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1.
Mol Nutr Food Res ; : e1900399, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31533195

RESUMO

SCOPE: A better understanding of factors contributing to interindividual variability in biomarkers of vitamin K can enhance the understanding of the equivocal role of vitamin K in cardiovascular disease. Based on the known biology of phylloquinone, the major form of vitamin K, it is hypothesized that plasma lipids contribute to the variable response of biomarkers of vitamin K metabolism to phylloquinone supplementation. METHODS AND RESULTS: The association of plasma lipids and 27 lipid-related genetic variants with the response of biomarkers of vitamin K metabolism is examined in a secondary analysis of data from a 3-year phylloquinone supplementation trial in men (n = 66) and women (n = 85). Year 3 plasma triglycerides (TG), but not total cholesterol, LDL-cholesterol, or HDL-cholesterol, are associated with the plasma phylloquinone response (men: ß = 1.01, p < 0.001, R2  = 0.34; women: ß = 0.61, p = 0.008, R2  = 0.11; sex interaction p = 0.077). Four variants and the TG-weighted genetic risk score are associated with the plasma phylloquinone response in men only. Plasma lipids are not associated with changes in biomarkers of vitamin K function (undercarboxylated osteocalcin and matrix gla protein) in either sex. CONCLUSION: Plasma TG are an important determinant of the interindividual response of plasma phylloquinone to phylloquinone supplementation, but changes in biomarkers of vitamin K carboxylation are not influenced by lipids.

2.
J Am Coll Cardiol ; 74(10): 1304-1314, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31488267

RESUMO

BACKGROUND: Observational studies suggest associations between extremes of sleep duration and myocardial infarction (MI), but the causal contribution of sleep to MI and its potential to mitigate genetic predisposition to coronary disease is unclear. OBJECTIVES: This study sought to investigate associations between sleep duration and incident MI, accounting for joint effects with other sleep traits and genetic risk of coronary artery disease, and to assess causality using Mendelian randomization (MR). METHODS: In 461,347 UK Biobank (UKB) participants free of relevant cardiovascular disease, the authors estimated multivariable adjusted hazard ratios (HR) for MI (5,128 incident cases) across habitual self-reported short (<6 h) and long (>9 h) sleep duration, and examined joint effects with sleep disturbance traits and a coronary artery disease genetic risk score. The authors conducted 2-sample MR for short (24 single nucleotide polymorphisms) and continuous (71 single nucleotide polymorphisms) sleep duration with MI (n = 43,676 cases/128,199 controls), and replicated results in UKB (n = 12,111/325,421). RESULTS: Compared with sleeping 6 to 9 h/night, short sleepers had a 20% higher multivariable-adjusted risk of incident MI (HR: 1.20; 95% confidence interval [CI]: 1.07 to 1.33), and long sleepers had a 34% higher risk (HR: 1.34; 95% CI: 1.13 to 1.58); associations were independent of other sleep traits. Healthy sleep duration mitigated MI risk even among individuals with high genetic liability (HR: 0.82; 95% CI: 0.68 to 0.998). MR was consistent with a causal effect of short sleep duration on MI in CARDIoGRAMplusC4D (Coronary ARtery DIsease Genome wide Replication and Meta-analysis plus Coronary Artery Disease Genetics Consortium) (HR: 1.19; 95% CI: 1.09 to 1.29) and UKB (HR: 1.21; 95% CI: 1.08 to 1.37). CONCLUSIONS: Prospective observational and MR analyses support short sleep duration as a potentially causal risk factor for MI. Investigation of sleep extension to prevent MI may be warranted.

3.
Nat Commun ; 10(1): 3503, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31409809

RESUMO

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.

