No abstract

Our sleep timing preference, or chronotype, is a manifestation of our internal biological clock. Variation in chronotype has been linked to sleep disorders, cognitive and physical performance, and chronic disease. Here we perform a genome-wide association study of self-reported chronotype within the UK Biobank cohort (n=100,420). We identify 12 new genetic loci that implicate known components of the circadian clock machinery and point to previously unstudied genetic variants and candidate genes that might modulate core circadian rhythms or light-sensing pathways. Pathway analyses highlight central nervous and ocular systems and fear-response-related processes. Genetic correlation analysis suggests chronotype shares underlying genetic pathways with schizophrenia, educational attainment and possibly BMI. Further, Mendelian randomization suggests that evening chronotype relates to higher educational attainment. These results not only expand our knowledge of the circadian system in humans but also expose the influence of circadian characteristics over human health and life-history variables such as educational attainment.

Chronic sleep disturbances, associated with cardio-metabolic diseases, psychiatric disorders and all-cause mortality 1,2 , affect 25-30% of adults worldwide 3 . While environmental factors contribute importantly to self-reported habitual sleep duration and disruption, these traits are heritable 4-9 , and gene identification should improve our understanding of sleep function, mechanisms linking sleep to disease, and development of novel therapies. We report single and multi-trait genome-wide association analyses (GWAS) of self-reported sleep duration, insomnia symptoms including difficulty initiating and/or maintaining sleep, and excessive daytime sleepiness in the UK Biobank (n=112,586), with discovery of loci for insomnia symptoms (near MEIS1, TMEM132E, CYCL1, TGFBI in females and WDR27 in males), excessive daytime sleepiness (near AR/OPHN1) and a composite sleep trait (near INADL and HCRTR2), as well as replication of a locus for sleep duration (at PAX-8). Genetic correlation was observed between longer sleep duration and schizophrenia (r G =0.29, p=1.90x10 -13 ) and between increased excessive daytime sleepiness and increased adiposity traits (BMI r G =0.20, p=3.12x10 -09 ; waist circumference r G =0.20, p=2.12x10 -07 ).Rather than being 'secondary', evidence suggests disordered sleep may play an important role in the etiology and maintenance of physical and mental health 1,2 . Heritability has been estimated at ~40% for sleep duration 4,6-8 , 25-45% for insomnia 9 and 17% for excessive daytime sleepiness 9 , but few genetic factors are known. A Mendelian short sleep mutation in BHLHE41 (P385R) has been identified, and confirmed in mouse models 10 . GWAS for sleep duration have been reported 11-14 , but only an association at the PAX8 locus reached genome-wide significance and was confirmed across ethnic groups 12 . There are several reported loci for restless legs syndrome (RLS) and narcolepsy, but no known robust genetic loci for insomnia symptoms or excessive daytime sleepiness 15,16 .

à These authors contributed equally to this work.Mutations in the colony stimulating factor 1 receptor (CSF1R) have recently been discovered as causal for hereditary diffuse leukoencephalopathy with axonal spheroids. We identified a novel, heterozygous missense mutation in CSF1R [c.1990G 4 A p.(E664K)] by exome sequencing in five members of a family with hereditary diffuse leukoencephalopathy with axonal spheroids. Three affected siblings had characteristic white matter abnormalities and presented with progressive neurological decline. In the fourth affected sibling, early progression halted after allogeneic haematopoietic stem cell transplantation from a related donor. Blood spot DNA from this subject displayed chimerism in CSF1R acquired after haematopoietic stem cell transplantation. Interestingly, both parents were unaffected but the mother's blood and saliva were mosaic for the CSF1R mutation. Our findings suggest that expression of wild-type CSF1R in some cells, whether achieved by mosaicism or chimerism, may confer benefit in hereditary diffuse leukoencephalopathy with axonal spheroids and suggest that haematopoietic stem cell transplantation might have a therapeutic role for this disorder.

The measurement of circulating levels of brain-derived neurotrophic factor (BDNF) has been proposed to be a marker of disease and an indicator of recovery. Thus, knowing the temporal pattern and influence of potential circadian rhythms is important. Although several studies have measured BDNF at different times of day, no studies have done so while controlling for potential masking influences such as sleep and activity. Further, no previous study has examined circadian rhythms within individuals. We examined circadian rhythms in plasma BDNF while minimizing masking from behavioral and environmental factors using a 30-h constant routine (CR) protocol. In a sample of 39 healthy adults, we found significant circadian rhythms in 75% of women and 52% of men. The timing of the acrophase of the BDNF rhythm, however, was unrelated to clock time in women, while it was related to clock time in men. These results indicate that the use of single-sample measures of plasma BDNF as a marker of disease will be unreliable, especially in women. Repeated plasma BDNF samples over a 24-h period within individuals would be needed to reveal abnormalities related to disease states.

