Causal Relationship Between Sleep Traits and Hypothalamic-Pituitary-Target Gland Axis Function: A Mendelian Randomization Study

Figures & data

Table 1 MR Estimation of Causal Associations Between Sleep Traits and Hypothalamo-Hypophyseal-Target Gland Axis Function

Exposure	Outcome	MR Methods	No. of SNP	β	lo_95% CI	up_95% CI	P-value	Q-pval	Steiger-pval	Correct Causal Direction
Short sleep	PrRP	Maximum likelihood	24	−1.899146	−3.603258	−0.19503447	0.02893869	0.7531616	0.5302767	TRUE
		MR Egger	24	4.6157694	−3.287855	12.5193938	0.26465393
		Simple median	24	−2.3324707	−4.675104	0.01016255	0.05099791
		Weighted median	24	−0.9160386	−3.328752	1.49667496	0.45678201
		Inverse variance weighted	24	−1.9545228	−3.637117	−0.27192873	0.0228005
		Weighted mode	24	0.6725403	−4.544513	5.88959368	0.80276975
Long sleep	PrRP	Maximum likelihood	8	−4.823441	−9.222075	−0.424807	0.03161134	0.6197573	0.02554583	TRUE
		MR Egger	8	−4.898108	−17.99487	8.19865	0.49117599
		Simple median	8	−5.120672	−11.20822	0.966873	0.11705592
		Weighted median	8	−2.736716	−8.506342	3.032911	0.3593918
		Inverse variance weighted	8	−4.726278	−9.038174	−0.414382	0.03168517
		Weighted mode	8	−2.970338	−10.2797	4.339025	0.43194594
Chronotype	CRFBP	Maximum likelihood	146	−0.2475692	−0.466149	−0.02898929	0.02642242	0.2962619	<0.001	TRUE
		MR Egger	146	−0.4353058	−1.120674	0.25006197	0.21519867
		Simple median	146	−0.2583349	−0.576041	0.05937126	0.11832664
		Weighted median	146	−0.2654122	−0.597622	0.06679789	0.11694828
		Inverse variance weighted	146	−0.2450328	−0.4674	−0.02266581	0.03078953
		Weighted mode	146	−0.4959749	−1.359726	0.36777612	0.29151923
Long sleep	SRIF	Maximum likelihood	8	−5.667209	−10.07735	−1.2570732	0.0117795	0.8221315	0.02796002	TRUE
		MR Egger	8	−12.456992	−25.54784	0.6338551	0.11143359
		Simple median	8	−6.073374	−11.79844	−0.348307	0.03911455
		Weighted median	8	−5.724122	−11.38927	−0.0589709	0.04765833
		Inverse variance weighted	8	−5.613575	−9.926155	−1.3009955	0.01073274
		Weighted mode	8	−5.770263	−12.65021	1.1096877	0.13103776
Sleep duration	FT4	Maximum likelihood	39	−0.003746815	−0.00631	−1.18E-03	0.004168562	0.4558611	<0.001	TRUE
		MR Egger	39	−0.006941392	−0.018453	4.57E-03	0.244804027
		Simple median	39	−0.003651685	−0.007521	2.18E-04	0.064352147
		Weighted median	39	−0.003655062	−0.007261	−4.94E-05	0.046936122
		Inverse variance weighted	39	−0.003724806	−0.006268	−1.18E-03	0.004098102
		Weighted mode	39	0.003323977	−0.005584	1.22E-02	0.469039815
Long sleep	TPO	Maximum likelihood	8	−5.338876	−9.755583	−0.9221694	0.01782513	0.3416165	0.08316805	TRUE
		MR Egger	8	3.039292	−10.25643	16.3350158	0.66984846
		Simple median	8	−6.409133	−12.64739	−0.1708776	0.04404229
		Weighted median	8	−5.219895	−11.1084	0.6686083	0.08230735
		Inverse variance weighted	8	−5.205568	−9.78661	−0.6245258	0.02593368
		Weighted mode	8	−3.512757	−11.43521	4.409695	0.41362227
Chronotype	Plasma cortisol	Maximum likelihood	62	−0.2207635	−0.397883	−0.04364421	0.0145671	0.1128979	0.4365012	FALSE
