polymorphism; SSS, sick sinus syndrome

SNP	effect_allele.exposure	other_allele.exposure	effect_allele.outcome	other_allele.outcome	beta.exposure	beta.outcome	eaf.exposure	eaf.outcome	pval.outcome	se.outcome	samplesize.outcome	chr.exposure	pos.exposure	se.exposure	pval.exposure	samplesize.exposure	R2	F
rs11676272	A	G	A	G	-0.0769	0.02550244	0.0288	NA	0.184	0.0192	1006656	2	24995042	0.0078	8.55E-23	35455.7	0.002733937	97.19389255
rs12041852	A	G	A	G	-0.0525	0.008203557	NA	NA	0.678	0.0197	1006656	1	74776088	0.0082	1.77E-10	31111	0.001315846	40.9885903
rs12429545	A	G	A	G	0.0745	-0.009696863	NA	NA	0.738	0.0291	1006656	13	53000207	0.0113	3.66E-11	35646	0.001217911	43.46416
rs13107325	T	C	T	C	0.1022	0.048199514	NA	NA	0.383	0.0553	1006656	4	103407732	0.0179	1.19E-08	35238.5	0.000924223	32.5965082
rs13130484	T	C	T	C	0.0506	-0.02899636	NA	NA	0.138	0.0195	1006656	4	44870448	0.0078	8.94E-11	35656.7	0.00117885	42.08113722
rs13253111	A	G	A	G	0.0492	-0.00249688	NA	NA	0.9	0.0197	1006656	8	28117893	0.0084	4.13E-09	30118	0.001137761	34.30384433
rs13387838	A	G	A	G	0.1507	0.120304299	NA	NA	0.091	0.0712	1006656	2	206989692	0.027	2.40E-08	26511.8	0.00117368	31.15058541
rs1421085	T	C	T	C	-0.0734	-0.036302999	NA	NA	0.0673	0.0198	1006656	16	52358455	0.0082	3.20E-19	33427	0.002391263	80.11953677
rs17309930	A	C	A	C	0.0529	-0.007004474	NA	NA	0.769	0.0239	1006656	11	27705069	0.0095	2.47E-08	35532.6	0.000871883	31.00556773
rs2590942	T	G	T	G	0.0598	0.037701867	NA	NA	0.123	0.0244	1006656	1	72657869	0.0102	3.88E-09	35652	0.000963163	34.3698519
rs4854349	T	C	T	C	-0.0974	-0.000300045	NA	NA	0.992	0.0323	1006656	2	637861	0.0104	6.00E-21	34909.9	0.002506183	87.70540403
rs4870949	T	C	T	C	1.8167	0.032796274	NA	NA	0.572	0.0581	1006656	8	126704776	0.2887	3.13E-10	923	0.041136556	39.512162
rs543874	A	G	A	G	-0.0819	0.007598798	NA	NA	0.752	0.0241	1006656	1	176156103	0.0097	2.38E-17	35668	0.001994704	71.2853001
rs6567160	T	C	T	C	-0.0649	-0.028704068	NA	NA	0.198	0.0223	1006656	18	55980115	0.0094	4.06E-12	35664.9	0.001334789	47.66606837
rs7132908	A	G	A	G	0.0768	-0.002302649	NA	NA	0.908	0.02	1006656	12	48549415	0.0086	4.99E-19	29915.4	0.002658732	79.7437219
rs7550711	T	C	T	C	0.12	0.059098752	NA	NA	0.269	0.0535	1006656	1	109884409	0.0212	1.50E-08	33434	0.000957385	32.03795524
rs8046312	A	C	A	C	0.0668	0.006098558	NA	NA	0.82	0.027	1006656	16	19886835	0.0107	4.06E-10	30085.9	0.001293779	38.9723414
rs987237	A	G	A	G	-0.0712	-0.001399021	NA	NA	0.956	0.0252	1006656	6	50911009	0.0098	3.81E-13	35663	0.001477909	52.78171286
Summary	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	0.067268552	916.9783403

Table 6. Independent IVs in the causal analysis of SSS and childhood BMI (EGG2020)BMI, body mass index; EGG, Early Growth Genetics; IVs, instrumental variables; NA, not applicable; SNP, single nucleotide polymorphism; SSS, sick sinus syndrome

SNP	effect_allele.exposure	other_allele.exposure	effect_allele.outcome	other_allele.outcome	beta.exposure	beta.outcome	eaf.exposure	eaf.outcome	chr.outcome	pos.outcome	se.outcome	pval.outcome	samplesize.outcome	pval.exposure	se.exposure	samplesize.exposure	R2	F
rs10149621	G	T	G	T	0.429799933	0.0031	NA	NA	14	23980080	0.0313	0.9215	35922	3.45E-14	0.0567	1006656	5.71E-05	57.46001123
rs116307579	T	C	T	C	0.293698935	0.004	NA	NA	14	24534471	0.0295	0.8919	36235	2.78E-09	0.0494	1006656	3.51E-05	35.34679019
rs11662320	T	C	T	C	0.119000073	-0.0102	NA	NA	18	67177899	0.0087	0.2386	39722	3.68E-08	0.0216	1006656	3.02E-05	30.35191429
rs11711941	T	C	T	C	0.115103894	0.0046	NA	NA	3	38778540	0.0078	0.5558	38160	6.93E-09	0.0199	1006656	3.32E-05	33.4559233
rs2106261	T	C	T	C	0.149703664	0.0297	NA	NA	16	73051620	0.0106	0.005114	35505	9.94E-10	0.0245	1006656	3.71E-05	37.33634715
rs35813871	A	G	A	G	0.122898817	0.0089	NA	NA	2	179650408	0.0096	0.353	37034.9	2.64E-08	0.0221	1006656	3.07E-05	30.92502019
Summary	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	0.000223381	224.8760064

Table 7. Independent IVs in the causal analysis of SSS and childhood BMI (EGG2015)BMI, body mass index;EGG, Early Growth Genetics; IVs, instrumental variables; NA, not applicable; SNP, single nucleotide polymorphism; SSS, sick sinus syndrome

SNP

effect_allele.exposure

other_allele.exposure

effect_allele.outcome

other_allele.outcome

beta.exposure

beta.outcome

eaf.exposure

eaf.outcome

chr.outcome

pos.outcome

se.outcome

pval.outcome

samplesize.outcome

pval.exposure

se.exposure

samplesize.exposure

R2

F

rs1009360

C

T

C

T

-0.093201405

-0.0026

NA

2

65129553

0.0084

0.754

30111

1.69E-06

0.0195

1006656

2.27E-05

22.84414097

rs11662320

T

C

T

C

0.119000073

-6.00E-04

NA

18

65328879

0.0095

0.9526

30106.8

3.68E-08

0.0216

1006656

3.02E-05

30.35191429

rs13023947

T

C

T

C

-0.258705964

-0.009

NA

2

129680524

0.0181

0.617

29990

1.51E-06

0.0538

1006656

2.30E-05

23.1231751

rs1867785

A

G

A

G

0.090900471

-0.0088

NA

2

46387842

0.0083

0.2903

29915

3.75E-06

0.0196

1006656

2.14E-05

21.5089527

rs2106261

T

C

T

C

0.149703664

0.0294

NA

16

71609121

0.0099

0.003091

35634

9.94E-10

0.0245

1006656

3.71E-05

37.33634715

Summary

NA

0.000134267

135.1645302

Table 8. Independent IVs in the causal analysis of adult BMI (FinnGen) and SSSBMI, body mass index; FinnGen, Finnish Health Research Environment for Genomic Research; IVs, instrumental variables; NA, not applicable; SNP, single nucleotide polymorphism; SSS, sick sinus syndrome

