Publications by authors named "Richa Saxena"

158 Publications

Objective assessment of sleep regularity in 60 000 UK Biobank participants using an open-source package.

Sleep 2021 Nov 8. Epub 2021 Nov 8.

Turner Institute for Brain and Mental Health, School of Psychological Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia.

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http://dx.doi.org/10.1093/sleep/zsab254DOI Listing
November 2021

Genetic risk for obesity and the effectiveness of the ChooseWell 365 workplace intervention to prevent weight gain and improve dietary choices.

Am J Clin Nutr 2021 Sep 28. Epub 2021 Sep 28.

Division of General Internal Medicine, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Background: It is unknown whether behavioral interventions to improve diet are effective in people with a genetic predisposition to obesity.

Objectives: To examine associations between BMI genetic risk and changes in weight and workplace purchases by employees participating in a randomized controlled trial of an automated behavioral workplace intervention to promote healthy food choices.

Methods: Participants were hospital employees enrolled in a 12-mo intervention followed by a 12-mo follow-up. Hospital cafeterias utilized a traffic-light labeling system (e.g., green = healthy, red = unhealthy) that was used to calculate a validated Healthy Purchasing Score (HPS; higher = healthier). A weighted genome-wide BMI genetic score was generated by summing BMI-increasing alleles.

Results: The study included 397 adults of European ancestry (mean age, 44.9 y; 80.9% female). Participants in the highest genetic quartile (Q4) had a lower HPS and higher purchases of red-labeled items relative to participants in the lowest quartile (Q1) at baseline [Q4-Q1 Beta HPS, -4.66 (95% CI, -8.01 to -1.32); red-labeled items, 4.26% (95% CI, 1.45%-7.07%)] and at the 12-mo [HPS, -3.96 (95% CI, -7.5 to -0.41); red-labeled items, 3.20% (95% CI, 0.31%-6.09%)] and 24-mo [HPS, -3.70 (95% CI, -7.40 to 0.00); red-labeled items, 3.48% (95% CI, 0.54%-6.41%)] follow-up periods. In the intervention group, increases in HPS were similar in Q4 and Q1 at 12 mo (Q4-Q1 Beta, 1.04; 95% CI, -2.42 to 4.50). At the 24-mo follow-up, the change in BMI from baseline was similar between Q4 and Q1 (0.17 kg/m2; 95% CI, -0.55 to 0.89 kg/m2) in the intervention group, but higher in Q4 than Q1 (1.20 kg/m2; 95% CI, 0.26-2.13 kg/m2) in the control group. No interaction was evident between the treatment arm and genetic score for BMI or HPS.

Conclusions: Having a high BMI genetic risk was associated with greater increases in BMI and lower quality purchases over 2 y. The 12-mo behavioral intervention improved employees' food choices, regardless of the genetic burden, and may have attenuated weight gain conferred by having the genetic risk.
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http://dx.doi.org/10.1093/ajcn/nqab303DOI Listing
September 2021

Association of poor sleep burden in middle age and older adults with risk for delirium during hospitalization.

J Gerontol A Biol Sci Med Sci 2021 Sep 24. Epub 2021 Sep 24.

Medical Biodynamics Program, Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA.

Background: Delirium is a distressing neurocognitive disorder recently linked to sleep disturbances. However, the longitudinal relationship between sleep and delirium remains unclear. This study assessed the associations of poor sleep burden, and its trajectory, with delirium risk during hospitalization.

Methods: 321,818 participants from the UK Biobank (mean age 58±8y[SD]; range 37-74y) reported (2006-2010) sleep traits (sleep duration, excessive daytime sleepiness, insomnia-type complaints, napping, and chronotype-a closely-related circadian measure for sleep timing), aggregated into a sleep burden score (0-9). New-onset delirium (n=4,775) was obtained from hospitalization records during 12y median follow-up. 42,291 (mean age 64±8; range 44-83y) had repeat sleep assessment on average 8y after their first.

Results: In the baseline cohort, Cox proportional hazards models showed that moderate (aggregate scores=4-5) and severe (scores=6-9) poor sleep burden groups were 18% (hazard ratio 1.18 [95% confidence interval 1.08-1.28], p<0.001) and 57% (1.57 [1.38-1.80], p<0.001), more likely to develop delirium respectively. The latter risk magnitude is equivalent to two additional cardiovascular risks. These findings appeared robust when restricted to postoperative delirium and after exclusion of underlying dementia. Higher sleep burden was also associated with delirium in the follow-up cohort. Worsening sleep burden (score increase ≥2 vs. no change) further increased the risk for delirium (1.79 [1.23-2.62], p=0.002) independent of their baseline sleep score and time-lag. The risk was highest in those under 65y at baseline (p for interaction <0.001).

Conclusion: Poor sleep burden and worsening trajectory were associated with increased risk for delirium; promotion of sleep health may be important for those at higher risk.
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http://dx.doi.org/10.1093/gerona/glab272DOI Listing
September 2021

Time spent in outdoor light is associated with mood, sleep, and circadian rhythm-related outcomes: A cross-sectional and longitudinal study in over 400,000 UK Biobank participants.

J Affect Disord 2021 12 27;295:347-352. Epub 2021 Aug 27.

School of Psychological Sciences and Turner Institute for Brain and Mental Health, Monash University, Melbourne, VIC, Australia. Electronic address:

Background: Light has powerful effects on mood, sleep, and the circadian system. Humans evolved in an environment with a clear distinction between day and night, but our modern environments have blurred this distinction. Negative effects of light exposure at night have been well characterized. The importance of daytime light exposure has been less well characterized. Here we examine the cross-sectional and longitudinal associations of time spent in daytime outdoor light with mood, sleep, and circadian-related outcomes.

Methods: Participants were drawn from the UK Biobank cohort, a large study of UK adults (n = 502,000; 37-73 years old; 54% women).