		MR Egger	62	−0.7172232	−1.358166	−0.07628007	0.03217503
		Simple median	62	−0.1776841	−0.434658	0.07928921	0.19719786
		Weighted median	62	−0.1729567	−0.429988	0.08407416	0.199798
		Inverse variance weighted	62	−0.2166846	−0.410016	−0.02335364	0.02803756
		Weighted mode	62	−0.1609874	−0.638596	0.31662118	0.52533509
Short sleep	Plasma cortisol	Maximum likelihood	13	−1.425964	−2.626342	−0.22558623	0.01989397	0.5959645	<0.001	TRUE
		MR Egger	13	0.7637364	−5.119942	6.64741476	0.80386482
		Simple median	13	−1.6658117	−3.369566	0.03794298	0.04794556
		Weighted median	13	−1.6455935	−3.215101	−0.07608565	0.04906724
		Inverse variance weighted	13	−1.4430481	−2.626589	−0.25950699	0.01685958
		Weighted mode	13	−1.6283951	−4.28097	1.02418017	0.2564192
Sleep duration	P4	Maximum likelihood	73	−0.003756578	−0.007388	−0.00012532	0.04259697	0.3033175	<0.001	TRUE
		MR Egger	73	−0.006114949	−0.020305	0.008075052	0.40115463
		Simple median	73	−0.002572424	−0.008073	0.002928463	0.35936766
		Weighted median	73	−0.001499494	−0.006973	0.003974004	0.59130042
		Inverse variance weighted	73	−0.00373919	−0.007466	−1.1902E-05	0.04926876
		Weighted mode	73	−0.000969822	−0.010812	0.008872459	0.84739999
Short sleep	P4	Maximum likelihood	24	1.1018929	0.1912548	2.012531	0.0177091	0.5720261	0.9564324	TRUE
		MR Egger	24	0.9695932	−3.23027	5.169456	0.65534533
		Simple median	24	0.6629186	−0.60048	1.926317	0.30374631
		Weighted median	24	0.545556	−0.779263	1.870375	0.41959646
		Inverse variance weighted	24	1.0580915	0.161611	1.954572	0.02070425
		Weighted mode	24	0.2686674	−2.302913	2.840248	0.83955149
Chronotype	DHEA-sulphate	Maximum likelihood	66	−0.1463097	−0.258454	−0.03416585	0.010553809	0.09756528	0.3208448	FALSE
		MR Egger	66	−0.2701208	−0.608886	0.06864401	0.123020786
		Simple median	66	−0.3004826	−0.474756	−0.12620961	0.000726324
		Weighted median	66	−0.257487	−0.436871	−0.07810275	0.004902497
		Inverse variance weighted	66	−0.1433748	−0.266336	−0.02041348	0.022289957
		Weighted mode	66	−0.4540321	−0.872123	−0.03594091	0.037091888
Chronotype	TT	Maximum likelihood	116	−0.03267482	−0.045464	−0.01988552	5.51367E-07	0.8961943	<0.001	TRUE
		MR Egger	116	−0.04713691	−0.084758	−0.00951612	0.01556704
		Simple median	116	−0.03405433	−0.052775	−0.01533414	0.00036319
		Weighted median	116	−0.03353506	−0.05296	−0.01411057	0.000714882
		Inverse variance weighted	116	−0.03274512	−0.045393	−0.02009696	3.88945E-07
		Weighted mode	116	−0.04783772	−0.094475	−0.00120081	0.04672182
Chronotype	BT	Maximum likelihood	113	−0.06704449	−0.087087	−0.04700196	5.51153E-11	0.5044926	<0.001	TRUE
		MR Egger	113	−0.08962342	−0.14682	−0.032427	0.002681427
		Simple median	113	−0.05656518	−0.086435	−0.02669532	0.000205878
		Weighted median	113	−0.05947425	−0.090864	−0.02808427	0.00020434
		Inverse variance weighted	113	−0.06700474	−0.086766	−0.04724375	3.01401E-11
		Weighted mode	113	−0.04421704	−0.116705	0.02827085	0.234384

Note: The red font that appears in the table indicates statistical significance for the analysis results (P < 0.05).