4.
BMJ ; 366: l4292, 2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31345923

RESUMO

OBJECTIVE: To investigate whether the genetic burden of type 2 diabetes modifies the association between the quality of dietary fat and the incidence of type 2 diabetes. DESIGN: Individual participant data meta-analysis. DATA SOURCES: Eligible prospective cohort studies were systematically sourced from studies published between January 1970 and February 2017 through electronic searches in major medical databases (Medline, Embase, and Scopus) and discussion with investigators. REVIEW METHODS: Data from cohort studies or multicohort consortia with available genome-wide genetic data and information about the quality of dietary fat and the incidence of type 2 diabetes in participants of European descent was sought. Prospective cohorts that had accrued five or more years of follow-up were included. The type 2 diabetes genetic risk profile was characterized by a 68-variant polygenic risk score weighted by published effect sizes. Diet was recorded by using validated cohort-specific dietary assessment tools. Outcome measures were summary adjusted hazard ratios of incident type 2 diabetes for polygenic risk score, isocaloric replacement of carbohydrate (refined starch and sugars) with types of fat, and the interaction of types of fat with polygenic risk score. RESULTS: Of 102 305 participants from 15 prospective cohort studies, 20 015 type 2 diabetes cases were documented after a median follow-up of 12 years (interquartile range 9.4-14.2). The hazard ratio of type 2 diabetes per increment of 10 risk alleles in the polygenic risk score was 1.64 (95% confidence interval 1.54 to 1.75, I2=7.1%, τ2=0.003). The increase of polyunsaturated fat and total omega 6 polyunsaturated fat intake in place of carbohydrate was associated with a lower risk of type 2 diabetes, with hazard ratios of 0.90 (0.82 to 0.98, I2=18.0%, τ2=0.006; per 5% of energy) and 0.99 (0.97 to 1.00, I2=58.8%, τ2=0.001; per increment of 1 g/d), respectively. Increasing monounsaturated fat in place of carbohydrate was associated with a higher risk of type 2 diabetes (hazard ratio 1.10, 95% confidence interval 1.01 to 1.19, I2=25.9%, τ2=0.006; per 5% of energy). Evidence of small study effects was detected for the overall association of polyunsaturated fat with the risk of type 2 diabetes, but not for the omega 6 polyunsaturated fat and monounsaturated fat associations. Significant interactions between dietary fat and polygenic risk score on the risk of type 2 diabetes (P>0.05 for interaction) were not observed. CONCLUSIONS: These data indicate that genetic burden and the quality of dietary fat are each associated with the incidence of type 2 diabetes. The findings do not support tailoring recommendations on the quality of dietary fat to individual type 2 diabetes genetic risk profiles for the primary prevention of type 2 diabetes, and suggest that dietary fat is associated with the risk of type 2 diabetes across the spectrum of type 2 diabetes genetic risk.


Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/etiologia , Dieta/efeitos adversos , Gorduras na Dieta/efeitos adversos , Adulto , Alelos , Diabetes Mellitus Tipo 2/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco
5.
Int J Epidemiol ; 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31263887

RESUMO

BACKGROUND: People who opt to participate in scientific studies tend to be healthier, wealthier and more educated than the broader population. Although selection bias does not always pose a problem for analysing the relationships between exposures and diseases or other outcomes, it can lead to biased effect size estimates. Biased estimates may weaken the utility of genetic findings because the goal is often to make inferences in a new sample (such as in polygenic risk score analysis). METHODS: We used data from UK Biobank, Generation Scotland and Partners Biobank and conducted phenotypic and genome-wide association analyses on two phenotypes that reflected mental health data availability: (i) whether participants were contactable by e-mail for follow-up; and (ii) whether participants responded to follow-up surveys of mental health. RESULTS: In UK Biobank, we identified nine genetic loci associated (P <5 × 10-8) with e-mail contact and 25 loci associated with mental health survey completion. Both phenotypes were positively genetically correlated with higher educational attainment and better health and negatively genetically correlated with psychological distress and schizophrenia. One single nucleotide polymorphism association replicated along with the overall direction of effect of all association results. CONCLUSIONS: Re-contact availability and follow-up participation can act as further genetic filters for data on mental health phenotypes.

6.
Am J Clin Nutr ; 110(2): 473-484, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31190057

RESUMO

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.

