GWAS in NMDAR Encephalitis

Autoimmune encephalitis are characterized by the subacute development of memory deficits, altered mental status, and psychiatric symptoms, generally in association with anti-neuronal antibodies. Two main groups of autoimmune encephalitis may be distinguished based on the location of the targeted antigen: 1) Intracellular antigens, in which the antibodies are thought not to be pathogenic, and the disorders are usually strongly associated with cancer, constituting therefore paraneoplastic neurological syndromes; 2) Synaptic proteins and surface receptors, in which the antibodies are pathogenic and the frequency of cancer is variable depending on the antibody and the demographic characteristics of the patient.

Encephalitis with antibodies against N-methy-D-aspartate receptor is the most common autoimmune encephalitis, being even more frequent than infectious etiologies. It is characterized by subacute onset of memory deficits, psychiatric symptoms, speech dysfunction, seizures, movement disorders, decreased level of consciousness, dysautonomia and central hypoventilation. Nearly 50% of women with anti-NMDAR encephalitis have an ovarian teratoma, while associated tumors in elderly patients are usually carcinomas. In contrast, most cases in children and young men are non-paraneoplastic. Recently, herpes-simplex encephalitis has been described as another trigger of NMDAR encephalitis. Conversely, for the vast majority of the non-paraneoplastic autoimmune encephalitis, no acquired triggers have been described so far.

In addition to acquired susceptibility, genetic predisposition may also be important in the pathogenesis of autoimmune encephalitis. The human leukocyte antigen (HLA) is the genetic factor most frequently associated with autoimmune diseases, and it has been already linked to a few autoimmune encephalitis, such as anti-leucine rich glioma inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2), IgLON5, and glutamic acid decarboxylase 65 (GAD65) encephalitis. However, no HLA association has been reported for NMDAR encephalitis, suggesting that in this condition, and likely in others, non-HLA loci might be involved in the pathogenesis as well.

Genome-wide association studies (GWAS) are useful tools to identify variants at genomic loci that are associated with complex diseases, and in particular, to detect associations between single-nucleotide polymorphisms (SNPs) and diseases. The aim of the study is to detect genetic variants in NMDAR encephalitis and other autoimmune encephalitis.