Figure 1 Forrest plot for the causal association between sleep traits and HPTGA.

Table 2 MR Estimation of Causal Associations Between Sleep Traits and Gonadal Function (Stratified by Gender)

Exposure	Outcome	MR Methods	No. of SNP	β	lo_95% CI	Up_95% CI	P-value	Q_pval	Steiger_pval	Correct Causal Direction
Chronotype	TT (Male)	Maximum likelihood	115	−0.06972461	−0.1000461	−0.03940308	6.5739E-06	0.5243261	<0.001	TRUE
		MR Egger	115	−0.03391672	−0.1197769	0.05194341	0.4404029
		Simple median	115	−0.0825231	−0.1304015	−0.03464471	0.00072948
		Weighted median	115	−0.06591712	−0.1125596	−0.01927464	0.00560641
		Inverse variance weighted	115	−0.06968647	−0.0996494	−0.03972355	5.1524E-06
		Weighted mode	115	0.03880046	−0.1159547	0.19355565	0.6240783
Chronotype	BT (Male)	Maximum likelihood	121	−0.05657817	−0.08612065	−0.027035696	0.00017425	0.5217495	<0.001	TRUE
		MR Egger	121	−0.08412406	−0.1684376	0.000189479	0.05285666
		Simple median	121	−0.04789414	−0.09010296	−0.005685312	0.02614831
		Weighted median	121	−0.05489468	−0.09779847	−0.011990886	0.01214899
		Inverse variance weighted	121	−0.05683917	−0.08604762	−0.027630718	0.00013666
		Weighted mode	121	−0.04302881	−0.14964928	0.063591664	0.43050637
Chronotype	E2 (Female)	Maximum likelihood	121	−0.120998638	−0.236846	−0.005151292	0.04064299	0.3165679	<0.001	TRUE
		MR Egger	121	−0.384823283	−0.7398531	−0.029793478	0.03569931
		Simple median	121	−0.008074901	−0.1831688	0.167018988	0.92646295
		Weighted median	121	−0.030894921	−0.2073956	0.145605771	0.72518333
		Inverse variance weighted	121	−0.119875322	−0.2376392	−0.002111469	0.04602737
		Weighted mode	121	0.061485928	−0.3409723	0.463944161	0.77404898
Chronotype	TT (Female)	Maximum likelihood	115	−0.05478464	−0.08365743	−0.025911848	0.00020001	0.701352	<0.001	TRUE
		MR Egger	115	−0.0272778	−0.1259152	0.071359604	0.58886475
		Simple median	115	−0.04176238	−0.0822543	−0.001270468	0.04322838
		Weighted median	115	−0.04296322	−0.08480631	−0.001120134	0.04417053
		Inverse variance weighted	115	−0.05495087	−0.08348665	−0.02641508	0.00016043
		Weighted mode	115	−0.03151171	−0.12919519	0.066171779	0.52847246
Chronotype	BT (Female)	Maximum likelihood	119	−0.0697034	−0.09446845	−0.04493834	3.4564E-08	0.6526455	<0.001	TRUE
		MR Egger	119	−0.09892209	−0.17138455	−0.02645963	0.0085268
		Simple median	119	−0.0846103	−0.11993993	−0.04928066	2.6796E-06
		Weighted median	119	−0.08673794	−0.12245326	−0.05102262	1.9355E-06
		Inverse variance weighted	119	−0.06984823	−0.09430962	−0.04538683	2.185E-08
		Weighted mode	119	−0.11450155	−0.1978315	−0.0311716	0.00810807
Sleep duration	BT (Female)	Maximum likelihood	57	0.001012833	2.51E-04	0.001774882	0.00918683	0.6830147	<0.001	TRUE
		MR Egger	57	0.003080642	3.32E-04	0.005829296	0.03227187
		Simple median	57	0.001470245	3.97E-04	0.002543191	0.00723644
		Weighted median	57	0.001545493	3.77E-04	0.002714352	0.0095542
		Inverse variance weighted	57	0.001009217	2.54E-04	0.001764385	0.00880918
		Weighted mode	57	0.002250903	7.17E-06	0.004494633	0.05423211

