ORCID Profile
0000-0003-2233-1065
Current Organisations
Massachusetts General Hospital
,
Harvard Medical School
,
Broad Institute
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Biological Psychology (Neuropsychology, Psychopharmacology, Physiological Psychology) | Psychology
Behaviour and Health | Expanding Knowledge in the Biological Sciences | Expanding Knowledge in Psychology and Cognitive Sciences |
Publisher: Cold Spring Harbor Laboratory
Date: 12-2022
DOI: 10.1101/2022.11.30.22282929
Abstract: Preecl sia and gestational hypertension are common pregnancy complications associated with adverse maternal and offspring outcomes. Current tools for prediction, prevention, and treatment are limited. We tested the association of maternal DNA sequence variants with preecl sia in 20,064 cases and 703,117 controls and with gestational hypertension in 11,027 cases and 412,788 controls across discovery and follow-up cohorts using multi-ancestry meta-analysis. Altogether, we identified 18 independent loci associated with preecl sia/ecl sia and/or gestational hypertension, 12 of which are novel (e.g., MTHFR-CLCN6 , WNT3A , NPR3 , PGR , and RGL3 ), including two loci ( PLCE1 , FURIN ) identified in multi-trait analysis. Identified loci highlight the role of natriuretic peptide signaling, angiogenesis, renal glomerular function, trophoblast development, and immune dysregulation. We derived genome-wide polygenic risk scores that predicted preecl sia/ecl sia and gestational hypertension in external datasets, independent of first trimester risk markers. Collectively, these findings provide mechanistic insights into the hypertensive disorders of pregnancy and advance pregnancy risk stratification.
Publisher: Cold Spring Harbor Laboratory
Date: 19-04-2018
DOI: 10.1101/303941
Abstract: Using genome-wide data from 697,828 research participants from 23andMe and UK Biobank, we increase the number of identified loci associated with being a morning person, a behavioural indicator of a person’s underlying circadian rhythm, from 24 to 351. Using data from 85,760 in iduals with activity-monitor derived measures of sleep timing we show that the chronotype loci influence sleep timing: the mean sleep timing of the 5% of in iduals carrying the most “morningness” alleles was 25 minutes earlier than the 5% carrying the fewest. The loci were enriched for genes involved in circadian regulation, cAMP, glutamate and insulin signalling pathways, and those expressed in the retina, hindbrain, hypothalamus, and pituitary. We provide evidence that being a morning person is causally associated with better mental health but does not appear to affect BMI or Type 2 diabetes. This study offers new insights into the biology of circadian rhythms and links to disease in humans.
Publisher: Cold Spring Harbor Laboratory
Date: 03-06-2019
DOI: 10.1101/652966
Abstract: Sleep-disordered breathing (SDB) is a common disorder associated with significant morbidity. Through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program we report the first whole-genome sequence analysis of SDB. We identified 4 rare gene-based associations with SDB traits in 7,988 in iduals of erse ancestry and 4 replicated common variant associations with inclusion of additional s les (n=13,257). We identified a multi-ethnic set-based rare-variant association (p = 3.48 × 10 −8 ) on chromosome X with ARMCX3 . Transcription factor binding site enrichment identified associations with genes implicated with respiratory and craniofacial traits. Results highlighted associations in genes that modulate lung development, inflammation, respiratory rhythmogenesis and HIF1A -mediated hypoxic response.
Publisher: Oxford University Press (OUP)
Date: 21-09-2023
Publisher: Elsevier BV
Date: 12-2021
Publisher: Springer Science and Business Media LLC
Date: 29-03-2019
DOI: 10.1038/S41598-019-41712-1
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-in idual variance). These findings provide a possible underlying biological mechanism for inter-in idual differences in chronotype, and support the central role of PER2 in the human circadian timing system.
Publisher: Springer Science and Business Media LLC
Date: 29-01-2019
DOI: 10.1038/S41467-018-08259-7
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 in iduals 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 in iduals 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.
Publisher: Cold Spring Harbor Laboratory
Date: 17-10-2022
DOI: 10.1101/2022.10.16.22280934
Abstract: Circadian rhythm disturbance is a common feature of many psychiatric disorders. Light is the primary input to the circadian clock, with daytime light strengthening rhythms and night light disrupting them. Therefore, habitual light exposure may represent an environmental risk factor for susceptibility to psychiatric disorders. We performed the largest to-date cross-sectional analysis of light, sleep, physical activity, and mental health ( n = 86,772 adults aged 62.4 ± 7.4 years 57% women). We examined the independent association of day and night light exposure with covariate-adjusted risk for psychiatric disorders and self-harm. Greater night light exposure was associated with increased risk for major depressive disorder, generalized anxiety disorder, PTSD, psychosis, bipolar disorder, and self-harm behavior. Independent of night light, greater day light exposure was associated with reduced risk for major depressive disorder, PTSD, psychosis, and self-harm behavior. These findings were robust to adjustment for sociodemographics, photoperiod, physical activity, and sleep quality. Avoiding light at night and seeking light during the day may be a simple and effective, non-pharmacological means of broadly improving mental health.
Publisher: Cold Spring Harbor Laboratory
Date: 08-09-2023
Publisher: Cold Spring Harbor Laboratory
Date: 30-06-2022
DOI: 10.1101/2022.06.29.22277078
Abstract: Light is the primary stimulus for synchronizing the circadian clock in humans. There are very large interin idual differences in the sensitivity of the circadian clock to light. Little is currently known about the genetic basis for these interin idual differences. We performed a genome-wide gene-by-environment interaction study (GWIS) in 280,897 in iduals from the UK Biobank cohort to identify genetic variants that moderate the effect of daytime light exposure on chronotype (in idual time of day preference), acting as ‘light sensitivity’ variants for the impact of daylight on the circadian system. We identified a genome-wide significant SNP mapped to the ARL14EP gene (rs3847634 p 5×10 −8 ), where additional minor alleles were found to enhance the morningness effect of daytime light exposure ( β GxE = -.03, SE = 0.005) and were associated with increased gene ARL14EP expression in brain and retinal tissues. Gene-property analysis showed light sensitivity loci were enriched for genes in the G protein-coupled glutamate receptor signaling pathway and in Per2 + hypothalamic neurons. Linkage disequilibrium score regression identified significant genetic correlations of the light sensitivity GWIS with chronotype and sleep duration, such that greater light sensitivity was associated with later chronotype, greater insomnia symptoms and shorter sleep duration. Greater light sensitivity was also genetically correlated with greater risk for PTSD. This study is the first to assess light as an important exposure in the genomics of chronotype and is a critical first step in uncovering the genetic architecture of human circadian light sensitivity and its links to sleep and mental health.
Publisher: American Thoracic Society
Date: 15-11-2022
Publisher: Springer Science and Business Media LLC
Date: 25-02-2019
Location: United States of America
Start Date: 03-2023
End Date: 03-2026
Amount: $430,986.00
Funder: Australian Research Council
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