Abstract Details

Title Genetic and Associated Clinical Features of Anti-NMDAR Encephalitis: A Large Multi-ethnic Genome-wide Study

Topic Autoimmune Neurology

Presentation(s) C6 - Genetics and Neurological Autoimmunity (2:36 PM-2:46 PM)
P3 - Poster Session 3 (11:30 AM-12:30 PM)

Poster/Presentation
Number 1-016

Objective

To identify the genetic risk factors underlying anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) through a large multi-ethnic GWAS.

Background

The genetic predisposition to NMDARE remains poorly understood. Previous studies in different ethnic populations have yielded heterogeneous findings involving HLA and non-HLA loci. A large multi-ethnic study was needed to clarify the genetic architecture underlying NMDARE.

Design/Methods

We performed a GWAS followed by PCA–based control matching in a cohort of 817 NMDARE patients and 11,620 healthy controls. Samples from France (n=256), Germany (n=224), Mexico (n=63), South Korea (n=63), the Netherlands (n=50), Brazil (n=42), Spain (n=36), the UK (n=30), New Zealand (n=25), the US (n=21), and Australia (n=7) were included. WGS was conducted in 20 Caucasian case-control pairs, ACP2-homozygous. Clinical and longitudinal data were also analyzed.

Results

Among cases, 77% were female, 58% Caucasian, with a mean age of onset of 25.4 ± 14.4 years; 19.5% had ovarian teratoma. Three major association peaks were identified: the NR1H3/ACP2 region (rs11039155, β=0.768, SE=0.079, p=3.5×10?²²), DMXL2 (rs2124876, β=−0.391, SE=0.060, p=6.1×10?¹¹), and HLA-DRB1 (rs9271146, β=0.319, SE=0.063, p=4.6×10?7). The ACP2 signal showed a recessive effect (OR=13.4, p=7.8×10?²³). ACP2-homozygous patients (n=57) were 84% Caucasian, all females of reproductive age, and 96.5% without ovarian teratomas. WGS in 20 ACP2-homozygous cases and controls did not reveal any effect. Compared with non-ACP2 carriers matched by sex, ethnicity, and age, ACP2-homozygous patients had more seizures (92%vs77%, p=0.002), more speech disturbance (88%vs57%), more abnormal EEGs (92%vs75%, p=0.02), less pleocytosis (28%vs49%, p=0.02), and lower mRS scores at follow-up (0.95 ± 0.91 vs 1.46 ± 1.39, p=0.008), with no differences in mortality, ICU admission, or relapse rates.

Conclusions

This study identifies HLA and non-HLA risk loci for NMDARE. DMXL2 represents a novel association present across ethnicities. The ACP2-homozygous subgroup, predominantly Caucasian females, appears to have a milder disease course. These findings identify potential biomarkers and provide insight into disease pathophysiology.