Results: UK Biobank participants reported spending a median of 2.5 daylight hours (IQR = 1.5-3.5 h) outdoors per day. Each additional hour spent outdoors during the day was associated with lower odds of lifetime major depressive disorder (95% CI OR:0.92-0.98), antidepressant usage (OR:0.92-0.98), less frequent anhedonia (OR:0.93-0.96) and low mood (OR:0.87-0.90), greater happiness (OR:1.41-1.48) and lower neuroticism (incident rate ratio, IRR:0.95-0.96), independent of demographic, lifestyle, and employment covariates. In addition, each hour of daytime light was associated with greater ease of getting up (OR:1.46-1.49), less frequent tiredness (OR:0.80-0.82), fewer insomnia symptoms (OR:0.94-0.97), and earlier chronotype (adjusted odds ratio; OR:0.75-0.77). Auto-Regressive Cross-Lagged (ARCL) models were used to examine the longitudinal association of time spent in outdoor light at baseline with later mood-, sleep- and circadian-related outcomes reported at time point 2. Overall, longitudinal associations support cross-sectional findings, though generally with smaller effect sizes.

Limitations: Future studies that examine the intensity of daytime light exposure at the ocular level are needed.

Conclusions: Our findings suggest that low daytime light exposure is an important environmental risk factor for mood, sleep, and circadian-related outcomes.
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http://dx.doi.org/10.1016/j.jad.2021.08.056DOI Listing
December 2021

Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program.

Genome Med 2021 08 26;13(1):136. Epub 2021 Aug 26.

Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, 10461, USA.

Background: Sleep-disordered breathing is a common disorder associated with significant morbidity. The genetic architecture of sleep-disordered breathing remains poorly understood. Through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, we performed the first whole-genome sequence analysis of sleep-disordered breathing.

Methods: The study sample was comprised of 7988 individuals of diverse ancestry. Common-variant and pathway analyses included an additional 13,257 individuals. We examined five complementary traits describing different aspects of sleep-disordered breathing: the apnea-hypopnea index, average oxyhemoglobin desaturation per event, average and minimum oxyhemoglobin saturation across the sleep episode, and the percentage of sleep with oxyhemoglobin saturation < 90%. We adjusted for age, sex, BMI, study, and family structure using MMSKAT and EMMAX mixed linear model approaches. Additional bioinformatics analyses were performed with MetaXcan, GIGSEA, and ReMap.

Results: We identified a multi-ethnic set-based rare-variant association (p = 3.48 × 10) on chromosome X with ARMCX3. Additional rare-variant associations include ARMCX3-AS1, MRPS33, and C16orf90. Novel common-variant loci were identified in the NRG1 and SLC45A2 regions, and previously associated loci in the IL18RAP and ATP2B4 regions were associated with novel phenotypes. Transcription factor binding site enrichment identified associations with genes implicated with respiratory and craniofacial traits. Additional analyses identified significantly associated pathways.

Conclusions: We have identified the first gene-based rare-variant associations with objectively measured sleep-disordered breathing traits. Our results increase the understanding of the genetic architecture of sleep-disordered breathing and highlight associations in genes that modulate lung development, inflammation, respiratory rhythmogenesis, and HIF1A-mediated hypoxic response.
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http://dx.doi.org/10.1186/s13073-021-00917-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394596PMC
August 2021

Genetic analysis of dietary intake identifies new loci and functional links with metabolic traits.

Nat Hum Behav 2021 Aug 23. Epub 2021 Aug 23.

Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.

Dietary intake is a major contributor to the global obesity epidemic and represents a complex behavioural phenotype that is partially affected by innate biological differences. Here, we present a multivariate genome-wide association analysis of overall variation in dietary intake to account for the correlation between dietary carbohydrate, fat and protein in 282,271 participants of European ancestry from the UK Biobank (n = 191,157) and Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (n = 91,114), and identify 26 distinct genome-wide significant loci. Dietary intake signals map exclusively to specific brain regions and are enriched for genes expressed in specialized subtypes of GABAergic, dopaminergic and glutamatergic neurons. We identified two main clusters of genetic variants for overall variation in dietary intake that were differently associated with obesity and coronary artery disease. These results enhance the biological understanding of interindividual differences in dietary intake by highlighting neural mechanisms, supporting functional follow-up experiments and possibly providing new avenues for the prevention and treatment of prevalent complex metabolic diseases.
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http://dx.doi.org/10.1038/s41562-021-01182-wDOI Listing
August 2021

Habitual Sleep Duration, Daytime Napping, and Dietary Intake: A Mendelian Randomization Study.

Curr Dev Nutr 2021 Mar 3;5(3):nzab019. Epub 2021 Mar 3.

Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.

Background: Chronic inadequate sleep and frequent daytime napping may inflict deleterious health effects including weight gain, cardiometabolic and psychiatric diseases, and cancer. It is plausible that these relations may be partly influenced by the consumption of suboptimal diets.

Objectives: The study aimed to identify potential causal links of genetically proxied longer habitual sleep duration and more frequent daytime napping on 61 dietary variables derived from an FFQ. In addition, the study aimed to assess potential bidirectional causal links between habitual sleep duration or daytime napping and macronutrient composition.

Methods: Genetic variants robustly associated with habitual sleep duration and daytime napping from published genome-wide association analyses were used. Outcomes included 61 dietary variables estimated from FFQs in the UK Biobank (= 361,194). For bidirectional associations with macronutrient composition, genetic variants associated with percentage of energy from carbohydrate, fat, and protein were used. Two-sample Mendelian randomization (MR) effects were estimated with inverse-variance weighted (IVW) analysis.