SNP	effect_allele.exposure	other_allele.exposure	effect_allele.outcome	other_allele.outcome	beta.exposure	beta.outcome	eaf.exposure	eaf.outcome	pval.outcome	se.outcome	samplesize.outcome	pval.exposure	se.exposure	samplesize.exposure	R2	F
rs1000940	G	A	G	A	0.0155263	0.026797712	0.42681	NA	0.194	0.0207	1006656	4.01E-11	0.0023511	321672	0.000135557	43.61049775
rs10269783	A	G	A	G	0.0147676	-0.007004474	0.458426	NA	0.724	0.0198	1006656	2.02E-10	0.00232208	321672	0.000125718	40.44480862
rs10275348	C	T	C	T	-0.0137198	0.010900374	0.332516	NA	0.59	0.0202	1006656	2.51E-08	0.00246194	321672	9.65E-05	31.05545751
rs10404037	A	G	A	G	-0.0194287	-0.00950503	0.131998	NA	0.722	0.0266	1006656	1.34E-08	0.00341988	321672	0.000100325	32.2747621
rs10456701	T	C	T	C	0.0225431	0.021702782	0.283021	NA	0.289	0.0205	1006656	2.40E-18	0.00258023	321672	0.000237243	76.332192
rs10757687	C	T	C	T	0.0176	-0.034105021	0.498315	NA	0.0803	0.0195	1006656	2.86E-14	0.00231447	321672	0.000179734	57.82551691
rs10769936	C	T	C	T	0.0162783	-0.015095488	0.74628	NA	0.5	0.0224	1006656	9.64E-10	0.00266189	321672	0.000116245	37.39686412
rs10787738	T	C	T	C	0.0166963	0.001598721	0.256679	NA	0.943	0.0227	1006656	3.33E-10	0.00265746	321672	0.000122699	39.47337917
rs10846920	T	C	T	C	0.0189662	-0.013902905	0.76721	NA	0.535	0.0224	1006656	5.47E-12	0.00275163	321672	0.000147674	47.50921779
rs10859055	T	C	T	C	-0.0149815	-0.011000282	0.364881	NA	0.582	0.02	1006656	4.77E-10	0.00240614	321672	0.000120504	38.76734964
rs10929925	A	C	A	C	-0.0195152	0.028295869	0.496719	NA	0.15	0.0197	1006656	3.69E-17	0.0023171	321672	0.000220469	70.93388692
rs10947793	G	A	G	A	-0.0131812	-0.012295278	0.388344	NA	0.543	0.0202	1006656	3.14E-08	0.00238222	321672	9.52E-05	30.61564872
rs10987749	C	A	C	A	-0.0145852	0.023104874	0.569461	NA	0.25	0.0201	1006656	4.38E-10	0.00233743	321672	0.000121027	38.93541874
rs11038839	G	A	G	A	0.0433566	0.07289724	0.0406188	NA	0.212	0.0584	1006656	2.31E-13	0.00591515	321672	0.000166991	53.72497361
rs1106236	C	T	C	T	-0.0133559	-0.046096296	0.401313	NA	0.0241	0.0204	1006656	1.84E-08	0.00237379	321672	9.84E-05	31.65621779
rs11098675	G	A	G	A	-0.0173683	-0.017997077	0.826396	NA	0.463	0.0246	1006656	1.31E-08	0.00305543	321672	0.000100441	32.31225346
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rs71627581	A	G	A	G	-0.0267146	0.003204859	0.171051	NA	0.917	0.0303	1006656	6.85E-18	0.00310011	321672	0.000230797	74.25752044
rs7200737	A	G	A	G	0.0174306	0.00449986	0.250946	NA	0.842	0.0223	1006656	7.45E-11	0.00267695	321672	0.000131787	42.39761767
rs7203844	G	A	G	A	0.0194812	0.042695439	0.149491	NA	0.194	0.0329	1006656	2.28E-09	0.00325966	321672	0.000111026	35.71775083
rs7259484	G	A	G	A	-0.0162593	0.027498429	0.227963	NA	0.238	0.0233	1006656	3.91E-09	0.00276149	321672	0.00010776	34.66682264
rs72634501	C	T	C	T	0.0153936	-0.060195964	0.22128	NA	0.00903	0.0231	1006656	4.39E-08	0.00281189	321672	9.32E-05	29.96960644
rs72654628	G	A	G	A	0.0193243	-0.023698607	0.266368	NA	0.36	0.0259	1006656	1.87E-13	0.00262638	321672	0.00016827	54.13644293
rs72733275	T	G	T	G	0.0286463	-0.010403934	0.076605	NA	0.822	0.0463	1006656	6.60E-11	0.00438716	321672	0.000132525	42.6351136
rs72734458	G	A	G	A	-0.0146259	-0.01899935	0.329342	NA	0.375	0.0214	1006656	3.54E-09	0.00247708	321672	0.000108369	34.86281358
rs72742731	G	A	G	A	0.021036	-0.00080032	0.274349	NA	0.977	0.0265	1006656	5.74E-16	0.00259871	321672	0.000203662	65.52514472
rs72759983	T	C	T	C	-0.036006	0.02940345	0.0376049	NA	0.573	0.0521	1006656	3.36E-09	0.00608922	321672	0.000108684	34.9642103
rs72911214	C	T	C	T	-0.0250905	0.024604804	0.090812	NA	0.537	0.0398	1006656	5.06E-10	0.00403564	321672	0.000120151	38.65370214
rs73082646	A	G	A	G	0.023245	0.08469954	0.0837369	NA	0.0476	0.0428	1006656	2.98E-08	0.00419401	321672	9.55E-05	30.71832122
rs73152535	A	G	A	G	0.0156425	-0.012204169	0.303444	NA	0.565	0.0213	1006656	5.24E-10	0.00251818	321672	0.000119943	38.58656209
rs73581567	T	C	T	C	-0.0222236	0.040700387	0.231091	NA	0.131	0.027	1006656	1.14E-14	0.00287777	321672	0.000185363	59.6367491
rs73614566	C	T	C	T	0.0363777	0.008702027	0.12056	NA	0.757	0.028	1006656	1.71E-24	0.00356142	321672	0.000324243	104.332926
rs738140	G	A	G	A	-0.0176172	-0.017298765	0.323525	NA	0.408	0.021	1006656	1.04E-12	0.00247274	321672	0.000157774	50.75912895
rs7426145	A	G	A	G	-0.0242062	-0.03699599	0.0759484	NA	0.361	0.0405	1006656	4.26E-08	0.00441744	321672	9.33E-05	30.02681135
rs7434143	T	G	T	G	0.0173908	-0.004101577	0.684757	NA	0.842	0.0208	1006656	3.04E-12	0.00249299	321672	0.000151258	48.66260435
rs755555	T	C	T	C	0.022451	-0.017003748	0.307999	NA	0.416	0.0209	1006656	4.36E-19	0.00251481	321672	0.000247708	79.70000016
rs75634909	G	A	G	A	-0.0237629	0.004101577	0.0819434	NA	0.92	0.0406	1006656	2.18E-08	0.00424539	321672	9.74E-05	31.33004332
rs7563544	G	A	G	A	0.0134052	0.02989855	0.452453	NA	0.126	0.0196	1006656	8.54E-09	0.00232833	321672	0.000103038	33.14780898
rs7588732	A	G	A	G	-0.0133673	-0.002197584	0.543352	NA	0.911	0.0193	1006656	1.18E-08	0.00234432	321672	0.000101064	32.51254036
rs75947329	G	A	G	A	0.0486974	0.011701272	0.0210389	NA	0.876	0.075	1006656	3.68E-09	0.00825676	321672	0.000108126	34.78480126
