Publications

2020
Lei Gao, Peng Li, Longcong Cui, Patricia M Wong, Oluwaseun Johnson-Akeju, Jacqueline Lane, Richa Saxena, Frank Scheer, and Kun Hu. 2020. “Sleep Disturbance and Incident Alzheimer’s Disease; a UK Biobank study of 502,538 Middle-Aged to Older Participants.” In 2020 Alzheimer's Association International Conference. ALZ.
Lei Gao, Peng Li, Longcong Cui, Patricia M Wong, Oluwaseun Johnson-Akeju, Jacqueline Lane, Richa Saxena, Frank Scheer, and Kun Hu. 2020. “Sleep disturbance and incident Alzheimer’s disease: A UK Biobank study of 502,538 middle-aged to older participants: Biomarkers (non-neuroimaging): Alzheimer's disease incidence, risk factors and biomarkers.” Alzheimer's & Dementia, 16, Pp. e044575.
2019
Jessica A Rhodes, Jacqueline M Lane, Irma M Vlasac, Martin K Rutter, Charles A Czeisler, and Richa Saxena. 2019. “Association of DAT1 genetic variants with habitual sleep duration in the UK Biobank.” Sleep, 42, 1, Pp. zsy193.
Jacqueline M Lane, Samuel E Jones, Hassan S Dashti, Andrew R Wood, Krishna G Aragam, Vincent T van Hees, Linn B Strand, Bendik S Winsvold, Heming Wang, Jack Bowden, Yanwei Song, Krunal Patel, Simon G Anderson, Robin N Beaumont, David A Bechtold, Brian E Cade, Mary Haas, Sekar Kathiresan, Max A Little, Annemarie I Luik, Andrew S Loudon, Shaun Purcell, Rebecca C Richmond, Frank AJL Scheer, Barbara Schormair, Jessica Tyrrell, John W Winkelman, Juliane Winkelmann, Kristian Hveem, Chen Zhao, Jonas B Nielsen, Cristen J Willer, Susan Redline, Kai Spiegelhalder, Simon D Kyle, David W Ray, John-Anker Zwart, Ben Brumpton, Timothy M Frayling, Deborah A Lawlor, Martin K Rutter, Michael N Weedon, and Richa Saxena. 2019. “Biological and clinical insights from genetics of insomnia symptoms.” Nat Genet, 51, 3, Pp. 387-393.Abstract
Insomnia is a common disorder linked with adverse long-term medical and psychiatric outcomes. The underlying pathophysiological processes and causal relationships of insomnia with disease are poorly understood. Here we identified 57 loci for self-reported insomnia symptoms in the UK Biobank (n = 453,379) and confirmed their effects on self-reported insomnia symptoms in the HUNT Study (n = 14,923 cases and 47,610 controls), physician-diagnosed insomnia in the Partners Biobank (n = 2,217 cases and 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 and of genes expressed in multiple brain regions, skeletal muscle, and adrenal glands. Evidence of shared genetic factors was found between frequent insomnia symptoms and restless legs syndrome, aging, and cardiometabolic, behavioral, psychiatric, and reproductive traits. Evidence was found for a possible causal link between insomnia symptoms and coronary artery disease, depressive symptoms, and subjective well-being.
Jacqueline M Lane, Samuel E Jones, Hassan S Dashti, Andrew R Wood, Krishna G Aragam, Vincent T van Hees, Linn B Strand, Bendik S Winsvold, Heming Wang, Jack Bowden, and others. 2019. “Biological and clinical insights from genetics of insomnia symptoms.” Nature genetics, 51, 3, Pp. 387–393.
Anne-Marie Chang, Jeanne F Duffy, Orfeu M Buxton, Jacqueline M Lane, Daniel Aeschbach, Clare Anderson, Andrew C Bjonnes, Sean W Cain, Daniel A Cohen, Timothy M Frayling, and others. 2019. “Chronotype genetic variant in PER2 is associated with intrinsic circadian period in humans.” Scientific reports, 9, 1, Pp. 1–10.
