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1.
Nat Commun ; 10(1): 4330, 2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31551420

RESUMO

Most genome-wide association studies are based on samples of European descent. We assess whether the genetic determinants of blood lipids, a major cardiovascular risk factor, are shared across populations. Genetic correlations for lipids between European-ancestry and Asian cohorts are not significantly different from 1. A genetic risk score based on LDL-cholesterol-associated loci has consistent effects on serum levels in samples from the UK, Uganda and Greece (r = 0.23-0.28, p < 1.9 × 10-14). Overall, there is evidence of reproducibility for ~75% of the major lipid loci from European discovery studies, except triglyceride loci in the Ugandan samples (10% of loci). Individual transferable loci are identified using trans-ethnic colocalization. Ten of fourteen loci not transferable to the Ugandan population have pleiotropic associations with BMI in Europeans; none of the transferable loci do. The non-transferable loci might affect lipids by modifying food intake in environments rich in certain nutrients, which suggests a potential role for gene-environment interactions.

2.
BMC Genomics ; 20(1): 366, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088362

RESUMO

BACKGROUND: There has been a steady increase in the number of studies aiming to identify DNA methylation differences associated with complex phenotypes. Many of the challenges of epigenetic epidemiology regarding study design and interpretation have been discussed in detail, however there are analytical concerns that are outstanding and require further exploration. In this study we seek to address three analytical issues. First, we quantify the multiple testing burden and propose a standard statistical significance threshold for identifying DNA methylation sites that are associated with an outcome. Second, we establish whether linear regression, the chosen statistical tool for the majority of studies, is appropriate and whether it is biased by the underlying distribution of DNA methylation data. Finally, we assess the sample size required for adequately powered DNA methylation association studies. RESULTS: We quantified DNA methylation in the Understanding Society cohort (n = 1175), a large population based study, using the Illumina EPIC array to assess the statistical properties of DNA methylation association analyses. By simulating null DNA methylation studies, we generated the distribution of p-values expected by chance and calculated the 5% family-wise error for EPIC array studies to be 9 × 10- 8. Next, we tested whether the assumptions of linear regression are violated by DNA methylation data and found that the majority of sites do not satisfy the assumption of normal residuals. Nevertheless, we found no evidence that this bias influences analyses by increasing the likelihood of affected sites to be false positives. Finally, we performed power calculations for EPIC based DNA methylation studies, demonstrating that existing studies with data on ~ 1000 samples are adequately powered to detect small differences at the majority of sites. CONCLUSION: We propose that a significance threshold of P < 9 × 10- 8 adequately controls the false positive rate for EPIC array DNA methylation studies. Moreover, our results indicate that linear regression is a valid statistical methodology for DNA methylation studies, despite the fact that the data do not always satisfy the assumptions of this test. These findings have implications for epidemiological-based studies of DNA methylation and provide a framework for the interpretation of findings from current and future studies.


Assuntos
Metilação de DNA , Epigenômica/métodos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Ilhas de CpG , Epigênese Genética , Estudo de Associação Genômica Ampla , Humanos , Modelos Lineares
3.
J Epidemiol Community Health ; 73(8): 693-702, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30944170

RESUMO

Social position is known to play a role in the quality of ageing, notably through the stimulation/dysregulation of key physiological systems in response to external stresses. Using data from one wave of Understanding Society including 9088 participants, we defined, as an extension of the allostatic load, a synthetic Biological Health Score (BHS) capturing the wear-and-tear of four physiological systems (endocrine, inflammatory, cardiovascular and metabolic systems) and two organs (liver and kidney). We used 16 established blood-derived biomarkers of these systems to calculate the BHS and explored the relative contribution of socioeconomic position to the BHS and its main components across age groups. We identified a systematic decreasing education-related gradient of the BHS (p<0.001) leading to lower biological risk in participants with longer education. Education-related differences in the BHS were detected early in life, and were not attributable to lifestyle and behavioural factors. We found a consistent contribution of the inflammatory and metabolic systems to the overall score throughout from early adulthood onwards, while the contribution of the other four systems seems to vary across age groups and gender. Our findings highlight the social-to-biological processes ultimately leading to health inequalities, and suggest that such disparities can already be detected in the 20-40 years old age group and cannot be fully explained by lifestyle and behavioural factors. This may define early adulthood social condition as a precursor to accelerated biological ageing and as an important target for public health policies.

