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.

Background Insomnia Disorder (ID) is the second-most prevalent mental disorder and a primary risk factor for depression. Inconsistent clinical and biomarker findings suggest heterogeneity and unrecognized subtypes. Previous top-down proposed subtypes had insufficient validity. The present large-scale study aimed to reveal robust subtypes using data-driven analyses on a high-dimensional set of biologically based traits. Methods Netherlands Sleep Registry participants (N=4,322; 2,224 with probable ID) completed up to 34 trait questionnaires. ID subtypes were identified using latent class analyses. Validity was evaluated in an independent sample and by assessing within-subject stability over years. Clinical relevance was extensively assessed in all subtypes for the development of sleep complaints, comorbidities including depression and response to benzodiazepines, and in two subtypes for an EEG biomarker and effectiveness of cognitive behavioral therapy. To facilitate implementation, a concise subtype questionnaire was constructed and validated in an independent sample. Outcomes Five novel ID subtypes were identified: one labelled as highly distressed, two as moderately distressed with either intact or weak responses to pleasurable emotions, and two as low distressed with either high or low reactivity to environment and life time events. A participant could be classified with high probability to only one subtype, and also in an independent replication sample five subtypes were again optimal (posterior probabilities 0•91-1•00). Participants reassessed 4•8±1•6 years later (N=215) maintained their subtype with high probability (0•87); indicating high stability. Clinical relevance showed from subtype differences in developmental etiology, response to treatment, an EEG biomarker, and up to five-fold differing risk of depression. Interpretation High-dimensional data-driven subtyping of people with insomnia solved an unmet need of heterogeneity reduction. Subtyping facilitates progress in finding mechanisms, developing personalized treatment, and selecting cases with the highest risk of depression for inclusion in preventive trials. Funding European Research Council (ERC-ADG-2014-671084-INSOMNIA); Netherlands Organization for Scientific Research (VICI-453-07-001). 4322 Sleep Registry database search for ISI and one additional questionnaire completed 2224 probable ID; Latent Class Analysis 2098 excluded ISI < 10 control reference values 1046 probable ID; subtype profiles and interpretation 1178 excluded for interpretation completed < 10 questionnaires 215 probable ID; Latent Transition Analysis 831 lost to follow-up 614 Sleep Registry database search for completed Insomnia Type Questionnaire and ISI 251 independent non-overlapping probable ID; Latent Class Analysis 363 excluded were included in original probable ID sample to develop model 244 received DSM-5 face-to-face diagnosis to validate ISI cutoff

The mechanisms underlying hyperarousal, the key symptom of insomnia, have remained elusive, hampering cause-targeted treatment. Recently, restless rapid-eye-movement (REM) sleep emerged as a robust signature of sleep in insomnia. Given the role of REM sleep in emotion regulation, we hypothesized that restless REM sleep could interfere with the overnight resolution of emotional distress, thus contributing to accumulation of arousal. Participants (n = 1,199) completed questionnaires on insomnia severity, hyperarousal, self-conscious emotional distress, and thought-like nocturnal mentation that was validated to be a specific proxy for restless REM sleep (selective fragmentation: R = 0.57, P < 0.001; eye movement density: R = 0.46, P < 0.01) in 32 polysomnographically assessed participants. The experience of distress lasting overnight increased with insomnia severity (β = 0.29, P < 10 −23 ), whereas shortlasting distress did not (β = −0.02, P = 0.41). Insomnia severity was associated with hyperarousal (β = 0.47, P < 10 −63 ) and with the thought-like nocturnal mentation that is specifically associated with restless REM sleep (β = 0.31, P < 10 −26 ). Structural equation modeling showed that 62.4% of the association between these key characteristics of insomnia was mediated specifically by reduced overnight resolution of emotional distress. The model outperformed all alternative mediation pathways. The findings suggest that restless REM sleep reflects a process that interferes with the overnight resolution of distress. Its accumulation may promote the development of chronic hyperarousal, giving clinical relevance to the role of REM sleep in emotion regulation in insomnia, depression, and posttraumatic stress disorder.B oth insomnia and affective disorders are among the most prevalent and burdening health concerns facing our society. Targeted prevention of affective disorders in people at risk, as well as identification of mechanisms of conversion, could be the most viable approach to mitigate their increasing global burden (1). For the prevention of new-onset or recurrent affective disorder, insomnia may be the major risk factor that can be targeted best (2, 3). About 13% of people with insomnia develop major depression disorder (MDD) within a year (2). Moreover, remission rates after cognitive behavioral therapy are 21% lower for depressed patients with abnormal sleep compared with patients with relatively intact sleep (4). It therefore appears highly relevant to understand the mechanisms involved in the role of insomnia in disturbed emotion regulation (2). The present study addresses the roles of restless rapid-eye-movement (REM) sleep (5) and chronic physiological arousal (6), which are characteristic of both insomnia and MDD.Although sleep contributes to the more robust consolidation of emotional memories, relative to neutral memories (7, 8), their later recall is not associated with anywhere near the same magnitude of subjective emotional distress, autonomic arousal, and amygdala activation (7, 9-11). REM sleep p...