睡眠性状与特发性正常压力脑积水的因果关联：一项两样本双向孟德尔随机化研究

doi:10.12122/j.issn.1673-4254.2024.08.21

摘要/Abstract

摘要：

目的利用双向孟德尔随机化研究方法探索睡眠性状与特发性正常压力脑积水之间的因果关系。方法采用GWAS catalog、芬兰公共数据库和MRCIEU GWAS数据库中8种睡眠性状的全基因组关联分析数据作为暴露，芬兰公共数据库中特发性正常压力脑积水（iNPH）的全基因组关联分析数据作为结局，使用逆方差加权法（IVW）作为主分析方法来评估睡眠性状与特发性正常压力脑积水之间的因果关系。敏感性分析方法采用Cochrane Q检验进行异质性检验和采用MR Egger‑intercept检验来检测潜在的水平多效性。同时，进行反向孟德尔随机化分析特发性正常压力脑积水与睡眠性状的因果关联。结果主分析方法IVW法显示经常白天小睡会增加iNPH的发病风险（OR=3.3393，95 CI%：1.0646-10.4742，P=0.0270）。Cochrane Q检验显示结果无潜在的异质性、MR Egger‑intercept检验显示结果无水平多效性（P>0.05）。外部验证复现了这一结果（OR=2.5660，95 CI%：1.1680-5.6373，P=0.0189）、（OR=4.0424，95 CI%：1.5709-10.4024，P=0.0038）。反向MR分析提示罹患iNPH不会影响睡眠性状。结论白天小睡的频率和特发性正常压力脑积水存在因果关联，对于老年人群，减少每周白天小睡的频率有助于降低iNPH的发生风险。

关键词: 孟德尔随机化研究, 睡眠性状, 特发性正常压力脑积水, 白天小睡

Abstract:

Objective To explore the causal relationship between sleep phenotype and idiopathic normal pressure hydrocephalus (iNPH) using two-sample bidirectional Mendelian randomization. Methods The exposure data including 8 sleep phenotypes used in this study were obtained from GWAS catalog, FinnGenR10 and MRCIEU GWAS. The outcome data for idiopathic normal-pressure hydrocephalus were obtained from FinnGen R10. We used the inverse-variance weighted (IVW) method to perform the principal analyses. Cochrane Q-statistics test was used to assess the heterogeneity and MR Egger‑intercept test performed to evaluate the pleiotropy for sensitivity analyses. Results IVW result showed that frequent daytime nap was associated with higher odds of iNPH (OR=3.3393, 95 CI%: 1.0646-10.4742, P=0.0270). Cochrane Q-statistics test and MR Egger‑intercept test showed that the MR analysis had no pleiotropy or heterogeneity (P>0.05). The external validation reproduced this result (OR=2.5660, 95 CI%: 1.1680-5.6373, P=0.0189; OR=4.0424, 95 CI%: 1.5709-10.4024, P=0.0038). Reverse Mendelian randomization suggested that iNPH did not have significant impact on sleep phenotype. Conclusion The frequency of daytime naps is causally associated with iNPH, and reducing the frequency of weekly daytime naps can reduce the risk of iNPH in the elderly population.

Key words: Mendelian randomization, sleep phenotype, idiopathic normal pressure hydrocephalus, day nap

钟帷韬, 李伟松, 李泽霖, 王强, 张旺明. 睡眠性状与特发性正常压力脑积水的因果关联：一项两样本双向孟德尔随机化研究[J]. 南方医科大学学报, 2024, 44(8): 1612-1619.

Weitao ZHONG, Weisong LI, Zelin LI, Qiang WANG, Wangming ZHANG. Causal relationship between sleep phenotype and idiopathic normal pressure hydrocephalus: a two-sample bidirectional Mendelian randomization study[J]. Journal of Southern Medical University, 2024, 44(8): 1612-1619.