rs7647305	C	T	C	T	0.0298999	0.030995434	0.817959	NA	0.194	0.0238	1006656	3.21E-23	0.00301225	321672	0.000306204	98.52688338
rs76569620	T	C	T	C	0.030548	-0.060100384	0.0462189	NA	0.225	0.0496	1006656	3.41E-08	0.00553509	321672	9.47E-05	30.45884914
rs76895963	G	T	G	T	0.0419681	0.199399888	0.0301208	NA	0.00328	0.0678	1006656	1.96E-09	0.00699298	321672	0.000111957	36.01731578
rs77159266	A	G	A	G	-0.022715	-0.053400777	0.125704	NA	0.0848	0.031	1006656	8.80E-11	0.00350205	321672	0.000130771	42.07054105
rs77479170	A	G	A	G	0.0157218	-0.016699779	0.489905	NA	0.391	0.0195	1006656	1.22E-11	0.00231953	321672	0.0001428	45.94114832
rs77505508	A	G	A	G	-0.06278	0.084396294	0.0210399	NA	0.191	0.0645	1006656	9.58E-15	0.00810614	321672	0.000186432	59.98072657
rs77669931	A	C	A	C	-0.0170119	-0.017095295	0.192026	NA	0.56	0.0293	1006656	9.00E-09	0.00295928	321672	0.000102725	33.04690744
rs7828742	G	A	G	A	0.0172232	0.015103486	0.530666	NA	0.452	0.0201	1006656	1.24E-13	0.00232369	321672	0.000170759	54.93746443
rs7860903	T	G	T	G	-0.0202718	-0.0009995	0.541401	NA	0.959	0.0196	1006656	3.17E-18	0.00232874	321672	0.00023552	75.77743828
rs7874346	C	T	C	T	0.0180998	-0.026898544	0.168513	NA	0.325	0.0273	1006656	5.64E-09	0.00310621	321672	0.000105542	33.95339647
rs78901918	A	G	A	G	0.0232993	0.017397777	0.117016	NA	0.687	0.0433	1006656	1.44E-10	0.00363411	321672	0.000127768	41.1042671
rs79027831	A	G	A	G	-0.0292904	-0.120203463	0.0655947	NA	0.00267	0.04	1006656	4.54E-10	0.00469825	321672	0.000120813	38.86652029
rs79585412	C	T	C	T	-0.032986	0.075404274	0.0827557	NA	0.0704	0.0417	1006656	4.01E-15	0.00419953	321672	0.000191761	61.69574785
rs80146384	G	A	G	A	-0.0175774	0.00809713	0.156992	NA	0.792	0.0309	1006656	3.57E-08	0.0031896	321672	9.44E-05	30.36925416
rs8022640	A	G	A	G	0.0146345	-0.050598799	0.32529	NA	0.0157	0.0209	1006656	3.69E-09	0.00248149	321672	0.000108111	34.77987517
rs80345943	A	C	A	C	0.0435029	0.153501898	0.0406849	NA	0.00557	0.0554	1006656	1.21E-13	0.005866	321672	0.000170948	54.99834239
rs8053333	G	T	G	T	-0.0150259	0.00079968	0.33531	NA	0.964	0.0171	1006656	1.03E-09	0.00246111	321672	0.000115866	37.27487863
rs8057911	T	C	T	C	0.0169455	-0.016902038	0.196804	NA	0.469	0.0233	1006656	6.49E-09	0.00291988	321672	0.000104694	33.68030911
rs8091425	C	T	C	T	-0.0147144	0.006598184	0.256797	NA	0.775	0.0232	1006656	3.03E-08	0.00265628	321672	9.54E-05	30.68560645
rs865637	C	T	C	T	0.0192927	0.008395141	0.610989	NA	0.686	0.0208	1006656	4.69E-16	0.00237613	321672	0.000204901	65.9239053
rs867559	G	A	G	A	0.0206026	-0.004600566	0.332917	NA	0.847	0.024	1006656	6.96E-17	0.00246805	321672	0.000216585	69.68406124
rs887508	G	A	G	A	0.016717	-0.000299955	0.634484	NA	0.992	0.0301	1006656	4.10E-12	0.00241096	321672	0.000149437	48.07662523
rs889970	A	G	A	G	-0.0142125	-0.00039992	0.595319	NA	0.986	0.0195	1006656	1.92E-09	0.00236703	321672	0.000112065	36.05211358
rs9272339	G	A	G	A	-0.0153092	-0.00449986	0.70339	NA	0.814	0.0193	1006656	1.89E-09	0.00254858	321672	0.000112162	36.08325869
rs9324397	T	C	T	C	-0.0327221	-0.011602431	0.953762	NA	0.843	0.0589	1006656	3.33E-09	0.00553236	321672	0.000108743	34.98313851
rs934935	A	G	A	G	0.014648	-0.027799975	0.688596	NA	0.162	0.0199	1006656	6.49E-09	0.002524	321672	0.000104693	33.68024649
rs9512706	C	A	C	A	0.0147377	-0.003304534	0.689528	NA	0.87	0.0205	1006656	3.82E-09	0.00250133	321672	0.000107909	34.71480576
rs9530843	C	A	C	A	-0.0170149	0.051500773	0.327123	NA	0.00837	0.0195	1006656	5.96E-12	0.00247288	321672	0.000147155	47.34237242
rs9549099	C	T	C	T	0.0183667	-0.012902885	0.32538	NA	0.558	0.022	1006656	1.12E-13	0.00247338	321672	0.000171393	55.141411
rs9563548	G	A	G	A	-0.0209766	-0.009797842	0.272336	NA	0.661	0.0224	1006656	7.45E-16	0.00260162	321672	0.000202061	65.00994044
rs9564356	A	G	A	G	-0.0179408	0.013695783	0.214767	NA	0.534	0.0221	1006656	2.09E-10	0.00282334	321672	0.000125513	40.3789059
rs9613199	T	C	T	C	0.0136818	-0.01640381	0.528607	NA	0.403	0.0196	1006656	3.61E-09	0.00231859	321672	0.000108238	34.82056856
rs9641640	C	A	C	A	0.0236058	-0.04160355	0.0785832	NA	0.344	0.044	1006656	4.05E-08	0.00430077	321672	9.36E-05	30.12605822
rs969960	G	A	G	A	-0.016772	0.005897355	0.767559	NA	0.791	0.0224	1006656	1.04E-09	0.00274784	321672	0.000115804	37.254962
rs982692	C	T	C	T	0.0172304	0.014602857	0.267095	NA	0.471	0.0203	1006656	4.92E-11	0.0026213	321672	0.000134303	43.20704488
rs9839020	C	T	C	T	0.0166072	0.017502275	0.539776	NA	0.378	0.0198	1006656	1.04E-12	0.00233101	321672	0.000157769	50.75769108
rs9847260	G	A	G	A	-0.0314128	0.040201002	0.0432806	NA	0.348	0.0428	1006656	3.96E-08	0.00571906	321672	9.38E-05	30.16902622
rs9866123	A	G	A	G	-0.0150171	-0.015895669	0.473977	NA	0.414	0.0195	1006656	1.21E-10	0.00233265	321672	0.000128826	41.44482255
rs989393	C	T	C	T	0.0142938	-0.001300846	0.299019	NA	0.951	0.0212	1006656	1.59E-08	0.00252932	321672	9.93E-05	31.93634019
rs9955276	T	C	T	C	0.024227	-0.010201862	0.17459	NA	0.709	0.0274	1006656	1.67E-15	0.00304218	321672	0.00019712	63.42007695
Summary	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	0.047964022	15432.70352

