Sleep is an essential state of decreased activity and alertness but molecular factors regulating sleep duration remain unknown. Through genome-wide association analysis in 446,118 adults of European ancestry from the UK Biobank, we identify 78 loci for self-reported habitual sleep duration ( p < 5 × 10 −8 ; 43 loci at p < 6 × 10 −9 ). Replication is observed for PAX8 , VRK2 , and FBXL12/UBL5/PIN1 loci in the CHARGE study ( n = 47,180; p < 6.3 × 10 −4 ), and 55 signals show sign-concordant effects. The 78 loci further associate with accelerometer-derived sleep duration, daytime inactivity, sleep efficiency and number of sleep bouts in secondary analysis ( n = 85,499). Loci are enriched for pathways including striatum and subpallium development, mechanosensory response, dopamine binding, synaptic neurotransmission and plasticity, among others. Genetic correlation indicates shared links with anthropometric, cognitive, metabolic, and psychiatric traits and two-sample Mendelian randomization highlights a bidirectional causal link with schizophrenia. This work provides insights into the genetic basis for inter-individual variation in sleep duration implicating multiple biological pathways.

While soliton microcombs offer the potential for integration of powerful frequency metrology and precision spectroscopy systems, their operation requires complex startup and feedback protocols that necessitate difficult-to-integrate optical and electrical components. Moreover, CMOS-rate microcombs, required in nearly all comb systems, have resisted integration because of their power requirements. Here, a regime for turnkey operation of soliton microcombs co-integrated with a pump laser is demonstrated and theoretically explained. Significantly, a new operating point is shown to appear from which solitons are generated through binary turn-on and turn-off of the pump laser, thereby eliminating all photonic/electronic control circuitry. These features are combined with high-Q Si3N4 resonators to fully integrate into a butterfly package microcombs with CMOS frequencies as low as 15 GHz, offering compelling advantages for high-volume production.

Insomnia is a common disorder linked with adverse long-term medical and psychiatric outcomes, but underlying pathophysiological processes and causal relationships with disease are poorly understood. Here we identify 57 loci for self-reported insomnia symptoms in the UK Biobank (n=453,379) and confirm their impact on self-reported insomnia symptoms in the HUNT study (n=14,923 cases, 47,610 controls), physician diagnosed insomnia in Partners Biobank (n=2,217 cases, 14,240 controls), and accelerometer-derived measures of sleep efficiency and sleep duration in the UK Biobank (n=83,726). Our results suggest enrichment of genes involved in ubiquitin-mediated proteolysis, phototransduction and muscle development pathways and of genes expressed in multiple brain regions, skeletal muscle and adrenal gland. Evidence of shared genetic factors is found between frequent insomnia symptoms and restless legs syndrome, aging, cardio-metabolic, behavioral, psychiatric and reproductive traits. Evidence is found for a possible causal link between insomnia symptoms and coronary heart disease, depressive symptoms and subjective well-being. One Sentence Summary: We identify 57 genomic regions associated with insomnia pointing to the involvement of phototransduction and ubiquitination and potential causal links to CAD and depression.

Glycemic traits are used to diagnose and monitor type 2 diabetes, and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here, we aggregated genome-wide association studies in up to 281,416 individuals without diabetes (30% non-European ancestry) with fasting glucose, 2h-glucose post-challenge, glycated hemoglobin, and fasting insulin data. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P <5x10 -8 ), 80% with no significant evidence of between-ancestry heterogeneity. Analyses restricted to European ancestry individuals with equivalent sample size would have led to 24 fewer new loci. Compared to single-ancestry, equivalent sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase understanding of diabetes pathophysiology by use of trans-ancestry studies for improved power and resolution.

For its many useful properties, including second and third-order optical nonlinearity as well as electro-optic control, lithium niobate is considered an important potential microcomb material. Here, a soliton microcomb is demonstrated in a monolithic high-Q lithium niobate resonator. Besides the demonstration of soltion mode locking, the photorefractive effect enables mode locking to self-start and soliton switching to occur bi-directionally. Second-harmonic generation of the soliton spectrum is also observed, an essential step for comb self-referencing. The Raman shock time constant of lithium niobate is also determined by measurement of soliton self-frequency-shift. Besides the considerable technical simplification provided by a self-starting soliton system, these demonstrations, together with the electro-optic and piezoelectric properties of lithium niobate, open the door to a multi-functional microcomb providing f-2f generation and fast electrical control of optical frequency and repetition rate, all of which are critical in applications including time keeping, frequency synthesis/division, spectroscopy and signal generation. arXiv:1812.09610v1 [physics.optics]Abstract In this supplement detailed information is provided on the following: the device design, the experimental setup, the numeric modeling of soliton comb generation with analysis of self-starting mode locking, and the characterization of key device parameters. * These two authors contributed equally. † Electronic

