Genome-wide Association Study Identifies 2 New Loci Associated With Anti-NMDAR Encephalitis
Jazyk angličtina Země Spojené státy americké Médium electronic-print
Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem
PubMed
34584012
PubMed Central
PMC8479862
DOI
10.1212/nxi.0000000000001085
PII: 8/6/e1085
Knihovny.cz E-zdroje
- MeSH
- celogenomová asociační studie * MeSH
- dospělí MeSH
- encefalitida s protilátkami proti NMDA receptorům genetika MeSH
- genetické lokusy MeSH
- lidé MeSH
- studie případů a kontrol MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
BACKGROUND AND OBJECTIVES: To investigate the genetic determinants of the most common type of antibody-mediated autoimmune encephalitis, anti-NMDA receptor (anti-NMDAR) encephalitis. METHODS: We performed a genome-wide association study in 178 patients with anti-NMDAR encephalitis and 590 healthy controls, followed by a colocalization analysis to identify putatively causal genes. RESULTS: We identified 2 independent risk loci harboring genome-wide significant variants (p < 5 × 10-8, OR ≥ 2.2), 1 on chromosome 15, harboring only the LRRK1 gene, and 1 on chromosome 11 centered on the ACP2 and NR1H3 genes in a larger region of high linkage disequilibrium. Colocalization signals with expression quantitative trait loci for different brain regions and immune cell types suggested ACP2, NR1H3, MADD, DDB2, and C11orf49 as putatively causal genes. The best candidate genes in each region are LRRK1, encoding leucine-rich repeat kinase 1, a protein involved in B-cell development, and NR1H3 liver X receptor alpha, a transcription factor whose activation inhibits inflammatory processes. DISCUSSION: This study provides evidence for relevant genetic determinants of antibody-mediated autoimmune encephalitides outside the human leukocyte antigen (HLA) region. The results suggest that future studies with larger sample sizes will successfully identify additional genetic determinants and contribute to the elucidation of the pathomechanism.
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Dalmau J, Armangué T, Planagumà J, et al. An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models. Lancet Neurol. 2019;18(11):1045-1057. PubMed
Dubey D, Pittock SJ, Kelly CR, et al. Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis. Ann Neurol. 2018;83(1):166-177. PubMed PMC
Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391-404. PubMed PMC
Mueller SH, Färber A, Prüss H, et al. Genetic predisposition in anti-LGI1 and anti-NMDA receptor encephalitis. Ann Neurol. 2018;83(4):863-869. PubMed
Nothlings U, Krawczak M, PopGen. A population-based biobank with prospective follow-up of a control group. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2012;55(6-7):831-835. PubMed
Krawczak M, Nikolaus S, von Eberstein H, Croucher PJ, El Mokhtari NE, Schreiber S. PopGen: population-based recruitment of patients and controls for the analysis of complex genotype-phenotype relationships. Community Genet. 2006;9(1):55-61. PubMed
Purcell S, Neale B, Todd-Brown K, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81(3):559-575. PubMed PMC
R Core Team. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing; 2020.
Meyer HV. plinkQC: Genotype Quality Control in Genetic Association Studies; 2020.
1000 Genomes Project Consortium. A global reference for human genetic variation. Nature. 2015;526(7571):68. PubMed PMC
Brown DW, Myers TA, Machiela MJ. PCAmatchR: a flexible R package for optimal case-control matching using weighted principal components. Bioinformatics 2020. PubMed PMC
Taliun D, Harris DN, Kessler MD, et al. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program. Nature. 2021;590(7845):290-299. PubMed PMC
Das S, Forer L, Schönherr S, et al. Next-generation genotype imputation service and methods. Nat Genet. 2016;48(10):1284-1287. PubMed PMC
Fuchsberger C, Abecasis GR, Hinds DA. minimac2: faster genotype imputation. Bioinformatics. 2015;31(5):782-784. PubMed PMC
Cattell RB. The scree test for the number of factors. Multivariate Behav Res. 1966;1(2):245-276. PubMed
Zheng J, Erzurumluoglu AM, Elsworth BL, et al. LD Hub: a centralized database and web interface to perform LD score regression that maximizes the potential of summary level GWAS data for SNP heritability and genetic correlation analysis. Bioinformatics. 2017;33(2):272-279. PubMed PMC
Zheng X, Shen J, Cox C, et al. HIBAG--HLA genotype imputation with attribute bagging. Pharmacogenomics J. 2014;14(2):192-200. PubMed PMC
Fan Y, Song YQ. PyHLA: tests for the association between HLA alleles and diseases. BMC Bioinformatics. 2017;18(1):90-95. PubMed PMC
GTEx Consortium. Genetic effects on gene expression across human tissues. Nature. 2017;550(7675):204. PubMed PMC
Chen L, Ge B, Casale FP, et al. Genetic drivers of epigenetic and transcriptional variation in human immune cells. Cell. 2016;167(5):1398.e24-1414.e24. PubMed PMC
Giambartolomei C, Vukcevic D, Schadt EE, et al. Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. Plos Genet. 2014;10(5):e1004383. PubMed PMC
Pruim RJ, Welch RP, Sanna S, et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics. 2010;26(18):2336-2337. PubMed PMC
Shu YQ, Qiu W, Zheng JF, et al. HLA class II allele DRB1*16:02 is associated with anti-NMDAR encephalitis. J Neurol Neurosur Psychiatry. 2019;90(6):652-658. PubMed
Giaime E, Tong Y, Wagner LK, Yuan Y, Huang G, Shen J. Age-dependent dopaminergic neurodegeneration and impairment of the autophagy-lysosomal pathway in LRRK-deficient mice. Neuron. 2017;96(4):796-e6. PubMed PMC
Thévenet J, Pescini Gobert R, Hooft van Huijsduijnen R, Wiessner C, Sagot YJ. Regulation of LRRK2 expression points to a functional role in human monocyte maturation. PLoS One. 2011;6(6):e21519. PubMed PMC
Morimoto K, Baba Y, Shinohara H, et al. LRRK1 is critical in the regulation of B-cell responses and CARMA1-dependent NF-κB activation. Sci Rep. 2016;6(1):25738-25813. PubMed PMC
Wenke NK, Kreye J, Andrzejak E, et al. N-methyl-D-aspartate receptor dysfunction by unmutated human antibodies against the NR1 subunit. Ann Neurol. 2019;85(5):771-776. PubMed PMC
Martinez-Hernandez E, Guasp M, Garcia-Serra A, et al. Clinical significance of anti-NMDAR concurrent with glial or neuronal surface antibodies. Neurology. 2020;94(22):e2302-e2310. PubMed
Hirano M, Itoh T, Fujimura H, et al. Pathological findings in male patients with anti-N-methyl-D-Aspartate receptor encephalitis. J Neuropathol Exp Neurol. 2019;78(8):735-741. PubMed
Zhao L, Lei W, Deng C, et al. The roles of liver X receptor α in inflammation and inflammation‐associated diseases. J Cell Physiol 2020. PubMed
Zhang-Gandhi CX, Drew PD. Liver X receptor and retinoid X receptor agonists inhibit inflammatory responses of microglia and astrocytes. J Neuroimmunol. 2007;183(1-2):50-59. PubMed PMC
Wouters E, de Wit NM, Vanmol J, et al. Liver X receptor alpha is important in maintaining blood-brain barrier function. Front Immunol. 2019;10:1811. PubMed PMC