Table 9. Independent IVs in the causal analysis of adult BMI (IEU OPEN GWAS) and SSSBMI, body mass index; IEU OPEN GWAS, Integrative Epidemiology Unit Open Genome-Wide Association Study; IVs, instrumental variables; NA, not applicable; SNP, single nucleotide polymorphism; SSS, sick sinus syndrome

SNP	effect_allele.exposure	other_allele.exposure	effect_allele.outcome	other_allele.outcome	beta.exposure	beta.outcome	eaf.exposure	eaf.outcome	pval.outcome	se.outcome	samplesize.outcome	se.exposure	pval.exposure	samplesize.exposure	R2	F
rs10063055	T	C	T	C	0.0136775	-0.011000282	0.253365	NA	0.628	0.0228	1006656	0.00226991	1.70E-09	461460	7.87E-05	36.30732798
rs10182416	G	A	G	A	0.0130378	0.001601281	0.512223	NA	0.934	0.0195	1006656	0.00197134	3.70E-11	461460	9.48E-05	43.74049351
rs10184537	T	C	T	C	-0.016303	-0.019998647	0.339341	NA	0.328	0.0204	1006656	0.00208355	5.10E-15	461460	0.000132659	61.22451043
rs10402950	C	T	C	T	0.0135545	0.008900275	0.289347	NA	0.672	0.0211	1006656	0.00218692	5.70E-10	461460	8.32E-05	38.41486655
rs10505836	C	A	C	A	0.0184851	0.012102946	0.860012	NA	0.66	0.0276	1006656	0.00287086	1.20E-10	461460	8.98E-05	41.45889263
rs10510025	T	C	T	C	0.0175643	0.001099395	0.247013	NA	0.96	0.0229	1006656	0.00229886	2.20E-14	461460	0.000126488	58.37605777
rs1064213	A	G	A	G	0.0149301	-0.025902594	0.478377	NA	0.186	0.0196	1006656	0.00197196	3.70E-14	461460	0.000124206	57.32279372
rs10742752	C	T	C	T	0.0117979	0.0010005	0.612239	NA	0.962	0.0201	1006656	0.00202961	6.10E-09	461460	7.32E-05	33.78954558
rs10760277	T	C	T	C	0.0138734	-0.007901132	0.385049	NA	0.69	0.0199	1006656	0.00203825	1.00E-11	461460	0.000100386	46.32858458
rs10771041	T	C	T	C	0.0213233	-0.000300045	0.116102	NA	0.992	0.0321	1006656	0.0030884	5.00E-12	461460	0.000103291	47.66941962
rs10780248	A	G	A	G	-0.0121232	0.02210247	0.559454	NA	0.265	0.0198	1006656	0.00199415	1.20E-09	461460	8.01E-05	36.95872767
rs1078141	T	C	T	C	0.0142239	0.015804449	0.383867	NA	0.428	0.02	1006656	0.00205862	4.90E-12	461460	0.000103444	47.74007786
rs10799778	G	T	G	T	-0.0182237	-0.034700899	0.833718	NA	0.202	0.0272	1006656	0.00264876	6.00E-12	461460	0.000102567	47.33539591
rs10824211	T	C	T	C	0.0207688	0.014297305	0.139491	NA	0.62	0.0288	1006656	0.00286631	4.30E-13	461460	0.000113761	52.50185018
rs10927006	C	T	C	T	-0.0168156	0.02810143	0.143704	NA	0.275	0.0257	1006656	0.00281467	2.30E-09	461460	7.73E-05	35.69175354
rs10960293	T	G	T	G	-0.0140984	0.02989855	0.333719	NA	0.149	0.0207	1006656	0.00210242	2.00E-11	461460	9.74E-05	44.96750748
rs10989067	A	G	A	G	0.0169514	-0.011000282	0.31593	NA	0.603	0.0212	1006656	0.00212349	1.40E-15	461460	0.000138076	63.72484994
rs11001963	T	C	T	C	0.0116794	-0.011404718	0.581338	NA	0.565	0.0198	1006656	0.00201921	7.30E-09	461460	7.25E-05	33.45616875
rs11009685	T	C	T	C	-0.0130834	-0.026600682	0.244096	NA	0.247	0.023	1006656	0.00230766	1.40E-08	461460	6.97E-05	32.14368858
rs11012732	G	A	G	A	0.0216425	0	0.331683	NA	1	0.0046	1006656	0.00210126	7.10E-25	461460	0.000229838	106.0848541
rs11057072	G	A	G	A	0.0128422	0.031101301	0.233706	NA	0.175	0.023	1006656	0.00233829	4.00E-08	461460	6.54E-05	30.1633957
rs11079849	T	C	T	C	-0.020093	-0.028697873	0.328531	NA	0.172	0.021	1006656	0.00211163	1.80E-21	461460	0.000196171	90.54240777
rs11099020	T	C	T	C	-0.0142038	-0.053597637	0.640609	NA	0.00839	0.0203	1006656	0.00206202	5.60E-12	461460	0.000102812	47.44838863
rs11115160	A	G	A	G	-0.0130768	0.020204507	0.237797	NA	0.368	0.0225	1006656	0.00233641	2.20E-08	461460	6.79E-05	31.32585751
rs11122450	G	T	G	T	-0.0116316	0.010201862	0.611739	NA	0.612	0.0201	1006656	0.00202425	9.10E-09	461460	7.15E-05	33.01784614
rs11134679	G	A	G	A	0.0182459	-0.002297359	0.684753	NA	0.916	0.0218	1006656	0.00213286	1.20E-17	461460	0.000158563	73.18195369
rs11150745	G	A	G	A	-0.0211611	0.001898197	0.317711	NA	0.927	0.0209	1006656	0.00212961	2.90E-23	461460	0.000213919	98.73575283
rs111598585	T	C	T	C	-0.0142245	0.012995195	0.208671	NA	0.589	0.024	1006656	0.00243798	5.40E-09	461460	7.38E-05	34.04174858
rs11165643	T	C	T	C	0.0193319	-0.02889839	0.590103	NA	0.146	0.0199	1006656	0.00200337	4.90E-22	461460	0.000201746	93.11611877
rs11218510	A	G	A	G	-0.0144616	0.016001294	0.40047	NA	0.421	0.0199	1006656	0.00202121	8.40E-13	461460	0.000110925	51.19268769
rs113079574	T	C	T	C	-0.0155896	-0.031098587	0.19279	NA	0.225	0.0256	1006656	0.00251598	5.80E-10	461460	8.32E-05	38.39314535
rs113603865	T	C	T	C	0.0186013	-0.075003758	0.21205	NA	0.00144	0.0235	1006656	0.00242689	1.80E-14	461460	0.000127291	58.74684226
rs113624107	A	G	A	G	0.0150461	-0.015205013	0.22586	NA	0.504	0.0228	1006656	0.00236876	2.10E-10	461460	8.74E-05	40.34631585
rs11525873	C	T	C	T	-0.0239781	0.023804413	0.097701	NA	0.486	0.0342	1006656	0.00333603	6.60E-13	461460	0.00011194	51.66158863
rs11607476	C	A	C	A	0.015712	0.009801805	0.486574	NA	0.604	0.0188	1006656	0.00199179	3.10E-15	461460	0.000134829	62.22629784
rs11608710	G	T	G	T	0.0248489	-0.033701572	0.062119	NA	0.409	0.0408	1006656	0.00415281	2.20E-09	461460	7.76E-05	35.80373476
rs11630647	A	G	A	G	-0.012674	0.019400586	0.251739	NA	0.384	0.0223	1006656	0.00228082	2.70E-08	461460	6.69E-05	30.87759725
rs116374395	A	G	A	G	0.0318817	-0.054804715	0.035444	NA	0.229	0.0455	1006656	0.00536236	2.80E-09	461460	7.66E-05	35.34834831
rs11642090	C	T	C	T	0.0114184	0.021399391	0.373536	NA	0.29	0.0202	1006656	0.00205925	2.90E-08	461460	6.66E-05	30.74613105
rs11656076	A	G	A	G	-0.0154285	-0.002102208	0.224774	NA	0.928	0.0235	1006656	0.00237054	7.60E-11	461460	9.18E-05	42.35951233
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rs852042	G	A	G	A	-0.0131207	0.003395759	0.758575	NA	0.885	0.0236	1006656	0.00231309	1.40E-08	461460	6.97E-05	32.17563057
rs862320	T	C	T	C	-0.0231703	0.019596724	0.40965	NA	0.338	0.0204	1006656	0.00201345	1.20E-30	461460	0.000286895	132.4279734
rs879620	T	C	T	C	0.0241136	0.00800193	0.613237	NA	0.693	0.0203	1006656	0.00203595	2.30E-32	461460	0.000303895	140.2774965
rs909892	A	G	A	G	-0.0184105	0.009197572	0.134817	NA	0.757	0.0298	1006656	0.00291255	2.60E-10	461460	8.66E-05	39.95604607
rs923994	G	A	G	A	-0.0145761	-0.024604804	0.783195	NA	0.305	0.024	1006656	0.00240219	1.30E-09	461460	7.98E-05	36.81849961
rs9294260	A	G	A	G	0.014782	0.001798382	0.476559	NA	0.924	0.019	1006656	0.00198818	1.00E-13	461460	0.000119776	55.27810063
rs9349235	T	C	T	C	0.0111809	0.019704583	0.410635	NA	0.32	0.0199	1006656	0.00200924	2.60E-08	461460	6.71E-05	30.96620704
rs935166	A	G	A	G	-0.0161066	0.031101301	0.506805	NA	0.112	0.0196	1006656	0.00197292	3.20E-16	461460	0.000144408	66.6479681
rs9366863	C	T	C	T	-0.0285083	-0.038200963	0.671833	NA	0.069	0.021	1006656	0.00210043	5.80E-42	461460	0.000399042	184.2147212
rs9461887	T	C	T	C	0.0148892	-0.006702411	0.277069	NA	0.77	0.023	1006656	0.00220206	1.40E-11	461460	9.91E-05	45.71750792
rs9463175	T	C	T	C	-0.0115	0.028704068	0.338958	NA	0.16	0.0204	1006656	0.00210115	4.40E-08	461460	6.49E-05	29.95571454
rs9478496	C	T	C	T	0.0181836	-0.026795823	0.164225	NA	0.31	0.0264	1006656	0.00267493	1.10E-11	461460	0.000100128	46.20968556
rs9515446	G	A	G	A	0.0151051	-0.00549507	0.447709	NA	0.78	0.0196	1006656	0.00199052	3.20E-14	461460	0.000124775	57.58537988
rs9522180	T	C	T	C	-0.0141095	0.007296555	0.553392	NA	0.71	0.0196	1006656	0.00199325	1.50E-12	461460	0.000108572	50.10693291
rs9571687	A	C	A	C	-0.0135388	-0.003496104	0.329363	NA	0.871	0.0214	1006656	0.0021094	1.40E-10	461460	8.93E-05	41.19462747
rs9638713	G	A	G	A	-0.0361735	-0.046597285	0.97477	NA	0.465	0.0638	1006656	0.00635399	1.20E-08	461460	7.02E-05	32.41052951
rs9673839	G	A	G	A	0.0130337	0.028801234	0.490967	NA	0.134	0.0192	1006656	0.00198783	5.50E-11	461460	9.32E-05	42.99075552
rs9674487	G	C	G	C	0.158445	-1.56882394	0.001338	0.377	0.0152	0.646	1006656	0.0286171	3.10E-08	461460	6.64E-05	30.65518583
rs9830592	A	C	A	C	0.0154849	0.012700309	0.582421	NA	0.518	0.0197	1006656	0.00200164	1.00E-14	461460	0.000129674	59.84708274
rs9839081	A	G	A	G	-0.011701	0.019704583	0.325232	NA	0.344	0.0208	1006656	0.00214045	4.60E-08	461460	6.48E-05	29.88366792
rs9843653	C	T	C	T	0.0294509	-0.019600848	0.511652	NA	0.304	0.0191	1006656	0.00197538	2.90E-50	461460	0.000481452	222.2767075
rs9876664	T	G	T	G	-0.0180478	-0.017797439	0.375389	NA	0.373	0.02	1006656	0.00204174	9.60E-19	461460	0.000169293	78.13502988
rs9888533	T	C	T	C	0.0120038	-0.001099395	0.538079	NA	0.956	0.0197	1006656	0.0020182	2.70E-09	461460	7.67E-05	35.37587705
rs9926784	C	T	C	T	-0.023818	-0.00020002	0.184576	NA	0.992	0.0267	1006656	0.00254677	8.60E-21	461460	0.000189502	87.46398262
rs9951619	G	T	G	T	0.0144231	0.012902885	0.767369	NA	0.571	0.0227	1006656	0.00235777	9.50E-10	461460	8.11E-05	37.42074866
Summary	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	0.053194807	24555.47146

