Novel risk loci in LGI1-antibody encephalitis: genome-wide association study discovery and validation cohorts

Abstract

Encephalitis with antibodies to leucine-rich glioma-inactivated 1 (LGI1-Ab-E) is a common form of autoimmune encephalitis, presenting with seizures and neuropsychiatric changes, predominantly in older males. More than 90% of patients carry the human leukocyte antigen (HLA) class II allele, HLA-DRB1*07:01. However, this is also present in 25% of healthy controls. Therefore, we hypothesized the presence of additional genetic predispositions. In this genome-wide association study and meta-analysis, we studied a discovery cohort of 131 French LGI1-Ab-E and a validation cohort of 126 American, British and Irish LGI1-Ab-E patients, ancestry-matched to 2613 and 2538 European controls, respectively. Outside the known major HLA signal, we found two single nucleotide polymorphisms at genome-wide significance (P < 5 × 10-8), implicating PTPRD, a protein tyrosine phosphatase, and LINC00670, a non-protein coding RNA gene. Meta-analysis defined four additional non-HLA loci, including the protein coding COBL gene. Polygenic risk scores with and without HLA variants proposed a contribution of non-HLA loci. In silico network analyses suggested LGI1 and PTPRD-mediated interactions via the established receptors of LGI1, ADAM22 and ADAM23. Our results identify new genetic loci in LGI1-Ab-E. These findings present opportunities for mechanistic studies and offer potential markers of susceptibility, prognostics and therapeutic responses.

Keywords: GWAS; HLA; LGI1; PTPRD; encephalitis; genetics.

Figure 1

Manhattan plots and LocusZoom local plots from the main discovery and replication association analyses. [A(i)] Manhattan plot of the discovery analysis including 131 French LGI1-Ab-E patients and 2613 matched UK Biobank controls. The analysis included 5 462 363 variants and had a lambda of 1.035. Ten single nucleotide polymorphisms (SNPs) achieving genome-wide significance outside the HLA region and the lead HLA SNP are labelled, with those achieving replication designated in teal labelling. [A(ii)] Manhattan plot of the validation analysis including 126 White British, Irish and North American patients and 2538 matched UK Biobank controls. The analysis included 5 385 978 variants and had a lambda of 1.015. Nine SNPs achieving genome-wide significance outside the HLA region and the lead HLA SNP are labelled, with those achieving replication designated in teal labelling. Both plots created using ggmanh. The two black bars on the y-axes delineate a scale change to accommodate the very low P-values associated with the MHC region. The heavy grey dotted line is set at genome-wide significance. [B(i)] Local LocusZoom plots of genetic architecture of the PTPRD hit in the discovery (top) and validation (bottom) cohorts. [B(ii)] Local LocusZoom plots of genetic architecture of the LINC00670 hit in the discovery (top) and validation (bottom) cohorts. Both plots were created using local linkage disequilibrium data imported from PLINK. The grey dotted line represents genomewide significance. HLA = human leukocyte antigen; LINC00670 = long intergenic non-protein coding RNA 670; LGI1-Ab-E = leucine-rich glioma-inactivated 1 antibody encephalitis; PTPRD = protein tyrosine phosphatase receptor type D.

Figure 2

Polygenic risk scores calculated using PRSice and in silico network analyses. [A(i–iv)] Scores calculated passing in all single nucleotide polymorphisms (SNPs) in chromosomes 1–22. [A(i)] Polygenic risk scores (PRSs) at different levels of genome-wide association study (GWAS) significance (x-axis) and the proportion of the phenotype accounted for by the model (y-axis). The significance of each model is shown as the P-value at the top of each bar. [A(ii)] Odds ratio of developing the phenotype at each of five quantiles of the PRS. Black dots show numbers of DRB1*07:01-negative patients in each risk quantile. A(iii and iv) show the same plots for the PRS calculated excluding the HLA region from the SNPs passed in excluding the HLA region on chromosome 6 (chr6:25607979–33607978). [B(i)] In silico network analysis created with Webgestalt passing in LGI1 and PTPRD as seed genes. [B(ii)] In silico network analysis created with Genemania passing in LGI1 and PTPRD as seed genes. Pink lines designate physical interactions; lilac, co-expression; light orange, predicted interactions; medium blue, co-localization; green, genetic interactions; and light blue, shared pathways. An intronic variant of PTPRS achieved suggestive significance in the discovery cohort. HLA = human leukocyte antigen; LGI1 = leucine-rich glioma-inactivated 1; PTPRS = receptor-type tyrosine-protein phosphatase S; PTPRD = protein tyrosine phosphatase receptor type D.