Results: In 2-sample MR, genetically proxied longer sleep duration was associated with a 0.068 (95% CI: 0.034, 0.103) category increase in salad/raw vegetable intake [  = 0.006] per hour of sleep and with "no major dietary changes in the past 5 years" (  = 0.043). No associations were evident for daytime napping on dietary variables (all  > 0.05). In addition, there were no bidirectional associations between habitual sleep duration or daytime napping with the relative intake of carbohydrate, fat, and protein (all  > 0.05).

Conclusions: In this MR study, there was modest evidence for associations between habitual sleep duration with dietary intake and no evidence for associations between daytime napping frequency with dietary intake. These preliminary findings suggest that changes to habitual sleep duration or daytime napping frequency may have limited impact on long-term changes in dietary intake.
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http://dx.doi.org/10.1093/cdn/nzab019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8171253PMC
March 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

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 comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, 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 our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Genetically Proxied Diurnal Preference, Sleep Timing, and Risk of Major Depressive Disorder.

JAMA Psychiatry 2021 Aug;78(8):903-910

Broad Institute of MIT and Harvard, Cambridge, Massachusetts.

Importance: Morning diurnal preference is associated with reduced risk of major depressive disorder (MDD); however, causality in this association is uncertain.

Objective: To examine the association of genetically proxied morning diurnal preference with depression risk using mendelian randomization.

Design, Setting, And Participants: This 2-sample mendelian randomization study used summary-level genetic associations with diurnal preference and MDD. Up to 340 genetic loci associated with diurnal preference in a meta-analysis of the UK Biobank and 23andMe cohorts were considered as genetic proxies for diurnal preference. The effect size of these variants was scaled using genetic associations with accelerometer-based measurement of sleep midpoint. Genetic associations with MDD were obtained from a meta-analysis of genome-wide association studies data from the Psychiatric Genomics Consortium and UK Biobank. The inverse-variance weighted method was used to estimate the association of genetically proxied morning diurnal preference, corresponding to a 1-hour earlier sleep midpoint, with MDD risk.

Exposures: Morning diurnal preference scaled to a 1-hour earlier, objectively measured sleep midpoint.

Main Outcomes And Measures: Risk of MDD, including self-reported and clinically diagnosed cases, as ascertained in meta-analyses of genome-wide association studies.

Results: A total of 697 828 individuals (all of European ancestry) were in the UK Biobank and 23andMe cohorts; 85 502 in the UK Biobank had measurements of the sleep midpoint. A further 170 756 individuals with MDD and 329 443 control participants (all of European ancestry) were in the Psychiatric Genomics Consortium and UK Biobank data. Genetically proxied earlier diurnal preference was associated with a 23% lower risk of depression (odds ratio [OR] per 1-hour earlier sleep midpoint, 0.77 [95% CI, 0.63-0.94]; P = .01). This association was similar when restricting analysis to individuals with MDD as stringently defined by the Psychiatric Genomics Consortium (OR, 0.73 [95% CI, 0.54-1.00]; P = .05) but not statistically significant when defined by hospital-based billing codes in the UK Biobank (OR, 0.64 [95% CI, 0.39-1.06]; P = .08). Sensitivity analyses examining potential bias due to pleiotropy or reverse causality showed similar findings (eg, intercept [SE], 0.00 [0.001]; P = .66 by Egger intercept test).

Conclusions And Relevance: The results of this mendelian randomization study support a protective association of earlier diurnal preference with risk of MDD and provide estimates contextualized to an objective sleep timing measure. Further investigation in the form of randomized clinical trials may be warranted.
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http://dx.doi.org/10.1001/jamapsychiatry.2021.0959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156187PMC
August 2021

Variant curation expert panel recommendations for RYR1 pathogenicity classifications in malignant hyperthermia susceptibility.

Genet Med 2021 07 25;23(7):1288-1295. Epub 2021 Mar 25.

Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

Purpose: As a ClinGen Expert Panel (EP) we set out to adapt the American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) pathogenicity criteria for classification of RYR1 variants as related to autosomal dominantly inherited malignant hyperthermia (MH).

Methods: We specified ACMG/AMP criteria for variant classification for RYR1 and MH. Proposed rules were piloted on 84 variants. We applied quantitative evidence calibration for several criteria using likelihood ratios based on the Bayesian framework.

Results: Seven ACMG/AMP criteria were adopted without changes, nine were adopted with RYR1-specific modifications, and ten were dropped. The in silico (PP3 and BP4) and hotspot criteria (PM1) were evaluated quantitatively. REVEL gave an odds ratio (OR) of 23:1 for PP3 and 14:1 for BP4 using trichotomized cutoffs of ≥0.85 (pathogenic) and ≤0.5 (benign). The PM1 hotspot criterion had an OR of 24:1. PP3 and PM1 were implemented at moderate strength. Applying the revised ACMG/AMP criteria to 44 recognized MH variants, 29 were classified as pathogenic, 13 as likely pathogenic, and 2 as variants of uncertain significance.

Conclusion: Curation of these variants will facilitate classification of RYR1/MH genomic testing results, which is especially important for secondary findings analyses. Our approach to quantitatively calibrating criteria is generalizable to other variant curation expert panels.
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http://dx.doi.org/10.1038/s41436-021-01125-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263483PMC
July 2021

Selection into shift work is influenced by educational attainment and body mass index: a Mendelian randomization study in the UK Biobank.

Int J Epidemiol 2021 08;50(4):1229-1240

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Background: Shift work is associated with increased cardiometabolic disease risk. This observation may be partly explained by cardiometabolic risk factors having a role in the selection of individuals into or out of shift work. We performed Mendelian randomization (MR) analyses in the UK Biobank (UKB) to test this hypothesis.

Methods: We used genetic risk scores (GRS) to proxy nine cardiometabolic risk factors and diseases (including educational attainment, body mass index (BMI), smoking, and alcohol consumption), and tested associations of each GRS with self-reported frequency of current shift work among employed UKB participants of European ancestry (n = 190 573). We used summary-level MR sensitivity analyses to assess robustness of the identified effects, and we tested whether effects were mediated through sleep timing preference.

