Identifying the potential role of insomnia on multimorbidity: A Mendelian randomization phenome-wide association study in UK Biobank

ObjectivesTo identify the breadth of potential causal effects of insomnia on health outcomes and hence its possible role in multimorbidity. DesignMendelian randomisation (MR) Phenome-wide association study (MR-PheWAS) with two-sample Mendelian randomisation follow-up. SettingIndividual data from UK Biobank and summary data from a number of genome-wide association studies. Participants336,975 unrelated white-British UK Biobank participants. ExposuresStandardised genetic risk of insomnia for the MR-PheWAS and genetically predicted insomnia for the two-sample MR follow-up, with insomnia instrumented by a genetic risk score (GRS) created from 129 single-nucleotide polymorphisms (SNPs). Main outcomes measures11,409 outcomes from UK Biobank extracted and processed by an automated pipeline (PHESANT). Potential causal effects (i.e., those passing a Bonferroni-corrected significance threshold) were followed up with two-sample MR in MR-Base, where possible. Results437 potential causal effects of insomnia were observed for a number of traits, including anxiety, stress, depression, mania, addiction, pain, body composition, immune, respiratory, endocrine, dental, musculoskeletal, cardiovascular and reproductive traits, as well as socioeconomic and behavioural traits. We were able to undertake two-sample MR for 71 of these 437 and found evidence of causal effects (with directionally concordant effect estimates across all analyses) for 25 of these. These included, for example, risk of anxiety disorders (OR=1.55 [95% confidence interval (CI): 1.30, 1.86] per category increase in insomnia), diseases of the oesophagus/stomach/duodenum (OR=1.32 [95% CI: 1.14, 1.53]) and spondylosis (OR=1.57 [95% CI: 1.22, 2.01]). ConclusionInsomnia potentially causes a wide range of adverse health outcomes and behaviours. This has implications for developing interventions to prevent and treat a number of diseases in order to reduce multimorbidity and associated polypharmacy. O_TEXTBOXWhat this paper addsO_ST_ABSWhat is already known on this topicC_ST_ABSO_LIInsomnia symptoms are widespread in the population and insomnia is the second most common mental health disorder after anxiety disorders. C_LIO_LIInsomnia might have broad and numerous effects on health and multimorbidity, but both observational and Mendelian randomisation studies have focused on select hypothesised associations/effects rather than taking a systematic hypothesis-free approach across many health outcomes. C_LI What this study addsO_LIThis study uses a hypothesis-free approach to systematically identify causal effects of insomnia on 11,409 health outcomes; it identified 437 potential causal effects and for 71 that could be followed-up with two-sample MR, 25 showed evidence of a causal effect and were directionally consistent across all analyses. C_LIO_LIThese findings identify potential routes for developing interventions to prevent and treat a number of diseases and reduce multimorbidity and polypharmacy. C_LI C_TEXTBOX