7.
BMJ ; 365: l2327, 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31243001

RESUMO

OBJECTIVE: To examine whether sleep traits have a causal effect on risk of breast cancer. DESIGN: Mendelian randomisation study. SETTING: UK Biobank prospective cohort study and Breast Cancer Association Consortium (BCAC) case-control genome-wide association study. PARTICIPANTS: 156 848 women in the multivariable regression and one sample mendelian randomisation (MR) analysis in UK Biobank (7784 with a breast cancer diagnosis) and 122 977 breast cancer cases and 105 974 controls from BCAC in the two sample MR analysis. EXPOSURES: Self reported chronotype (morning or evening preference), insomnia symptoms, and sleep duration in multivariable regression, and genetic variants robustly associated with these sleep traits. MAIN OUTCOME MEASURE: Breast cancer diagnosis. RESULTS: In multivariable regression analysis using UK Biobank data on breast cancer incidence, morning preference was inversely associated with breast cancer (hazard ratio 0.95, 95% confidence interval 0.93 to 0.98 per category increase), whereas there was little evidence for an association between sleep duration and insomnia symptoms. Using 341 single nucleotide polymorphisms (SNPs) associated with chronotype, 91 SNPs associated with sleep duration, and 57 SNPs associated with insomnia symptoms, one sample MR analysis in UK Biobank provided some supportive evidence for a protective effect of morning preference on breast cancer risk (0.85, 0.70, 1.03 per category increase) but imprecise estimates for sleep duration and insomnia symptoms. Two sample MR using data from BCAC supported findings for a protective effect of morning preference (inverse variance weighted odds ratio 0.88, 95% confidence interval 0.82 to 0.93 per category increase) and adverse effect of increased sleep duration (1.19, 1.02 to 1.39 per hour increase) on breast cancer risk (both oestrogen receptor positive and oestrogen receptor negative), whereas evidence for insomnia symptoms was inconsistent. Results were largely robust to sensitivity analyses accounting for horizontal pleiotropy. CONCLUSIONS: Findings showed consistent evidence for a protective effect of morning preference and suggestive evidence for an adverse effect of increased sleep duration on breast cancer risk.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etiologia , Sono , Adulto , Idoso , Estudos de Casos e Controles , Ritmo Circadiano , Comorbidade , Fatores de Confusão (Epidemiologia) , Feminino , Estudo de Associação Genômica Ampla , Humanos , Incidência , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Análise Multivariada , Estudos Prospectivos , Fatores de Risco , Distúrbios do Início e da Manutenção do Sono/epidemiologia , Fatores de Tempo , Reino Unido/epidemiologia
8.
Adv Nutr ; 10(4): 606-620, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31046092

RESUMO

Observations that mistimed food intake may have adverse metabolic health effects have generated interest in personalizing food timing recommendations in interventional studies and public health strategies for the purpose of disease prevention and improving overall health. Small, controlled, and short-termed intervention studies suggest that food timing may be modified as it is presumed to be primarily regulated by choice. Identifying and evaluating social and biological factors that explain variability in food timing may determine whether changes in food timing in uncontrolled, free-living environments are sustainable in the long term, and may facilitate design of successful food timing-based interventions. Based on a comprehensive literature search, we summarize 1) cultural and environmental factors; 2) behavioral and personal preference factors; and 3) physiological factors that influence the time when people consume foods. Furthermore, we 1) highlight vulnerable populations who have been identified in experimental and epidemiological studies to be at risk of mistimed food intake and thus necessitating intervention; 2) identify currently used food timing assessment tools and their limitations; and 3) indicate other important considerations for the design of food timing interventions based on successful strategies that address timing of other lifestyle behaviors. Conclusions drawn from this overview may help design practical food timing interventions, develop feasible public health programs, and establish guidelines for effective lifestyle recommendations for prevention and treatment of adverse health outcomes attributed to mistimed food intake.

9.
Nat Commun ; 10(1): 1585, 2019 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-30952852

RESUMO

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 × 10-8, of which 20 reach a stricter threshold of P < 8 × 10-10. 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.


Assuntos
Polissonografia/métodos , Transtornos do Sono-Vigília/genética , Sono/genética , Acelerometria/métodos , Ritmo Circadiano , Humanos , Polimorfismo de Nucleotídeo Único , Serotonina/genética , Serotonina/metabolismo , Transtornos do Sono-Vigília/diagnóstico , Relação Cintura-Quadril
10.
Nat Commun ; 10(1): 1100, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30846698

RESUMO

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


Assuntos
Loci Gênicos , Sono/genética , Acelerometria , Adulto , Idoso , Grupo com Ancestrais do Continente Europeu , Feminino , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Esquizofrenia/genética , Esquizofrenia/fisiopatologia , Autorrelato , Sono/fisiologia , Reino Unido
11.
Nat Genet ; 51(3): 387-393, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804566

RESUMO

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.