Results: Genetically instrumented liability to lower educational attainment (odds ratio (OR) per 3.6 fewer years in educational attainment = 2.40, 95% confidence interval (CI) = 2.22-2.59, P = 4.84 × 10-20) and higher body mass index (OR per 4.7 kg/m2 higher BMI = 1.30, 95% CI = 1.14-1.47, P = 5.85 × 10-5) increased odds of reporting participation in frequent shift work. Results were unchanged in sensitivity analyses allowing for different assumptions regarding horizontal pleiotropy. No selection effects were evident for the remaining exposures, nor for any exposures on selection out of shift work. Sleep timing preference did not mediate the effects of BMI and educational attainment on selection into shift work.

Conclusions: Liability to lower educational attainment and higher BMI may influence selection into shift work. This phenomenon may bias epidemiological studies of shift work that are performed in the UKB.
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http://dx.doi.org/10.1093/ije/dyab031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8562336PMC
August 2021

Genetic determinants of daytime napping and effects on cardiometabolic health.

Nat Commun 2021 02 10;12(1):900. Epub 2021 Feb 10.

Center for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Daytime napping is a common, heritable behavior, but its genetic basis and causal relationship with cardiometabolic health remain unclear. Here, we perform a genome-wide association study of self-reported daytime napping in the UK Biobank (n = 452,633) and identify 123 loci of which 61 replicate in the 23andMe research cohort (n = 541,333). Findings include missense variants in established drug targets for sleep disorders (HCRTR1, HCRTR2), genes with roles in arousal (TRPC6, PNOC), and genes suggesting an obesity-hypersomnolence pathway (PNOC, PATJ). Association signals are concordant with accelerometer-measured daytime inactivity duration and 33 loci colocalize with loci for other sleep phenotypes. Cluster analysis identifies three distinct clusters of nap-promoting mechanisms with heterogeneous associations with cardiometabolic outcomes. Mendelian randomization shows potential causal links between more frequent daytime napping and higher blood pressure and waist circumference.
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http://dx.doi.org/10.1038/s41467-020-20585-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876146PMC
February 2021

C-reactive Protein and Risk of OSA in Four US Cohorts.

Chest 2021 06 30;159(6):2439-2448. Epub 2021 Jan 30.

Division of Sleep Medicine, Harvard Medical School, Boston, MA; Division of Sleep and Circadian Disorders, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

Background: Individuals with OSA have elevated levels of inflammatory markers, but no prospective study has examined the role of inflammation in the development of OSA.

Research Question: Is C-reactive protein (CRP) prospectively associated with risk of developing OSA?

Study Design And Methods: We followed 1,882 women from the Nurses' Health Study (NHS) (2002-2012), 3,854 women from Nurses' Health Study II (NHSII) (1995-2013), 3,075 men from the Health Professionals Follow-up Study (HPFS) (1996-2012), and 1,919 women and men from the Multi-Ethnic Study of Atherosclerosis (MESA) (2000-2012) who did not have diagnosed OSA at baseline and for whom CRP levels were available. In NHS/NHSII/HPFS, physician-diagnosed OSA was self-reported. In MESA, at-home polysomnography was performed and OSA was identified as an apnea-hypopnea index ≥ 30. Logistic regression was used to estimate the OR for OSA risk according to baseline CRP level, adjusted for multiple inflammation-related factors.

Results: After multivariable adjustment not including BMI, the pooled OR for OSA risk per doubling of baseline CRP level was 1.24 (95% CI, 1.18-1.30). Additional adjustment for BMI substantially attenuated the association (pooled OR, 1.07; 95% CI, 1.01-1.12). The fully adjusted association was consistently stronger in individuals < 55 vs ≥ 55 years of age (P interaction = .01), in individuals with BMI < 25 vs ≥ 25 kg/m (P interaction = .02), and in pre- vs postmenopausal women (P interaction = .002). CRP was more strongly associated with risk of OSA associated with excessive daytime sleepiness, high airway collapsibility, and low arousal threshold (P heterogeneity < .05).

Interpretation: Higher CRP was prospectively associated with increased OSA risk, particularly among younger individuals, underweight/normal-weight individuals, or premenopausal women. The differential associations by OSA phenotype/endotype suggest possible mechanisms through which inflammation operates to modulate OSA risk. Given our reliance on a single CRP level measured a decade before OSA assessment, future studies with repeated CRP measurements are warranted to confirm these prospective associations.
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http://dx.doi.org/10.1016/j.chest.2021.01.060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213962PMC
June 2021

Resting Heartbeat Complexity Predicts All-Cause and Cardiorespiratory Mortality in Middle- to Older-Aged Adults From the UK Biobank.

J Am Heart Assoc 2021 02 19;10(3):e018483. Epub 2021 Jan 19.

Medical Biodynamics Program Brigham and Women's Hospital Boston MA.

Background Spontaneous heart rate fluctuations contain rich information related to health and illness in terms of physiological complexity, an accepted indicator of plasticity and adaptability. However, it is challenging to make inferences on complexity from shorter, more practical epochs of data. Distribution entropy (DistEn) is a recently introduced complexity measure that is designed specifically for shorter duration heartbeat recordings. We hypothesized that reduced DistEn predicted increased mortality in a large population cohort. Method and Results The prognostic value of DistEn was examined in 7631 middle-older-aged UK Biobank participants who had 2-minute resting ECGs conducted (mean age, 59.5 years; 60.4% women). During a median follow-up period of 7.8 years, 451 (5.9%) participants died. In Cox proportional hazards models with adjustment for demographics, lifestyle factors, physical activity, cardiovascular risks, and comorbidities, for each 1-SD decrease in DistEn, the risk increased by 36%, 56%, and 73% for all-cause, cardiovascular, and respiratory disease-related mortality, respectively. These effect sizes were equivalent to the risk of death from being >5 years older, having been a former smoker, or having diabetes mellitus. Lower DistEn was most predictive of death in those <55 years with a prior myocardial infarction, representing an additional 56% risk for mortality compared with older participants without prior myocardial infarction. These observations remained after controlling for traditional mortality predictors, resting heart rate, and heart rate variability. Conclusions Resting heartbeat complexity from short, resting ECGs was independently associated with mortality in middle- to older-aged adults. These risks appear most pronounced in middle-aged participants with prior MI, and may uniquely contribute to mortality risk screening.
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http://dx.doi.org/10.1161/JAHA.120.018483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955428PMC
February 2021

Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.

