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1.
Mol Psychiatry ; 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33414500

RESUMO

Maternal anxiety during pregnancy is associated with adverse foetal, neonatal, and child outcomes, but biological mechanisms remain unclear. Altered foetal DNA methylation (DNAm) has been proposed as a potential underlying mechanism. In the current study, we performed a meta-analysis to examine the associations between maternal anxiety, measured prospectively during pregnancy, and genome-wide DNAm from umbilical cord blood. Sixteen non-overlapping cohorts from 12 independent longitudinal studies of the Pregnancy And Childhood Epigenetics Consortium participated, resulting in a combined dataset of 7243 mother-child dyads. We examined prenatal anxiety in relation to genome-wide DNAm and differentially methylated regions. We observed no association between the general symptoms of anxiety during pregnancy or pregnancy-related anxiety, and DNAm at any of the CpG sites, after multiple-testing correction. Furthermore, we identify no differentially methylated regions associated with maternal anxiety. At the cohort-level, of the 21 associations observed in individual cohorts, none replicated consistently in the other cohorts. In conclusion, contrary to some previous studies proposing cord blood DNAm as a promising potential mechanism explaining the link between maternal anxiety during pregnancy and adverse outcomes in offspring, we found no consistent evidence for any robust associations between maternal anxiety and DNAm in cord blood. Larger studies and analysis of DNAm in other tissues may be needed to establish subtle or subgroup-specific associations between maternal anxiety and the foetal epigenome.

2.
Sci Rep ; 10(1): 12908, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737344

RESUMO

A focus in recent decades has involved examining the potential causal impact of educational attainment (schooling years) on a variety of disease and life-expectancy outcomes. Numerous studies have broadly revealed a link suggesting that as years of formal schooling increase so too does health and wellbeing; however, it is unclear whether the associations are causal. Here we use Mendelian randomization, an instrumental variables technique, with a two-sample design, to probe whether more years of schooling are causally linked to type 2 diabetes (T2D) and 10 of its attendant risk factors. The results revealed a protective effect of more schooling years against T2D (odds ratio = 0.39; 95% confidence interval: 0.26, 0.58; P = 3.89 × 10-06), which in turn might be partly mediated by more years of schooling being protective against the following: having a father with T2D, being overweight, having higher blood pressure and higher levels of circulating triglycerides, and having lower levels of HDL cholesterol. More schooling years had no effect on risk for gestational diabetes or polycystic ovarian syndrome and was associated with a decreased likelihood of moderate physical activity. These findings imply that strategies to retain adults in higher education may help reduce the risk for a major source of metabolic morbidity and mortality.

4.
Sci Rep ; 10(1): 12223, 2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32699327

RESUMO

Whether telomere attrition reducing proliferative reserve in blood-cell progenitors is causal has important public-health implications. Mendelian randomization (MR) is an analytic technique using germline genetic variants as instrumental variables. If certain assumptions are met, estimates from MR should be free from most environmental sources of confounding and reverse causation. Here, two-sample MR is performed to test whether longer telomeres cause changes to hematological traits. Summary statistics for genetic variants strongly associated with telomere length were extracted from a genome-wide association (GWA) study for telomere length in individuals of European ancestry (n = 9190) and from GWA studies of blood-cell traits, also in those of European ancestry (n ~ 173,000 participants). A standard deviation increase in genetically influenced telomere length increased red blood cell and white blood cell counts, decreased mean corpuscular hemoglobinand mean cell volume, and had no observable impact on mean corpuscular hemoglobin concentration, red cell distribution width, hematocrit, or hemoglobin. Sensitivity tests for pleiotropic distortion were mostly inconsistent with glaring violations to the MR assumptions. Similar to germline mutations in telomere biology genes leading to bone-marrow failure, these data provide evidence that genetically influenced common variation in telomere length impacts hematologic traits in the population.