4.
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
6.
Sci Rep ; 9(1): 4555, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30872618

RESUMO

Evidence on the association between functioning of the hypothalamic pituitary adrenal (HPA) axis and cognitive capability at older ages is mixed. We undertook a systematic review (until October 2016) and individual participant data (IPD) meta-analysis to test if dysregulation of the HPA axis is associated with worse cognitive capability. Five cohort studies were included in the IPD meta-analysis of diurnal cortisol patterns with crystallised and fluid cognitive ability. Higher night time cortisol was associated with worse fluid ability (standardised coefficient per SD increase -0.063, 95% CI -0.124, -0.002, P = 0.04; I2 = 79.9%; age and gender adjusted). A larger diurnal drop was associated with better fluid ability (standardised coefficient per SD increase 0.037, 95% CI 0.008, 0.065, P = 0.01; I2 = 49.2%; age and gender adjusted). A bigger cortisol awakening response (CAR) was weakly associated with better fluid (P = 0.09; I2 = 0.0%; age and gender adjusted) and crystallised (P = 0.10; I2 = 0.0%; age and gender adjusted) ability. There is weak evidence that a greater diurnal decline of the HPA axis and a larger CAR are associated with improvements in cognition at older ages. As associations are cross-sectional, we cannot rule out reverse causation.

7.
Bioinformatics ; 35(6): 981-986, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30875430

RESUMO

MOTIVATION: The datasets generated by DNA methylation analyses are getting bigger. With the release of the HumanMethylationEPIC micro-array and datasets containing thousands of samples, analyses of these large datasets using R are becoming impractical due to large memory requirements. As a result there is an increasing need for computationally efficient methodologies to perform meaningful analysis on high dimensional data. RESULTS: Here we introduce the bigmelon R package, which provides a memory efficient workflow that enables users to perform the complex, large scale analyses required in epigenome wide association studies (EWAS) without the need for large RAM. Building on top of the CoreArray Genomic Data Structure file format and libraries packaged in the gdsfmt package, we provide a practical workflow that facilitates the reading-in, preprocessing, quality control and statistical analysis of DNA methylation data.We demonstrate the capabilities of the bigmelon package using a large dataset consisting of 1193 human blood samples from the Understanding Society: UK Household Longitudinal Study, assayed on the EPIC micro-array platform. AVAILABILITY AND IMPLEMENTATION: The bigmelon package is available on Bioconductor (http://bioconductor.org/packages/bigmelon/). The Understanding Society dataset is available at https://www.understandingsociety.ac.uk/about/health/data upon request. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

8.
Mol Pharm ; 16(3): 952-966, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30629454

RESUMO

Noscapine is effective to inhibit cellular proliferation and induced apoptosis in nonsmall cell, lung, breast, lymphoma, and prostate cancer. It also shows good efficiency to skin cancer cells. In the current work, we studied the mechanism of interaction between the anticancer drug noscapine (NOS) and carrier protein human serum albumin (HSA) by using a variety of spectroscopic techniques (fluorescence spectroscopy, time-resolved fluorescence, UV-visible, fluorescence resonance energy transfer (FRET), Fourier transform infrared (FTIR), and circular dichroism (CD) spectroscopy), electrochemistry (cyclic voltammetry), and computational methods (molecular docking and molecular dynamic simulation). The steady-state fluorescence results showed that fluorescence intensity of HSA decreased in the presence of NOS via a static quenching mechanism, which involves ground state complex formation between NOS and HSA. UV-visible and FRET results also supported the fluorescence result. The corresponding thermodynamic result shows that binding of NOS with HSA is exothermic in nature, involving electrostatic interactions as major binding forces. The binding results were further confirmed through a cyclic voltammetry approach. The FRET result signifies the energy transfer from Trp214 of HSA to the NOS. Molecular site marker, molecular docking, and MD simulation results indicated that the principal binding site of HSA for NOS is site I. Synchronous fluorescence spectra, FTIR, 3D fluorescence, CD spectra, and MD simulation results reveal that NOS induced the structural change in HSA. In addition, the MTT assay study on a human skin cancer cell line (A-431) was also performed for NOS, which shows that NOS induced 80% cell death of the population at a 320 µM concentration. Moreover, the esterase-like activity of HSA with NOS was also done to determine the variation in protein functionality after binding with NOS.