Nat Commun 2021 01 5;12(1):24. Epub 2021 Jan 5.

Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA.

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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http://dx.doi.org/10.1038/s41467-020-19366-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785747PMC
January 2021

Night shift work is associated with an increased risk of asthma.

Thorax 2021 01 16;76(1):53-60. Epub 2020 Nov 16.

Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK

Introduction: Shift work causes misalignment between internal circadian time and the external light/dark cycle and is associated with metabolic disorders and cancer. Approximately 20% of the working population in industrialised countries work permanent or rotating night shifts, exposing this large population to the risk of circadian misalignment-driven disease. Analysis of the impact of shift work on chronic inflammatory diseases is lacking. We investigated the association between shift work and asthma.

Methods: We describe the cross-sectional relationship between shift work and prevalent asthma in >280000 UK Biobank participants, making adjustments for major confounding factors (smoking history, ethnicity, socioeconomic status, physical activity, body mass index). We also investigated chronotype.

Results: Compared with day workers, 'permanent' night shift workers had a higher likelihood of moderate-severe asthma (OR 1.36 (95% CI 1.03 to 1.8)) and all asthma (OR 1.23 (95% CI 1.03 to 1.46)). Individuals doing any type of shift work had higher adjusted odds of wheeze/whistling in the chest. Shift workers who never or rarely worked on nights and people working permanent nights had a higher adjusted likelihood of having reduced lung function (FEV <80% predicted). We found an increase in the risk of moderate-severe asthma in morning chronotypes working irregular shifts, including nights (OR 1.55 (95% CI 1.06 to 2.27)).

Conclusions: The public health implications of these findings are far-reaching due to the high prevalence and co-occurrence of both asthma and shift work. Future longitudinal follow-up studies are needed to determine if modifying shift work schedules to take into account chronotype might present a public health measure to reduce the risk of developing inflammatory diseases such as asthma.
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http://dx.doi.org/10.1136/thoraxjnl-2020-215218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803886PMC
January 2021

Is disrupted sleep a risk factor for Alzheimer's disease? Evidence from a two-sample Mendelian randomization analysis.

Int J Epidemiol 2021 07;50(3):817-828

MRC Integrative Epidemiology Unit, at the University of Bristol, Bristol, UK.

Background: It is established that Alzheimer's disease (AD) patients experience sleep disruption. However, it remains unknown whether disruption in the quantity, quality or timing of sleep is a risk factor for the onset of AD.

Methods: We used the largest published genome-wide association studies of self-reported and accelerometer-measured sleep traits (chronotype, duration, fragmentation, insomnia, daytime napping and daytime sleepiness), and AD. Mendelian randomization (MR) was used to estimate the causal effect of self-reported and accelerometer-measured sleep parameters on AD risk.

Results: Overall, there was little evidence to support a causal effect of sleep traits on AD risk. There was some suggestive evidence that self-reported daytime napping was associated with lower AD risk [odds ratio (OR): 0.70, 95% confidence interval (CI): 0.50-0.99). Some other sleep traits (accelerometer-measured 'eveningness' and sleep duration, and self-reported daytime sleepiness) had ORs of a similar magnitude to daytime napping, but were less precisely estimated.

Conclusions: Overall, we found very limited evidence to support a causal effect of sleep traits on AD risk. Our findings provide tentative evidence that daytime napping may reduce AD risk. Given that this is the first MR study of multiple self-report and objective sleep traits on AD risk, findings should be replicated using independent samples when such data become available.
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http://dx.doi.org/10.1093/ije/dyaa183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271193PMC
July 2021

Habitual sleep disturbances and migraine: a Mendelian randomization study.

Ann Clin Transl Neurol 2020 12 30;7(12):2370-2380. Epub 2020 Oct 30.

Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts, 02142, USA.

Objective: Sleep disturbances are associated with increased risk of migraine, however the extent of shared underlying biology and the direction of causal relationships between these traits is unclear. Delineating causality between sleep patterns and migraine may offer new pathophysiologic insights and inform subsequent intervention studies. Here, we used genetic approaches to test for shared genetic influences between sleep patterns and migraine, and to test whether habitual sleep patterns may be causal risk factors for migraine and vice versa.

Methods: To quantify genetic overlap, we performed genome-wide genetic correlation analyses using genome-wide association studies of nine sleep traits in the UK Biobank (n ≥ 237,627), and migraine from the International Headache Genetics Consortium (59,674 cases and 316,078 controls). We then tested for potential causal effects between sleep traits and migraine using bidirectional, two-sample Mendelian randomization.

Results: Seven sleep traits demonstrated genetic overlap with migraine, including insomnia symptoms (rg = 0.29, P < 10 ) and difficulty awakening (rg = 0.11, P < 10 ). Mendelian randomization analyses provided evidence for potential causal effects of difficulty awakening on risk of migraine (OR [95% CI] = 1.37 [1.12-1.68], P = 0.002), and nominal evidence that liability to insomnia symptoms increased the risk of migraine (1.09 [1.02-1.16], P = 0.02). In contrast, there was minimal evidence for an effect of migraine liability on sleep patterns or disturbances.

