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[Preprint]. 2023 Apr 3:2023.01.31.23284682.

doi: 10.1101/2023.01.31.23284682.

HLA in isolated REM sleep behavior disorder and Lewy body dementia

Eric Yu^{1

2}, Lynne Krohn^{1

2}, Jennifer A Ruskey^{2

3}, Farnaz Asayesh^{2

3}, Dan Spiegelman^{2

3}, Zalak Shah⁴, Ruth Chia⁵, Isabelle Arnulf⁶, Michele T M Hu^{7

8}, Jacques Y Montplaisir^{9

10}, Jean-François Gagnon^{9

11}, Alex Desautels^{9

12}, Yves Dauvilliers¹³, Gian Luigi Gigli^{14

15}, Mariarosaria Valente^{14

15}, Francesco Janes¹⁴, Andrea Bernardini¹⁴, Birgit Högl¹⁶, Ambra Stefani¹⁶, Abubaker Ibrahim¹⁶, Anna Heidbreder^{16

17}, Karel Sonka¹⁸, Petr Dusek¹⁸, David Kemlink¹⁸, Wolfgang Oertel¹⁹, Annette Janzen¹⁹, Giuseppe Plazzi^{20

21}, Elena Antelmi²², Michela Figorilli²³, Monica Puligheddu²³, Brit Mollenhauer^{24

25}, Claudia Trenkwalder^{24

25}, Friederike Sixel-Döring^{19

24}, Valérie Cochen De Cock^{26

27}, Luigi Ferini-Strambi²⁸, Femke Dijkstra^{29

30

31}, Mineke Viaene^{29

30}, Beatriz Abril³², Bradley F Boeve³³, Guy A Rouleau^{1

2

3}, Ronald B Postuma^{2

3

9}, Sonja W Scholz^{4

34}; International LBD Genomics Consortium; Ziv Gan-Or^{1

2

3}

Affiliations

¹ Department of Human Genetics, McGill University, Montréal, QC, Canada.
² The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montréal, QC, Canada.
³ Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada.
⁴ Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
⁵ Neuromuscular Diseases Research Section, National Institute on Aging, Bethesda, MD, USA.
⁶ Sleep Disorders Unit, Pitié Salpêtrière Hospital, Paris Brain Institute and Sorbonne University, Paris, France.
⁷ Oxford Parkinson's Disease Centre (OPDC), University of Oxford, Oxford, United Kingdom.
⁸ Division of Neurology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.
⁹ Center for Advanced Research in Sleep Medicine, Centre Intégré Universitaire de Santé et de Services Sociaux du Nord-de-l'île-de-Montréal - Hopital du Sacré-Coeur de Montréal, Montréal, QC, Canada.
¹⁰ Department of Psychiatry, Université de Montréal, Montréal, QC, Canada.
¹¹ Department of Psychology, Université du Québec à Montreal, Montréal, QC, Canada.
¹² Department of Neurosciences, Universite de Montréal, Montréal, QC, Canada.
¹³ National Reference Center for Narcolepsy, Sleep Unit, Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, University of Montpellier, Inserm U1061, Montpellier, France.
¹⁴ Clinical Neurology Unit, Department of Neurosciences, University Hospital of Udine, Udine, Italy.
¹⁵ Department of Medicine (DAME), University of Udine, Udine, Italy.
¹⁶ Sleep Disorders Clinic, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
¹⁷ Department for Sleep Medicine and Neuromuscular disease, University Hospital Muenster, Muenster, Germany.
¹⁸ Department of Neurology and Centre of Clinical Neuroscience, Charles University, First Faculty of Medicine and General University Hospital, Prague, Czech Republic.
¹⁹ Department of Neurology, Philipps University, Marburg, Germany.
²⁰ Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio-Emilia, Modena, Italy.
²¹ IRCCS, Institute of Neurological Sciences of Bologna, Bologna, Italy.
²² Neurology Unit, Movement Disorders Division, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
²³ Department of Medical Sciences and Public Health, Sleep Disorder Research Center, University of Cagliari, Cagliari, Italy.
²⁴ Paracelsus-Elena-Klinik, Kassel, Germany.
²⁵ Department of Neurosurgery, University Medical Centre Gættingen, Gottingen, Germany.
²⁶ Sleep and Neurology Unit, Beau Soleil Clinic, Montpellier, France.
²⁷ EuroMov Digital Health in Motion, University of Montpellier IMT Mines Ales, Montpellier, France.
²⁸ Department of Neurological Sciences, Università Vita-Salute San Raffaele, Milan, Italy.
²⁹ Laboratory for Sleep Disorders, St. Dimpna Regional Hospital, Geel, Belgium.
³⁰ Department of Neurology, St. Dimpna Regional Hospital, Geel, Belgium.
³¹ Department of Neurology, University Hospital Antwerp, Edegem, Antwerp, Belgium.
³² Sleep disorder Unit, Carémeau Hospital, University Hospital of Nîmes, France.
³³ Department of Neurology, Mayo Clinic, Rochester, MN, USA.
³⁴ Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA.