Note: The red font that appears in the table indicates statistical significance for the analysis results (P < 0.05).

Figure 2 Forrest plot for the causal association between sleep traits and gonadal function (stratified by gender).

Table 3 Bi-Directional MR Estimation of the Causal Effects Between Hypothalamic-Pituitary System Function and Sleep Traits

Exposure (Thalamo-Pituitary Axis Function)	Outcome (Sleep Traits)	MR Methods	No. of SNP	OR	lo_95% CI	Up_95% CI	P-value
PrRP	Short sleep	Maximum likelihood	3	0.9987461	0.9898189	1.007754	0.7841667
		MR Egger	3	1.0160767	0.9570099	1.078789	0.6937526
		Simple median	3	1.0005278	0.9895579	1.011619	0.9252642
		Weighted median	3	1.0002122	0.9893568	1.011187	0.9696024
		Inverse variance weighted	3	0.9987516	0.9898483	1.007735	0.7845314
		Weighted mode	3	1.0006889	0.9882896	1.013244	0.9236736
PrRP	Long sleep	Maximum likelihood	3	1.0039558	0.9970556	1.010904	0.2618652
		MR Egger	3	0.9799676	0.9364789	1.025476	0.542826
		Simple median	3	1.0013267	0.9926593	1.01007	0.7650155
		Weighted median	3	1.0013211	0.9921362	1.010591	0.7788664
		Inverse variance weighted	3	1.0038955	0.9971085	1.010729	0.2612888
		Weighted mode	3	1.0011251	0.9910015	1.011352	0.848444
CRFBP	Chronotype	Maximum likelihood	4	1.003153	0.9955674	1.010797	0.4162498
		MR Egger	4	0.999969	0.9850131	1.015152	0.9971484
		Simple median	4	1.005796	0.9894698	1.022391	0.4888615
		Weighted median	4	1.002738	0.9949929	1.010544	0.4894318
		Inverse variance weighted	4	1.003152	0.99557	1.010792	0.4161873
		Weighted mode	4	1.002628	0.9953678	1.009941	0.5300779
SRIF	Long sleep	Maximum likelihood	5	1.0022044	0.9973202	1.007113	0.3770068
		MR Egger	5	0.9928414	0.9607473	1.026008	0.6971697
		Simple median	5	1.0012235	0.9949451	1.007542	0.7032092
		Weighted median	5	1.000765	0.9948504	1.006715	0.8003837
		Inverse variance weighted	5	1.0021707	0.9973343	1.007031	0.3796533
		Weighted mode	5	0.9996751	0.9918165	1.007596	0.9395648
FT4	Sleep duration	Maximum likelihood	22	1.0012716	0.9837059	1.019151	0.88808823
		MR Egger	22	0.9383519	0.8732612	1.008294	0.09816261
		Simple median	22	0.999449	0.9722247	1.027436	0.9687994
		Weighted median	22	0.995096	0.968645	1.022269	0.72060663
		Inverse variance weighted	22	1.0012382	0.9736835	1.029573	0.93074443
		Weighted mode	22	0.9895829	0.9566205	1.023681	0.55110027
TPO	Long sleep	Maximum likelihood	4	1.002556	0.9967781	1.008366	0.3867225
		MR Egger	4	1.002047	0.9886251	1.015652	0.7943025
		Simple median	4	1.001999	0.9950762	1.00897	0.5723859
		Weighted median	4	1.00315	0.9962755	1.010072	0.3700283
		Inverse variance weighted	4	1.002525	0.9967844	1.008299	0.389386
		Weighted mode	4	1.003631	0.9951823	1.012152	0.4624206