9.
Nat Genet ; 51(3): 445-451, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30643256

RESUMO

We introduce two novel methods for multivariate genome-wide-association meta-analysis (GWAMA) of related traits that correct for sample overlap. A broad range of simulation scenarios supports the added value of our multivariate methods relative to univariate GWAMA. We applied the novel methods to life satisfaction, positive affect, neuroticism, and depressive symptoms, collectively referred to as the well-being spectrum (Nobs = 2,370,390), and found 304 significant independent signals. Our multivariate approaches resulted in a 26% increase in the number of independent signals relative to the four univariate GWAMAs and in an ~57% increase in the predictive power of polygenic risk scores. Supporting transcriptome- and methylome-wide analyses (TWAS and MWAS, respectively) uncovered an additional 17 and 75 independent loci, respectively. Bioinformatic analyses, based on gene expression in brain tissues and cells, showed that genes differentially expressed in the subiculum and GABAergic interneurons are enriched in their effect on the well-being spectrum.


Assuntos
Genoma Humano/genética , Encéfalo/fisiologia , Biologia Computacional/métodos , Expressão Gênica/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Interneurônios/fisiologia , Herança Multifatorial/genética , Análise Multivariada , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Transcriptoma/genética
10.
Biologicals ; 58: 1-6, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30639575

RESUMO

The present study was aimed to establish the First National Reference Standard (NRS) for Insulin lispro to allow stakeholders including manufacturer's laboratories, drug testing laboratories, drug regulatory authorities and academic institutions to demonstrate accuracy of the test results and to enable comparison and validation of analytical methods. The candidate standard for Insulin lispro was evaluated in a collaborative study to assign the vial content in order to serve it as NRS to support the Indian Pharmacopoeia (IP) monograph. The candidate standard was calibrated against the Ph. Eur. Insulin lispro reference standard by each of six participant laboratories in India using HPLC assay method as per the requirements of IP monograph. The results indicate that the candidate standard has an average content of 5.79 mg per vial with purity of 99.87%. Based on the study results the candidate standard was judged suitable to serve as the first NRS for Insulin lispro.


Assuntos
Insulina Lispro/química , Insulina Lispro/normas , Europa (Continente) , Humanos , Índia , Padrões de Referência
11.
Stat Med ; 38(9): 1529-1542, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-30565280

RESUMO

The "some invalid, some valid instrumental variable estimator" (sisVIVE) is a lasso-based method for instrumental variables (IVs) regression of outcome on an exposure. In principle, sisVIVE is robust to some of the IVs in the analysis being invalid, in the sense of being related to the outcome variable through pathways not mediated by the exposure. In this paper, we consider the application of sisVIVE to a Mendelian randomization study in which multiple genetic variants are used as IVs to estimate the causal effect of body mass index on personal income in the presence of unobserved confounding. In addition to analyzing data from the large-scale longitudinal household survey Understanding Society, we conduct a simulation study to (a) assess the performance of sisVIVE in relation to that of competing robust methods like "MR-Egger" and "MR-Median" and (b) identify scenarios under which its absolute performance is poor. We find that sisVIVE outperforms alternative robust methods, in terms of mean-square error, across a wide range of scenarios, but that its performance is poor in absolute terms when the presence of indirect pleiotropy leads to failure of the "InSIDE" condition, which is not explicitly required for identification. We argue that this is because the consistency criterion for sisVIVE does not identify the true causal effect when InSIDE fails.

12.
Artigo em Inglês | MEDLINE | ID: mdl-30381465

RESUMO

BACKGROUND: Although social networks' influence on obesity has been increasingly recognised, it remains unclear if different dimensions of social support, for example, emotional or practical support, received from one's closest relationship are associated with weight outcomes over mid-life and old age. METHODS: Using linear mixed models we examined whether person-level body mass index (BMI) and waist to hip ratio (WHR) trajectories vary according to levels of emotional, practical and negative aspects of social support in a large UK-based cohort of healthy civil servant workers (n=5460) with objectively measured anthropometry data on five occasions over two decades (1989-1990 to 2012-2013). RESULTS: We found that gender modified the associations, with more consistent patterns found in men. In men, high negative aspects of support compared with low were consistently associated with steeper increase in BMI (0.024, 95% CI 0.001 to 0.047 kg/m2) and WHR (0.00020, 95% CI -0.00001 to 0.00040) after adjustment for demographic and socioeconomic covariates, mental health, health behaviours and long-standing illness. We found that low emotional support, compared with high, was associated with steeper BMI gain in men (0.024, 95% CI 0.0001 to 0.047 kg/m2). CONCLUSIONS: Low levels of negative aspects of the relationships with the closest person and high levels of emotional support may be protective against weight gain over time, particularly in men. If replicated in other studies, these results would suggest that the quality of social support in close relationships has been an overlooked risk factor for weight gain in an ageing population.