Anne-Marie Chang, Jeanne F Duffy, Orfeu M Buxton, Jacqueline M Lane, Daniel Aeschbach, Clare Anderson, Andrew C Bjonnes, Sean W Cain, Daniel A Cohen, Timothy M Frayling, Joshua J Gooley, Samuel E Jones, Elizabeth B Klerman, Steven W Lockley, Mirjam Munch, Shantha MW Rajaratnam, Melanie Rueger, Martin K Rutter, Nayantara Santhi, Karine Scheuermaier, Eliza Van Reen, Michael N Weedon, Charles A Czeisler, Frank AJL Scheer, and Richa Saxena. 2019. “Chronotype Genetic Variant in PER2 is Associated with Intrinsic Circadian Period in Humans.” Sci Rep, 9, 1, Pp. 5350.Abstract
The PERIOD2 (PER2) gene is a core molecular component of the circadian clock and plays an important role in the generation and maintenance of daily rhythms. Rs35333999, a missense variant of PER2 common in European populations, has been shown to associate with later chronotype. Chronotype relates to the timing of biological and behavioral activities, including when we sleep, eat, and exercise, and later chronotype is associated with longer intrinsic circadian period (cycle length), a fundamental property of the circadian system. Thus, we tested whether this PER2 variant was associated with circadian period and found significant associations with longer intrinsic circadian period as measured under forced desynchrony protocols, the 'gold standard' for intrinsic circadian period assessment. Minor allele (T) carriers exhibited significantly longer circadian periods when determinations were based on either core body temperature or plasma melatonin measurements, as compared to non-carriers (by 12 and 11 min, respectively; accounting for ~7% of inter-individual variance). These findings provide a possible underlying biological mechanism for inter-individual differences in chronotype, and support the central role of PER2 in the human circadian timing system.
Daniel A Lee, Justin Liu, Young Hong, Jacqueline M Lane, Andrew J Hill, Sarah L Hou, Heming Wang, Grigorios Oikonomou, Uyen Pham, Jae Engle, and others. 2019. “Evolutionarily conserved regulation of sleep by epidermal growth factor receptor signaling.” Science advances, 5, 11, Pp. eaax4249.
Samuel E Jones, Vincent T van Hees, Diego R Mazzotti, Pedro Marques-Vidal, Séverine Sabia, Ashley van der Spek, Hassan S Dashti, Jorgen Engmann, Desana Kocevska, Jessica Tyrrell, and others. 2019. “Genetic studies of accelerometer-based sleep measures yield new insights into human sleep behaviour.” Nature communications, 10, 1, Pp. 1–12.
Samuel E Jones, Vincent T van Hees, Diego R Mazzotti, Pedro Marques-Vidal, Séverine Sabia, Ashley van der Spek, Hassan S Dashti, Jorgen Engmann, Desana Kocevska, Jessica Tyrrell, Robin N Beaumont, Melvyn Hillsdon, Katherine S Ruth, Marcus A Tuke, Hanieh Yaghootkar, Seth A Sharp, Yingjie Ji, Jamie W Harrison, Rachel M Freathy, Anna Murray, Annemarie I Luik, Najaf Amin, Jacqueline M Lane, Richa Saxena, Martin K Rutter, Henning Tiemeier, Zoltán Kutalik, Meena Kumari, Timothy M Frayling, Michael N Weedon, Philip R Gehrman, and Andrew R Wood. 2019. “Genetic studies of accelerometer-based sleep measures yield new insights into human sleep behaviour.” Nat Commun, 10, 1, Pp. 1585.Abstract
Sleep is an essential human function but its regulation is poorly understood. Using accelerometer data from 85,670 UK Biobank participants, we perform a genome-wide association study of 8 derived sleep traits representing sleep quality, quantity and timing, and validate our findings in 5,819 individuals. We identify 47 genetic associations at P < 5 × 10, of which 20 reach a stricter threshold of P < 8 × 10. These include 26 novel associations with measures of sleep quality and 10 with nocturnal sleep duration. The majority of identified variants associate with a single sleep trait, except for variants previously associated with restless legs syndrome. For sleep duration we identify a missense variant (p.Tyr727Cys) in PDE11A as the likely causal variant. As a group, sleep quality loci are enriched for serotonin processing genes. Although accelerometer-derived measures of sleep are imperfect and may be affected by restless legs syndrome, these findings provide new biological insights into sleep compared to previous efforts based on self-report sleep measures.
Samuel E Jones, Jacqueline M Lane, Andrew R Wood, Vincent T van Hees, Jessica Tyrrell, Robin N Beaumont, Aaron R Jeffries, Hassan S Dashti, Melvyn Hillsdon, Katherine S Ruth, and others. 2019. “Genome-wide association analyses of chronotype in 697,828 individuals provides insights into circadian rhythms.” Nature communications, 10, 1, Pp. 1–11.