Plasma cortisol	Chronotype	Maximum likelihood	4	0.9950271	0.9753313	1.015121	0.6250234
		MR Egger	4	0.9995786	0.9302549	1.074068	0.9918726
		Simple median	4	1.0053052	0.9790907	1.032222	0.6946861
		Weighted median	4	1.0002195	0.9767892	1.024212	0.9855206
		Inverse variance weighted	4	0.9951855	0.9641964	1.027171	0.7649265
		Weighted mode	4	0.9932686	0.9718005	1.015211	0.587385
Plasma cortisol	Short sleep	Maximum likelihood	4	1.000816	0.993804	1.007878	0.8201188
		MR Egger	4	0.9989501	0.9859728	1.012098	0.8893515
		Simple median	4	1.0020582	0.9920696	1.012147	0.6874903
		Weighted median	4	1.0022161	0.9940702	1.010429	0.5949804
		Inverse variance weighted	4	1.0008118	0.9938128	1.00786	0.8207155
		Weighted mode	4	1.0022706	0.9935772	1.01104	0.6450339
P4	Sleep duration	Maximum likelihood	5	1.019139	0.9924249	1.046571	0.16184236
		MR Egger	5	1.062437	1.0116354	1.115791	0.09393702
		Simple median	5	1.004104	0.9624167	1.047597	0.84984615
		Weighted median	5	1.015164	0.9790411	1.052619	0.41556104
		Inverse variance weighted	5	1.018121	0.9781486	1.059726	0.37950092
		Weighted mode	5	1.005514	0.9608197	1.052288	0.82426422
P4	Short sleep	Maximum likelihood	5	0.9952397	0.984377	1.006222	0.3941073
		MR Egger	5	0.9911876	0.9715402	1.011232	0.4499488
		Simple median	5	0.9879256	0.9733402	1.00273	0.1094232
		Weighted median	5	0.9908298	0.9773948	1.00445	0.1859649
		Inverse variance weighted	5	0.9953435	0.9846257	1.006178	0.3981215
		Weighted mode	5	0.9878879	0.9714243	1.00463	0.2283014
DHEA-sulphate	Chronotype	Maximum likelihood	7	0.9928568	0.9627972	1.023855	0.6476483
		MR Egger	7	0.9539083	0.9113098	0.998498	0.0988033
		Simple median	7	1.0389116	0.9806824	1.100598	0.1945773
		Weighted median	7	0.9781299	0.9435486	1.013979	0.2285526
		Inverse variance weighted	7	0.9929891	0.9611874	1.025843	0.6718237
		Weighted mode	7	0.9680047	0.9332975	1.004003	0.131494
TT	Chronotype	Maximum likelihood	218	0.9245942	0.8939888	0.9562474	5.00E-06
		MR Egger	218	0.9746326	0.8870323	1.070884	5.93E-01
		Simple median	218	0.9455388	0.8886737	1.0060426	7.68E-02
		Weighted median	218	0.9838269	0.9289919	1.0418986	5.77E-01
		Inverse variance weighted	218	0.9244457	0.8770543	0.974398	3.43E-03
		Weighted mode	218	0.9601648	0.8932942	1.0320412	2.71E-01
BT	Chronotype	Maximum likelihood	154	0.9814087	0.9543583	1.009226	0.1881759
		MR Egger	154	0.9536476	0.8771526	1.036814	0.2676587
		Simple median	154	0.9838948	0.9392938	1.030614	0.4927235
		Weighted median	154	0.9840045	0.9342489	1.03641	0.5424594
		Inverse variance weighted	154	0.9819652	0.9416689	1.023986	0.3946097
		Weighted mode	154	0.9711541	0.9183106	1.027038	0.3068024

Note: The red font that appears in the table indicates statistical significance for the analysis results (P < 0.05).