Authors/Disclosures
Bruna de Freitas Dias, MD (Stanford university) PRESENTER	Dr. de Freitas Dias has nothing to disclose.
Eric Yu, PhD	Dr. Yu has nothing to disclose.
Sergio Muniz-Castrillo, MD, PhD (Stanford university)	Dr. Muniz-Castrillo has nothing to disclose.
Frank Leypoldt, MD (University Hospital Schleswig-Holstein, Campus Kiel Department of Neurology)	Frank Leypoldt, MD has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Roche. Frank Leypoldt, MD has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Argenx. Frank Leypoldt, MD has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. The institution of Frank Leypoldt, MD has received research support from German Ministry of Research BMBF.
Gregor Kuhlenbäumer	Gregor Kuhlenbäumer has nothing to disclose.
Livia A. Dutra, MD (Hospital Israelita Albert Einstein)	Dr. Dutra has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Kyverna. The institution of Dr. Dutra has received research support from Hospital Israelita Albert Einstein. The institution of Dr. Dutra has received research support from Laboratório Fleury. Dr. Dutra has received personal compensation in the range of $0-$499 for serving as a Speaker with Roche.
Soon-Tae Lee, MD, PhD (Department of Neurology, Seoul National University Hospital)	Prof. Lee has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Advanced Neural Technologies. Prof. Lee has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Piehealthcare. Prof. Lee has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Salted. Prof. Lee has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche/Genentech. Prof. Lee has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for argenx. Prof. Lee has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Arialys. The institution of Prof. Lee has received research support from Roche. Prof. Lee has received intellectual property interests from a discovery or technology relating to health care.
Kon Chu (Seoul National University Hospital)	Kon Chu has nothing to disclose.
Maarten J. Titulaer, MD, PhD, FAAN (Erasmus Medical Center)	The institution of Dr. Titulaer has received research support from Dutch Epilepsy Foundations (NEF 19-08). The institution of Dr. Titulaer has received research support from CSL Behring. The institution of Dr. Titulaer has received research support from UCB. The institution of Dr. Titulaer has received research support from Netherlands Organisation for Scientific Research (ZonMW, Memorabel initiative and E-RARE UltraAIE) . The institution of Dr. Titulaer has received research support from Amgen. The institution of Dr. Titulaer has received research support from Dioraphte (charity). The institution of Dr. Titulaer has received research support from Guidepoint Global LLC. The institution of Dr. Titulaer has received research support from ArgenX. The institution of Dr. Titulaer has received research support from ItsME, patient charity foundation. The institution of Dr. Titulaer has received research support from Erasmus Trustfonds. The institution of Dr. Titulaer has received research support from Erasmus MC Foundation. Dr. Titulaer has received intellectual property interests from a discovery or technology relating to health care. Dr. Titulaer has received publishing royalties from a publication relating to health care.
Anna Bastiaansen	Anna Bastiaansen has nothing to disclose.
Enrique Gomez Figueroa, MD, MSc	Dr. Gomez Figueroa has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen Mexico. Dr. Gomez Figueroa has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Astra Zeneca Mexico. Dr. Gomez Figueroa has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Johnson & Johnson LATAM.
Jose J. Flores-Rivera, MD	Dr. Flores-Rivera has nothing to disclose.
Graciela Ordoñez-Lozano	Graciela Ordoñez-Lozano has nothing to disclose.
Hannah F. Jones, MBBS, PhD, FRACP	Dr. Jones has received research support from Health Research Council of New Zealand. Dr. Jones has received research support from Neurological Foundation.
Russell Dale (The Children's Hospital At Westmead)	Mr. Dale has nothing to disclose.
Josep O. Dalmau, MD, PhD, FAAN	Dr. Dalmau has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Astellas Research Institute of America. Dr. Dalmau has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janssen Research & Development . Dr. Dalmau has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for ��ɫ��. An immediate family member of Dr. Dalmau has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Dr. Dalmau has received research support from Sage Therapeutics. The institution of Dr. Dalmau has received research support from Edmond J.Safra Foundation . The institution of Dr. Dalmau has received research support from La Caixa Foundation. The institution of Dr. Dalmau has received research support from Spanish Ministry of Health (ISCIII). The institution of Dr. Dalmau has received research support from Euroimmun, Inc. Dr. Dalmau has received intellectual property interests from a discovery or technology relating to health care. An immediate family member of Dr. Dalmau has received intellectual property interests from a discovery or technology relating to health care. Dr. Dalmau has received intellectual property interests from a discovery or technology relating to health care. An immediate family member of Dr. Dalmau has received intellectual property interests from a discovery or technology relating to health care. Dr. Dalmau has received publishing royalties from a publication relating to health care. Dr. Dalmau has received publishing royalties from a publication relating to health care. Dr. Dalmau has received publishing royalties from a publication relating to health care.
