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. 2025 Feb 17;15(1):55.
doi: 10.1038/s41398-025-03259-w.

Narcolepsy as a potential risk factor for Schizophrenia

Reyhane Eghtedarian  1 , Anniina M Tervi  1 , Samuel E Jones  1 ; FinnGen; Markku Partinen  2 , Essi Viippola  1 , Hanna M Ollila  3   4   5   6
Collaborators, Affiliations

Narcolepsy as a potential risk factor for Schizophrenia

Reyhane Eghtedarian et al. Transl Psychiatry. .

Abstract

Narcolepsy is a severe sleep disorder with characteristics of fatigue, fragmented sleep, cataplexy and hypnagogic hallucinations. Earlier clinical studies have reported the onset of schizophrenia after narcolepsy but the causality behind narcolepsy and schizophrenia is unknown. Our goal was to understand the causality between narcolepsy and schizophrenia. To estimate the comorbidity between narcolepsy and schizophrenia, we employed data from the FinRegistry that contains data for the total population of Finland in total 7.2 million individuals (N = 1664 individuals with narcolepsy and 55,372 with schizophrenia). We then used Mendelian randomization and previously published genome-wide association data to test the causality between narcolepsy and schizophrenia. We observed a robust causal association from narcolepsy to schizophrenia using the HLA-independent lead variants (P-value = 6.0 × 10-4), which was accentuated when including the HLA locus (P-value = 4.48 × 10-7). Furthermore, we observed a modest bidirectional causality from schizophrenia to narcolepsy (P-value = 0.015). There was no evidence of pleiotropy. Our findings indicate a causal relationship where narcolepsy may increase the risk for schizophrenia, and a bidirectional causality from schizophrenia to narcolepsy. Additionally, our results clarify the psychiatric burden in narcolepsy.

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Conflict of interest statement

Competing interests: The authors declare no competing interests. Ethics statement and materials & methods: Patients and control subjects in FinnGen provided informed consent for biobank research, based on the Finnish Biobank Act. Alternatively, separate research cohorts, collected prior the Finnish Biobank Act came into effect (in September 2013) and start of FinnGen (August 2017), were collected based on study-specific consents and later transferred to the Finnish biobanks after approval by Fimea (Finnish Medicines Agency), the National Supervisory Authority for Welfare and Health. Recruitment protocols followed the biobank protocols approved by Fimea. The Coordinating Ethics Committee of the Hospital District of Helsinki and Uusimaa (HUS) statement number for the FinnGen study is Nr HUS/990/2017. The FinnGen study is approved by Finnish Institute for Health and Welfare (permit numbers: THL/2031/6.02.00/2017, THL/1101/5.05.00/2017, THL/341/6.02.00/2018, THL/2222/6.02.00/2018, THL/283/6.02.00/2019, THL/1721/5.05.00/2019 and THL/1524/5.05.00/2020), Digital and population data service agency (permit numbers: VRK43431/2017-3, VRK/6909/2018-3, VRK/4415/2019-3), the Social Insurance Institution (permit numbers: KELA 58/522/2017, KELA 131/522/2018, KELA 70/522/2019, KELA 98/522/2019, KELA 134/522/2019, KELA 138/522/2019, KELA 2/522/2020, KELA 16/522/2020), Findata permit numbers THL/2364/14.02/2020, THL/4055/14.06.00/2020, THL/3433/14.06.00/2020, THL/4432/14.06/2020, THL/5189/14.06/2020, THL/5894/14.06.00/2020, THL/6619/14.06.00/2020, THL/209/14.06.00/2021, THL/688/14.06.00/2021, THL/1284/14.06.00/2021, THL/1965/14.06.00/2021, THL/5546/14.02.00/2020, THL/2658/14.06.00/2021, THL/4235/14.06.00/2021, Statistics Finland (permit numbers: TK-53-1041-17 and TK/143/07.03.00/2020 (earlier TK-53-90-20) TK/1735/07.03.00/2021, TK/3112/07.03.00/2021) and Finnish Registry for Kidney Diseases permission/extract from the meeting minutes on 4th July 2019. The Biobank Access Decisions for FinnGen samples and data utilized in FinnGen Data Freeze 10 include: THL Biobank BB2017_55, BB2017_111, BB2018_19, BB_2018_34, BB_2018_67, BB2018_71, BB2019_7, BB2019_8, BB2019_26, BB2020_1, BB2021_65, Finnish Red Cross Blood Service Biobank 7.12.2017, Helsinki Biobank HUS/359/2017, HUS/248/2020, HUS/150/2022 § 12, §13, §14, §15, §16, §17, §18, and §23, Auria Biobank AB17-5154 and amendment #1 (August 17 2020) and amendments BB_2021-0140, BB_2021-0156 (August 26 2021, Feb 2 2022), BB_2021-0169, BB_2021-0179, BB_2021-0161, AB20-5926 and amendment #1 (April 23 2020)and it´s modification (Sep 22 2021), Biobank Borealis of Northern Finland_2017_1013, 2021_5010, 2021_5018, 2021_5015, 2021_5023, 2021_5017, 2022_6001, Biobank of Eastern Finland 1186/2018 and amendment 22 § /2020, 53§/2021, 13§/2022, 14§/2022, 15§/2022, Finnish Clinical Biobank Tampere MH0004 and amendments (21.02.2020 & 06.10.2020), §8/2021, §9/2022, §10/2022, §12/2022, §20/2022, §21/2022, §22/2022, §23/2022, Central Finland Biobank 1-2017, and Terveystalo Biobank STB 2018001 and amendment 25th Aug 2020, Finnish Hematological Registry and Clinical Biobank decision 18th June 2021, Arctic biobank P0844: ARC_2021_1001.

Figures

Fig. 1
Fig. 1. MR shows causality from NT1 to schizophrenia in European ancestry.
A shows the results using non-HLA lead variants and B shows the results after including one lead variant in LD with HLA-DQB1*06:02. The x and y axes show the effect sizes (log odds ratio) of each SNP for both phenotypes. The horizontal and the vertical lines demonstrate the standard errors of the effect sizes.
Fig. 2
Fig. 2. MR analysis to test causality between schizophrenia and NT1.
A and B show the schizophrenia Trubetskoy et al. cohort [32] and FinnGen release 12, and Narcolepsy meta-analysis [1], respectively. The x and y axes show the effect sizes (log odds ratio) of each SNP for both diseases. The horizontal and the vertical lines show the standard errors of the effect sizes.
Fig. 3
Fig. 3. Leave-one-out results for NT1 against schizophrenia in European ancestry.
A shows the results using non-HLA lead variants and B shows the results using the lead variants including one HLA- region variant.
See this image and copyright information in PMC

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