Genome-wide association analysis of insomnia complaints identifies risk genes and genetic overlap with psychiatric and metabolic traits

Abstract

Persistent insomnia is among the most frequent complaints in general practice. To identify genetic factors for insomnia complaints, we performed a genome-wide association study (GWAS) and a genome-wide gene-association study (GWGAS) in 113,006 individuals. We identify three loci and seven genes of which one locus and five genes are supported by joint analysis with an independent sample (n=7,565). Our top association (MEIS1, P<5×10-8) has previously been implicated in Restless Legs Syndrome (RLS). Additional analyses favor the hypothesis that MEIS1 shows pleiotropy for insomnia and RLS, and that the observed association with insomnia complaints cannot be explained only by the presence of an RLS subgroup. Sex-specific analyses suggested different genetic architectures across sexes in addition to common genetic factors. We show substantial positive genetic overlap with internalizing and metabolic traits and negative overlap with subjective well-being and educational attainment. These findings provide novel insight into the genetic architecture of insomnia.

Polygenic score for neuroticism is related to sleep difficulties

“…In particular, higher genetic propensity to experience negative emotions was related to higher sleeping difficulties because it fostered risk factors for such difficulties, such as phenotypical neuroticism, anxiety and depressive symptoms. This finding adds to existing research that has identified genetic correlations between neuroticism and sleep‐related outcomes by highlighting the potential pathways through which this relationship may operate. However, the mediators tested in the present study explained only part of the relationship between PGS for neuroticism and sleep quality, and other factors may operate in this association.…”

“…The relationship between neuroticism and sleep quality may be explained in part by shared genetic factors, with genetic variants having pleiotropic effects on neuroticism and sleep quality. The evidence for genetic correlations between neuroticism and markers of sleep is mixed, with studies reporting positive genetic correlations with measures of sleep duration and insomnia complaints but not with insomnia disorder . In addition, polygenic risk for disrupted rest‐activity rhythm (an indicator of disrupted circadian function) is related to higher neuroticism .…”

The impact of stress on sleep: Pathogenic sleep reactivity as a vulnerability to insomnia and circadian disorders

“…Given the normal distribution of insomnia in the population (Beattie, Espie, Kyle, & Biello, 2015) and its polygenic basis (Gehrman, Byrne, Gillespie, & Martin, 2011;Hammerschlag et al, 2017;Lane et al, 2017;Lind & Gehrman, 2016), individual differences in vulnerability to sleep disturbance and insomnia are likely to constitute a continuum from outright resilience to vulnerability to acute/transient sleep disturbance through overt chronic insomnia disorder. Although sleep profiles on PSG adaptation nights successfully identify individuals with high sleep reactivity, this method of assessment is hindered by exorbitant resource demands.…”

“…Given the heritability of sleep-wake characteristics and insomnia (Gehrman, Byrne et al, 2011;Gehrman, Meltzer et al, 2011;Hammerschlag et al, 2017;Lane et al, 2017;Lind & Gehrman, 2016;Pack, Keenan, Byrne, & Gehrman, 2016;Palagini et al, 2014), and prognostic value of familial insomnia (Bastien & Morin, 2000;Dauvilliers et al, 2005;Kalmbach, Pillai, Arnedt, Anderson et al, 2016;Singareddy et al, 2012), it is not surprising that early evidence points to a substantial genetic influence on sleep reactivity. The first data to support heritability examined familial aggregation for self-reported sleep reactivity on the FIRST among 23 insomnia-free sibling pairs (Drake et al, 2008).…”

Systematic genetic analyses of GWAS data reveal an association between the immune system and insomnia

“…To assess insomnia complaints, subjects were asked, “Do you have trouble falling asleep at night or do you wake up in the middle of the night?” with four possible responses: “never/rarely,” “sometimes,” “usually,” or “prefer not to answer.” Responses of “usually” were considered complaints, while responses of “never/rarely” or “sometimes” were analyzed as controls. Genome‐wide association studies analyses were run for insomnia complaints, which are predictive of insomnia disorder with little confounding from comorbidity, using logistic regression adjusting for sex, age, top five principal components, and genotyping array (Hammerschlag et al, ).…”