Samuel E Jones, Jacqueline M Lane, Andrew R Wood, Vincent T van Hees, Jessica Tyrrell, Robin N Beaumont, Aaron R Jeffries, Hassan S Dashti, Melvyn Hillsdon, Katherine S Ruth, Marcus A Tuke, Hanieh Yaghootkar, Seth A Sharp, Yingjie Jie, William D Thompson, Jamie W Harrison, Amy Dawes, Enda M Byrne, Henning Tiemeier, Karla V Allebrandt, Jack Bowden, David W Ray, Rachel M Freathy, Anna Murray, Diego R Mazzotti, Philip R Gehrman, Debbie A Lawlor, Timothy M Frayling, Martin K Rutter, David A Hinds, Richa Saxena, and Michael N Weedon. 2019. “Genome-wide association analyses of chronotype in 697,828 individuals provides insights into circadian rhythms.” Nat Commun, 10, 1, Pp. 343.Abstract
Being a morning person is a behavioural indicator of a person's underlying circadian rhythm. Using genome-wide data from 697,828 UK Biobank and 23andMe participants we increase the number of genetic loci associated with being a morning person from 24 to 351. Using data from 85,760 individuals with activity-monitor derived measures of sleep timing we find that the chronotype loci associate with sleep timing: the mean sleep timing of the 5% of individuals carrying the most morningness alleles is 25 min earlier than the 5% carrying the fewest. The loci are enriched for genes involved in circadian regulation, cAMP, glutamate and insulin signalling pathways, and those expressed in the retina, hindbrain, hypothalamus, and pituitary. Using Mendelian Randomisation, we show that being a morning person is causally associated with better mental health but does not affect BMI or risk of Type 2 diabetes. This study offers insights into circadian biology and its links to disease in humans.
Heming Wang, Jacqueline M Lane, Samuel E Jones, Hassan S Dashti, Hanna M Ollila, Andrew R Wood, Vincent T van Hees, Ben Brumpton, Bendik S Winsvold, Katri Kantojärvi, Teemu Palviainen, Brian E Cade, Tamar Sofer, Yanwei Song, Krunal Patel, Simon G Anderson, David A Bechtold, Jack Bowden, Richard Emsley, Simon D Kyle, Max A Little, Andrew S Loudon, Frank AJL Scheer, Shaun M Purcell, Rebecca C Richmond, Kai Spiegelhalder, Jessica Tyrrell, Xiaofeng Zhu, Christer Hublin, Jaakko A Kaprio, Kati Kristiansson, Sonja Sulkava, Tiina Paunio, Kristian Hveem, Jonas B Nielsen, Cristen J Willer, John-Anker Zwart, Linn B Strand, Timothy M Frayling, David Ray, Deborah A Lawlor, Martin K Rutter, Michael N Weedon, Susan Redline, and Richa Saxena. 2019. “Genome-wide association analysis of self-reported daytime sleepiness identifies 42 loci that suggest biological subtypes.” Nat Commun, 10, 1, Pp. 3503.Abstract
Excessive daytime sleepiness (EDS) affects 10-20% of the population and is associated with substantial functional deficits. Here, we identify 42 loci for self-reported daytime sleepiness in GWAS of 452,071 individuals from the UK Biobank, with enrichment for genes expressed in brain tissues and in neuronal transmission pathways. We confirm the aggregate effect of a genetic risk score of 42 SNPs on daytime sleepiness in independent Scandinavian cohorts and on other sleep disorders (restless legs syndrome, insomnia) and sleep traits (duration, chronotype, accelerometer-derived sleep efficiency and daytime naps or inactivity). However, individual daytime sleepiness signals vary in their associations with objective short vs long sleep, and with markers of sleep continuity. The 42 sleepiness variants primarily cluster into two predominant composite biological subtypes - sleep propensity and sleep fragmentation. Shared genetic links are also seen with obesity, coronary heart disease, psychiatric diseases, cognitive traits and reproductive ageing.
Heming Wang, Jacqueline M Lane, Samuel E Jones, Hassan S Dashti, Hanna M Ollila, Andrew R Wood, Vincent T van Hees, Ben Brumpton, Bendik S Winsvold, Katri Kantojärvi, and others. 2019. “Genome-wide association analysis of self-reported daytime sleepiness identifies 42 loci that suggest biological subtypes.” Nature communications, 10, 1, Pp. 1–12.
H Wangs, J Lane, S Jones, H Dashti, H Ollila, A Wood, V van Hees, B Brumpton, B Winsvold, K Kantoj, and others. 2019. “GENOME-WIDE ASSOCIATION ANALYSIS OF SELF-REPORTED DAYTIME SLEEPINESS IDENTIFIES 42 LOCI THAT SUGGEST BIOLOGICAL SUBTYPES”.
