The Pathophysiology of Insomnia

From Models to Molecules (and Back)

Wilfred R. Pigeon; Matthew R. Cribbet


Curr Opin Pulm Med. 2012;18(6):546-553. 

In This Article

Genetic Variants in Humans

Twin studies have been utilized to help untangle genetic and environmental phenotypes associated with the behavioral expression of insomnia. Recent results include to date heritability estimates (30–50%) for insomnia symptoms[38] that share considerable genetic overlap with depression and anxiety.[39] Drake et al.[40] previously designed and validated a self-report measure of stress-related sleep reactivity that was associated with vulnerability to insomnia. In a recent twin study, the genetic variances in heritable insomnia and heritable stress-related sleep reactivity were strongly correlated, suggesting that sleep reactivity may indeed represent a genetic vulnerability for developing insomnia.[41]

A population-based study found that carriers of the previously identified polymorphism of the enzyme responsible for the clearance of extracellular adenosine, which is strongly implicated in the regulation of sleep homeostasis, had higher sleep efficiency than noncarriers, but no other significant differences in sleep continuity or sleep architecture.[44] Among participants who consumed caffeine, an adenosine receptor blocker, carriers for the adenosine deaminase enzyme polymorphism had lower SOL, higher sleep efficiency, less wake time, and higher REM percentage than noncarriers, with no such differences in noncaffeine drinkers. Findings confirm the role of the adenosinergic system in sleep homoeostasis. It would now be of interest to undertake similar investigations in primary insomnia patients compared with good sleepers.

The PER3 gene is involved in sleep regulation, with one variant of the gene, PER34/4, associated with increased SOL and lower homeostatic sleep drive. Among alcohol-dependent patients, presence of the PER34/4 gene was significantly associated with insomnia severity.[45] Despite the limitations and lack of generalizability of these findings, this study implicates PER4/4 as a genetic vulnerability for insomnia.