Assuntos
Células Sanguíneas/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Telômero/genética , Telômero/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Estudo de Associação Genômica Ampla/métodos , Mutação em Linhagem Germinativa/genética , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Fenótipo , Fatores de Risco , Homeostase do Telômero/genética , Adulto Jovem
5.
Sci Rep ; 10(1): 6018, 2020 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-32265532

RESUMO

Education and intelligence are highly correlated and inversely associated with schizophrenia. Counterintuitively, education genetically associates with an increased risk for the disease. To investigate why, this study applies a multivariable Mendelian randomization of intelligence and education. For those without college degrees, older age of finishing school associates with a decreased likelihood of schizophrenia-independent of intelligence-and, hence, may be entangled with the health inequalities reflecting differences in education. A different picture is observed for schooling years inclusive of college: more years of schooling increases the likelihood of schizophrenia, whereas higher intelligence distinctly and independently decreases it. This implies the pleiotropy between years of schooling and schizophrenia is horizontal and likely confounded by a third trait influencing education. A multivariable Mendelian randomization of schooling years and bipolar disorder reveals that the increased risk of schizophrenia conferred by more schooling years is an artefact of bipolar disorder - not education.

6.
Clin Interv Aging ; 15: 185-193, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32103921

RESUMO

Background: Alzheimer's disease is a devastating neurodegenerative disorder. Its worldwide prevalence is over 24 million and is expected to double by 2040. Finding ways to prevent its cognitive decline is urgent. Methods: A two-sample Mendelian randomization study was performed instrumenting glutamine, which is abundant in blood, capable of crossing the blood-brain barrier, and involved in a metabolic cycle with glutamate in the brain. Results: The results reveal a protective effect of circulating glutamine against Alzheimer's disease (inverse-variance weighted method, odds ratio per 1-standard deviation increase in circulating glutamine = 0.83; 95% CI 0.71, 0.97; P = 0.02). Conclusion: These findings lend credence to the emerging story supporting the modifiability of glutamine/glutamate metabolism for the prevention of cognitive decline. More circulating glutamine might mean that more substrate is available during times of stress, acting as a neuroprotectant. Modifications to exogenous glutamine may be worth exploring in future efforts to prevent and/or treat Alzheimer's disease.


Assuntos
Doença de Alzheimer , Barreira Hematoencefálica/fisiologia , Encéfalo/metabolismo , Disfunção Cognitiva/prevenção & controle , Glutamina , Idoso , Doença de Alzheimer/sangue , Doença de Alzheimer/metabolismo , Cognição/fisiologia , Feminino , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Glutamina/sangue , Glutamina/genética , Glutamina/metabolismo , Humanos , Masculino , Análise da Randomização Mendeliana/métodos , Fármacos Neuroprotetores/metabolismo , Receptores de Glutamato/metabolismo
7.
Mol Genet Metab Rep ; 21: 100539, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31844628

RESUMO

Most women with epithelial ovarian cancer (EOC) present with late-stage disease. As a result, globally, EOC is responsible for >150,000 deaths a year. Thus, a better understanding of risk factors for developing EOC is crucial for earlier screening and detection to improve survival. To that effort, there have been suggestions that there is an association of schizophrenia and cancer, possibly because metabolic changes are a hallmark of both cancer and schizophrenia (SZ). Perturbed choline metabolism has been documented in both diseases. Our objective was to use Mendelian randomization to evaluate whether SZ increased risk for developing EOC or the converse, and, whether SZ impacted 1- or 2-glycerophosphocholine (1- or 2-GPC) metabolites. We found that SZ conferred a weak but increased risk for EOC, but not the reverse (no evidence that EOC caused SZ). SZ was also causally associated with lower levels of two 1- or 2-GPC species and with suggestively lower levels in an additional three 1- or 2-GPCs. We postulate that perturbed choline metabolism in SZ may mimic or contribute to a "cholinic" phenotype, as observed in EOC cells.

