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1.
Mol Psychiatry ; 26(6): 2056-2069, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-32393786

RESUMO

We conducted genome-wide association studies (GWAS) of relative intake from the macronutrients fat, protein, carbohydrates, and sugar in over 235,000 individuals of European ancestries. We identified 21 unique, approximately independent lead SNPs. Fourteen lead SNPs are uniquely associated with one macronutrient at genome-wide significance (P < 5 × 10-8), while five of the 21 lead SNPs reach suggestive significance (P < 1 × 10-5) for at least one other macronutrient. While the phenotypes are genetically correlated, each phenotype carries a partially unique genetic architecture. Relative protein intake exhibits the strongest relationships with poor health, including positive genetic associations with obesity, type 2 diabetes, and heart disease (rg ≈ 0.15-0.5). In contrast, relative carbohydrate and sugar intake have negative genetic correlations with waist circumference, waist-hip ratio, and neighborhood deprivation (|rg| ≈ 0.1-0.3) and positive genetic correlations with physical activity (rg ≈ 0.1 and 0.2). Relative fat intake has no consistent pattern of genetic correlations with poor health but has a negative genetic correlation with educational attainment (rg ≈-0.1). Although our analyses do not allow us to draw causal conclusions, we find no evidence of negative health consequences associated with relative carbohydrate, sugar, or fat intake. However, our results are consistent with the hypothesis that relative protein intake plays a role in the etiology of metabolic dysfunction.


Assuntos
Diabetes Mellitus Tipo 2 , Estudo de Associação Genômica Ampla , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/genética , Dieta , Genômica , Humanos , Estilo de Vida
2.
Proc Natl Acad Sci U S A ; 116(38): 19064-19070, 2019 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-31481615

RESUMO

Britain and Ireland are known to show population genetic structure; however, large swathes of Scotland, in particular, have yet to be described. Delineating the structure and ancestry of these populations will allow variant discovery efforts to focus efficiently on areas not represented in existing cohorts. Thus, we assembled genotype data for 2,554 individuals from across the entire archipelago with geographically restricted ancestry, and performed population structure analyses and comparisons to ancient DNA. Extensive geographic structuring is revealed, from broad scales such as a NE to SW divide in mainland Scotland, through to the finest scale observed to date: across 3 km in the Northern Isles. Many genetic boundaries are consistent with Dark Age kingdoms of Gaels, Picts, Britons, and Norse. Populations in the Hebrides, the Highlands, Argyll, Donegal, and the Isle of Man show characteristics of isolation. We document a pole of Norwegian ancestry in the north of the archipelago (reaching 23 to 28% in Shetland) which complements previously described poles of Germanic ancestry in the east, and "Celtic" to the west. This modern genetic structure suggests a northwestern British or Irish source population for the ancient Gaels that contributed to the founding of Iceland. As rarer variants, often with larger effect sizes, become the focus of complex trait genetics, more diverse rural cohorts may be required to optimize discoveries in British and Irish populations and their considerable global diaspora.


Assuntos
DNA Antigo/análise , Etnicidade/genética , Variação Genética , Genética Populacional , Genoma Humano , Humanos , Irlanda , Ilhas , Escócia
3.
Clin Exp Allergy ; 51(2): 318-328, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33150670

RESUMO

BACKGROUND: Underlying biological mechanisms involved in sex differences in asthma status changes from pre- to post-adolescence are unclear. DNA methylation (DNAm) has been shown to be associated with the risk of asthma. OBJECTIVE: We hypothesized that asthma acquisition from pre- to post-adolescence was associated with changes in DNAm during this period at asthma-associated cytosine-phosphate-guanine (CpG) sites and such an association was sex-specific. METHODS: Subjects from the Isle of Wight birth cohort (IOWBC) with DNAm in blood at ages 10 and 18 years (n = 124 females, 151 males) were studied. Using a training-testing approach, epigenome-wide CpGs associated with asthma were identified. Logistic regression was used to examine sex-specific associations of DNAm changes with asthma acquisition between ages 10 and 18 at asthma-associated CpGs. The ALSPAC birth cohort was used for independent replication. To assess functional relevance of identified CpGs, association of DNAm with gene expression in blood was assessed. RESULTS: We identified 535 CpGs potentially associated with asthma. Significant interaction effects of DNAm changes and sex on asthma acquisition in adolescence were found at 13 of the 535 CpGs in IOWBC (P-values <1.0 × 10-3 ). In the replication cohort, consistent interaction effects were observed at 10 of the 13 CpGs. At 7 of these 10 CpGs, opposite DNAm changes across adolescence were observed between sexes in both cohorts. In both cohorts, cg20891917, located on IFRD1 linked to asthma, shows strong sex-specific effects on asthma transition (P-values <.01 in both cohorts). CONCLUSION AND CLINICAL RELEVANCE: Gender reversal in asthma acquisition is associated with opposite changes in DNAm (males vs females) from pre- to post-adolescence at asthma-associated CpGs. These CpGs are potential biomarkers of sex-specific asthma acquisition in adolescence.