Driven by narrow-linewidth bench-top lasers, coherent optical systems spanning optical communications, metrology and sensing provide unrivalled performance. To transfer these capabilities from the laboratory to the real world, a key missing ingredient is a mass-produced integrated laser with superior coherence. Here, we bridge conventional semiconductor lasers and coherent optical systems using CMOS-foundry-fabricated microresonators with record high Q factor over 260 million and finesse over 42,000. Five orders-of-magnitude noise reduction in the pump laser is demonstrated, and for the first time, fundamental noise below 1 Hz 2 Hz −1 is achieved in an electrically-pumped integrated laser. Moreover, the same configuration is shown to relieve dispersion requirements for microcomb generation that have handicapped certain nonlinear platforms. The simultaneous realization of record-high Q factor, highly coherent lasers and frequency combs using foundry-based technologies paves the way for volume manufacturing of a wide range of coherent optical systems.

High blood pressure (BP) is more prevalent and contributes to more severe manifestations of cardiovascular disease (CVD) in African Americans than in any other United States ethnic group. Several small African-ancestry (AA) BP genome-wide association studies (GWASs) have been published, but their findings have failed to replicate to date. We report on a large AA BP GWAS meta-analysis that includes 29,378 individuals from 19 discovery cohorts and subsequent replication in additional samples of AA (n = 10,386), European ancestry (EA) (n = 69,395), and East Asian ancestry (n = 19,601). Five loci (EVX1-HOXA, ULK4, RSPO3, PLEKHG1, and SOX6) reached genome-wide significance (p < 1.0 × 10(-8)) for either systolic or diastolic BP in a transethnic meta-analysis after correction for multiple testing. Three of these BP loci (EVX1-HOXA, RSPO3, and PLEKHG1) lack previous associations with BP. We also identified one independent signal in a known BP locus (SOX6) and provide evidence for fine mapping in four additional validated BP loci. We also demonstrate that validated EA BP GWAS loci, considered jointly, show significant effects in AA samples. Consequently, these findings suggest that BP loci might have universal effects across studied populations, demonstrating that multiethnic samples are an essential component in identifying, fine mapping, and understanding their trait variability.

Optical microcavities are essential in numerous technologies and scientific disciplines. However, their application in many areas relies exclusively upon discrete microcavities in order to satisfy challenging combinations of ultra-low-loss performance (high cavity-Q-factor) and cavity design requirements. Indeed, finding a microfabrication bridge connecting ultra-high-Q device functions with micro and nanophotonic circuits has been a long-term priority of the microcavity field. Here, an integrated ridge resonator having a record Q factor over 200 million is presented. Its ultralow-loss and flexible cavity design brings performance that has been the exclusive domain of discrete silica and crytalline microcavity devices to integrated systems. Two distinctly different devices are demonstrated: soliton sources with electronic repetition rates and high-coherence Brillouin lasers. This multi-device capability and performance from a single integrated cavity platform represents a critical advance for future nanophotonic circuits and systems.Optical microcavities 1 provide diverse device functions that include frequency microcombs 2,3 , soliton modelocked microcombs 4-8 , Brillouin lasers 9-13 , bio and nanoparticle sensors 14-16 , cavity optomechanical oscillators 17 , parametric oscillators 18,19 , Raman lasers 20 , reference cavities/sources 21-24 , and quantum optical devices 25,26 . Key performance metrics improve with increasing Qfactor across all applications areas 1 . For example, higher Q factors dramatically reduce power consumption as well as phase and intensity noise in signal sources, because these quantities scale inverse quadratically with Q factor. Also, higher Q improves the ability to resolve a resonance for sensing or for frequency stabilization. Such favorable scalings of performance with Q factor have accounted for a sustained period of progress in boosting Q factor by reducing optical loss in resonators across a range of materials 27-31 . Likewise, the need for complex microcavity systems that leverage high-Q factors has driven interest in low-loss monolithically integrated resonators 28,29,[32][33][34][35][36][37][38] . For example, Q values in waveguide-integrated devices to values as high as 80 million 35 and 67 million 38 in strongly-confined resonators have been attained.Nonetheless, the highest Q-factor resonators remain discrete devices that are crystalline 39 or silica based 1,11,40,41 . These discrete resonators are moreover unique in the microcavity world in terms of overall per-formance and breadth of capability. This includes generation of electronic-repetition-rate soliton streams as required in optical clocks 42-44 and optical synthesizers 45 , rotation measurement at near-earth-rate sensitivity in micro-optical-gyros 46,47 , synthesis of high-performance microwave signals 48-51 , and operation as high-stability optical frequency references 21-23 and reference sources 24 . Functions such as these belong to a new class of compact photonic systems that rely upon ultra-high-Q fabrication m...