ImmunoChip study implicates antigen presentation to T cells in narcolepsy

Abstract

Recent advances in the identification of susceptibility genes and environmental exposures provide broad support for a post-infectious autoimmune basis for narcolepsy/hypocretin (orexin) deficiency. We genotyped loci associated with other autoimmune and inflammatory diseases in 1,886 individuals with hypocretin-deficient narcolepsy and 10,421 controls, all of European ancestry, using a custom genotyping array (ImmunoChip). Three loci located outside the Human Leukocyte Antigen (HLA) region on chromosome 6 were significantly associated with disease risk. In addition to a strong signal in the T cell receptor alpha (TRA@), variants in two additional narcolepsy loci, Cathepsin H (CTSH) and Tumor necrosis factor (ligand) superfamily member 4 (TNFSF4, also called OX40L), attained genome-wide significance. These findings underline the importance of antigen presentation by HLA Class II to T cells in the pathophysiology of this autoimmune disease.

Figure 1. Manhattan Plot of association statistics.

The significance threshold used (blue line) was P = 5×10⁻⁸; The insets depict plots of 1) association results in a broad region encompassing the HLA locus (chr 6:24,067–35,474 kb) that were excluded from the present analysis (see Methods) and 2) QQ plot of results for 109,777 markers after excluding a 1 Mb window surrounding the associated loci (λ = 1.004). The inflation statistic for all 111,240 tested markers is 1.04.

Figure 2. Association signal at the mapping intervals flanking rs34593439 and rs7553711.

Association scores at 15q25.1 (panel A) and 1q25.1 (panel B). Genotyped (diamonds) and imputed (circles) SNPs are indicated and the top genotyped SNP in the interval is outlined in orange. A SNP in 15q25.1 previously associated with Diabetes is outlined in blue. The degree of red color in each diamond or circle indicates the strength of LD with the top SNP (on a scale shown in the legend at the upper left hand corner of the plot). The X-axis shows the chromosome and physical distance (kb) from the human genome reference sequence (hg19), the left Y-axis shows the negative base ten logarithm of the p-value and the right Y-axis shows recombination rate (cM/Mb) as a navy line. The genome-wide significance threshold (P<5×10⁻⁸) is given by the dashed grey line. Genes in the regions are annotated at the bottom as green arrows. Also indicated in 1q25.1 is a ∼130 kb region with no SNPs on the ImmunoChip.