Interpretation: These data support a shared genetic basis between several sleep traits and migraine, and support potential causal effects of difficulty awakening and insomnia symptoms on migraine risk. Treatment of sleep disturbances may therefore be a promising clinical intervention in the management of migraine.
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http://dx.doi.org/10.1002/acn3.51228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732254PMC
December 2020

Associations of self-reported obstructive sleep apnea with total and site-specific cancer risk in older women: a prospective study.

Sleep 2021 03;44(3)

Division of Sleep and Circadian Disorders, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

Background And Objectives: Chronic intermittent hypoxia resulting from obstructive sleep apnea (OSA) may activate multiple carcinogenic pathways and lead to cancer development.

Methods: We prospectively examined the association between OSA and cancer risk among 65,330 women in the Nurses' Health Study who were free of cancer in 2008 (mean age: 73.3 years). Incident cancer diagnoses were collected until 2016 and confirmed by pathology reports. Clinically diagnosed OSA was self-reported in 2008 and updated in 2012. We used time-dependent Cox regression to estimate hazard ratios (HR) for the associations of OSA with total and site-specific cancer risk.

Results: We documented 5,257 incident cancer diagnoses during follow-up. In the age-adjusted model, OSA was associated with a 15% (95% CI: 1.03, 1.29) increase in total cancer risk. The association became nonsignificant after adjustment for multiple cancer risk factors (HR: 1.08; 95% CI: 0.96, 1.21). When examining cancer risk by site, OSA was associated with significantly increased risk for lung (fully adjusted HR: 1.52; 95% CI: 1.07, 2.17), bladder (fully adjusted HR: 1.94; 95% CI: 1.12, 3.35), and thyroid cancer (fully adjusted HR: 2.06; 95% CI: 1.01, 4.22) and possibly increased risk for kidney cancer (fully adjusted HR: 1.59; 95% CI: 0.84, 3.01). When grouping cancer sites by risk factor profiles, OSA was positively associated with smoking-related cancers (fully adjusted HR: 1.37; 95% CI: 1.11, 1.67), and this association was stronger in never smokers than ever smokers.

Conclusion: While OSA was not independently associated with overall cancer risk in older women, significant associations were observed for smoking-related cancers, especially in nonsmokers.
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http://dx.doi.org/10.1093/sleep/zsaa198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953220PMC
March 2021

Sleep health, diseases, and pain syndromes: findings from an electronic health record biobank.

Sleep 2021 03;44(3)

Mass General Brigham Personalized Medicine, Mass General Brigham, Boston, MA.

Study Objectives: Implementation of electronic health record biobanks has facilitated linkage between clinical and questionnaire data and enabled assessments of relationships between sleep health and diseases in phenome-wide association studies (PheWAS). In the Mass General Brigham Biobank, a large health system-based study, we aimed to systematically catalog associations between time in bed, sleep timing, and weekly variability with clinical phenotypes derived from ICD-9/10 codes.

Methods: Self-reported habitual bed and wake times were used to derive variables: short (<7 hours) and long (≥9 hours) time in bed, sleep midpoint, social jetlag, and sleep debt. Logistic regression and Cox proportional hazards models were used to test cross-sectional and prospective associations, respectively, adjusted for age, gender, race/ethnicity, and employment status and further adjusted for body mass index.

Results: In cross-sectional analysis (n = 34,651), sleep variable associations were most notable for circulatory system, mental disorders, and endocrine/metabolic phenotypes. We observed the strongest associations for short time in bed with obesity, for long time in bed and sleep midpoint with major depressive disorder, for social jetlag with hypercholesterolemia, and for sleep debt with acne. In prospective analysis (n = 24,065), we observed short time in bed associations with higher incidence of acute pain and later sleep midpoint and higher sleep debt and social jetlag associations with higher incidence of major depressive disorder.

Conclusions: Our analysis reinforced that sleep health is a multidimensional construct, corroborated robust known findings from traditional cohort studies, and supported the application of PheWAS as a promising tool for advancing sleep research. Considering the exploratory nature of PheWAS, careful interrogation of novel findings is imperative.
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http://dx.doi.org/10.1093/sleep/zsaa189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953212PMC
March 2021

Morning diurnal preference and food intake: a Mendelian randomization study.

Am J Clin Nutr 2020 11;112(5):1348-1357

Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.

Background: Poor dietary choices may underlie known associations between having an evening diurnal preference and cardiometabolic diseases. Assessing causal links between diurnal preference and food intake is now possible in Mendelian randomization (MR) analyses.

Objectives: We aimed to use a 2-sample MR to determine potential causal effects of genetic liability to a morning preference on food intake. We also examined potential causal effects of a morning preference on objectively captured response performances to email-administered 24-h diet recalls.

Methods: We used genetic variants associated with a morning preference from a published genome-wide association meta-analysis. Our outcomes included 61 food items with estimates from a food-frequency questionnaire in the UK Biobank (n = 361,194). For significant findings, we repeated the analysis using intake estimates from modified 24-h diet recalls in a subset of overlapping participants (n = 146,086). In addition, we examined 7 response performance outcomes, including the time and duration of responses to 24-h diet recalls (n = 123,035). MR effects were estimated using an inverse-variance weighted analysis.

Results: Genetic liability to a morning preference was associated with increased intake of 6 food items (fresh fruit, alcohol with meals, bran cereal, cereals, dried fruit, and water), decreased intake of 4 food items (beer plus cider, processed meat, other cereals [e.g., corn or frosted flakes], and full cream milk), increased temperature of hot drinks, and decreased variation in diet (PFalse Discovery Rate < 0.05). There was no evidence for an effect on coffee or tea intake. Findings for fresh fruit, beer plus cider, bran cereal, and cereal were consistent when intakes were estimated by 24-h diet recalls (P < 0.05). We also identified potential causal links between a morning preference with earlier timing and a shorter duration for completing email-administered 24-h diet recalls.