Assuntos
Asma/genética , Ilhas de CpG/genética , Metilação de DNA/genética , Expressão Gênica , Adolescente , Asma/epidemiologia , Coorte de Nascimento , Criança , Epigenoma , Feminino , Humanos , Incidência , Modelos Logísticos , Masculino , Remissão Espontânea , Caracteres Sexuais , Distribuição por Sexo , Fatores Sexuais
4.
Hum Mol Genet ; 27(16): 2927-2939, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-29860447

RESUMO

Genomic imprinting is an epigenetic mechanism leading to parent-of-origin silencing of alleles. So far, the precise number of imprinted regions in humans is uncertain. In this study, we leveraged genome-wide DNA methylation in whole blood measured longitudinally at three time points (birth, childhood and adolescence) and genome-wide association studies (GWAS) data in 740 mother-child duos from the Avon Longitudinal Study of parents and children to identify candidate imprinted loci. We reasoned that cis-meQTLs at genomic regions that were imprinted would show strong evidence of parent-of-origin associations with DNA methylation, enabling the detection of imprinted regions. Using this approach, we identified genome-wide significant cis-meQTLs that exhibited parent-of-origin effects (POEs) at 82 loci, 34 novel and 48 regions previously implicated in imprinting (3.7-10


Assuntos
Metilação de DNA/genética , Epigênese Genética/genética , Impressão Genômica/genética , Locos de Características Quantitativas/genética , Adolescente , Alelos , Criança , Ilhas de CpG/genética , Feminino , Genoma Humano/genética , Estudo de Associação Genômica Ampla , Humanos , Recém-Nascido , Estudos Longitudinais , Masculino , Inquéritos e Questionários
5.
Hum Mol Genet ; 27(4): 742-756, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29309628

RESUMO

Genome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86 577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P < 5 × 10-8. In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate that genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.


Assuntos
Peso ao Nascer/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único/genética , Actinas/genética , Proteínas Adaptadoras de Transdução de Sinal , Alelos , Peso ao Nascer/fisiologia , Citocromo P-450 CYP3A/genética , Proteínas de Ligação a DNA/genética , Feminino , Variação Genética/genética , Genótipo , Quinases do Centro Germinativo , Idade Gestacional , Proteína HMGA2/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Canal de Potássio Kv1.3/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas/genética , Receptor MT2 de Melatonina/genética , Transativadores/genética , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética
6.
Hum Genomics ; 13(1): 6, 2019 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-30704525

RESUMO

BACKGROUND: Mitochondrial DNA copy number (mtDNA CN) exhibits interindividual and intercellular variation, but few genome-wide association studies (GWAS) of directly assayed mtDNA CN exist. We undertook a GWAS of qPCR-assayed mtDNA CN in the Avon Longitudinal Study of Parents and Children (ALSPAC) and the UK Blood Service (UKBS) cohort. After validating and harmonising data, 5461 ALSPAC mothers (16-43 years at mtDNA CN assay) and 1338 UKBS females (17-69 years) were included in a meta-analysis. Sensitivity analyses restricted to females with white cell-extracted DNA and adjusted for estimated or assayed cell proportions. Associations were also explored in ALSPAC children and UKBS males. RESULTS: A neutrophil-associated locus approached genome-wide significance (rs709591 [MED24], ß (change in SD units of mtDNA CN per allele) [SE] - 0.084 [0.016], p = 1.54e-07) in the main meta-analysis of adult females. This association was concordant in magnitude and direction in UKBS males and ALSPAC neonates. SNPs in and around ABHD8 were associated with mtDNA CN in ALSPAC neonates (rs10424198, ß [SE] 0.262 [0.034], p = 1.40e-14), but not other study groups. In a meta-analysis of unrelated individuals (N = 11,253), we replicated a published association in TFAM (ß [SE] 0.046 [0.017], p = 0.006), with an effect size much smaller than that observed in the replication analysis of a previous in silico GWAS. CONCLUSIONS: In a hypothesis-generating GWAS, we confirm an association between TFAM and mtDNA CN and present putative loci requiring replication in much larger samples. We discuss the limitations of our work, in terms of measurement error and cellular heterogeneity, and highlight the need for larger studies to better understand nuclear genomic control of mtDNA copy number.