Assuntos
Predisposição Genética para Doença/genética , Distúrbios do Início e da Manutenção do Sono/genética , Sono/genética , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Expressão Gênica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Proteólise , Autorrelato , Ubiquitina/genética
12.
Nat Commun ; 10(1): 343, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30696823

RESUMO

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.


Assuntos
Ritmo Circadiano , Grupo com Ancestrais do Continente Europeu/genética , Estudo de Associação Genômica Ampla , Adulto , Idoso , AMP Cíclico/metabolismo , Feminino , Loci Gênicos , Ácido Glutâmico/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Sono , Reino Unido
13.
Sleep ; 2018 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-30521049

RESUMO

Study Objectives: We aimed to detect cross-sectional phenotype and polygenic risk score (PRS) associations between sleep duration and prevalent diseases using the Partners Biobank, a hospital-based cohort study linking electronic medical record (EMR) with genetic information. Methods: Disease prevalence was determined from EMR, and sleep duration was self-reported. A PRS for sleep duration was derived using 78 previously associated SNPs from GWAS for self-reported sleep duration. We tested for associations between 1) self-reported sleep duration and 22 prevalent diseases (n=30,251), 2) the PRS and self-reported sleep duration (n=6,903), and 3) the PRS and the 22 prevalent diseases (n=16,033). For observed PRS-disease associations, we tested causality using two-sample Mendelian randomization (MR). Results: In the age-, sex-, and race-adjusted model, u-shaped associations were observed for sleep duration and asthma, depression, hypertension, insomnia, obesity, obstructive sleep apnea, and type 2 diabetes, where both short and long sleepers had higher odds for these diseases than normal sleepers (P<2.27x10-3). Next, we confirmed associations between the PRS and longer sleep duration (0.65 ± 0.19 SD minutes per effect allele; P=7.32×10-04). The PRS collectively explained 1.4% of the phenotypic variance in sleep duration. After adjusting for age, sex, genotyping array, and principal components of ancestry, we observed that the PRS was also associated with congestive heart failure (P=0.015), obesity (P=0.019), hypertension (P=0.039), restless legs syndrome (RLS; P=0.041), and insomnia (P=0.049). Associations were maintained following additional adjustment for obesity status, except for hypertension and insomnia. For all diseases, except RLS, carrying a higher genetic burden of the 78 sleep duration-increasing alleles (i.e. higher sleep duration PRS) associated with lower odds for prevalent disease. In MR, we estimated causal associations between genetically defined longer sleep duration with decreased risk of CHF [IVW OR per minute of sleep (95% CI) =0.978 (0.961-0.996); P =0.019] and hypertension [IVW OR (95% CI) =0.993 (0.986-1.000); P =0.049], and increased risk of RLS [IVW OR (95% CI) =1.018 (1.000-1.036); P =0.045]. Conclusion: By validating the PRS for sleep duration and identifying cross-phenotype associations, we lay the groundwork for future investigations on the intersection between sleep, genetics, clinical measures, and diseases using large EMR datasets.

14.
Diabetes ; 2018 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-30352877

RESUMO

This study aims to investigate the causal relation between circulating phylloquinone (vitamin K1) concentrations and type 2 diabetes using a Mendelian Randomization (MR) approach. We used data from thee cohorts: the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study, Diabetes Genetics Replication and Meta-analysis (DIAGRAM) and the UK Biobank, resulting in 69,647 type 2 diabetes cases. We calculated a weighted genetic risk score including four genetic variants previously found to be associated with circulating phylloquinone concentrations. Inverse-variance weighted analysis was used to obtain a risk ratio (RR) for the causal relation between circulating phylloquinone concentrations and risk of type 2 diabetes. Presence of pleiotropy and the robustness of the results were assessed using MR-Egger and weighted-median analyses. Genetically-predicted concentrations of circulating phylloquinone was associated with lower risk of type 2 diabetes with a RR of 0.93 (95% confidence interval: 0.89;0.97) per every ln-nmol/L unit increase in circulating phylloquinone. The MR-Egger and weighted median analyses showed RRs of 0.94 (0.86;1.02) and 0.93 (0.88;0.98), respectively, indicating no pleiotropy. In conclusion, our study supports that higher circulating phylloquinone may be causally related with lower risk of type 2 diabetes, highlighting the importance of sufficient phylloquinone in the human diet.

