Genome-wide meta-analysis of insomnia prioritizes genes associated with metabolic and psychiatric pathways

Watanabe, Kyoko; Jansen, Philip R.; Savage, Jeanne E.; Nandakumar, Priyanka; Wang, Xin; Agee, Michelle; Aslibekyan, Stella; Auton, Adam; Bell, Robert K.; Bryc, Katarzyna; Clark, Sarah; Elson, Sarah L.; Fletez-Brant, Kipper; Fontanillas, Pierre; Furlotte, Nicholas A.; Gandhi, Pooja; Heilbron, Karl; Hicks, Barry; Jewett, Ethan M.; Jiang, Yunxuan; Kleinman, Aaron; Lin, Keng-Han; Litterman, Nadia K.; McCreight, Jennifer C.; McIntyre, Matthew H.; McManus, Kimberly F.; Mountain, Joanna L.; Mozaffari, Sahar V.; Noblin, Elizabeth S.; Northover, Carrie A. M.; O’Connell, Jared; Pitts, Steven J.; Poznik, G. David; Sathirapongsasuti, J. Fah; Shelton, Janie F.; Shi, Jing; Shringarpure, Suyash; Tian, Chao; Tung, Joyce Y.; Tunney, Robert J.; Vacic, Vladimir; Wang, Wei; Hinds, David A.; Levey, Daniel F.; Polimanti, Renato; Stein, Murray B.; Someren, Eus J.W. Van; Smit, August B.; Posthuma, Daniëlle

doi:10.1038/s41588-022-01124-w

Cited by 96 publications

(105 citation statements)

References 87 publications

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“…3E ). MEIS1 has commonly been associated with insomnia (Jansen et al ., 2019; Watanabe et al ., 2022) and restless leg syndrome (Lam et al ., 2022; Salminen et al ., 2017; Schulte et al ., 2014; Spieler et al ., 2014), and knockdown in Drosophila resulted in reduced sleep with no change to activity(Palermo et al ., 2021). Likewise, in zebrafish, we observed no significant change to daytime activity (mean difference (95% CI) = 10.93 s/h (−1.62, 23.48), P = 0.2, smd = 0.23) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Work by Lam and colleagues 42 further identified expression quantitative trait loci (eQTL) residing within this region specific to brain cell types, including within the cerebellum, one of the few brain regions where MEIS1 is highly expressed. It has repeatedly been identified as a candidate gene for insomnia 5, 6, 8 ; however, there is debate as to whether its role in sleep disturbance is primarily due to its association with RLS 7, 37 . MEIS1 knockouts have shown hyperactive phenotypes in animal models 43, 44 , but it is unclear if this phenotype translates to sleep.…”

Section: Discussionmentioning

confidence: 99%

“…Large-scale genome-wide association studies (GWAS) have been conducted for insomnia and other sleep traits revealing hundreds of genomic loci 4–8 . Publicly available datasets for chromatin accessibility and gene expression have improved gene mapping in these GWAS studies; however, the majority of loci are still positionally mapped to the nearest gene or mapped using in silico prediction on aggregate data 7 . These approaches may misidentify the true causal gene at a GWAS locus 9–14 , which in turn can lead to mischaracterization of mechanisms underlying insomnia.…”

Section: Introductionmentioning

confidence: 99%

“…Large-scale genome-wide association studies (GWAS) have revealed several hundred genomic loci for insomnia and other sleep traits (Dashti et al ., 2019; Hammerschlag et al ., 2017; Jansen et al ., 2019; Lane et al ., 2017; Watanabe et al ., 2022). Publicly available datasets for chromatin accessibility and gene expression have aided gene mapping at these GWAS loci; however, the majority of loci are still typically positionally mapped to the nearest gene or mapped using in silico prediction on aggregate data (Watanabe et al ., 2022). These approaches can misidentify the true causal effector gene(s) at a GWAS locus (Claussnitzer et al ., 2020; Forgetta et al ., 2022; Fulco et al ., 2019; Lappalainen and MacArthur, 2021; Smemo et al ., 2014; Tam et al ., 2019), which in turn can lead to mischaracterization of mechanisms underlying insomnia and limit the utility of human genomics data for informing clinical care.…”