Assuntos
Variações do Número de Cópias de DNA , DNA Mitocondrial/genética , Estudo de Associação Genômica Ampla/métodos , Adolescente , Adulto , Criança , Estudos de Coortes , Feminino , Humanos , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
7.
Am J Phys Anthropol ; 172(2): 314-332, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32155296

RESUMO

OBJECTIVES: The objective of this study was to explore potential relationships between neonatal line (NNL) width and early life history variables such as maternal health, gestation, the birth process, and perinatal health. MATERIALS AND METHODS: Histological thin sections of deciduous canines were studied from 71 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). The width of the NNL was measured in three locations on the tooth crown using spatial mapping techniques (ArcGIS) from digital images from an Olympus VS-120 microscope. Life history variables were collected prospectively through a combination of clinical observations and questionnaires. RESULTS: Infants born late term or post term had narrower neonatal lines than those born prematurely or at full term. Infants born in Autumn (September to November) had narrower NNLs than those born at other times of year. NNLs in infants born to mothers with hypertension were wider than those without. Infants resuscitated at birth or born to obese mothers had narrower NNLs than those that were not. There was no association between NNL width and either the type or duration of delivery. DISCUSSION: The NNL in enamel is an irregular accentuated line, but the factors underlying its formation and width remain unclear. In contrast to some previous studies, we found no association between wider NNLs and long or difficult births. Instead, we found that the width of the neonatal line NNL varied in relation to parameters that reflected the prenatal environment and length of gestation.


Assuntos
Saúde Materna , Dente Decíduo/anatomia & histologia , Adulto , Peso ao Nascer/fisiologia , Criança , Dente Canino/anatomia & histologia , Esmalte Dentário/anatomia & histologia , Feminino , Humanos , Recém-Nascido , Estudos Longitudinais , Masculino , Gravidez/fisiologia , Reino Unido
8.
PLoS Med ; 16(6): e1002828, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31211782

RESUMO

BACKGROUND: Systematic reviews of randomised controlled trials (RCTs) have suggested that maternal vitamin D (25[OH]D) and calcium supplementation increase birth weight. However, limitations of many trials were highlighted in the reviews. Our aim was to combine genetic and RCT data to estimate causal effects of these two maternal traits on offspring birth weight. METHODS AND FINDINGS: We performed two-sample mendelian randomisation (MR) using genetic instrumental variables associated with 25(OH)D and calcium that had been identified in genome-wide association studies (GWAS; sample 1; N = 122,123 for 25[OH]D and N = 61,275 for calcium). Associations between these maternal genetic variants and offspring birth weight were calculated in the UK Biobank (UKB) (sample 2; N = 190,406). We used data on mother-child pairs from two United Kingdom birth cohorts (combined N = 5,223) in sensitivity analyses to check whether results were influenced by fetal genotype, which is correlated with the maternal genotype (r ≈ 0.5). Further sensitivity analyses to test the reliability of the results included MR-Egger, weighted-median estimator, 'leave-one-out', and multivariable MR analyses. We triangulated MR results with those from RCTs, in which we used randomisation to supplementation with vitamin D (24 RCTs, combined N = 5,276) and calcium (6 RCTs, combined N = 543) as an instrumental variable to determine the effects of 25(OH)D and calcium on birth weight. In the main MR analysis, there was no strong evidence of an effect of maternal 25(OH)D on birth weight (difference in mean birth weight -0.03 g [95% CI -2.48 to 2.42 g, p = 0.981] per 10% higher maternal 25[OH]D). The effect estimate was consistent across our MR sensitivity analyses. Instrumental variable analyses applied to RCTs suggested a weak positive causal effect (5.94 g [95% CI 2.15-9.73, p = 0.002] per 10% higher maternal 25[OH]D), but this result may be exaggerated because of risk of bias in the included RCTs. The main MR analysis for maternal calcium also suggested no strong evidence of an effect on birth weight (-20 g [95% CI -44 to 5 g, p = 0.116] per 1 SD higher maternal calcium level). Some sensitivity analyses suggested that the genetic instrument for calcium was associated with birth weight via exposures that are independent of calcium levels (horizontal pleiotropy). Application of instrumental variable analyses to RCTs suggested that calcium has a substantial effect on birth weight (178 g [95% CI 121-236 g, p = 1.43 × 10-9] per 1 SD higher maternal calcium level) that was not consistent with any of the MR results. However, the RCT instrumental variable estimate may have been exaggerated because of risk of bias in the included RCTs. Other study limitations include the low response rate of UK Biobank, which may bias MR estimates, and the lack of suitable data to test whether the effects of genetic instruments on maternal calcium levels during pregnancy were the same as those outside of pregnancy. CONCLUSIONS: Our results suggest that maternal circulating 25(OH)D does not influence birth weight in otherwise healthy newborns. However, the effect of maternal circulating calcium on birth weight is unclear and requires further exploration with more research including RCT and/or MR analyses with more valid instruments.


