Association of genetic variations in the NOS1 gene with insomnia, sleep duration and obstructive sleep apnea-related clinical quantitative traits

doi:10.3969/j.issn.1674-8115.2024.12.002

Abstract

Abstract:

Objective ·To explore the correlation between the genetic variations rs7305526 and rs11615756 of nitric oxide synthase 1 (NOS1) and the human sleep traits, including insomnia, sleep duration, and clinical quantitative traits related to obstructive sleep apnea (OSA). Methods ·The NOS1 gene expression pattern at the whole-brain level using the Allen Human Brain Atlas dataset was analyzed. Subsequently, we performed expression quantitative trait locus (eQTL) analysis to investigate the impact of rs7305526 and rs11615756 on NOS1 gene expression. Regression analysis was conducted to assess the associations between rs7305526 and rs11615756 with insomnia and sleep duration based on the United Kingdom Biobank (UKB) Genome-Wide Association Study (GWAS) dataset. Furthermore, we explored the relationships between rs7305526 and rs11615756 with clinical quantitative traits of OSA, such as respiratory events, oxygen levels, and sleep traits, using clinical monitoring data from the Shanghai Sleep Health Study Cohort (SSHS) based on standard polysomnography (PSG). Results ·The NOS1 genedemonstrated elevated levels of expression in various brain regions crucial for regulating sleep, namely the amygdala, basal forebrain, striatum, and thalamus, as well as in the respiratory center, including the mesencephalon and pontine tegmentum. In contrast, the expression level of NOS1 gene was significantly reduced or absent in areas such as the cerebral cortex and cerebellum. Variants rs7305526 and rs11615756 were significantly negatively correlated with the expression levels of NOS1 in the cerebral cortex. Additionally, rs11615756 was also significantly negatively correlated with the expression level of NOS1 in the amygdala. Analysis of the UKB GWAS data revealed that the variant rs7305526 was not significantly associated with either insomnia or sleep duration, while rs11615756 demonstrated a noteworthy negative correlation specifically with sleep duration. Data obtained from the SSHS indicated a significant association between rs7305526 and alterations in clinical quantitative traits of OSA, including lowest pulse blood oxygen saturation (LSpO₂), apnea-hypopnea index (AHI), and the ratio of non-rapid eye movement (NREM) stage 2 sleep duration. Although rs11615756 showed a notable negative correlation solely with the quantity of NREM stages 2 and 3, both rs11615756 and rs7305526 showed significant correlations with some respiratory events and oxygen traits after stratification according to the severity of OSA. Conclusion ·Genetic variants of NOS1 gene are respectively associated with human sleep duration traits and OSA-related variables, suggesting that NOS1 gene plays a crucial regulatory role in human sleep and clinical quantitative traits of OSA. The regulation of sleep traits by rs7305526 (C>A) is independent of its regulation of respiratory events and oxygen traits.

Key words: obstructive sleep apnea (OSA), nitric oxide synthase 1 (NOS1)gene, human sleep, clinical quantitative trait, genetic variation

CLC Number:

R762

YUAN Haolin, LI Niannian, HU Junhui, SHEN Jinhong, GAO Zhenfei, GUAN Jian, LIU Feng, YIN Shankai. Association of genetic variations in the NOS1 gene with insomnia, sleep duration and obstructive sleep apnea-related clinical quantitative traits[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(12): 1490-1503.