8.
Nutr Metab Cardiovasc Dis ; 29(11): 1176-1184, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31378628

RESUMO

BACKGROUND AND AIMS: Preference for activity in the morning or evening (chronotype) may impact type 2 diabetes (T2D) risk factors. Our objective was to use Mendelian randomization (MR) to evaluate whether there are causal links between chronotype and one potential T2D risk factor, total fatty acids (TOTFA), and between TOTFA and T2D. METHODS AND RESULTS: We estimated the causal effect of: 1) morning chronotype on TOTFA; and 2) higher TOTFA on T2D. We found that: a) morning compared to evening chronotype was associated with lower TOTFA levels (inverse-weighted variance (IVW) estimate -0.21; 95% CI -0.38, -0.03; raw P = 0.02; FDR-corrected P 0.04) and b) elevated TOTFA levels were protective against T2D (IVW estimate -0.23; 95% CI -0.41, -0.05; raw P = 0.01; FDR-corrected P = 0.03). Based on this finding, we further hypothesized that healthy fats would show a similar pattern and performed MR of a) morning chronotype on omega-3 (Omega-3), monounsaturated (MUFA), and polyunsaturated (PUFA) fatty acids; and b) MR of each of these fat types on T2D. We observed the same mediating-type pattern for chronotype, MUFA, and T2D as we had for chronotype, TOTFA, and T2D, and morning chronotype was associated with lower Omega-3. CONCLUSION: Our findings provide suggestive, new information about relationships among chronotype, TOTFA, and T2D and about chronotype as a factor influencing Omega-3, MUFA, and TOTFA levels. In addition, we validated previous knowledge about MUFA and T2D. Morning chronotypes may predispose towards lower levels of TOTFA and some healthy fats, whereas higher levels of TOTFA and MUFA may protect against T2D.


Assuntos
Ciclos de Atividade/genética , Diabetes Mellitus Tipo 2/genética , Ácidos Graxos/sangue , Polimorfismo de Nucleotídeo Único , Biomarcadores/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/fisiopatologia , Predisposição Genética para Doença , Humanos , Análise da Randomização Mendeliana , Fenótipo , Prognóstico , Medição de Risco , Fatores de Risco
9.
Public Health Ethics ; 12(1): 44-53, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30891097

RESUMO

Shift work (working outside of 6:00 AM to 6:00 PM) is a fixture of our 24-hour economy, with approximately 18 per cent of workers in the USA engaging in shift work, many overnight. Since shift work has been linked to an increased risk for an array of serious maladies, including cardiometabolic disorders and cancer, and is done disproportionately by the poor and by minorities, shift work is a highly prevalent economic and occupational health disparity. Here we draw primarily on the state of science around shift work and breast cancer to argue that shift work represents a public health threat serious enough to warrant a precautionary stance. We use the precautionary principle to advance our case and view it as a moral compass for shift work research, empowering public health to cast shift work within the domain of health disparities deserving action despite scientific uncertainty. With the precautionary principle, we call for a deliberative decision-making process and formation of a broad shift work research collaboration to protect the health of many millions who work at night.

10.
Cancer Epidemiol Biomarkers Prev ; 28(1): 208-216, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30352818

RESUMO

BACKGROUND: Whether associations between circulating metabolites and prostate cancer are causal is unknown. We report on the largest study of metabolites and prostate cancer (2,291 cases and 2,661 controls) and appraise causality for a subset of the prostate cancer-metabolite associations using two-sample Mendelian randomization (MR). METHODS: The case-control portion of the study was conducted in nine UK centers with men ages 50-69 years who underwent prostate-specific antigen screening for prostate cancer within the Prostate Testing for Cancer and Treatment (ProtecT) trial. Two data sources were used to appraise causality: a genome-wide association study (GWAS) of metabolites in 24,925 participants and a GWAS of prostate cancer in 44,825 cases and 27,904 controls within the Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. RESULTS: Thirty-five metabolites were strongly associated with prostate cancer (P < 0.0014, multiple-testing threshold). These fell into four classes: (i) lipids and lipoprotein subclass characteristics (total cholesterol and ratios, cholesterol esters and ratios, free cholesterol and ratios, phospholipids and ratios, and triglyceride ratios); (ii) fatty acids and ratios; (iii) amino acids; (iv) and fluid balance. Fourteen top metabolites were proxied by genetic variables, but MR indicated these were not causal. CONCLUSIONS: We identified 35 circulating metabolites associated with prostate cancer presence, but found no evidence of causality for those 14 testable with MR. Thus, the 14 MR-tested metabolites are unlikely to be mechanistically important in prostate cancer risk. IMPACT: The metabolome provides a promising set of biomarkers that may aid prostate cancer classification.