Section: Introductionmentioning

confidence: 99%

“…Insomnia, along with other sleep traits including sleep duration, napping, and daytime dozing, are heritable and extremely polygenic (Dashti et al ., 2019; Lane et al ., 2017). Large-scale genome-wide association studies (GWAS) have revealed several hundred genomic loci for insomnia and other sleep traits (Dashti et al ., 2019; Hammerschlag et al ., 2017; Jansen et al ., 2019; Lane et al ., 2017; Watanabe et al ., 2022). Publicly available datasets for chromatin accessibility and gene expression have aided gene mapping at these GWAS loci; however, the majority of loci are still typically positionally mapped to the nearest gene or mapped using in silico prediction on aggregate data (Watanabe et al ., 2022).…”

Section: Introductionmentioning

confidence: 99%

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Zebrafish screen of high-confidence effector genes at insomnia GWAS loci implicates conserved regulators of sleep-wake behaviors

Zimmerman

Doldur-Balli

Keenan

et al. 2022

Preprint

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Study objectives: Insomnia is a pervasive sleep disorder with heritability estimates ranging from 22-59 percent. Human genome-wide association studies (GWAS) have identified more than 200 genome-wide significant loci associated with the pathogenesis of insomnia; however, few of the implicated effector genes at these loci have undergone functional characterization, and little is known of their relevance to sleep dysfunction in insomnia. High-throughput phenotyping in model organisms, especially for conserved traits like sleep, provides an opportunity for enhanced gene prioritization to improve mechanistic understanding of this complex polygenic disorder and to yield strong genetic candidates for therapeutic intervention. Methods: Leveraging existing datasets, we performed a functional screen of candidate insomnia-associated genes in zebrafish. Our previous 3D-genomics approach, which integrated ATAC-seq RNA-seq and high-resolution promoter-focused Capture C in neural progenitor cells, revealed putatively causal variants and corresponding effector genes at insomnia GWAS loci. We went on to report first-pass neuron-specific RNA interference screening in Drosophila to implicate high-confidence effector genes at these genetic signals. This current study builds on those initial observations by leveraging CRISPR/Cas9 in a diurnal vertebrate model, namely larval zebrafish (5-7 days post fertilization), to perform functional validation of six top candidates to determine conserved regulators of sleep behaviors relevant to insomnia. Results: CRISPR mutation of three high-confidence insomnia-implicated effector genes (MEIS1, SKIV2L, and ARFGAP2) resulted in robust changes to sleep and activity patterns in larval zebrafish. Specifically, we observed phenotypes that reflect insomnia-like behaviors, including altered sleep duration, poor sleep consolidation, and impaired latency to sleep onset after lights off. Moreover, mutation of ARFGAP2 also impacted development resulting in a significant motor phenotype. Conclusions: Our results reveal the utility of CRISPR/Cas9 in F0 larval zebrafish for high-throughput screening of GWAS-implicated candidate effector genes. We validated three of the six strongest candidate effector genes identified in our previous combined 3D Genomic and Drosophila screen, two of which were 3D-mapped to different genes rather than the nearest gene reported in the original insomnia GWAS study. Together, we demonstrate the necessity for functional validation of GWAS-implicated effector genes, and we provide evidence for two novel genes producing sleep-wake phenotypes not previously suggested through positional mapping alone.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Zebrafish screen of high-confidence effector genes at insomnia GWAS loci implicates conserved regulators of sleep-wake behaviors

Zimmerman

Doldur-Balli

Keenan

et al. 2022

Preprint

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The Role of Circadian Rhythms and Sleep in Anorexia Nervosa