图/表 6

参考文献 33

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Item	Case	Control	Author
Normal pressure hydrocephalus	1456	409726	FinnGen consortium
Sleep duration	446118	-	Dashti HS^[17]
Long sleep duration	34184	305742	Dashti HS^[17]
Short sleep duration	106192	305742	Dashti HS^[17]
Snoring	152302	256015	Campos AI^[18]
Daytime nap	196887	255746	Dashti HS^[19]
Moring person	252287	150908	Jones SE^[20]
OSA	13818	463035	MRCIEU
Insomnia	283595	-	Schoeler T^[21]
Nap during day	337074	-	Neale Lab

Item	Case	Control	Author
Normal pressure hydrocephalus	1456	409726	FinnGen consortium
Sleep duration	446118	-	Dashti HS^[17]
Long sleep duration	34184	305742	Dashti HS^[17]
Short sleep duration	106192	305742	Dashti HS^[17]
Snoring	152302	256015	Campos AI^[18]
Daytime nap	196887	255746	Dashti HS^[19]
Moring person	252287	150908	Jones SE^[20]
OSA	13818	463035	MRCIEU
Insomnia	283595	-	Schoeler T^[21]
Nap during day	337074	-	Neale Lab

SNP	Chromosome	effect_allele	other_allele	beta	se	P	F
Sleep duration
rs10173260	2	T	C	-0.0128	0.0023	2.9×10^-8	30.7950
rs10483350	14	A	G	-0.0174	0.0029	1.5×10^-9	36.6870
rs10761674	10	C	T	0.0123	0.0023	4.2×10^-8	29.6241
……
Long sleep duration
rs10899257	11	G	A	-0.0056	0.0010	4.6×10^-8	29.8890
rs146467757	17	G	T	0.0056	0.0009	8.1×10^-11	42.0042
rs147114641	17	C	A	0.0057	0.0009	4.9×10^-11	42.9989
Short sleep duration
rs1229762	7	C	T	-0.0072	0.0010	1.0×10^-12	50.7143
rs12518468	5	T	C	-0.0059	0.0010	8.5×10^-9	33.2250
rs12567114	1	G	A	0.0063	0.0011	4.1×10^-9	34.4974
……
Snoring
rs10878269	12	C	T	-0.0089	0.0011	2.3×10^-16	66.4774
rs1108431	16	C	T	-0.0066	0.0011	1.2×10^-9	37.3157
rs12119849	1	G	A	-0.0123	0.0019	4.1×10^-11	43.3981
……
Daytime nap
rs10149986	14	T	G	-0.0109	0.0016	4.4×10^-12	48.7843
rs10840017	11	A	G	0.0089	0.0015	2.0×10^-9	36.4500
rs10875606	5	C	A	0.0074	0.0013	1.3×10^-8	31.8238
……
Morning person
rs10067113	5	C	T	-0.0281	0.0047	2.5×10^-9	36.3080
rs10123584	9	G	A	0.0270	0.0050	4.0×10^-8	29.7517
rs10149448	14	A	G	0.0272	0.0046	5.6×10^-9	34.8024
……
OSA
rs11075985	16	A	C	0.1036	0.0130	1.9×10^-15	63.5086
Insomnia
rs10840253	11	A	G	-0.0117	0.0020	4.4×10^-9	34.4422
rs11679120	2	A	G	0.0516	0.0048	1.1×10^-26	114.3790
rs11790060	9	C	T	-0.0114	0.0020	1.5×10^-8	32.0215
……
iNPH
rs10828247	10	G	A	-0.2544	0.0408	4.5×10^-10	38.8929
rs11217863	11	A	G	0.2986	0.0528	1.5×10^-8	32.0368
rs4843226	16	T	C	0.2056	0.0375	4.4×10^-8	29.9681
……
Nap during day
rs10840017	11	G	A	-0.0100	0.0018	1.1×10^-8	32.5966
rs10875622	5	A	G	0.0098	0.0015	1.9×10^-11	45.0836
rs11125776	2	G	T	-0.0146	0.0020	8.9×10^-13	51.0623
……