PMID: 36778313
PMCID: PMC9915822
DOI: 10.1101/2023.01.31.23284682

HLA in isolated REM sleep behavior disorder and Lewy body dementia

Eric Yu et al. medRxiv. 2023.

[Preprint]. 2023 Apr 3:2023.01.31.23284682.

doi: 10.1101/2023.01.31.23284682.

Authors

Affiliations

¹ Department of Human Genetics, McGill University, Montréal, QC, Canada.
² The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montréal, QC, Canada.
³ Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada.
⁴ Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
⁵ Neuromuscular Diseases Research Section, National Institute on Aging, Bethesda, MD, USA.
⁶ Sleep Disorders Unit, Pitié Salpêtrière Hospital, Paris Brain Institute and Sorbonne University, Paris, France.
⁷ Oxford Parkinson's Disease Centre (OPDC), University of Oxford, Oxford, United Kingdom.
⁸ Division of Neurology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.
⁹ Center for Advanced Research in Sleep Medicine, Centre Intégré Universitaire de Santé et de Services Sociaux du Nord-de-l'île-de-Montréal - Hopital du Sacré-Coeur de Montréal, Montréal, QC, Canada.
¹⁰ Department of Psychiatry, Université de Montréal, Montréal, QC, Canada.
¹¹ Department of Psychology, Université du Québec à Montreal, Montréal, QC, Canada.
¹² Department of Neurosciences, Universite de Montréal, Montréal, QC, Canada.
¹³ National Reference Center for Narcolepsy, Sleep Unit, Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, University of Montpellier, Inserm U1061, Montpellier, France.
¹⁴ Clinical Neurology Unit, Department of Neurosciences, University Hospital of Udine, Udine, Italy.
¹⁵ Department of Medicine (DAME), University of Udine, Udine, Italy.
¹⁶ Sleep Disorders Clinic, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
¹⁷ Department for Sleep Medicine and Neuromuscular disease, University Hospital Muenster, Muenster, Germany.
¹⁸ Department of Neurology and Centre of Clinical Neuroscience, Charles University, First Faculty of Medicine and General University Hospital, Prague, Czech Republic.
¹⁹ Department of Neurology, Philipps University, Marburg, Germany.
²⁰ Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio-Emilia, Modena, Italy.
²¹ IRCCS, Institute of Neurological Sciences of Bologna, Bologna, Italy.
²² Neurology Unit, Movement Disorders Division, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
²³ Department of Medical Sciences and Public Health, Sleep Disorder Research Center, University of Cagliari, Cagliari, Italy.
²⁴ Paracelsus-Elena-Klinik, Kassel, Germany.
²⁵ Department of Neurosurgery, University Medical Centre Gættingen, Gottingen, Germany.
²⁶ Sleep and Neurology Unit, Beau Soleil Clinic, Montpellier, France.
²⁷ EuroMov Digital Health in Motion, University of Montpellier IMT Mines Ales, Montpellier, France.
²⁸ Department of Neurological Sciences, Università Vita-Salute San Raffaele, Milan, Italy.
²⁹ Laboratory for Sleep Disorders, St. Dimpna Regional Hospital, Geel, Belgium.
³⁰ Department of Neurology, St. Dimpna Regional Hospital, Geel, Belgium.
³¹ Department of Neurology, University Hospital Antwerp, Edegem, Antwerp, Belgium.
³² Sleep disorder Unit, Carémeau Hospital, University Hospital of Nîmes, France.
³³ Department of Neurology, Mayo Clinic, Rochester, MN, USA.
³⁴ Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA.