15.
Mol Psychiatry ; 2018 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-29988085

RESUMO

Macronutrient intake, the proportion of calories consumed from carbohydrate, fat, and protein, is an important risk factor for metabolic diseases with significant familial aggregation. Previous studies have identified two genetic loci for macronutrient intake, but incomplete coverage of genetic variation and modest sample sizes have hindered the discovery of additional loci. Here, we expanded the genetic landscape of macronutrient intake, identifying 12 suggestively significant loci (P < 1 × 10-6) associated with intake of any macronutrient in 91,114 European ancestry participants. Four loci replicated and reached genome-wide significance in a combined meta-analysis including 123,659 European descent participants, unraveling two novel loci; a common variant in RARB locus for carbohydrate intake and a rare variant in DRAM1 locus for protein intake, and corroborating earlier FGF21 and FTO findings. In additional analysis of 144,770 participants from the UK Biobank, all identified associations from the two-stage analysis were confirmed except for DRAM1. Identified loci might have implications in brain and adipose tissue biology and have clinical impact in obesity-related phenotypes. Our findings provide new insight into biological functions related to macronutrient intake.

16.
Nat Genet ; 50(5): 668-681, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29700475

RESUMO

Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype.

17.
Adv Nutr ; 9(2): 128-135, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29659694

RESUMO

The increasing prevalence in polygenic diseases, such as obesity, cardiovascular disease, and type 2 diabetes, observed over the past few decades is more likely linked to a rapid transition in lifestyle rather than to changes in the sequence of the nuclear genome. In the new era of precision medicine, nutritional genomics holds the promise to be translated into tailored nutritional strategies to prevent and manage polygenic diseases more effectively. Nutritional genomics aims to prevent, treat, and manage polygenic diseases through targeted therapies formulated from individuals' genetic makeup and dietary intake. Direct-to-consumer genetic testing (DTC-GT) has become commercially available to equip individuals with information on their genetic vulnerability to different diseases. This information may potentially prompt behavioral changes against adverse factors. However, scientific evidence behind the clinical recommendations is a matter of continuous debate, and behavioral modifications after disclosing genetic information remain inconclusive. In this review, we provide an overview of nutritional genomics and related nutritional DTC-GT services and discuss whether available data are sufficient to be translated into clinical recommendations and public health initiatives. Overall, the scientific evidence supporting the dissemination of genomic information for nutrigenomic purposes remains sparse. Therefore, additional knowledge needs to be generated, particularly for polygenic traits.

18.
Clin Nutr ; 2018 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-29571565

RESUMO

BACKGROUND & AIMS: While environmental factors are presumed to be primary drivers of food timing, preliminary evidence suggests that genetics may be an additional determinant. The aim was to explore the relative contribution of genetics and environmental factors to variation in the timing of food intake in a Spanish twin population. Because chronotype, bedtime and wake time are related to food timing, covariance with food timing was further assessed. METHODS: In this observational study, 53 pairs of adult (mean (SD) = 52 (6.03) years) female twins (28 monozygotic; 25 dizygotic) were recruited from the Murcia Twin Register. Zygosity was determined by DNA-testing. Timing of the three main meals of the day was assessed via 7-day dietary records, and the midpoint of food intake was computed by calculating the midpoint between breakfast and dinner times. Chronotype, bedtime and wake time were self-reported. Heritability of food timing and related traits were estimated by comparing monozygotic and dizygotic twin correlations and fitting genetic structural equation models to measured variables. RESULTS: We observed genetic influences for food timing, with highest heritability for the midpoint of food intake (64%) in an overweight/obese population (BMI = 26.01 ± 3.77). Genetic factors contributed to a higher degree to the timing of breakfast (56%) than the timing of lunch (38%) or dinner (n.s.). Similarly, heritability estimates were larger in related behavioral traits earlier on in the day (i.e. wake time, (55%)), than those later on in the day (i.e. bedtime, (38%)). Bivariate analyses revealed a significant genetic overlap between food timing and bedtime and chronotype (rG between 0.78 and 0.91). CONCLUSIONS: Genetic influences appear to account for a significant proportion of the variability in food timing, particularly breakfast. Thus, interventions related to food timing may be more effective when targeting afternoon/evening traits, such as lunch or dinner times. Furthermore, our data suggest shared genetic architecture underlying food timing and phenotypically related traits. CLINICAL TRIAL: NCT03059576. https://clinicaltrials.gov/ct2/show/NCT03059576.