Wilcox,

Paz,

Saxena

et al. 2024

JAMA Netw Open

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ImportanceObservational studies have associated anorexia nervosa with circadian rhythms and sleep traits. However, the direction of causality and the extent of confounding by psychosocial comorbidities in these associations are unknown.ObjectivesTo investigate the association between anorexia nervosa and circadian and sleep traits through mendelian randomization and to test the associations between a polygenic risk score (PRS) for anorexia nervosa and sleep disorders in a clinical biobank.Design, Setting, and ParticipantsThis genetic association study used bidirectional 2-sample mendelian randomization with summary-level genetic associations between anorexia nervosa (from the Psychiatric Genomics Consortium) and chronotype and sleep traits (primarily from the UK Biobank). The inverse-variance weighted method, in addition to other sensitivity approaches, was used. From the clinical Mass General Brigham (MGB) Biobank (n = 47 082), a PRS for anorexia nervosa was calculated for each patient and associations were tested with prevalent sleep disorders derived from electronic health records. Patients were of European ancestry. All analyses were performed between February and August 2023.ExposuresGenetic instruments for anorexia nervosa, chronotype, daytime napping, daytime sleepiness, insomnia, and sleep duration.Main Outcomes and MeasuresChronotype, sleep traits, risk of anorexia nervosa, and sleep disorders derived from a clinical biobank.ResultsThe anorexia nervosa genome-wide association study included 16 992 cases (87.7%-97.4% female) and 55 525 controls (49.6%-63.4% female). Genetic liability for anorexia nervosa was associated with a more morning chronotype (β = 0.039; 95% CI, 0.006-0.072), and conversely, genetic liability for morning chronotype was associated with increased risk of anorexia nervosa (β = 0.178; 95% CI, 0.042-0.315). Associations were robust in sensitivity and secondary analyses. Genetic liability for insomnia was associated with increased risk of anorexia nervosa (β = 0.369; 95% CI, 0.073-0.666); however, sensitivity analyses indicated bias due to horizontal pleiotropy. The MGB Biobank analysis included 47 082 participants with a mean (SD) age of 60.4 (17.0) years and 25 318 (53.8%) were female. A PRS for anorexia nervosa was associated with organic or persistent insomnia in the MGB Biobank (odds ratio, 1.10; 95% CI, 1.03-1.17). No associations were evident for anorexia nervosa with other sleep traits.Conclusions and RelevanceThe results of this study suggest that in contrast to other metabo-psychiatric diseases, anorexia nervosa is a morningness eating disorder and further corroborate findings implicating insomnia in anorexia nervosa. Future studies in diverse populations and with subtypes of anorexia nervosa are warranted.

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Association of Genetically Predicted Insomnia With Risk of Sepsis

et al. 2023

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ImportanceInsomnia has been associated with altered inflammatory response as well as increased risk of infections and sepsis in observational studies. However, these studies are prone to bias, such as residual confounding. To further understand the potential causal association between insomnia and sepsis risk, a 2-sample Mendelian randomization (MR) approach should be explored.ObjectiveTo evaluate whether genetically predicted insomnia is associated with risk of sepsis.Design, Setting, and ParticipantsTwo-sample MR was performed to estimate the association between genetically predicted insomnia and sepsis risk. Data were obtained from a genome-wide association study identifying 555 independent genetic variants (R2 &lt; 0.01) strongly associated with insomnia (P &lt; 5 × 10−8). Sensitivity analyses were conducted to address bias due to pleiotropy and sample overlap, along with mediation analyses and sex-stratified analyses. The insomnia data set included 2.4 million individuals of European ancestry from the UK Biobank and 23andMe. For sepsis, 462 918 individuals of European ancestry from the UK Biobank were included. Data were extracted between February and December 2022 and analyzed between March 2022 and March 2023.ExposureGenetically predicted insomnia.Main Outcome and MeasureSepsis.ResultsThere were 593 724 individuals with insomnia and 10 154 cases of sepsis. A doubling in the population prevalence of genetically predicted insomnia was associated with an odds ratio of 1.37 (95% CI, 1.19-1.57; P = 7.6 × 10−6) for sepsis. Sensitivity analyses supported this observation. One-third of the association between genetically predicted insomnia and risk of sepsis was mediated through a combination of cardiometabolic risk factors for sepsis (body mass index, type 2 diabetes, smoking, or cardiovascular disease; overall proportion, 35.2%; 95% CI, 5.1-76.9). The association between insomnia and sepsis was more pronounced among women compared with men (women: odds ratio, 1.44; 95% CI, 1.24-1.68; men: OR, 1.10; 95% CI, 0.86-1.40).Conclusions and RelevanceThe concordance between these findings and previous observational studies supports that insomnia is potentially causally associated with the risk of sepsis. Thus, insomnia is a potential preventable risk factor of sepsis that should be further investigated, also in non-European populations.

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Genome-wide meta-analysis of insomnia prioritizes genes associated with metabolic and psychiatric pathways

Cited by 96 publications

References 87 publications

Zebrafish screen of high-confidence effector genes at insomnia GWAS loci implicates conserved regulators of sleep-wake behaviors

Zebrafish screen of high-confidence effector genes at insomnia GWAS loci implicates conserved regulators of sleep-wake behaviors

The Role of Circadian Rhythms and Sleep in Anorexia Nervosa

Association of Genetically Predicted Insomnia With Risk of Sepsis

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