PMID: 36778313
PMCID: PMC9915822
DOI: 10.1101/2023.01.31.23284682

Update in

HLA in isolated REM sleep behavior disorder and Lewy body dementia.
Yu E, Krohn L, Ruskey JA, Asayesh F, Spiegelman D, Shah Z, Chia R, Arnulf I, Hu MTM, Montplaisir JY, Gagnon JF, Desautels A, Dauvilliers Y, Gigli GL, Valente M, Janes F, Bernardini A, Högl B, Stefani A, Ibrahim A, Heidbreder A, Sonka K, Dusek P, Kemlink D, Oertel W, Janzen A, Plazzi G, Antelmi E, Figorilli M, Puligheddu M, Mollenhauer B, Trenkwalder C, Sixel-Döring F, Cochen De Cock V, Ferini-Strambi L, Dijkstra F, Viaene M, Abril B, Boeve BF, Rouleau GA, Postuma RB; International LBD Genomics Consortium; Scholz SW, Gan-Or Z. Yu E, et al. Ann Clin Transl Neurol. 2023 Sep;10(9):1682-1687. doi: 10.1002/acn3.51841. Epub 2023 Jul 4. Ann Clin Transl Neurol. 2023. PMID: 37401389 Free PMC article.

Abstract

Background and objectives: Isolated/idiopathic REM sleep behavior disorder (iRBD) and Lewy body dementia (LBD) are synucleinopathies that have partial genetic overlap with Parkinson's disease (PD). Previous studies have shown that neuroinflammation plays a substantial role in these disorders. In PD, specific residues of the human leukocyte antigen ( HLA ) were suggested to be associated with a protective effect. This study examined whether the HLA locus plays a similar role in iRBD, LBD and PD.

Methods: We performed HLA imputation on iRBD genotyping data (1,072 patients and 9,505 controls) and LBD whole-genome sequencing (2,604 patients and 4,032 controls) using the multi-ethnic HLA reference panel v2 from the Michigan Imputation Server. Using logistic regression, we tested the association of HLA alleles, amino acids and haplotypes with disease susceptibility. We included age, sex and the top 10 principal components as covariates. We also performed an omnibus test to examine which HLA residue positions explain the most variance.

Results: In iRBD, HLA-DRB1 *11:01 was the only allele passing FDR correction (OR=1.57, 95% CI=1.27-1.93, p =2.70e-05). We also discovered associations between iRBD and HLA-DRB1 70D (OR=1.26, 95%CI=1.12-1.41, p =8.76e-05), 70Q (OR=0.81, 95% CI=0.72-0.91, p =3.65e-04) and 71R (OR=1.21, 95% CI=1.08-1.35, p =1.35e-03). In HLA-DRB1 , position 71 ( p _omnibus =0.00102) and 70 ( p _omnibus =0.00125) were associated with iRBD. We found no association in LBD.

Discussion: This study identified an association between HLA-DRB1 11:01 and iRBD, distinct from the previously reported association in PD. Therefore, the HLA locus may play different roles across synucleinopathies. Additional studies are required better to understand HLA's role in iRBD and LBD.

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References

1. Dauvilliers Y, Schenck CH, Postuma RB, et al. REM sleep behaviour disorder. Nature reviews Disease primers. 2018;4(1):1–16. - PubMed
1. Postuma RB, Iranzo A, Hu M, et al. Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study. Brain. Mar 1 2019;142(3):744–759. doi:10.1093/brain/awz030 - DOI - PMC - PubMed
1. Krohn L, Heilbron K, Blauwendraat C, et al. Genome-wide association study of REM sleep behavior disorder identifies polygenic risk and brain expression effects. Nature Communications. 2022;13(1):1–16. - PMC - PubMed
1. Stokholm MG, Iranzo A, Østergaard K, et al. Assessment of neuroinflammation in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a case-control study. The Lancet Neurology. 2017/10/01/ 2017;16(10):789–796. doi:10.1016/S1474-4422(17)30173-4 - DOI - PubMed
1. Hirsch EC, Vyas S, Hunot S. Neuroinflammation in Parkinson’s disease. Parkinsonism & related disorders. 2012;18:S210–S212. - PubMed

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This is a preprint.

HLA in isolated REM sleep behavior disorder and Lewy body dementia

Affiliations

HLA in isolated REM sleep behavior disorder and Lewy body dementia

Authors

Affiliations

Update in

Abstract

References

Publication types

Grants and funding

LinkOut - more resources

Full Text Sources

Research Materials