Conclusions: Our findings provide evidence for a potentially causal effect of a morning preference with the increased intake of foods known to constitute a healthy diet, suggesting possible health benefits of adopting a more morning diurnal preference.
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http://dx.doi.org/10.1093/ajcn/nqaa219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657324PMC
November 2020

Polygenic risk score for obesity and the quality, quantity, and timing of workplace food purchases: A secondary analysis from the ChooseWell 365 randomized trial.

PLoS Med 2020 07 21;17(7):e1003219. Epub 2020 Jul 21.

Division of General Internal Medicine, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.

Background: The influence of genetic risk for obesity on food choice behaviors is unknown and may be in the causal pathway between genetic risk and weight gain. The aim of this study was to examine associations between genetic risk for obesity and food choice behaviors using objectively assessed workplace food purchases.

Methods And Findings: This study is a secondary analysis of baseline data collected prior to the start of the "ChooseWell 365" health-promotion intervention randomized control trial. Participants were employees of a large hospital in Boston, MA, who enrolled in the study between September 2016 and February 2018. Cafeteria sales data, collected retrospectively for 3 months prior to enrollment, were used to track the quantity (number of items per 3 months) and timing (median time of day) of purchases, and participant surveys provided self-reported behaviors, including skipping meals and preparing meals at home. A previously validated Healthy Purchasing Score was calculated using the cafeteria traffic-light labeling system (i.e., green = healthy, yellow = less healthy, red = unhealthy) to estimate the healthfulness (quality) of employees' purchases (range, 0%-100% healthy). DNA was extracted and genotyped from blood samples. A body mass index (BMI) genome-wide polygenic score (BMIGPS) was generated by summing BMI-increasing risk alleles across the genome. Additionally, 3 polygenic risk scores (PRSs) were generated with 97 BMI variants previously identified at the genome-wide significance level (P < 5 × 10-8): (1) BMI97 (97 loci), (2) BMICNS (54 loci near genes related to central nervous system [CNS]), and (3) BMInon-CNS (43 loci not related to CNS). Multivariable linear and logistic regression tested associations of genetic risk score quartiles with workplace purchases, adjusted for age, sex, seasonality, and population structure. Associations were considered significant at P < 0.05. In 397 participants, mean age was 44.9 years, and 80.9% were female. Higher genetic risk scores were associated with higher BMI. The highest quartile of BMIGPS was associated with lower Healthy Purchasing Score (-4.8 percentage points [95% CI -8.6 to -1.0]; P = 0.02), higher quantity of food purchases (14.4 more items [95% CI -0.1 to 29.0]; P = 0.03), later time of breakfast purchases (15.0 minutes later [95% CI 1.5-28.5]; P = 0.03), and lower likelihood of preparing dinner at home (Q4 odds ratio [OR] = 0.3 [95% CI 0.1-0.9]; P = 0.03) relative to the lowest BMIGPS quartile. Compared with the lowest quartile, the highest BMICNS quartile was associated with fewer items purchased (P = 0.04), and the highest BMInon-CNS quartile was associated with purchasing breakfast at a later time (P = 0.01), skipping breakfast (P = 0.03), and not preparing breakfast (P = 0.04) or lunch (P = 0.01) at home. A limitation of this study is our data come from a relatively small sample of healthy working adults of European ancestry who volunteered to enroll in a health-promotion study, which may limit generalizability.

Conclusions: In this study, genetic risk for obesity was associated with the quality, quantity, and timing of objectively measured workplace food purchases. These findings suggest that genetic risk for obesity may influence eating behaviors that contribute to weight and could be targeted in personalized workplace wellness programs in the future.

Trial Registration: Clinicaltrials.gov NCT02660086.
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http://dx.doi.org/10.1371/journal.pmed.1003219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373257PMC
July 2020

Dimensionality reduction reveals fine-scale structure in the Japanese population with consequences for polygenic risk prediction.

Nat Commun 2020 03 26;11(1):1569. Epub 2020 Mar 26.

Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, 565-0871, Japan.

The diversity in our genome is crucial to understanding the demographic history of worldwide populations. However, we have yet to know whether subtle genetic differences within a population can be disentangled, or whether they have an impact on complex traits. Here we apply dimensionality reduction methods (PCA, t-SNE, PCA-t-SNE, UMAP, and PCA-UMAP) to biobank-derived genomic data of a Japanese population (n = 169,719). Dimensionality reduction reveals fine-scale population structure, conspicuously differentiating adjacent insular subpopulations. We further enluciate the demographic landscape of these Japanese subpopulations using population genetics analyses. Finally, we perform phenome-wide polygenic risk score (PRS) analyses on 67 complex traits. Differences in PRS between the deconvoluted subpopulations are not always concordant with those in the observed phenotypes, suggesting that the PRS differences might reflect biases from the uncorrected structure, in a trait-dependent manner. This study suggests that such an uncorrected structure can be a potential pitfall in the clinical application of PRS.
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http://dx.doi.org/10.1038/s41467-020-15194-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099015PMC
March 2020

Melatonin Effects on Glucose Metabolism: Time To Unlock the Controversy.

Trends Endocrinol Metab 2020 03 1;31(3):192-204. Epub 2020 Jan 1.