Assuntos
Biomarcadores Tumorais/sangue , Metaboloma , Neoplasias da Próstata/sangue , Idoso , Estudos de Casos e Controles , Colesterol/sangue , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Fosfolipídeos/sangue , Antígeno Prostático Específico/sangue , Triglicerídeos/sangue , Reino Unido
11.
Curr Opin Psychol ; 27: 36-40, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30121470

RESUMO

The epidemiologic study of DNA methylation (DNAm) and mental health is a burgeoning area, but confounding and reverse causation remain important to know about. Whether use of non-brain tissues is appropriate when investigating brain phenotypes depends on the hypothesis and whether the goal is causality or to identify biomarkers. Look-ups of the correspondence between DNAm in blood and brain and use of Mendelian randomization (MR) can be done to follow-up, to some degree, on the causal nature of some findings. Social scientists, health methodologists (epidemiologists), and basic scientists-thinkers who view epigenetics and mental health from different perspectives-can come together in the design and framing of findings to avoid pitfalls and innovate beyond what each could do alone.


Assuntos
Metilação de DNA/genética , Epidemiologia , Epigênese Genética , Saúde Mental , Humanos
12.
Epigenetics ; 12(10): 833-840, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28837395

RESUMO

Molecular mechanisms underlying the negative health effects of shift work are poorly understood, which remains a barrier to developing intervention strategies to protect the long-term health of shift workers. We evaluated genome-wide differences in DNA methylation (measured in blood) between 111 actively employed female nightshift and 86 actively employed female dayshift workers from the Seattle metropolitan area. We also explored the effect of chronotype (i.e., measure of preference for activity earlier or later in the day) on DNA methylation among 110 of the female nightshift workers and an additional group of 131 male nightshift workers. Methylation data were generated using the Illumina Infinium HumanMethylation450 BeadChip (450K) Array. After applying the latest methylation data processing methods, we compared methylation levels at 361,210 CpG loci between the groups using linear regression models adjusted for potential confounders and applied the false-discovery rate (FDR) ≤ 0.05 to account for multiple comparisons. No statistically significant associations at the genome-wide level were observed with shift work or chronotype, though based on raw P values and absolute effect sizes, there were suggestive associations in genes that have been previously linked with cancer (e.g., BACH2, JRK, RPS6KA2) and type-2 diabetes (e.g., KCNQ1). Given that our study was underpowered to detect moderate effects, examining these suggestive results in well-powered independent studies or in pooled data sets may improve our understanding of the pathways underlying the negative health effects of shift work and the influence of personal factors such as chronotype. Such an approach may help identify potential interventions that can be used to protect the long-term health of shift workers.


Assuntos
Ritmo Circadiano/genética , Metilação de DNA/genética , DNA/sangue , Jornada de Trabalho em Turnos , Adulto , Ritmo Circadiano/fisiologia , Ilhas de CpG/genética , DNA/genética , Feminino , Genoma Humano/genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos/métodos
13.
Pediatr Blood Cancer ; 63(12): 2139-2145, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27428025