Assuntos
Peso ao Nascer/fisiologia , Cálcio/sangue , Estudo de Associação Genômica Ampla/métodos , Análise da Randomização Mendeliana/métodos , Vitamina D/análogos & derivados , Adulto , Biomarcadores/sangue , Feminino , Variação Genética/genética , Humanos , Recém-Nascido , Estudos Longitudinais , Masculino , Saúde Materna , Gravidez , Vitamina D/sangue , Vitamina D/genética
9.
Am J Epidemiol ; 188(10): 1784-1793, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31241132

RESUMO

Genetic predisposition might affect neurodevelopmental outcomes of prenatal methylmercury exposure. We examined suspected heterogeneities for modification of exposure-related neurodevelopment in children from the Avon Longitudinal Study of Parents and Children (1991-2000), Bristol, United Kingdom. A subgroup (n = 1,127 from a pilot study and 1,045 from the present study) was identified based on the availability of the mercury concentration of cord tissue as a measure of prenatal methylmercury exposure, data on 247 single-nucleotide polymorphisms (SNPs), and Wechsler Intelligence Scale for Children intelligence quotient (IQ) scores. Log10-transformed mercury concentration was positively associated with IQ, but adjustment for confounding cofactors attenuated this association. A finding of enhanced interaction with methylmercury was replicated in this study for the minor allele of rs1042838 (progesterone receptor) (ß = -11.8, 95% confidence interval: -23.0, -0.6; P for interaction = 0.004) and weakly for rs662 (paraoxonase 1) (ß = -3.6, 95% confidence interval: -11.4, 4.3; P = 0.117). In the joint sample, new interacting single-nucleotide polymorphisms were discovered in relation to superoxide dismutase 2, ATP binding cassette subfamily A member 1, and metallothionein 1M genes. While the low-level prenatal exposure to methylmercury was not associated with child cognition, progesterone receptor rs1042838 minor alleles revealed a negative association of mercury exposure with IQ.


Assuntos
Desenvolvimento Infantil/efeitos dos fármacos , Predisposição Genética para Doença/genética , Compostos de Metilmercúrio/toxicidade , Efeitos Tardios da Exposição Pré-Natal/genética , Criança , Estudos de Coortes , Deficiências do Desenvolvimento/induzido quimicamente , Deficiências do Desenvolvimento/genética , Feminino , Humanos , Masculino , Compostos de Metilmercúrio/análise , Polimorfismo de Nucleotídeo Único/genética , Gravidez , Cordão Umbilical/química , Escalas de Wechsler
10.
Hum Genomics ; 12(1): 24, 2018 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-29695297