Table 10. Independent IVs in the causal analysis of SSS and adult BMI (FinnGen)BMI, body mass index; FinnGen, Finnish Health Research Environment for Genomic Research; IVs, instrumental variables; NA, not applicable; SNP, single nucleotide polymorphism; SSS, sick sinus syndrome

SNP	effect_allele.exposure	other_allele.exposure	effect_allele.outcome	other_allele.outcome	beta.exposure	beta.outcome	eaf.exposure	eaf.outcome	pval.outcome	se.outcome	samplesize.outcome	pval.exposure	se.exposure	samplesize.exposure	R2	F
rs10149621	G	T	G	T	0.429799933	0.0141335	NA	0.0172529	0.120772	0.00910934	321672	3.45E-14	0.0567	1006656	5.71E-05	57.4600112
rs116307579	T	C	T	C	0.293698935	0.0100673	NA	0.0263378	0.166239	0.00727204	321672	2.78E-09	0.0494	1006656	3.51E-05	35.34679025
rs11662320	T	C	T	C	0.119000073	-0.00418987	NA	0.246742	0.119551	0.00269158	321672	3.68E-08	0.0216	1006656	3.02E-05	30.35191452
rs11711941	T	C	T	C	0.115103894	0.00337125	NA	0.465516	0.14772	0.0023288	321672	6.93E-09	0.0199	1006656	3.32E-05	33.45592306
rs2106261	T	C	T	C	0.149703664	0.00420746	NA	0.224326	0.129989	0.00277877	321672	9.94E-10	0.0245	1006656	3.71E-05	37.33634734
rs551862772	A	G	A	G	0.787101897	-0.012287	0.863	0.00298336	0.578393	0.0221095	321672	9.92E-27	0.0735	1006656	0.000113909	114.6796548
rs7689774	T	G	T	G	0.188303628	-0.00179769	NA	0.236627	0.508591	0.00271953	321672	2.26E-15	0.0238	1006656	6.22E-05	62.59830851
Summary	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	0.00036875	371.2289497

Table 11. Independent IVs in the causal analysis of SSS and adult BMI (IEU OPEN GWAS)BMI, body mass index; IEU OPEN GWAS, Integrative Epidemiology Unit Open Genome-Wide Association Study; IVs, instrumental variables; NA, not applicable; SNP, single nucleotide polymorphism; SSS, sick sinus syndrome