Medical Chronobiology Program, Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women's Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA. Electronic address:

The past decade has witnessed a revival of interest in the hormone melatonin, partly attributable to the discovery that genetic variation in MTNR1B - the melatonin receptor gene - is a risk factor for impaired fasting glucose and type 2 diabetes (T2D). Despite intensive investigation, there is considerable confusion and seemingly conflicting data on the metabolic effects of melatonin and MTNR1B variation, and disagreement on whether melatonin is metabolically beneficial or deleterious, a crucial issue for melatonin agonist/antagonist drug development and dosing time. We provide a conceptual framework - anchored in the dimension of 'time' - to reconcile paradoxical findings in the literature. We propose that the relative timing between elevated melatonin concentrations and glycemic challenge should be considered to better understand the mechanisms and therapeutic opportunities of melatonin signaling in glycemic health and disease.
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http://dx.doi.org/10.1016/j.tem.2019.11.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349733PMC
March 2020

Operating characteristics of the rank-based inverse normal transformation for quantitative trait analysis in genome-wide association studies.

Biometrics 2020 12 13;76(4):1262-1272. Epub 2020 Jan 13.

Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

Quantitative traits analyzed in Genome-Wide Association Studies (GWAS) are often nonnormally distributed. For such traits, association tests based on standard linear regression are subject to reduced power and inflated type I error in finite samples. Applying the rank-based inverse normal transformation (INT) to nonnormally distributed traits has become common practice in GWAS. However, the different variations on INT-based association testing have not been formally defined, and guidance is lacking on when to use which approach. In this paper, we formally define and systematically compare the direct (D-INT) and indirect (I-INT) INT-based association tests. We discuss their assumptions, underlying generative models, and connections. We demonstrate that the relative powers of D-INT and I-INT depend on the underlying data generating process. Since neither approach is uniformly most powerful, we combine them into an adaptive omnibus test (O-INT). O-INT is robust to model misspecification, protects the type I error, and is well powered against a wide range of nonnormally distributed traits. Extensive simulations were conducted to examine the finite sample operating characteristics of these tests. Our results demonstrate that, for nonnormally distributed traits, INT-based tests outperform the standard untransformed association test, both in terms of power and type I error rate control. We apply the proposed methods to GWAS of spirometry traits in the UK Biobank. O-INT has been implemented in the R package RNOmni, which is available on CRAN.
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http://dx.doi.org/10.1111/biom.13214DOI Listing
December 2020

Evolutionarily conserved regulation of sleep by epidermal growth factor receptor signaling.

Sci Adv 2019 11 13;5(11):eaax4249. Epub 2019 Nov 13.

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.

The genetic bases for most human sleep disorders and for variation in human sleep quantity and quality are largely unknown. Using the zebrafish, a diurnal vertebrate, to investigate the genetic regulation of sleep, we found that epidermal growth factor receptor (EGFR) signaling is necessary and sufficient for normal sleep levels and is required for the normal homeostatic response to sleep deprivation. We observed that EGFR signaling promotes sleep via mitogen-activated protein kinase/extracellular signal-regulated kinase and RFamide neuropeptide signaling and that it regulates RFamide neuropeptide expression and neuronal activity. Consistent with these findings, analysis of a large cohort of human genetic data from participants of European ancestry revealed that common variants in genes within the EGFR signaling pathway are associated with variation in human sleep quantity and quality. These results indicate that EGFR signaling and its downstream pathways play a central and ancient role in regulating sleep and provide new therapeutic targets for sleep disorders.
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http://dx.doi.org/10.1126/sciadv.aax4249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853770PMC
November 2019

Assessment of Type 2 Diabetes Genetic Risk Modification by Shift Work and Morningness-Eveningness Preference in the UK Biobank.

Diabetes 2020 02 22;69(2):259-266. Epub 2019 Nov 22.

Center for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA

Night shift work, behavioral rhythms, and the common risk single nucleotide polymorphism (SNP), rs10830963, associate with type 2 diabetes; however, whether they exert joint effects to exacerbate type 2 diabetes risk is unknown. Among employed participants of European ancestry in the UK Biobank ( = 189,488), we aimed to test the cross-sectional independent associations and joint interaction effects of these risk factors on odds of type 2 diabetes ( = 5,042 cases) and HbA levels ( = 175,156). Current shift work, definite morning or evening preference, and rs10830963 risk allele associated with type 2 diabetes and HbA levels. The effect of rs10830963 was not modified by shift work schedules. While marginal evidence of interaction between self-reported morningness-eveningness preference and rs10830963 on risk of type 2 diabetes was seen, this interaction did not persist when analysis was expanded to include all participants regardless of employment status and when accelerometer-derived sleep midpoint was used as an objective measure of morningness-eveningness preference. Our findings suggest that risk allele carriers who carry out shift work or have more extreme morningness-eveningness preference may not have enhanced risk of type 2 diabetes.
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http://dx.doi.org/10.2337/db19-0606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971490PMC
February 2020

Optimizing cardiac ischemic preconditioning and postconditioning via epitranscriptional regulation.

Med Hypotheses 2020 Feb 24;135:109451. Epub 2019 Oct 24.

Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA, USA. Electronic address:

Ischemic cardiac preconditioning protects the heart during myocardial infarction by activating critical cardioprotective genes such as eNOS, SOD, and HO-1. Clinical trials only show marginal effects of conventional preconditioning strategies, however, in part due to transient activation of cardioprotective genes. Recent studies have shown that N6-methyladenosine (m6A) mRNA methylation is the most abundant RNA modification in eukaryotes, and governs mRNA stability and, in turn, the level of protein expression. We hypothesize that regulation of m6A mRNA methylation levels of cardioprotective mRNAs will result in stable expression of the cardioprotective proteins, rendering ischemic cardiac preconditioning more robust and reducing infarct size. To test this hypothesis, we will test the effects of introducing m6A methylases/demethylases into ischemic preconditioned/post conditioned hearts and subjecting them to myocardial infarction. We will assess the half-life of key cardioprotective mRNAs (e.g., eNOS, SOD, and HO-1) and cardiac apoptosis to determine which m6A methylases/demethylases have a synergistic effect on cardiac preconditioning.
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http://dx.doi.org/10.1016/j.mehy.2019.109451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983341PMC
February 2020
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