What is the role of genetics in the pathophysiology of narcolepsy?

Updated: Sep 04, 2019
  • Author: Sagarika Nallu, MD; Chief Editor: Selim R Benbadis, MD  more...
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The genetics of narcolepsy are complex. Whereas the concordance is only 35% in monozygotic twins, the risk is as high as 40% in first-degree relatives. [32] Narcolepsy with cataplexy can be produced in animal models by disrupting the gene that encodes the hypocretin (orexin) receptor or ligand gene, thereby disrupting hypocretin neurotransmission. [16]

There is a striking association between narcolepsy and the HLA haplotype DQA1*01:02-DQB1*06:02. A study in individuals of European descent found that nearly all of those with a diagnosis of narcolepsy with cataplexy carry the HLA haplotype DQA1*01:02-DQB1*06:02, compared with only 24% of the general population. [33] Thus, carriage of this haplotype may be necessary but not sufficient for the development of narcolepsy.

A study of genome-wide expression in narcolepsy patients and controls showed an independent effect of allelic dosage of DQB1*06:02 on DQB1*06:02 mRNA levels and protein. [34] This finding supports the suspicion that the risk of narcolepsy is higher in DQB1*06:02 homozygotes than in heterozygotes, suggesting that HLA is functionally involved in the occurrence of narcolepsy. [34]

A genome-wide association study proposed a protective variant (DQB1*06:03). This allele may protect against autoimmune disorders; it is almost never seen in patients with narcolepsy. [35]

Genome-wide association studies in Caucasians, with replication in 3 ethnic groups, have revealed associations between single-nucleotide polymorphisms (SNPs) in the T-cell receptor alpha locus and narcolepsy. [36] This association further supports the autoimmune basis of narcolepsy.

An SNP in the purinergic receptor subtype P2Y11 gene (P2RY11) also appears to be associated with narcolepsy. [37] P2RY11 has been identified as an important regulator of immune cell survival; the disease-associated P2RY11 correlates with a 3-fold lower expression of P2RY11 in CD8+ T-cells and natural killer cells, as well as with decreased P2RY11-mediated resistance to adenosine triphosphate–induced death in those cells.

A genome-wide association study that investigated 202 candidate genes in a replication study in 222 narcoleptic patients and 380 controls identified 6 genes that were associated with narcolepsy: NFATC2, SCP2, CACNA1C, TCRA, POLE, and FAM3D. These gene associations with narcolepsy were further supported by gene expression analyses showing that these same genes are also associated with essential hypersomnia, which is similar to narcolepsy. [38]

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