13.
Am J Hum Genet ; 103(5): 654-665, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30401456

RESUMO

Characterizing the complex relationship between genetic, epigenetic, and transcriptomic variation has the potential to increase understanding about the mechanisms underpinning health and disease phenotypes. We undertook a comprehensive analysis of common genetic variation on DNA methylation (DNAm) by using the Illumina EPIC array to profile samples from the UK Household Longitudinal study. We identified 12,689,548 significant DNA methylation quantitative trait loci (mQTL) associations (p < 6.52 × 10-14) occurring between 2,907,234 genetic variants and 93,268 DNAm sites, including a large number not identified by previous DNAm-profiling methods. We demonstrate the utility of these data for interpreting the functional consequences of common genetic variation associated with > 60 human traits by using summary-data-based Mendelian randomization (SMR) to identify 1,662 pleiotropic associations between 36 complex traits and 1,246 DNAm sites. We also use SMR to characterize the relationship between DNAm and gene expression and thereby identify 6,798 pleiotropic associations between 5,420 DNAm sites and the transcription of 1,702 genes. Our mQTL database and SMR results are available via a searchable online database as a resource to the research community.

14.
Genet Epidemiol ; 2018 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-30478852

RESUMO

Observational studies find an association between increased body mass index (BMI) and short self-reported sleep duration in adults. However, the underlying biological mechanisms that underpin these associations are unclear. Recent findings from the UK Biobank suggest a weak genetic correlation between BMI and self-reported sleep duration. However, the potential shared genetic aetiology between these traits has not been examined using a comprehensive approach. To investigate this, we created a polygenic risk score (PRS) of BMI and examined its association with self-reported sleep duration in a combination of individual participant data and summary-level data, with a total sample size of 142,209 individuals. Although we observed a nonsignificant genetic correlation between BMI and sleep duration, using LD score regression (rg = -0.067 [SE = 0.039], P = 0.092) we found that a PRS of BMI is associated with a decrease in sleep duration (unstandardized coefficient = -1.75 min [SE = 0.67], P = 6.13 × 10-7 ), but explained only 0.02% of the variance in sleep duration. Our findings suggest that BMI and self-reported sleep duration possess a small amount of shared genetic aetiology and other mechanisms must underpin these associations.

15.
Soc Sci Med ; 220: 129-140, 2018 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-30423482

RESUMO

Lower testosterone levels in men are observationally associated with worse health, but it is unclear whether they contribute to well-established social gradients in health. Mendelian Randomization studies suggest positive testosterone-health associations may not be causal, with some intervention studies suggesting testosterone administration could be harmful. Since testosterone is rarely measured in general population studies, very little is known about how testosterone varies by social position. Differences by education and household income in British men aged 60-64y were recently reported, but it is unclear whether this reflects an influence of socioeconomic position (SEP) on testosterone, influence of testosterone on SEP, or confounding. In the UK Household Longitudinal Study, a nationally-representative survey of UK adults, we examine social differences in testosterone in 3663 men aged 16-97y in 2010-12. We consider diverse dimensions of SEP: education, employment status, equivalized household income and personal earnings. Multivariable regression is used to explore social differences in testosterone across the adult life-span (16-97y). Secondly, Mendelian Randomization (MR), an approach which uses gene variants as instrumental variables for endogenous exposures, is used to investigate causal directionality. We examine associations with risk-taking, a plausible mediator of testosterone-SEP associations. In observational models no social differences in testosterone are seen, but MR models suggest a positive influence of testosterone on earnings (increase in log-transformed monthly earnings (GBP) per standard deviation increase in testosterone: 0.51, 95%CI: 0.03,1.05, p = 0.07) and probability of being in work (probit coefficient:0.25, 95%CI: 0.01,0.51, p = 0.06). Though MR estimates are less precise, results are consistent with previous literature linking testosterone with labour market success. The discrepancy may reflect suppression of observational associations by factors positively correlated with testosterone and negatively correlated with SEP, or indicate an influence of typical lifetime testosterone, which may be better indexed by genetic variants than by single testosterone measurements subject to noise.

