Genome Wide Analysis of Narcolepsy in China Implicates Novel Immune Loci and Reveals Changes in Association Prior to Versus After the 2009 H1N1 Influenza Pandemic

Abstract

Previous studies in narcolepsy, an autoimmune disorder affecting hypocretin (orexin) neurons and recently associated with H1N1 influenza, have demonstrated significant associations with five loci. Using a well-characterized Chinese cohort, we refined known associations in TRA@ and P2RY11-DNMT1 and identified new associations in the TCR beta (TRB@; rs9648789 max P = 3.7×10−9 OR 0.77), ZNF365 (rs10995245 max P = 1.2×10−11 OR 1.23), and IL10RB-IFNAR1 loci (rs2252931 max P = 2.2×10−9 OR 0.75). Variants in the Human Leukocyte Antigen (HLA)- DQ region were associated with age of onset (rs7744020 P = 7.9×10−9 beta −1.9 years) and varied significantly among cases with onset after the 2009 H1N1 influenza pandemic compared to previous years (rs9271117 P = 7.8×10−10 OR 0.57). These reflected an association of DQB1*03:01 with earlier onset and decreased DQB1*06:02 homozygosity following 2009. Our results illustrate how genetic association can change in the presence of new environmental challenges and suggest that the monitoring of genetic architecture over time may help reveal the appearance of novel triggers for autoimmune diseases.

EIF3G is associated with narcolepsy across ethnicities

“…In the paper by Kornum et al, 5 SNPs rs2305795 and rs12460842 were fine typed in many of the Caucasian samples. Further, rs2305795 was also retyped in the Chinese cohort 6 and all the results were consistent with imputed results. The imputation quality score for rs3826784 was consistently above 0.8 and the overall association on pooled imputed genotypes is considered valid.…”

“…2,6 Statistical analysis of genotyped and imputed genotype data were performed using the PLINK software package (v.1.07) (http://pngu.mgh.harvard.edu/purcell/plink/), 13 and in Haploview 4.2. 11 Associations within ethnic groups were performed with basic allelic χ 2 statistic tests.…”

“…2,6 The initial European ancestry GWA data set was comprised of 807 cases and 1074 DQB1*06:02-positive controls: 415 cases and 753 controls were recruited from the United States and Canada; 392 cases and 321 controls were recruited from European centers. The Chinese GWA data set was comprised of 1078 cases and 1903 controls.…”

“…Analysis of the GWA data (549 596 SNPs in Europeans and 603 382 SNPs in Chinese) was performed as described. 2,6 The African-American sample 1 Molecular Sleep Laboratory, Department of Diagnostics, Glostrup University Hospital, Glostrup, Denmark; contained 1297 individuals (249 cases, 1048 controls). The controls were recruited from the National Institute of Mental Health (NIMH).…”

“…4 One of the genetic associations in narcolepsy is rs2305795, a polymorphism located in the purinergic receptor P2RY11. 5,6 The disease-associated allele of rs2305795 decreases P2RY11 expression and increases the sensitivity of CD8 + T cells to cell death induced by ATP. Interestingly, we also recently found that missense mutation in exon 21 of the DNA methyltransferase 1 (DNMT1) gene causes a rare hereditary form of narcolepsy-associated deafness, cerebellar ataxia and eventually dementia (ADCA-DN).…”