RESUMO

BACKGROUND: Genomic and biosocial research data about individuals is rapidly proliferating, bringing the potential for novel opportunities for data integration and use. The scale, pace and novelty of these applications raise a number of urgent sociotechnical, ethical and legal questions, including optimal methods of data storage, management and access. Although the open science movement advocates unfettered access to research data, many of the UK's longitudinal cohort studies operate systems of managed data access, in which access is governed by legal and ethical agreements between stewards of research datasets and researchers wishing to make use of them. Amongst other things, these agreements aim to respect the reasonable expectations of the research participants who provided data and samples, as expressed in the consent process. Arguably, responsible data management and governance of data and sample use are foundational to the consent process in longitudinal studies and are an important source of trustworthiness in the eyes of those who contribute data to genomic and biosocial research. METHODS: This paper presents an ethnographic case study exploring the foundational principles of a governance infrastructure for Managing Ethico-social, Technical and Administrative issues in Data ACcess (METADAC), which are operationalised through a committee known as the METADAC Access Committee. METADAC governs access to phenotype, genotype and 'omic' data and samples from five UK longitudinal studies. FINDINGS: Using the example of METADAC, we argue that three key structural features are foundational for practising responsible data sharing: independence and transparency; interdisciplinarity; and participant-centric decision-making. We observe that the international research community is proactively working towards optimising the use of research data, integrating/linking these data with routine data generated by health and social care services and other administrative data services to improve the analysis, interpretation and utility of these data. The governance of these new complex data assemblages will require a range of expertise from across a number of domains and disciplines, including that of study participants. Human-mediated decision-making bodies will be central to ensuring achievable, reasoned and responsible decisions about the use of these data; the METADAC model described in this paper provides an example of how this could be realised.


Assuntos
Big Data , Pesquisa Biomédica/ética , Genômica/ética , Disseminação de Informação/ética , Pesquisa Biomédica/economia , Bases de Dados Genéticas/economia , Bases de Dados Genéticas/ética , Genótipo , Humanos
11.
Hum Mol Genet ; 25(2): 382-8, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26604150

RESUMO

Anti-Müllerian hormone (AMH) is an essential messenger of sexual differentiation in the foetus and is an emerging biomarker of postnatal reproductive function in females. Due to a paucity of adequately sized studies, the genetic determinants of circulating AMH levels are poorly characterized. In samples from 2815 adolescents aged 15 from the ALSPAC study, we performed the first genome-wide association study of serum AMH levels across a set of ∼9 m '1000 Genomes Reference Panel' imputed genetic variants. Genetic variants at the AMH protein-coding gene showed considerable allelic heterogeneity, with both common variants [rs4807216 (P(Male) = 2 × 10(-49), Beta: ∼0.9 SDs per allele), rs8112524 (P(Male) = 3 × 10(-8), Beta: ∼0.25)] and low-frequency variants [rs2385821 (P(Male) = 6 × 10(-31), Beta: ∼1.2, frequency 3.6%)] independently associated with apparently large effect sizes in males, but not females. For all three SNPs, we highlight mechanistic links to AMH gene function and demonstrate highly significant sex interactions (P(Het) 0.0003-6.3 × 10(-12)), culminating in contrasting estimates of trait variance explained (24.5% in males versus 0.8% in females). Using these SNPs as a genetic proxy for AMH levels, we found no evidence in additional datasets to support a biological role for AMH in complex traits and diseases in men.


Assuntos
Hormônio Antimülleriano/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Adolescente , Alelos , Hormônio Antimülleriano/sangue , Feminino , Genes , Humanos , Masculino , Fatores Sexuais
12.
Hum Mol Genet ; 25(19): 4339-4349, 2016 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-27559110

RESUMO

BACKGROUND: Single variant approaches have been successful in identifying DNA methylation quantitative trait loci (mQTL), although as with complex traits they lack the statistical power to identify the effects from rare genetic variants. We have undertaken extensive analyses to identify regions of low frequency and rare variants that are associated with DNA methylation levels. METHODS: We used repeated measurements of DNA methylation from five different life stages in human blood, taken from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Variants were collapsed across CpG islands and their flanking regions to identify variants collectively associated with methylation, where no single variant was individually responsible for the observed signal. All analyses were undertaken using the sequence kernel association test. RESULTS: For loci where no individual variant mQTL was observed based on a single variant analysis, we identified 95 unique regions where the combined effect of low frequency variants (MAF ≤ 5%) provided strong evidence of association with methylation. For loci where there was previous evidence of an individual variant mQTL, a further 3 regions provided evidence of association between multiple low frequency variants and methylation levels. Effects were observed consistently across 5 different time points in the lifecourse and evidence of replication in the TwinsUK and Exeter cohorts was also identified. CONCLUSION: We have demonstrated the potential of this novel approach to mQTL analysis by analysing the combined effect of multiple low frequency or rare variants. Future studies should benefit from applying this approach as a complementary follow up to single variant analyses.


