Variant between CPT1B and CHKB associated with susceptibility to narcolepsy

Area of Science:

• Genetics
• Neuroscience
• Sleep Medicine

Background:

• Narcolepsy is a sleep disorder associated with hypocretin deficiency, characterized by excessive daytime sleepiness, cataplexy, and REM sleep abnormalities.
• Strong associations exist with HLA-DRB1*1501 and HLA-DQB1*0602, but other susceptibility genes are likely involved.

Purpose of the Study:

• To identify novel genetic susceptibility loci for narcolepsy beyond the HLA region.
• To investigate the role of candidate genes CPT1B and CHKB in narcolepsy pathogenesis.

Main Methods:

• Genome-wide association study (GWAS) using 500K SNP microarrays in Japanese individuals.
• Replication in Japanese, Korean, European, and African American populations.
• Gene expression analysis using real-time quantitative PCR in white blood cells.

Main Results:

• A single nucleotide polymorphism (SNP), rs5770917, located between CPT1B and CHKB, showed significant association with narcolepsy across multiple ancestries.
• Individuals with the associated allele (rs5770917[C]) exhibited decreased expression of both CPT1B and CHKB.
• CPT1B is involved in beta-oxidation regulating REM sleep theta frequency, and CHKB is crucial for acetylcholine metabolism, a neurotransmitter regulating REM sleep and wakefulness.

Conclusions:

• A genetic variant regulating CPT1B or CHKB expression is associated with narcolepsy.
• CPT1B and CHKB are plausible candidate genes contributing to narcolepsy susceptibility.
• These findings expand our understanding of the genetic underpinnings of narcolepsy.