Thais Armangue, MD (IDIBAPS-HClinic)	Dr. Armangue has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. The institution of Dr. Armangue has received research support from ISCIII(Spanish institute of health) -PI21/00316, Marato TV3, La Caixa Research Foundadion, Pablove Foundation (689368), Torrons Vicens Foundation (PFNR0144), 2021 Invest AEP.
Alexander Sandweiss, MD, PhD	Dr. Sandweiss has nothing to disclose.
Ivan K. Chinn, MD	The institution of Dr. Chinn has received research support from National Institutes of Health. Dr. Chinn has received publishing royalties from a publication relating to health care.
Eyal Muscal	Eyal Muscal has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for sobi. An immediate family member of Eyal Muscal has stock in pfizer.
Sarosh R. Irani, MD, PhD, FRCP, FEAN (Mayo Clinic)	Dr. Irani has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Alexion, Argenex, Atheneum, AZ, Clarivate, IQVIA, BioHaven therapeutics. Dr. Irani has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion US, Amgen, Argenx . Dr. Irani has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Brain. The institution of Dr. Irani has received research support from Amgen. Dr. Irani has received intellectual property interests from a discovery or technology relating to health care. Dr. Irani has received intellectual property interests from a discovery or technology relating to health care.
Sophie Binks, MD, MBBS, PhD	The institution of Dr. Binks has received research support from Wellcome Trust. The institution of Dr. Binks has received research support from PetSavers. The institution of Dr. Binks has received research support from PetPlan. The institution of Dr. Binks has received research support from NIHR. The institution of Dr. Binks has received research support from Morris Animal Foundation. Dr. Binks has received personal compensation in the range of $0-$499 for serving as a Speaker with ECTRIMS. Dr. Binks has received personal compensation in the range of $0-$499 for serving as a Speaker with Vetmeduni Wien. Dr. Binks has received personal compensation in the range of $0-$499 for serving as a Speaker with ANA. Dr. Binks has a non-compensated relationship as a Speaker with Encephalitis Society UK that is relevant to AAN interests or activities. Dr. Binks has a non-compensated relationship as a Scientific Panel Member with Encephalitis International that is relevant to AAN interests or activities. Dr. Binks has a non-compensated relationship as a Editorial Fellow with JAMA Neurology that is relevant to AAN interests or activities. Dr. Binks has a non-compensated relationship as a Scientific Panel with Autoimmune Encephalitis Alliance that is relevant to AAN interests or activities.
Adam Al-Diwani, MBBS, PhD	Dr. Al-Diwani has nothing to disclose.
Carsten Finke, MD (Charité Berlin)	Carsten Finke, MD has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Bristol Myer Squibb. The institution of Carsten Finke, MD has received research support from Euroimmun.
Harald Pruess	Harald Pruess has nothing to disclose.
Michael R. Wilson, MD, FAAN (University of California San Francisco)	Dr. Wilson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pfizer. Dr. Wilson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ouro Medicines. Dr. Wilson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Vertex Pharmaceuticals. Dr. Wilson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Indapta Therapeutics. Dr. Wilson has received personal compensation in the range of $50,000-$99,999 for serving as an officer or member of the Board of Directors for Delve Bio. Dr. Wilson has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Cambridge Medical Experts. Dr. Wilson has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Dunham Hallmark. Dr. Wilson has stock in Delve Bio. The institution of Dr. Wilson has received research support from Genentech / Roche. The institution of Dr. Wilson has received research support from NIH. The institution of Dr. Wilson has received research support from Novartis. The institution of Dr. Wilson has received research support from National Multiple Sclerosis Society. The institution of Dr. Wilson has received research support from Fanconi Anemia Research Foundation. The institution of Dr. Wilson has received research support from Department of Defense. The institution of Dr. Wilson has received research support from Chan Zuckerberg Initiative. The institution of Dr. Wilson has received research support from Kyverna Therapeutics. Dr. Wilson has received intellectual property interests from a discovery or technology relating to health care. Dr. Wilson has received intellectual property interests from a discovery or technology relating to health care. Dr. Wilson has received personal compensation in the range of $10,000-$49,999 for serving as a Expert Witness with US Dept of Justice.
Greer Waldrop, MD	Dr. Waldrop has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Delve Bio. Dr. Waldrop has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech.
Anne-Laurie Pinto	Anne-Laurie Pinto has nothing to disclose.
Geraldine Picard, MSc	Mrs. PICARD has nothing to disclose.
Emmanuel Mignot, MD, PhD (Stanford University)	Dr. Mignot has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Takeda. Dr. Mignot has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Jazz Pharmaceutical. Dr. Mignot has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eisai Pharmaceuticals, Inc. . Dr. Mignot has received personal compensation in the range of $0-$499 for serving as a Consultant for EcoR1. Dr. Mignot has received personal compensation in the range of $0-$499 for serving as a Consultant for ApneaCo. Dr. Mignot has received personal compensation in the range of $0-$499 for serving as a Consultant for Eisai Pharmaceuticals. Dr. Mignot has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Centessa .

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