SNP	Chromosome	effect_allele	other_allele	beta	se	P	F
Sleep duration
rs10173260	2	T	C	-0.0128	0.0023	2.9×10^-8	30.7950
rs10483350	14	A	G	-0.0174	0.0029	1.5×10^-9	36.6870
rs10761674	10	C	T	0.0123	0.0023	4.2×10^-8	29.6241
……
Long sleep duration
rs10899257	11	G	A	-0.0056	0.0010	4.6×10^-8	29.8890
rs146467757	17	G	T	0.0056	0.0009	8.1×10^-11	42.0042
rs147114641	17	C	A	0.0057	0.0009	4.9×10^-11	42.9989
Short sleep duration
rs1229762	7	C	T	-0.0072	0.0010	1.0×10^-12	50.7143
rs12518468	5	T	C	-0.0059	0.0010	8.5×10^-9	33.2250
rs12567114	1	G	A	0.0063	0.0011	4.1×10^-9	34.4974
……
Snoring
rs10878269	12	C	T	-0.0089	0.0011	2.3×10^-16	66.4774
rs1108431	16	C	T	-0.0066	0.0011	1.2×10^-9	37.3157
rs12119849	1	G	A	-0.0123	0.0019	4.1×10^-11	43.3981
……
Daytime nap
rs10149986	14	T	G	-0.0109	0.0016	4.4×10^-12	48.7843
rs10840017	11	A	G	0.0089	0.0015	2.0×10^-9	36.4500
rs10875606	5	C	A	0.0074	0.0013	1.3×10^-8	31.8238
……
Morning person
rs10067113	5	C	T	-0.0281	0.0047	2.5×10^-9	36.3080
rs10123584	9	G	A	0.0270	0.0050	4.0×10^-8	29.7517
rs10149448	14	A	G	0.0272	0.0046	5.6×10^-9	34.8024
……
OSA
rs11075985	16	A	C	0.1036	0.0130	1.9×10^-15	63.5086
Insomnia
rs10840253	11	A	G	-0.0117	0.0020	4.4×10^-9	34.4422
rs11679120	2	A	G	0.0516	0.0048	1.1×10^-26	114.3790
rs11790060	9	C	T	-0.0114	0.0020	1.5×10^-8	32.0215
……
iNPH
rs10828247	10	G	A	-0.2544	0.0408	4.5×10^-10	38.8929
rs11217863	11	A	G	0.2986	0.0528	1.5×10^-8	32.0368
rs4843226	16	T	C	0.2056	0.0375	4.4×10^-8	29.9681
……
Nap during day
rs10840017	11	G	A	-0.0100	0.0018	1.1×10^-8	32.5966
rs10875622	5	A	G	0.0098	0.0015	1.9×10^-11	45.0836
rs11125776	2	G	T	-0.0146	0.0020	8.9×10^-13	51.0623
……

Exposures SNPs	Methods	OR	95% CI	P	Heterogeneity P	Intercept P
Sleep duration 53	IVW	2.0487	0.8660-4.8465	0.1026	0.0176
	WM	2.0255	0.6881-5.9623	0.2001
	MR Egger	0.6244	0.0257-15.1643	0.7734	0.0164	0.4516
Long sleep duration 6	IVW	17.8189	0.0017-186566	0.5419	0.2413
	WM	0.8095	2.7144×10^-5-241406	0.9679
	MR Egger	0.0003	1.6655×10-¹⁷-4.2×10⁹	0.6238	0.2074	0.4920
Short sleep duration 17	IVW	0.08452	0.0026-2.7223	0.1631	0.2864
	WM	0.2127	0.0028-16.2415	0.4841
	MR Egger	0.1345	1.02×¹⁰-14-1.78×10¹²	0.8982	0.2294	0.9762
Snoring 25	IVW	02725	0.0310-2.3986	0.2414	0.6120
	WM	0.2328	0.0116-4.6691	0.3407
	MR Egger	0.0004	1.1551×¹⁰-8-11.8438	0.1490	0.6526	0.2148
Daytime nap 71	IVW	3.3393	1.0646-10.4742	0.0270	0.1908
	WM	3.6663	0.7525-17.8642	0.1159
	MR Egger	2.1600	0.0289-161.3769	0.7274	0.1700	0.8379
Moring person 94	IVW	0.8212	0.6336-1.0644	0.1367	0.2386
	WM	0.9308	0.6400-1.3536	0.7073
	MR Egger	1.6397	0.7706-3.4890	0.2025	0.2946	0.0708
OSA 1	Wald ratio	0.8832	0.4315-1.8078	0.7341	-	-
Insomnia 14	IVW	0.6407	0.1409-2.9137	0.5646	0.7890
	WM	0.8028	0.1088-5.9238	0.8294
	MR Egger	2.4364	0.0609-97.4229	0.6446	0.7710	0.4514
External validation
Nap during day 48	IVW	2.5660	1.1680-5.6373	0.0189	0.9975
	WM	2.8691	0.6631-12.4139	0.1584
	MR Egger	9.1129	0.1423-583.7281	0.3032	0.9970	0.5390
Nap during day 30	IVW	4.0424	1.5709-10.4024	0.0038	0.9886
	WM	3.4034	0.5439-21.2969	0.1905
	MR Egger	3.0155	0.0277-327.7487	0.6481	0.9834	0.8992