19.
Diabetes Care ; 41(4): 762-769, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29440150

RESUMO

OBJECTIVE: To examine the effects of past and current night shift work and genetic type 2 diabetes vulnerability on type 2 diabetes odds. RESEARCH DESIGN AND METHODS: In the UK Biobank, we examined associations of current (N = 272,214) and lifetime (N = 70,480) night shift work exposure with type 2 diabetes risk (6,770 and 1,191 prevalent cases, respectively). For 180,704 and 44,141 unrelated participants of European ancestry (4,002 and 726 cases, respectively) with genetic data, we assessed whether shift work exposure modified the relationship between a genetic risk score (comprising 110 single-nucleotide polymorphisms) for type 2 diabetes and prevalent diabetes. RESULTS: Compared with day workers, all current night shift workers were at higher multivariable-adjusted odds for type 2 diabetes (none or rare night shifts: odds ratio [OR] 1.15 [95% CI 1.05-1.26]; some nights: OR 1.18 [95% CI 1.05-1.32]; and usual nights: OR 1.44 [95% CI 1.19-1.73]), except current permanent night shift workers (OR 1.09 [95% CI 0.93-1.27]). Considering a person's lifetime work schedule and compared with never shift workers, working more night shifts per month was associated with higher type 2 diabetes odds (<3/month: OR 1.24 [95% CI 0.90-1.68]; 3-8/month: OR 1.11 [95% CI 0.90-1.37]; and >8/month: OR 1.36 [95% CI 1.14-1.62]; Ptrend = 0.001). The association between genetic type 2 diabetes predisposition and type 2 diabetes odds was not modified by shift work exposure. CONCLUSIONS: Our findings show that night shift work, especially rotating shift work including night shifts, is associated with higher type 2 diabetes odds and that the number of night shifts worked per month appears most relevant for type 2 diabetes odds. Also, shift work exposure does not modify genetic risk for type 2 diabetes, a novel finding that warrants replication.


Assuntos
Bancos de Espécimes Biológicos/estatística & dados numéricos , Diabetes Mellitus Tipo 2/epidemiologia , Predisposição Genética para Doença/epidemiologia , Jornada de Trabalho em Turnos/estatística & dados numéricos , Adulto , Idoso , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/genética , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Prevalência , Fatores de Risco , Jornada de Trabalho em Turnos/efeitos adversos , Reino Unido/epidemiologia , Tolerância ao Trabalho Programado/fisiologia
20.
Sci Rep ; 8(1): 945, 2018 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-29343740

RESUMO

Evening chronotype associates with health complications possibly via lifestyle factors, while the contribution of genetics is unknown. The aim was to study the relative contributions of genetics, lifestyle, and circadian-related physiological characteristics in metabolic risk of evening chronotype. In order to capture a biological contribution to chronotype, a genetic-risk-score (GRS), comprised of 15 chronotype-related variants, was tested. Moreover, a wide range of behavioral and emotional eating factors was studied within the same population. Chronotype, lifestyle, and metabolic syndrome (MetS) outcomes were assessed (n = 2,126), in addition to genetics (n = 1,693) and rest-activity/wrist-temperature rhythms (n = 100). Evening chronotype associated with MetS and insulin resistance (P < 0.05), and several lifestyle factors including poorer eating behaviors, lower physical activity and later sleep and wake times. We observed an association between higher evening GRS and evening chronotype (P < 0.05), but not with MetS. We propose a GRS as a tool to capture the biological component of the inter-individual differences in chronotype. Our data show that several modifiable factors such as sedentary lifestyle, difficulties in controlling the amount of food eaten, alcohol intake and later wake and bed times that characterized evening-types, may underlie chronotype-MetS relationship. Our findings provide insights into the development of strategies, particularly for evening chronotype.


Assuntos
Ritmo Circadiano/fisiologia , Síndrome Metabólica/etiologia , Síndrome Metabólica/fisiopatologia , Sono/fisiologia , Adulto , Feminino , Humanos , Estilo de Vida , Masculino , Fatores de Risco , Inquéritos e Questionários
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