SNP	effect_allele.exposure	other_allele.exposure	effect_allele.outcome	other_allele.outcome	beta.exposure	beta.outcome	eaf.exposure	eaf.outcome	se.outcome	pval.outcome	samplesize.outcome	pval.exposure	se.exposure	samplesize.exposure	R2	F
rs10149621	G	T	G	T	0.429799933	-0.000834236	NA	0.02829	0.00630369	0.889999986	461460	3.45E-14	0.0567	1006656	5.71E-05	57.46001123
rs116307579	T	C	T	C	0.293698935	5.43E-05	NA	0.029299	0.00588997	0.98999999	461460	2.78E-09	0.0494	1006656	3.51E-05	35.34679019
rs11662320	T	C	T	C	0.119000073	0.00196918	NA	0.264916	0.00225052	0.380000353	461460	3.68E-08	0.0216	1006656	3.02E-05	30.35191429
rs2106261	T	C	T	C	0.149703664	-0.00414536	NA	0.167612	0.00264264	0.119999932	461460	9.94E-10	0.0245	1006656	3.71E-05	37.33634715
rs35813871	A	G	A	G	0.122898817	-0.00182352	NA	0.242476	0.00229329	0.429999549	461460	2.64E-08	0.0221	1006656	3.07E-05	30.92502019
rs551862772	A	G	A	G	0.787101897	-0.0150544	0.863	0.008463	0.0114767	0.190000175	461460	9.92E-27	0.0735	1006656	0.000113909	114.6796548
rs7689774	T	G	T	G	0.188303628	0.00127801	NA	0.196754	0.00248707	0.610000232	461460	2.26E-15	0.0238	1006656	6.22E-05	62.59830882
Summary	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	0.000366236	368.6980466

Table 12. MVMR resultsCI, confidence interval; FinnGen, Finnish Health Research Environment for Genomic Research; IEU OPEN GWAS, Integrative Epidemiology Unit Open Genome-Wide Association Study; IVW, inverse variance weighted; MR, Mendelian randomization; OR, odds ratio

Exposure sources	Methods	nSNP	OR (95%CI)	P-value
FinnGen	MV-IVW	300	1.22 (1.04-1.44)	0.016
	MV- median		1.37 (1.09-1.71)	0.006
	MV- Egger		1.29 (0.95-1.76)	0.099
Cochrane’s Q = 352.4 (P = 0.02); MR-Egger intercept (P = 0.66); F-statistic = 41.3
IEU OPEN GWAS	MV-IVW	368	1.19 (1.04-1.36)	0.011
	MV-median		1.04 (0.80-1.35)	0.795
	MV-Egger		1.40 (1.06-1.85)	0.017
Cochrane’s Q = 391.5(P = 0.17); MR-Egger intercept (P = 0.18); F-statistic = 55.6

Keywords

body mass indexcausalitylife course epidemiologymendelian randomizationsick sinus syndrome

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TopicsSalivary Gland Disorders and Functions · Effects of Environmental Stressors on Livestock · Hearing, Cochlea, Tinnitus, Genetics

Full text

Introduction

Sick sinus syndrome (SSS) collectively refers to diseases caused due to abnormal cardiac impulses and conduction that are clinically manifested as sinus bradycardia, sinus arrest, and other arrhythmias [1]. Owing to the complex etiology and pathogenesis of SSS, there are currently no effective long-term therapeutic strategies targeting the underlying pathways. With advancing age, the increase in comorbidities is associated with a poorer prognosis observed in studies of patients with SSS. Permanent pacemaker implantation is considered the only effective treatment among patients with irreversible etiology [2]. In the United States, new SSS cases are expected to rise from 172,000 patients per year by 2060, which will undoubtedly impose a tremendous burden on the healthcare system [3,4]. Therefore, it is worth exploring the risk factors of SSS to facilitate early disease management and prevent progression.

Studies have highlighted high body mass index (BMI), age, and low heart rate as risk factors for SSS [4]. In particular, age is considered as a major risk factor, as aging is accompanied by a gradual decline in the sinoatrial conduction time and high fibrosis [5,6]. Although the onset of SSS is predominately reported among the elderly population, SSS is regarded as a disease at all ages [7].

BMI is an indirect measure of body fat. Research findings have projected that more than half of the global population will be overweight (BMI ≥ 30 kg/m^2^) or obese (BMI ≥ 25 kg/m^2^) by 2030 [8]. Elevated BMI increases the risk of atrial fibrillation, ischemic stroke, and type 2 diabetes mellitus [9-11] and was found to significantly raise the worldwide disease burden [12]. To date, no randomized controlled trial has been performed to investigate the causality between BMI and SSS. Clarification of the relationship between BMI and SSS is essential for promoting early disease prevention strategies and precision treatment.

When observational studies are scarce, Mendelian randomization (MR) serves as an intuitive method for inferring causality. Considering the fact that genetic variation is already determined at the time of conception, MR equivalently assesses the relationship between exposure and the level of genetic prediction of the outcome. In addition, it avoids any interference from reverse causality and confounders in observational studies and provides researchers with valid etiological insight [13,14].

Materials and methods

Study overview

This study is reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology using Mendelian Randomization (STROBE-MR) statement [15]. This study explored the causalities of childhood and adult BMI on SSS. To enhance the robustness of the causal inference, replication analyses were conducted using different exposure data sources. The Phenoscanner database and multivariate Mendelian randomization (MVMR) were used to examine any interference from confounding factors. In addition, MR results were meta-merged. The study overview is shown in Figure 1. All analyses were performed using the “TwoSampleMR” package (0.6.5), “MendelianRandomization” package (0.10.0), “MVMR” package (0.4), and “meta” (8.0-1) in the R program (4.3.2; R Development Core Team, Vienna, Austria).

Overview of the Mendelian randomization studyThe extraction of instrumental variables (IVs) adheres to three core assumptions: (1) the IVs are strongly associated with the exposure (relevance assumption), (2) the IVs are independent of confounders (independence assumption), and (3) the IVs have no direct effect on the outcome, influencing the outcome only through the exposure (exclusion restriction assumption).BMI, body mass index; EGG, Early Growth Genetics; FinnGen, Finnish Health Research Environment for Genomic Research; GWAS, Genome-Wide Association Study; IVW, inverse-variance weighted; LD, linkage disequilibrium; MR, Mendelian randomization; MRC-IEU, Medical Research Council Integrated Epidemiology Unit; MR-PRESSO, Mendelian Randomization - Pleiotropy Residual Sum and Outlier; MVMR, multivariate Mendelian randomization; SSS, sick sinus syndrome; WM, weighted median

Data source

Childhood BMI data were derived from a meta-analysis of genome-wide association studies (GWAS) of BMI conducted among 39,620 children between two and 10 years of age from 26 studies and updated by the Early Growth Genetics (EGG) consortium [16]. Another meta-analysis of genome-wide association studies of BMI in 35,668 children of 2-10 years from earlier studies was included in the replication analysis [17].

The data on adult BMI were obtained from the FinnGen study where approximately 500,000 participants with a median age of 53 years old were enrolled [18]. The Integrative Epidemiology Unit (IEU) open GWAS database (IEU Open GWAS project (mrcieu.ac.uk)) carrying genetic and health information from approximately 500,000 European individuals aged 40-69 years was employed for replication analysis [19]. While sample overlapping may have occurred between exposure and outcome in the replication analysis, efforts were taken to use non-overlapping samples in line with the STROBE statement recommendation. The direct calculation of the rate of sample overlap is challenging. We thus employed the MRlap method to correct for potential winner’s curse and weak instrument bias. A detailed description of the MRlap method is provided in the subsequent section.

Telomere length (TL) has been incorporated into aging-related proxies, and telomere shortening has been observed during normal aging in humans and mice [20]. TL data were derived from the IEU OPEN GWAS database harboring genetic information of 472,174 European individuals.

SSS summary data were obtained from the largest meta-analysis available where SSS diagnoses were conducted in accordance with the International Classification of Diseases, 9th (ICD-9: 427.8) or 10th (ICD-10: I49.5) editions [6]. Table 1 shows specific information on data sources.