RESUMO

BACKGROUND: The inherited bone marrow failure syndromes (IBMFSs) are diverse disorders with syndrome-specific features; their otologic and audiologic manifestations have not been well described. Our objective was to characterize these in patients with Fanconi anemia (FA), dyskeratosis congenita (DC), Diamond-Blackfan anemia (DBA), and Shwachman-Diamond syndrome (SDS), and to determine the association between physical findings and hearing loss. METHODS: Patients with an IBMFS underwent comprehensive clinical and laboratory evaluations and testing for syndrome-specific gene mutations. Hearing loss was measured by pure tone audiometry and otologic abnormalities by otomicroscopy. RESULTS: Patients included 33 with FA, 37 with DC, 32 with DBA, and nine with SDS. Hearing loss was most frequent in patients with FA (45%) and DBA (14%). The most common type of hearing loss in FA was conductive (65%). Absent or hypoplastic radius, noted in 21% of the patients with FA, was associated with hearing loss in all cases. Otomicroscopy was abnormal in 66% of patients with FA. Characteristic ear abnormalities included small tympanic membrane (66%), malformed malleus (57%), aberrant tympanic bony island (48%), narrow external auditory canal (EAC) (32%), and abnormal course of chorda tympani (34%). Ear malformations were almost always associated with hearing loss. Hearing loss was rare in patients with DC and SDS. CONCLUSIONS: FA is the major IBMFS with associated hearing loss, which is most commonly conductive. Radial hypoplasia or aplasia and characteristic congenital ear malformations are associated with hearing loss in patients with FA. Recognition of these syndrome-specific abnormalities should lead to earlier management of hearing loss.


Assuntos
Anemia Aplástica/complicações , Doenças da Medula Óssea/complicações , Anemia de Fanconi/complicações , Perda Auditiva/etiologia , Hemoglobinúria Paroxística/complicações , Adolescente , Adulto , Idoso , Anemia de Diamond-Blackfan/complicações , Transtornos da Insuficiência da Medula Óssea , Criança , Pré-Escolar , Insuficiência Pancreática Exócrina/complicações , Feminino , Humanos , Lactente , Lipomatose/complicações , Masculino , Pessoa de Meia-Idade , Síndrome de Shwachman-Diamond , Adulto Jovem
14.
Cancer Epidemiol Biomarkers Prev ; 24(10): 1614-21, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26265202

RESUMO

BACKGROUND: Human testicular germ cell tumors (TGCT) have a strong genetic component and a high familial relative risk. However, linkage analyses have not identified a rare, highly penetrant familial TGCT (FTGCT) susceptibility locus. Currently, multiple low-penetrance genes are hypothesized to underlie the familial multiple-case phenotype. The observation that two is the most common number of affected individuals per family presents an impediment to FTGCT gene discovery. Clinically, the prospective TGCT risk in the multiple-case family context is unknown. METHODS: We performed a prospective analysis of TGCT incidence in a cohort of multiple-affected-person families and sporadic-bilateral-case families; 1,260 men from 140 families (10,207 person-years of follow-up) met our inclusion criteria. Age-, gender-, and calendar time-specific standardized incidence ratios (SIR) for TGCT relative to the general population were calculated using SEER*Stat. RESULTS: Eight incident TGCTs occurred during prospective FTGCT cohort follow-up (versus 0.67 expected; SIR = 11.9; 95% CI, 5.1-23.4; excess absolute risk = 7.2/10,000). We demonstrate that the incidence rate of TGCT is greater among bloodline male relatives from multiple-case testicular cancer families than that expected in the general population, a pattern characteristic of adult-onset Mendelian cancer susceptibility disorders. Two of these incident TGCTs occurred in relatives of sporadic-bilateral cases (0.15 expected; SIR = 13.4; 95% CI, 1.6-48.6). CONCLUSIONS: Our data are the first to indicate that despite relatively low numbers of affected individuals per family, members of both multiple-affected-person FTGCT families and sporadic-bilateral TGCT families comprise high-risk groups for incident testicular cancer. IMPACT: Men at high TGCT risk might benefit from tailored risk stratification and surveillance strategies.


Assuntos
Família , Predisposição Genética para Doença , Neoplasias Embrionárias de Células Germinativas/epidemiologia , Medição de Risco/métodos , Programa de SEER , Neoplasias Testiculares/epidemiologia , Adulto , Seguimentos , Humanos , Incidência , Masculino , Maryland/epidemiologia , Neoplasias Embrionárias de Células Germinativas/genética , Fenótipo , Estudos Prospectivos , Fatores de Risco , Neoplasias Testiculares/genética
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