16.
Anal Biochem ; 566: 20-22, 2018 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-30312619

RESUMO

Protein reduction and alkylation is routinely used for analysis of protein dimers and protein complexes in cell fractions using two dimensional gel electrophoresis and mass spectrometry. To resolve the heterogeneity of a high molecular weight protein band that is highlighted by an antibody to the beta subunit of alpha glucosidase II (GIIß), we performed reduction and alkylation of cytosolic proteins extracted from mouse brain. The presence of urea in the reduction/alkylation buffer inhibited the chemical processes. It is thus recommended that protein reduction/alkylation be performed both in the presence and absence of urea for the separation of mono-/hetero-mers.

17.
Psychoneuroendocrinology ; 100: 41-47, 2018 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-30290284

RESUMO

The objective was to investigate the relationship between various aspects of informal caregiving and diurnal patterns of salivary cortisol, with special attention to the moderating effect of sex and work status. The study population was composed of 3727 men and women from the British Whitehall II study. Salivary cortisol was measured six times during a weekday. Aspects of caregiving included the relationship of caregiver to recipient, weekly hours of caregiving, and length of caregiving. Diurnal cortisol profiles were assessed using the cortisol awakening response (CAR) and diurnal cortisol slopes. Results showed that men, but not women, providing informal care had a blunted CAR compared with non-caregivers (PInteraction = 0.03). Furthermore, we found a dose-response relationship showing that more weekly hours of informal care was associated with a more blunted CAR for men (Ptrend = 0.03). Also, the blunted CAR for men was especially pronounced in short-term caregivers and those in paid work. In women, the steepest cortisol slope was seen among those in paid work who provided informal care (PInteraction = 0.01). To conclude, we found different cortisol profiles in male and female informal caregivers. Male caregivers had a blunted CAR, which has previously been associated with chronic stress and burnout. Future research should investigate whether results are generalizable beyond UK citizens with a working history in the civil service.

18.
Obes Surg ; 28(11): 3524-3530, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30043144

RESUMO

BACKGROUND: To date, little attention has been paid to supportive relationships as factors contributing to weight loss from bariatric surgery. MATERIAL AND METHODS: This prospective study examined whether total percentage weight loss (%TWL) at 3, 12 and 24 months post-surgery varies by distinct aspects of pre-surgery social support (received emotional and practical support and contact with friends and family) in a sample of bariatric surgery candidates (n = 182). These associations were tested with linear regression models adjusted for gender, age, ethnicity, employment status, self-esteem, mastery and time elapsed since the day of surgery. RESULTS: One hundred fifty-four participants underwent a bariatric procedure, and all but seven provided weight loss data at least at one occasion. Emotional support and contact with friends were positively associated with %TWL at 3, 12 and 24 months, and the magnitude of these associations was large. For instance, in the fully adjusted models, %TWL at 24 months increased by 2.36% (SE 1.17, p = 0.048) with each increase of one standard deviation in emotional support and was higher by 9.23% (SE 4.31, p = 0.035) for participants who reported seeing 1-5 friends per month compared with those who saw none. There was some evidence for a positive association between practical support and %TWL at 3 and 12 months post-surgery. CONCLUSION: Supportive relationships are important contributors to weight loss from bariatric surgery. If replicated in future studies, these findings could inform clinical care and interventions aimed at improving support systems of bariatric surgery candidates.

19.
Am J Epidemiol ; 187(11): 2346-2354, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30060108

RESUMO

Accelerated DNA methylation age is linked to all-cause mortality and environmental factors, but studies of associations with socioeconomic position are limited. Researchers generally use small selected samples, and it is unclear how findings obtained with 2 commonly used methods for calculating methylation age (the Horvath method and the Hannum method) translate to general population samples including younger and older adults. Among 1,099 United Kingdom adults aged 28-98 years in 2011-2012, we assessed the relationship of Horvath and Hannum DNA methylation age acceleration with a range of social position measures: current income and employment, education, income and unemployment across a 12-year period, and childhood social class. Accounting for confounders, participants who had been less advantaged in childhood were epigenetically "older" as adults: In comparison with participants who had professional/managerial parents, Hannum age was 1.07 years higher (95% confidence interval: 0.20, 1.94) for participants with parents in semiskilled/unskilled occupations and 1.85 years higher (95% confidence interval: 0.67, 3.02) for those without a working parent at age 14 years. No other robust associations were seen. Results accord with research implicating early life circumstances as critical for DNA methylation age in adulthood. Since methylation age acceleration as measured by the Horvath and Hannum estimators appears strongly linked to chronological age, researchers examining associations with the social environment must take steps to avoid age-related confounding.

20.
Nat Genet ; 50(8): 1112-1121, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30038396

RESUMO

Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.

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