HLA in isolated REM sleep behavior disorder and Lewy body dementia

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. ### Competing Interest Statement S.W.S. serves on the Scientific Advisory Council of the Lewy Body Dementia Association and the Multiple System Atrophy Coalition. S.W.S. receives research support from Cerevel Therapeutics. ### Funding Statement This work was financially supported by the Canadian Institutes of Health Research (#476751), the Michael J. Fox Foundation, Parkinson's Society Canada, the Canadian Consortium on Neurodegeneration in Aging (CCNA), and the Canada First Research Excellence Fund (CFREF) awarded to McGill University for the Healthy Brains Healthy Lives (HBHL) program. The Montreal iRBD cohort is supported by the Canadian Institutes of Health Research. J.-F.G. holds a Canada Research Chair on Cognitive Decline in Pathological Aging. Z.G.O. is supported by the Fonds de recherche du QuebecSante (FRQS) Chercheurs boursiers award, and is a William Dawson and Killam Scholar. This research was supported in part by the Intramural Research Program of the U.S. National Institutes of Health (National Institute of NEurological Disorders and Stroke; project number: ZIANS003154). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Study participants signed informed consent forms and the study protocol was approved by the Institutional Review Board at McGill University. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Anonymized data not published within this article will be made available by request from any qualified investigator.