A variant at 9q34.11 is associated with HLA-DQB1*06:02 negative essential hypersomnia

Area of Science:

• Genetics
• Neurology
• Metabolomics

Background:

• Essential hypersomnia (EHS) is a lifelong disorder of excessive daytime sleepiness.
• EHS is associated with HLA-DQB1*06:02, similar to narcolepsy.
• DQB1*06:02-positive and -negative EHS may have different pathological pathways.

Purpose of the Study:

• To identify genetic associations for DQB1*06:02-negative EHS.
• To investigate the functional consequences of identified genetic variants.

Main Methods:

• Genome-wide association study with replication in Japanese individuals (408 EHS patients, 2247 controls).
• Analysis of single-nucleotide polymorphism (SNP) rs10988217 near the CRAT gene.
• Correlation of risk allele with CRAT expression and blood succinylcarnitine levels.

Main Results:

• A significant association was found between rs10988217 and DQB1*06:02-negative EHS (P = 7.5 × 10⁻⁹).
• The risk allele correlated with higher CRAT expression in various tissues, including brain.
• The risk allele was strongly associated with increased blood succinylcarnitine levels (P = 1.4 × 10⁻¹⁸).

Conclusions:

• DQB1*06:02-negative EHS is associated with a specific genetic variant near the CRAT gene.
• This finding suggests a potential underlying dysfunction in energy metabolic pathways in EHS.