Figures/Tables 12

TrendMD

References 26

1	JORDAN A S, MCSHARRY D G, MALHOTRA A. Adult obstructive sleep apnoea[J]. Lancet, 2014, 383(9918): 736-747.
2	GOTTLIEB D J, PUNJABI N M. Diagnosis and management of obstructive sleep apnea: a review[J]. JAMA, 2020, 323(14): 1389-1400.
3	MARLETTA M A. Nitric oxide synthase: aspects concerning structure and catalysis[J]. Cell, 1994, 78(6): 927-930.
4	ABU-SOUD H M, STUEHR D J. Nitric oxide synthases reveal a role for calmodulin in controlling electron transfer[J]. Proc Natl Acad Sci USA, 1993, 90(22): 10769-10772.
5	MONCADA S, BOLAÑOS J P. Nitric oxide, cell bioenergetics and neurodegeneration[J]. J Neurochem, 2006, 97(6): 1676-1689.
6	ZHOU L, ZHU D Y. Neuronal nitric oxide synthase: structure, subcellular localization, regulation, and clinical implications[J]. Nitric Oxide, 2009, 20(4): 223-230.
7	ZHU L J, LI F, ZHU D Y. nNOS and neurological, neuropsychiatric disorders: a 20-year story[J]. Neurosci Bull, 2023, 39(9): 1439-1453.
8	CHANRION B, MANNOURY LA COUR C, BERTASO F, et al. Physical interaction between the serotonin transporter and neuronal nitric oxide synthase underlies reciprocal modulation of their activity[J]. Proc Natl Acad Sci USA, 2007, 104(19): 8119-8124.
9	DASHTI H S, DAGHLAS I, LANE J M, et al. Genetic determinants of daytime napping and effects on cardiometabolic health[J]. Nat Commun, 2021, 12(1): 900.
10	XU H J, LIU F, LI Z Q, et al. Genome-wide association study of obstructive sleep apnea and objective sleep-related traits identifies novel risk loci in Han Chinese individuals[J]. Am J Respir Crit Care Med, 2022, 206(12): 1534-1545.
11	HAMMERSCHLAG A R, STRINGER S, DE LEEUW C A, et al. Genome-wide association analysis of insomnia complaints identifies risk genes and genetic overlap with psychiatric and metabolic traits[J]. Nat Genet, 2017, 49(11): 1584-1592.
12	SCHOELER T, SPEED D, PORCU E, et al. Participation bias in the UK Biobank distorts genetic associations and downstream analyses[J]. Nat Hum Behav, 2023, 7(7): 1216-1227.
13	JONES S E, TYRRELL J, WOOD A R, et al. Genome-wide association analyses in 128,266 individuals identifies new morningness and sleep duration loci[J]. PLoS Genet, 2016, 12(8): e1006125.
14	DOHERTY A, SMITH-BYRNE K, FERREIRA T, et al. GWAS identifies 14 loci for device-measured physical activity and sleep duration[J]. Nat Commun, 2018, 9(1): 5257.
15	DASHTI H S, JONES S E, WOOD A R, et al. Genome-wide association study identifies genetic loci for self-reported habitual sleep duration supported by accelerometer-derived estimates[J]. Nat Commun, 2019, 10(1): 1100.
16	DAMIANI M F, QUARANTA V N, FALCONE V A, et al. The Epworth Sleepiness Scale: conventional self vs physician administration[J]. Chest, 2013, 143(6): 1569-1575.
17	岳丽萍, 金泽奇. Epworth嗜睡量表联合鼾声量表在阻塞性睡眠呼吸暂停低通气综合征筛查中的应用[J]. 中国耳鼻咽喉头颈外科, 2011, 18(10): 566, 568.
	YUE L P, JIN Z Q. Application of Scale Epworth Sleepiness Score combined with Snore Scale in screening obstructive sleep apnea hypopnea syndrome[J]. Chinese Archives of Otolaryngology-Head and Neck Surgery, 2011, 18(10): 566, 568.
18	HASEGAWA E, MIYASAKA A, SAKURAI K, et al. Rapid eye movement sleep is initiated by basolateral amygdala dopamine signaling in mice[J]. Science, 2022, 375(6584): 994-1000.
19	KLINE D D, YANG T, PREMKUMAR D R, et al. Blunted respiratory responses to hypoxia in mutant mice deficient in nitric oxide synthase-3[J]. J Appl Physiol, 2000, 88(4): 1496-1508.
20	LIPTON A J, JOHNSON M A, MACDONALD T, et al. S-nitrosothiols signal the ventilatory response to hypoxia[J]. Nature, 2001, 413(6852): 171-174.
21	GAUTIER-SAUVIGNÉ S, COLAS D, PARMANTIER P, et al. Nitric oxide and sleep[J]. Sleep Med Rev, 2005, 9(2): 101-113.
22	TRAN T T, SPECK C L, PISUPATI A, et al. Increased hippocampal activation in ApoE-4 carriers and non-carriers with amnestic mild cognitive impairment[J]. Neuroimage Clin, 2016, 13: 237-245.
23	NAKAMURA T, OH C K, LIAO L J, et al. Noncanonical transnitrosylation network contributes to synapse loss in Alzheimer's disease[J]. Science, 2021, 371(6526): eaaw0843.
24	HE H S, BOEHRINGER R, HUANG A J Y, et al. CA2 inhibition reduces the precision of hippocampal assembly reactivation[J]. Neuron, 2021, 109(22): 3674-3687.e7.
25	KUMAR D, KOYANAGI I, CARRIER-RUIZ A, et al. Sparse activity of hippocampal adult-born neurons during REM sleep is necessary for memory consolidation[J]. Neuron, 2020, 107(3): 552-565.e10.
26	YU B, ICHINOSE F, BLOCH D B. Inhaled nitric oxide[J]. Br J Pharmacol, 2019, 176(2): 246-255.