Hassan S Dashti, Samuel E Jones, Andrew R Wood, Jacqueline M Lane, Vincent T van Hees, Heming Wang, Jessica A Rhodes, Yanwei Song, Krunal Patel, Simon G Anderson, Robin N Beaumont, David A Bechtold, Jack Bowden, Brian E Cade, Marta Garaulet, Simon D Kyle, Max A Little, Andrew S Loudon, Annemarie I Luik, Frank AJL Scheer, Kai Spiegelhalder, Jessica Tyrrell, Daniel J Gottlieb, Henning Tiemeier, David W Ray, Shaun M Purcell, Timothy M Frayling, Susan Redline, Deborah A Lawlor, Martin K Rutter, Michael N Weedon, and Richa Saxena. 2019. “Genome-wide association study identifies genetic loci for self-reported habitual sleep duration supported by accelerometer-derived estimates.” Nat Commun, 10, 1, Pp. 1100.Abstract
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; 43 loci at p < 6 × 10). Replication is observed for PAX8, VRK2, and FBXL12/UBL5/PIN1 loci in the CHARGE study (n = 47,180; p < 6.3 × 10), 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.
Hassan S Dashti, Samuel E Jones, Andrew R Wood, Jacqueline M Lane, Vincent T van Hees, Heming Wang, Jessica A Rhodes, Yanwei Song, Krunal Patel, Simon G Anderson, and others. 2019. “Genome-wide association study identifies genetic loci for self-reported habitual sleep duration supported by accelerometer-derived estimates.” Nature communications, 10, 1, Pp. 1–12.
Hassan S Dashti, Jordi Merino, Jacqueline M Lane, Yanwei Song, Caren E Smith, Toshiko Tanaka, Nicola M McKeown, Chandler Tucker, Dianjianyi Sun, Traci M Bartz, and others. 2019. “Genome-wide association study of breakfast skipping links clock regulation with food timing.” The American journal of clinical nutrition, 110, 2, Pp. 473–484.
Hassan S Dashti, Jordi Merino, Jacqueline M Lane, Yanwei Song, Caren E Smith, Toshiko Tanaka, Nicola M McKeown, Chandler Tucker, Dianjianyi Sun, Traci M Bartz, Ruifang Li-Gao, Hoirun Nisa, Sirimon Reutrakul, Rozenn N Lemaitre, Tahani M Alshehri, Renée de Mutsert, Lydia Bazzano, Lu Qi, Kristen L Knutson, Bruce M Psaty, Dennis O Mook-Kanamori, Vesna Boraska Perica, Marian L Neuhouser, Frank AJL Scheer, Martin K Rutter, Marta Garaulet, and Richa Saxena. 2019. “Genome-wide association study of breakfast skipping links clock regulation with food timing.” Am J Clin Nutr, 110, 2, Pp. 473-484.Abstract
BACKGROUND: Little is known about the contribution of genetic variation to food timing, and breakfast has been determined to exhibit the most heritable meal timing. As breakfast timing and skipping are not routinely measured in large cohort studies, alternative approaches include analyses of correlated traits. OBJECTIVES: The aim of this study was to elucidate breakfast skipping genetic variants through a proxy-phenotype genome-wide association study (GWAS) for breakfast cereal skipping, a commonly assessed correlated trait. METHODS: We leveraged the statistical power of the UK Biobank (n = 193,860) to identify genetic variants related to breakfast cereal skipping as a proxy-phenotype for breakfast skipping and applied several in silico approaches to investigate mechanistic functions and links to traits/diseases. Next, we attempted validation of our approach in smaller breakfast skipping GWAS from the TwinUK (n = 2,006) and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium (n = 11,963). RESULTS: In the UK Biobank, we identified 6 independent GWAS variants, including those implicated for caffeine (ARID3B/CYP1A1), carbohydrate metabolism (FGF21), schizophrenia (ZNF804A), and encoding enzymes important for N6-methyladenosine RNA transmethylation (METTL4, YWHAB, and YTHDF3), which regulates the pace of the circadian clock. Expression of identified genes was enriched in the cerebellum. Genome-wide correlation analyses indicated positive correlations with anthropometric traits. Through Mendelian randomization (MR), we observed causal links between genetically determined breakfast skipping and higher body mass index, more depressive symptoms, and smoking. In bidirectional MR, we demonstrated a causal link between being an evening person and skipping breakfast, but not vice versa. We observed association of our signals in an independent breakfast skipping GWAS in another British cohort (P = 0.032), TwinUK, but not in a meta-analysis of non-British cohorts from the CHARGE consortium (P = 0.095). CONCLUSIONS: Our proxy-phenotype GWAS identified 6 genetic variants for breakfast skipping, linking clock regulation with food timing and suggesting a possible beneficial role of regular breakfast intake as part of a healthy lifestyle.
Rebecca C Richmond, Emma L Anderson, Hassan S Dashti, Samuel E Jones, Jacqueline M Lane, Linn Beate Strand, Ben Brumpton, Martin K Rutter, Andrew R Wood, Kurt Straif, and others. 2019. “Investigating causal relations between sleep traits and risk of breast cancer in women: mendelian randomisation study.” bmj, 365.

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