Our sleep timing preference, or chronotype, is a manifestation of our internal biological clock. Variation in chronotype has been linked to sleep disorders, cognitive and physical performance, and chronic disease. Here, we perform a genome-wide association study of self-reported chronotype within the UKBiobank cohort (n=100,420). We identify 12 new genetic loci that implicate known components of the circadian clock machinery and point to previously unstudied genetic variants and candidate genes that might modulate core circadian rhythms or lightsensing pathways. Pathway analyses highlight central nervous and ocular systems and fearresponse related processes. Genetic correlation analysis suggests chronotype shares underlying genetic pathways with schizophrenia, educational attainment and possibly BMI. Further, Mendelian randomization suggests that evening chronotype relates to higher educational attainment. These results not only expand our knowledge of the circadian system in humans, but also expose the influence of circadian characteristics over human health and lifehistory variables such as educational attainment.. CC-BY-NC-ND 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/038620 doi: bioRxiv preprint first posted online Feb. 2, 2016; Chronotype is a behavioral manifestation of our internal timing system, the circadian clock. Individual variation within our biological clock drives our morning or evening preferences, thereby making us into "morning larks" or "night owls". Chronotype is influenced by many factors, including age, sex, social constraints, and environmental factors, among others 1 .Chronotype has been associated with sleep disorders, cognitive and physical performance, chronic metabolic and neurologic disease, cancer and premature aging, 2 in particular when there is desynchrony between internal chronotype and external environment increasing disease risk 3 . Despite the importance of circadian rhythms to human health and their fundamental role demonstrated in model organisms, 4,5 little is known about biological mechanisms underlying inter-individual variation in human chronotype or how it impacts on our health and physiology.Genes that encode molecular components of the core circadian clock (PER2, PER3) or regulate the pace of the clock (CSNK1D) are disrupted in Advanced Sleep Phase Syndrome (ASPS) and Delayed Sleep Phase Syndrome (DSPS) both of which are monogenic circadian rhythm disorders causing extreme advance or delay in sleep onset 6 . ASPS mutations shorten circadian period in humans and mice 7,8 , linking the change in pace of the clock with sleep timing preference. More detailed biochemical and functional characterization of these mutations have greatly enhanced understanding mechanisms regulating the circadian clock. Emerging evidence suggests that subjects with ASPS may be at inc...

Short sleep duration has been linked to negative health effects, but is a complex phenotype with many contributing factors, including genetic. We evaluated 27 common single nucleotide polymorphisms (SNPs) in candidate genes previously reported to be associated with other sleep variables for association with self-reported habitual sleep duration in the UK Biobank in 111 975 individuals of European ancestry. Genetic variation in DAT1 (rs464049) was significantly associated with sleep duration after correction for multiple testing (p = 4.00 × 10 −5 ), whereas SNPs correlated to a previously studied variable number tandem repeat (VNTR) in DAT1 were not significant in this population. We also replicated a previously reported association in DRD2. Independent replication of these associations and a second signal in DRD2 (rs11214607) was observed in an additional 261 870 participants of European ancestry from the UK Biobank. Meta-analysis confirmed genome-wide significant association of DAT1 rs464049 (G, beta [standard error, SE] = −0.96 [0.18] minutes/allele, p = 5.71 × 10 −10 ) and studywide significant association of DRD2 (rs17601612, C, beta [SE] = −0.66 [0.18] minutes/allele, p = 1.77 × 10 −5 ; rs11214607, C, beta [SE] = 1.08 (0.24) minutes/allele, p = 1.39 × 10 −6 ). Overall, SNPs in two dopamine-related genes were significantly associated with sleep duration, highlighting the important link of the dopamine system with adult sleep duration in humans.

SLEEP, Volume 40, Abstract Supplement, 201710-repeat allele showed less amplification of the TOT effect during TSD than subjects with the 9-repeat allele. Conclusion: DAT1 genotype modulates the TOT effect on the PVT during TSD. DAT1 is preferentially expressed in the striatum, where genotype affects DAT1 expression and dopamine availability. This suggests a role for striatal dopamine in shaping the impact of TOT and sleep deprivation on performance as measured with the PVT.