SNP	Tissue	Effect size	P value
rs7305526	Brain cortex	-0.127	0.044
	Lung	-0.136	<0.001
	Tibial nerve	0.178	<0.001
	Colon sigmoid	-0.061	0.039
	Heart atrial appendage	-0.155	0.014
	Minor salivary gland	0.141	0.033
	Thyroid	0.099	0.049
rs11615756	Brain amygdala	-0.224	0.008
	Brain cortex	-0.151	0.028
	Esophagus mucosa	-0.084	0.031
	Thyroid	0.104	0.049
	Skeletal muscle	0.061	0.017
	Pancreas	0.114	0.020

SNP	Tissue	Effect size	P value
rs7305526	Brain cortex	-0.127	0.044
	Lung	-0.136	<0.001
	Tibial nerve	0.178	<0.001
	Colon sigmoid	-0.061	0.039
	Heart atrial appendage	-0.155	0.014
	Minor salivary gland	0.141	0.033
	Thyroid	0.099	0.049
rs11615756	Brain amygdala	-0.224	0.008
	Brain cortex	-0.151	0.028
	Esophagus mucosa	-0.084	0.031
	Thyroid	0.104	0.049
	Skeletal muscle	0.061	0.017
	Pancreas	0.114	0.020

Sleep trait	GWAS catalog accession	PMID	Author and year	Population	Number
Insomnia	GCST004695	28604731	HAMMERSCHLAG 2017	European (UK)	113 006
	GCST90267286	37106081	SCHOELER 2023	European (UK)	283 595
Sleep duration	GCST003839	27494321	JONES 2016	European (UK)	127 573
	GCST006914	30531941	DOHERTY 2018	European (UK)	91 105
	GCST007561	30846698	DASHTI 2019	European (UK)	446 118

Sleep trait	GWAS catalog accession	PMID	Author and year	Population	Number
Insomnia	GCST004695	28604731	HAMMERSCHLAG 2017	European (UK)	113 006
	GCST90267286	37106081	SCHOELER 2023	European (UK)	283 595
Sleep duration	GCST003839	27494321	JONES 2016	European (UK)	127 573
	GCST006914	30531941	DOHERTY 2018	European (UK)	91 105
	GCST007561	30846698	DASHTI 2019	European (UK)	446 118

Variable	Overall (n=6 026)	AA (n=1 941)	CA (n=2 867)	CC (n=1 077)	P value
Genotype/n(%)					<0.001
AA	1 941 (32.2)	1 941 (100.0)	0 (0)	0 (0)
CA	2 867 (47.6)	0 (0)	2 867 (100.0)	0 (0)
CC	1 077 (17.9)	0 (0)	0 (0)	1 077 (100.0)
NA	141 (2.3)	0 (0)	0 (0)	0 (0)
Gender/n(%)					0.175
Male	5 325 (88.4)	1 699 (87.5)	2 538 (88.5)	967 (89.8)
Female	701 (11.6)	242 (12.5)	329 (11.5)	110 (10.2)
Smoking status/n(%)					0.924
Never	3 926 (65.2)	1 262 (65.0)	1 872 (65.3)	708 (65.7)
Ever	2 100 (34.8)	679 (35.0)	995 (34.7)	369 (34.3)
Drinking status/n(%)					0.862
Never	3 637 (60.4)	1 181 (60.8)	1 722 (60.1)	650 (60.4)
Ever	2 389 (39.6)	760 (39.2)	1 145 (39.9)	427 (39.6)
AHI (events/h)^①/n(%)					<0.001
AHI< 5 (Non-OSA)	764 (12.7)	212 (10.9)	360 (12.6)	173 (16.1)
5 ≤AHI < 15 (Mild-OSA)	318 (5.3)	90 (4.6)	161 (5.6)	63 (5.9)
15 ≤AHI < 30 (Moderate-OSA)	1 245 (20.7)	407 (21.0)	577 (20.1)	235 (21.9)
≥30 (Severe-OSA)	3 692 (61.3)	1 231 (63.4)	1 766 (61.6)	603 (56.1)
T2DM status/n(%)					0.787
No	5 580 (92.6)	1 790 (92.2)	2 658 (92.7)	999 (92.8)
Yes	446 (7.4)	151 (7.8)	209 (7.3)	78 (7.2)
Hypertension status/n(%)					0.761
No	5 141 (85.3)	1 649 (85.0)	2 452 (85.5)	925 (85.9)
Yes	885 (14.7)	292 (15.0)	415 (14.5)	152 (14.1)