Assuntos
Metilação de DNA/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas/genética , Adolescente , Adulto , Criança , Pré-Escolar , Ilhas de CpG/genética , Feminino , Regulação da Expressão Gênica/genética , Frequência do Gene , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética
13.
Hum Mol Genet ; 25(1): 191-201, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26546615

RESUMO

DNA methylation-based biomarkers of aging are highly correlated with actual age. Departures of methylation-estimated age from actual age can be used to define epigenetic measures of child development or age acceleration (AA) in adults. Very little is known about genetic or environmental determinants of these epigenetic measures of aging. We obtained DNA methylation profiles using Infinium HumanMethylation450 BeadChips across five time-points in 1018 mother-child pairs from the Avon Longitudinal Study of Parents and Children. Using the Horvath age estimation method, we calculated epigenetic age for these samples. AA was defined as the residuals from regressing epigenetic age on actual age. AA was tested for associations with cross-sectional clinical variables in children. We identified associations between AA and sex, birth weight, birth by caesarean section and several maternal characteristics in pregnancy, namely smoking, weight, BMI, selenium and cholesterol level. Offspring of non-drinkers had higher AA on average but this difference appeared to resolve during childhood. The associations between sex, birth weight and AA found in ARIES were replicated in an independent cohort (GOYA). In children, epigenetic AA measures are associated with several clinically relevant variables, and early life exposures appear to be associated with changes in AA during adolescence. Further research into epigenetic aging, including the use of causal inference methods, is required to better our understanding of aging.


Assuntos
Envelhecimento/genética , Metilação de DNA , Epigênese Genética , Peso ao Nascer , Criança , Estudos de Coortes , Humanos , Estudos Longitudinais , Mães
14.
Hum Mol Genet ; 25(18): 4127-4142, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27559109

RESUMO

More than a million childhood diarrhoeal episodes occur worldwide each year, and in developed countries a considerable part of them are caused by viral infections. In this study, we aimed to search for genetic variants associated with diarrhoeal disease in young children by meta-analyzing genome-wide association studies, and to elucidate plausible biological mechanisms. The study was conducted in the context of the Early Genetics and Lifecourse Epidemiology (EAGLE) consortium. Data about diarrhoeal disease in two time windows (around 1 year of age and around 2 years of age) was obtained via parental questionnaires, doctor interviews or medical records. Standard quality control and statistical tests were applied to the 1000 Genomes imputed genotypic data. The meta-analysis (N = 5758) followed by replication (N = 3784) identified a genome-wide significant association between rs8111874 and diarrhoea at age 1 year. Conditional analysis suggested that the causal variant could be rs601338 (W154X) in the FUT2 gene. Children with the A allele, which results in a truncated FUT2 protein, had lower risk of diarrhoea. FUT2 participates in the production of histo-blood group antigens and has previously been implicated in the susceptibility to infections, including Rotavirus and Norovirus Gene-set enrichment analysis suggested pathways related to the histo-blood group antigen production, and the regulation of ion transport and blood pressure. Among others, the gastrointestinal tract, and the immune and neuro-secretory systems were detected as relevant organs. In summary, this genome-wide association meta-analysis suggests the implication of the FUT2 gene in diarrhoeal disease in young children from the general population.


Assuntos
Diarreia/genética , Fucosiltransferases/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Alelos , Pré-Escolar , Diarreia/patologia , Feminino , Genótipo , Humanos , Lactente , Masculino , Polimorfismo de Nucleotídeo Único , Galactosídeo 2-alfa-L-Fucosiltransferase
15.
Hum Mol Genet ; 24(20): 5930-9, 2015 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-26231221

RESUMO

Whooping cough is currently seeing resurgence in countries despite high vaccine coverage. There is considerable variation in subject-specific response to infection and vaccine efficacy, but little is known about the role of human genetics. We carried out a case-control genome-wide association study of adult or parent-reported history of whooping cough in two cohorts from the UK: the ALSPAC cohort and the 1958 British Birth Cohort (815/758 cases and 6341/4308 controls, respectively). We also imputed HLA alleles using dense SNP data in the MHC region and carried out gene-based and gene-set tests of association and estimated the amount of additive genetic variation explained by common SNPs. We observed a novel association at SNPs in the MHC class II region in both cohorts [lead SNP rs9271768 after meta-analysis, odds ratio [95% confidence intervals (CIs)] 1.47 (1.35, 1.6), P-value 1.21E - 18]. Multiple strong associations were also observed at alleles at the HLA class II loci. The majority of these associations were explained by the lead SNP rs9271768. Gene-based and gene-set tests and estimates of explainable common genetic variation could not establish the presence of additional associations in our sample. Genetic variation at the MHC class II region plays a role in susceptibility to whooping cough. These findings provide additional perspective on mechanisms of whooping cough infection and vaccine efficacy.