Selection of instrumental variables (IVs)

The IVs were extracted in line with the assumptions of association, independence, and exclusivity in MR [21]. Single nucleotide polymorphisms (SNPs) were critically screened as follows. (a) To identify exposure-associated and independent SNPs, a threshold of P < 5 × 10^−8^ was set with the removal of SNPs that were in linkage disequilibrium (LD) (r² = 0.001, kb = 10,000). (b) Exposure-associated SNPs were extracted from the outcome dataset, and SNPs associated with the outcome phenotype were removed (P < 5 × 10^−8^). (c) Alleles were harmonized for exposure and outcome, and palindromic and incompatible SNPs were removed. (d) Building on previous findings that identified age-related ion channel disorders and idiopathic fibrosis as major risk factors for SSS [22-25], we employed univariate MR (UVMR) analysis to evaluate aging-related phenotypic SNPs through the PhenoScanner database [26]. (e) SNPs with F < 10 were eliminated, as they are in general considered to represent weak instrumental variables [27]. Additionally, statistical power for the estimates derived from the inverse variance weighted (IVW) method was calculated using an online computational tool (https://sb452.shinyapps.io/power/). After the above screening steps, any potential horizontal pleiotropy outliers were determined by MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO) [28]. The screened SNPs were finally used in the MR study.

UVMR analysis

In UVMR, the causality of childhood and adult BMI with SSS and the reverse causality of SSS with BMI were separately examined. The IVW method was employed for the main analysis and provided robust causal inference under the hypothesis that all IVs were valid [14]. A value of P < 0.05 in the IVW method indicated significant causality between exposure and outcome data. In addition, the weighted median method and the MR-Egger method served as supplements, wherein the former allowed for a more precise estimation if half of the IVs were valid [29]. Although the MR-Egger method had lower statistical performance, it alleviated the reliability of the causal inference when the direction of the MR-Egger estimate was consistent with that of the other methods.

During sensitivity analysis, a Cochran’s Q test was employed for heterogeneity analysis. A value of P < 0.05 indicated the presence of heterogeneity. A random-effect IVW method analysis was performed to mitigate any effect of heterogeneity. In addition, horizontal pleiotropy was assessed using the MR-Egger intercept. An intercept value of P < 0.05 indicated potential pleiotropy in the results and weakened the validity of the causal inference conclusion.

MVMR analysis

MVMR, as an extension of UVMR, is more advantageous than UVMR when several relevant exposures have common genetic predictors. Based on previous studies, we included adult BMI, TL, and SSS in the MVMR model to differentiate the effects of confounding factors (TL) and to examine the independent causal relationship between adult BMI and SSS [25]. The shortening and damage of TL are recognized causes of aging and cellular senescence [30-32]. Epidemiological data on TL have demonstrated that shorter TL is associated with age [33]. In healthy newborns, median leukocyte TLs (LTLs) ranged from 8.5 to 13.5 kb. LTL was observed to shorten at an average annual rate of 30-35 bp, reaching about 5-6 kb in people over 60 years old [30]. Similarly, three complementary analysis methods, IVW, weighted median, and MR-Egger, were performed. Cochran's Q test was conducted for heterogeneity analysis, and random-effect IVW results were used for causal inference once heterogeneity was detected in MVMR.

MRlap

The MRlap method addresses the issues of weak IVs bias and winner’s curse arising from sample overlap and is beneficial in situations where the use of overlapping samples is unavoidable. In particular, the method adjusts for causality estimates using linkage disequilibrium score regression and other techniques based on the hypothesis that the exposure adopts a spike-and-slab genomic structure. The effect estimates can be used as sensitivity analysis. Herein, we employed strict thresholds (MR threshold = 5 × 10 −8 , MR pruning distribution = 10,000, MR pruning LD = 0.001). The bias did not affect the results for non-overlapping samples. In the case of sample overlapping, corrected results were used if they were statistically significant compared to the IVW results (P < 0.05) because the bias of the corrected results was small and unrelated to sample overlapping. In the absence of any significant difference(P > 0.05), the IVW-MR estimates were used [34,35].

Meta-analysis

In meta-analysis, MR estimates were combined using a fixed-effects meta-analysis. Heterogeneity across different data sources was assessed by the I² statistic, with I² values of <25%, 25-75%, and >75%, indicating low, moderate, and high heterogeneity, respectively. The meta-analysis of IVW methods in UVMR and MVMR results further increased the robustness and generalizability of causal inference.

Results

UVMR and meta-analysis

In the MR analysis, the causal relationship between childhood BMI and SSS was not supported (Figure 2). This was observed in both the analyses based on the EGG (2020) (odds ratio (OR) = 1.06, 95% confidence interval (CI) 0.89-1.27, P = 0.513) and the replication analyses using the EGG (2015) (OR = 1.02, 95% CI 0.97-1.09, P = 0.423). In reverse MR, no association was detected between SSS susceptibility and childhood BMI. No outliers, heterogeneity, or horizontal pleiotropy were recorded in all the above analyses. The meta-analysis found no evidence supporting a causal relationship between childhood BMI and the risk of SSS (OR = 1.02, 95% CI 0.97-1.08, P = 0.405).

Forest plot of the MR causal estimates for childhood BMI and SSSBMI, body mass index; CI, confidence interval; EGG, Early Growth Genetics; MR, Mendelian randomization; OR, odds ratio; SSS, sick sinus syndrome

Adult BMI showed a positive association with SSS, which demonstrated a consistent causal inference across different sources of the BMI database (Figure 3). During the analysis of FinnGen’s adult BMI data, outliers were screened and eliminated by MR-PRESSO (rs914187). The results showed that adult BMI elevated the risk of SSS (OR = 1.17, 95% CI 1.01-1.35, P = 0.031) without any heterogeneity (P_Cochran’s Q_ = 0.13) and horizontal pleiotropy (P_Intercept_ = 0.30). As per reverse MR results, the identified causality was not affected by reverse causality (OR = 1.01, 95% CI 0.99-1.03, P = 0.397). In the replication analysis, we excluded the SNP (rs2870111) associated with aging. The causality conclusion was consistent in the adult BMI data of IEU OPEN GWAS (OR = 1.18, 95% CI 1.04-1.34, P = 0.009) and showed no heterogeneity (P_Cochran’s Q_ = 0.07) and horizontal pleiotropy (P_Intercept_ = 0.74). Similarly, causality was not affected by reverse causality (OR = 0.99, 95% CI 0.98-1.01, P = 0.373). MRlap analyses supported the causality between adult BMI and SSS. Sample overlapping did not affect MR results, while the difference between observed and corrected effects was statistically insignificant and in agreement with the findings of the IVW results. This observation further confirms that the causal inference was robust (Observed_effect_p = 0.014, Corrected_effect_p = 0.029, P_difference = 0.667). The meta-analysis further corroborated the causal relationship between elevated adult BMI and an increased risk of sick sinus syndrome SSS (OR = 1.18, 95% CI 1.07-1.29, P = 0.0009).

Forest plot of the MR causal estimates for adult BMI and SSSBMI, body mass index; CI, confidence interval; FinnGen, Finnish Health Research Environment for Genomic Research; MR, Mendelian randomization; OR, odds ratio; MRC-IEU, Medical Research Council Integrated Epidemiology Unit; SSS, sick sinus syndrome

The visualized scatterplot is shown in Figure 4, and the detailed results of IVs and MR analysis are described in Tables 2-11.