Table 4 Bi-Directional MR Estimation of the Causal Effects Between Gonadal Function and Sleep Traits (Stratified by Gender)

Exposure (Thalamo-Pituitary Axis Function)	Outcome (Sleep Traits)	MR Methods	No. of SNP	OR	lo_95% CI	Up_95% CI	P-value
TT	Chronotype (Male)	Maximum likelihood	208	1.0014666	0.9877552	1.015368	0.8349462
		MR Egger	208	1.0123555	0.9696498	1.056942	0.5771562
		Simple median	208	0.9970741	0.9711706	1.023669	0.8272888
		Weighted median	208	0.9968513	0.9702438	1.024188	0.8192776
		Inverse variance weighted	208	1.0014531	0.976287	1.027268	0.9109645
		Weighted mode	208	1.0020812	0.9779265	1.026833	0.867529
BT	Chronotype (Male)	Maximum likelihood	109	0.990263	0.971203	1.009697	0.3237499
		MR Egger	109	1.0159862	0.950798	1.085644	0.6401937
		Simple median	109	0.9902011	0.9563692	1.02523	0.578768
		Weighted median	109	0.9942141	0.9581592	1.031626	0.7581632
		Inverse variance weighted	109	0.9906581	0.9538689	1.028866	0.6268832
		Weighted mode	109	0.9970363	0.9635948	1.031638	0.8649189
E2	Chronotype (Female)	Maximum likelihood	10	0.9962145	0.9700705	1.023063	0.7798388
		MR Egger	10	0.9615864	0.8926802	1.035811	0.3320252
		Simple median	10	0.9823719	0.9463031	1.019815	0.351393
		Weighted median	10	0.9815298	0.9449055	1.019574	0.3366073
		Inverse variance weighted	10	0.9963021	0.9617757	1.032068	0.8368846
		Weighted mode	10	0.9709655	0.9105736	1.035363	0.3919141
TT	Chronotype (Female)	Maximum likelihood	246	0.9700781	0.9563419	0.9840116	2.98E-05
		MR Egger	246	0.9528544	0.9120446	0.9954902	3.16E-02
		Simple median	246	0.9785467	0.9544844	1.0032155	8.78E-02
		Weighted median	246	0.9779916	0.9501006	1.0067014	1.32E-01
		Inverse variance weighted	246	0.9700718	0.9486441	0.9919835	7.67E-03
		Weighted mode	246	0.9811323	0.9460072	1.0175615	3.07E-01
BT	Chronotype (Female)	Maximum likelihood	179	0.9512116	0.9320084	0.9708105	1.53E-06
		MR Egger	179	0.9598556	0.8978559	1.0261366	2.31E-01
		Simple median	179	0.9564012	0.9225337	0.9915121	1.54E-02
		Weighted median	179	0.9829208	0.9452296	1.022115	3.88E-01
		Inverse variance weighted	179	0.9509987	0.9193241	0.9837646	3.65E-03
		Weighted mode	179	0.9705716	0.9305674	1.0122956	1.66E-01
BT	Sleep duration (Female)	Maximum likelihood	179	1.02982	1.012431	1.047509	7.20E-04
		MR Egger	179	1.027148	0.9807259	1.075767	2.58E-01
		Simple median	179	1.042219	1.0115288	1.073841	6.69E-03
		Weighted median	179	1.026838	0.9965426	1.058054	8.30E-02
		Inverse variance weighted	179	1.029193	1.0053297	1.053623	1.62E-02
		Weighted mode	179	1.026289	0.9910995	1.062727	1.47E-01

Note: The red font that appears in the table indicates statistical significance for the analysis results (P < 0.05).