Assuntos
Genes MHC da Classe II , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Coqueluche/genética , Adulto , Idoso , Alelos , Feminino , Estudo de Associação Genômica Ampla , Humanos , Pessoa de Meia-Idade , Razão de Chances , Autorrelato , Reino Unido , Coqueluche/epidemiologia
16.
Hum Mol Genet ; 24(13): 3752-63, 2015 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-25869828

RESUMO

Gestational age (GA) and birth weight have been implicated in the determination of long-term health. It has been hypothesized that changes in DNA methylation may mediate these long-term effects. We obtained DNA methylation profiles from cord blood and peripheral blood at ages 7 and 17 in the same children from the Avon Longitudinal Study of Parents and Children. Repeated-measures data were used to investigate changes in birth-related methylation during childhood and adolescence. Ten developmental phenotypes (e.g. height) were analysed to identify possible mediation of health effects by DNA methylation. In cord blood, methylation at 224 CpG sites was found to be associated with GA and 23 CpG sites with birth weight. Methylation changed in the majority of these sites over time, but neither birth characteristic was strongly associated with methylation at age 7 or 17 (using a conservative correction for multiple testing of P < 1.03 × 10(-7)), suggesting resolution of differential methylation by early childhood. Associations were observed between birth weight-associated CpG sites and phenotypic characteristics in childhood. One strong association involved birth weight, methylation of a CpG site proximal to the NFIX locus and bone mineral density at age 17. Analysis of serial methylation from birth to adolescence provided evidence for a lack of persistence of methylation differences beyond early childhood. Sites associated with birth weight were linked to developmental genes and have methylation levels which are associated with developmental phenotypes. Replication and interrogation of causal relationships are needed to substantiate whether methylation differences at birth influence the association between birth weight and development.


Assuntos
Peso ao Nascer , Metilação de DNA , Adolescente , Criança , Ilhas de CpG , Feminino , Sangue Fetal/metabolismo , Idade Gestacional , Humanos , Estudos Longitudinais , Masculino , Fatores de Transcrição NFI/genética , Fatores de Transcrição NFI/metabolismo
17.
Hum Mol Genet ; 24(8): 2201-17, 2015 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-25552657

RESUMO

Maternal smoking during pregnancy has been found to influence newborn DNA methylation in genes involved in fundamental developmental processes. It is pertinent to understand the degree to which the offspring methylome is sensitive to the intensity and duration of prenatal smoking. An investigation of the persistence of offspring methylation associated with maternal smoking and the relative roles of the intrauterine and postnatal environment is also warranted. In the Avon Longitudinal Study of Parents and Children, we investigated associations between prenatal exposure to maternal smoking and offspring DNA methylation at multiple time points in approximately 800 mother-offspring pairs. In cord blood, methylation at 15 CpG sites in seven gene regions (AHRR, MYO1G, GFI1, CYP1A1, CNTNAP2, KLF13 and ATP9A) was associated with maternal smoking, and a dose-dependent response was observed in relation to smoking duration and intensity. Longitudinal analysis of blood DNA methylation in serial samples at birth, age 7 and 17 years demonstrated that some CpG sites showed reversibility of methylation (GFI1, KLF13 and ATP9A), whereas others showed persistently perturbed patterns (AHRR, MYO1G, CYP1A1 and CNTNAP2). Of those showing persistence, we explored the effect of postnatal smoke exposure and found that the major contribution to altered methylation was attributed to a critical window of in utero exposure. A comparison of paternal and maternal smoking and offspring methylation showed consistently stronger maternal associations, providing further evidence for causal intrauterine mechanisms. These findings emphasize the sensitivity of the methylome to maternal smoking during early development and the long-term impact of such exposure.