Scatter plot depicting causal associations between childhood/adult BMI and SSS(A) Between childhood BMI (EGG2020) and SSS. (B) Between SSS and childhood BMI (EGG2020). (C) Between childhood BMI (EGG2015) and SSS. (D) Between SSS and childhood BMI (EGG2015). (E) Between adult BMI (FinnGen) and SSS. (F) Between SSS and adult BMI (FinnGen). (G) Between adult BMI (IEU OPEN GWAS) and SSS. (H) Between SSS and adult BMI (IEU OPEN GWAS). BMI, body mass index; EGG, Early Growth Genetics; FinnGen, Finnish Health Research Environment for Genomic Research; IEU OPEN GWAS, Integrative Epidemiology Unit Open Genome-Wide Association Study; MR, Mendelian randomization; SNP, single nucleotide polymorphism; SSS, sick sinus syndrome

MVMR and meta-analysis

The MVMR analysis findings demonstrated independent effects of adult BMI on SSS after correction of TL. Analysis of the Finngen BMI data in relation to SSS indicated a causal inference supporting the effect of increased adult BMI on SSS risk. Owing to the presence of heterogeneity (P Cochran’s Q = 0.02), we used the random-effects IVW results for causal inference (OR = 1.22, 95% CI 1.04-1.44, P = 0.016). A consistent causal inference was noted in the IEU OPEN GWAS BMI data (OR = 1.19, 95% CI 1.04-1.36, P = 0.011).

The results of the meta-analysis supported the causality between adult BMI and SSS (OR = 1.20, 95% CI 1.08-1.33, P = 0.0005). The results of MVMR and the meta-analysis are shown in Table 12 and Figure 5, respectively.

Forest plot of the MVMR causal estimates for adult BMI and SSSBMI, body mass index; CI, confidence interval; FinnGen, Finnish Health Research Environment for Genomic Research; IVW, inverse-variance weighted; MRC-IEU, Medical Research Council Integrated Epidemiology Unit; MVMR,multivariate Mendelian randomization; OR, odds ratio; SSS, sick sinus syndrome

Discussion

Evidence generated from published epidemiological studies has highlighted the association of BMI with SSS, which contradicts the findings of Thorolfsdottir et al. who used the polygenic score to investigate the relationship between BMI and SSS [4,6]. This uncertainty in association and causality paves an opportunity for an MR study. Our study findings suggest a positive association of adult BMI with SSS, and the results of replication and meta-analysis further confirmed the causal inference that the risk of SSS is increased with adult BMI and that this effect is independent of reverse causality. Given the large median age of the adult BMI population enrolled in the study, the results suggest that the risk of SSS increases with an increase in BMI among the middle-aged and older populations.

The Centers for Disease Control and Prevention predicts that children or adolescents with high BMI percentiles on the BMI growth charts are at an increased risk of becoming overweight or obese as they age [36]. Although higher BMI during childhood was not associated with an increased risk of SSS in our study, the persistence of obesity in this population may lead to a higher risk of developing SSS as they grow older. The statistical power of our study to detect associations between childhood BMI and SSS was limited, which implies a reduced likelihood of identifying true effects. This limitation may be related to smaller sample sizes and effect sizes [37]. Although we incorporated studies from diverse sources to enhance the robustness of causal inferences, future GWAS studies with larger sample sizes are necessary to validate our findings.

BMI is a simple measure of obesity. In economically developed regions, the highest prevalence of obesity is observed among individuals aged 60-69, while the upward trend in BMI among children and adolescents remains at a notably high level [38,39]. In patients with permanent pacemaker implantation, obesity is known to elevate cardiac mortality and reduce the opportunity for patients with SSS to receive optimal pacemaker therapy [40,41]. The total cost of permanent pacemaker implantation has already surged, and the growing obese population and the increase in the incidence of SSS will pose significant pressure on the healthcare economy [42].

The sinoatrial node (SN) is a heterogeneous pacemaker comprising a specialized population of cardiomyocytes. These clusters of cardiomyocytes generate action potentials spontaneously to maintain cardiac contraction [43,44]. A previous Polish study on aging and obesity in SN found that the SN of obese patients was enriched with connective tissue content, had reduced myocyte content, and showed alterations in cellular morphology as compared with the SN of non-obese patients. This observation implies that elevated SN fibrosis, apoptosis, and cellular hypertrophy in obese patients can contribute to the development of SSS. Microstructural manifestations of young obese right atrial (RA) muscle are more noteworthy than those of aging RA fibrosis [45]. In addition, the increased fat content can stimulate the release of inflammatory cytokines, which affect the SN via paracrine effects [45-47]. Studies in aged obese rats have reported SN cell hypertrophy and extracellular matrix remodeling, which are suggestive of the interaction between obesity and age that can cause SN dysfunction [45,48].

As the positive influence of weight loss on cardiovascular diseases such as heart failure and atrial fibrillation has been well documented [49-51], we anticipate that modulation of BMI could be effective for the prevention and treatment of SSS. However, there are no observational clinical studies to support this hypothesis, which may be limited by reasons such as time or costly expenses [52]. The present study offers several advantages as follows: (1) This, to the best of our knowledge, is the first comprehensive study to address the causalities between childhood and adult BMI and SSS through MR analysis. (2) The causal inference derived with SSS using a large, independent, high-quality BMI GWAS study may enhance the accuracy of the results. (3) Different methods were employed to eliminate confounders. The direction of the consistent effect estimates indicates that the causal inference findings are not by chance and that the use of reverse MR reduces the error in the causal inference [53,54]. (4) With respect to sample overlapping, which is unavoidable with the use of publicly available pooled data, the estimates were corrected using MRlap to increase the confidence of the causal inference. (5) The use of meta-analysis helped us synthesize the results of the studies, lower the possible errors in a single study, and increase the credibility of the causal interference.

The present study has some limitations: (1) There may be inconsistency in the degree of the effect of different ages on SSS, and as BMI is a continuous variable, we were unable to determine the effect of BMI on SSS at a specific age using MR. (2) To minimize bias, participants included in the MR analysis were of European descent. The causal relationships should be validated in more diverse populations to enhance the generalizability of the conclusions. (3) We cannot entirely exclude the possibility that the IVs in this study are associated with unmeasured confounders, a limitation inherent to most MR analyses. We evaluated the potential for risk factors to act as confounders in the BMI-SSS causal relationship by assessing whether they met the three key criteria for confounding. We also examined the associations between IVs and potential confounders using the Phenoscanner database. Although we cannot confirm that IVs are entirely independent of unmeasured confounders, this possibility is likely small. Additionally, the results from MVMR analyses strengthen confidence in our conclusions. (4) The potential for horizontal pleiotropy cannot be entirely excluded in this study - a methodological challenge inherent to MR analyses. Completely eliminating pleiotropic effects remains difficult, particularly for risk factors influenced by multiple genetic variants. Notably, the consistency of causal estimates across three MR approaches (IVW, MR-Egger, and weighted median) supports the robustness of our findings. (5) We cannot rule out potential influences of limited statistical power and weak instrument bias on the findings, particularly in the context of BMI reverse causation. Some results exhibited suboptimal statistical power (<80%), which may be attributed to the small sample size or effect values. Therefore, future studies with larger samples are warranted to validate these inferences. However, any bias from weak instruments is in the direction of the null, as we are considering the analyses in the two-sample setting [55].

Our findings provide MR evidence for researchers exploring the causal relationship between BMI and SSS. Specifically, focusing on adult BMI (middle-aged and older individuals), future studies should investigate the biological mechanisms underlying the association between BMI and SSS or develop targeted prevention and management strategies (e.g., weight management programs for middle-aged adults and obesity screening in primary care).

Conclusions

This study demonstrates that a higher BMI is associated with an increased risk of SSS, particularly among middle-aged and older adults. In contrast, no causal relationship was identified between childhood BMI and SSS, suggesting that the influence of BMI on SSS susceptibility may manifest predominantly in later life stages. These findings highlight the necessity of targeted public health strategies to address adult obesity as a modifiable risk factor for SSS. Future research should focus on elucidating the biological pathways connecting adult BMI to SSS and evaluating the efficacy of interventions, such as weight reduction and lifestyle modifications, in attenuating SSS risk among individuals with elevated BMI.

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