Assuntos
Metilação de DNA , Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/genética , Fumar/efeitos adversos , Adolescente , Criança , Estudos de Coortes , Feminino , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Linhagem , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo
18.
Hum Mol Genet ; 24(4): 1155-68, 2015 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-25281659

RESUMO

Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 × 10(-6)) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; ß = 0.046, SE = 0.008, P = 2.46 × 10(-8), explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 × 10(-4)) and adult height (N = 127 513; P = 1.45 × 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Estatura/genética , Estudos de Associação Genética , Variação Genética , Proteínas de Membrana/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Fatores Etários , Alelos , Biologia Computacional , Bases de Dados Genéticas , Genótipo , Humanos , Recém-Nascido , Proteínas de Membrana/metabolismo , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Característica Quantitativa Herdável , Reprodutibilidade dos Testes
19.
Pediatr Allergy Immunol ; 28(2): 191-198, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27779810

RESUMO

BACKGROUND: Animal data have suggested that the transient receptor potential ankyrin-1 (TRPA1) ion channel plays a key role in promoting airway inflammation in asthma and may mediate effects of paracetamol on asthma, yet confirmatory human data are lacking. To study associations of TRPA1 gene variants with childhood asthma and total IgE concentration, and interactions between TRPA1 and prenatal paracetamol exposure on these outcomes. METHODS: We analysed associations between 31 TRPA1 single nucleotide polymorphisms (SNPs) and current doctor-diagnosed asthma and total IgE concentration at 7.5 years in the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. We sought to confirm the most significant associations with comparable outcomes in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) and Generation R birth cohorts. In ALSPAC, we explored interactions with prenatal paracetamol exposure. RESULTS: In ALSPAC, there was strong evidence for association between six SNPs and asthma: rs959974 and rs1384001 (per-allele odds ratio for both: 1.30 (95% CI: 1.15-1.47), p = 0.00001), rs7010969 (OR 1.28 (1.13-1.46), p = 0.00004), rs3735945 (OR 1.30 (1.09-1.55), p = 0.003), rs920829 (OR 1.30 (1.09-1.54), p = 0.004) and rs4738202 (OR 1.22 (1.07-1.39), p = 0.004). In a meta-analysis across the three cohorts, the pooled effect estimates confirmed that all six SNPs were significantly associated with asthma. In ALSPAC, TRPA1 associations with asthma were not modified by prenatal paracetamol, although associations with IgE concentration were. CONCLUSION: This study suggests that TRPA1 may play a role in the development of childhood asthma. (249 words).


Assuntos
Asma/genética , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Canal de Cátion TRPA1/genética , Acetaminofen/administração & dosagem , Acetaminofen/efeitos adversos , Asma/epidemiologia , Pré-Escolar , Estudos de Coortes , Feminino , Seguimentos , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Imunoglobulina E/sangue , Exposição Materna/efeitos adversos , Países Baixos/epidemiologia , Polimorfismo de Nucleotídeo Único , Gravidez
20.
Eur J Epidemiol ; 32(8): 701-710, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28624884

RESUMO

A trend towards earlier menarche in women has been associated with childhood factors (e.g. obesity) and hypothesised environmental exposures (e.g. endocrine disruptors present in household products). Observational evidence has shown detrimental effects of early menarche on various health outcomes including adult lung function, but these might represent spurious associations due to confounding. To address this we used Mendelian randomization where genetic variants are used as proxies for age at menarche, since genetic associations are not affected by classical confounding. We estimated the effects of age at menarche on forced vital capacity (FVC), a proxy for restrictive lung impairment, and ratio of forced expiratory volume in one second to FVC (FEV1/FVC), a measure of airway obstruction, in both adulthood and adolescence. We derived SNP-age at menarche association estimates for 122 variants from a published genome-wide meta-analysis (N = 182,416), with SNP-lung function estimates obtained by meta-analysing three studies of adult women (N = 46,944) and two of adolescent girls (N = 3025). We investigated the impact of departures from the assumption of no pleiotropy through sensitivity analyses. In adult women, in line with previous evidence, we found an effect on restrictive lung impairment with a 24.8 mL increase in FVC per year increase in age at menarche (95% CI 1.8-47.9; p = 0.035); evidence was stronger after excluding potential pleiotropic variants (43.6 mL; 17.2-69.9; p = 0.001). In adolescent girls we found an opposite effect (-56.5 mL; -108.3 to -4.7; p = 0.033), suggesting that the detrimental effect in adulthood may be preceded by a short-term post-pubertal benefit. Our secondary analyses showing results in the same direction in men and boys, in whom age at menarche SNPs have also shown association with sexual development, suggest a role for pubertal timing in general rather than menarche specifically. We found no effect on airway obstruction (FEV1/FVC).


Assuntos
Volume Expiratório Forçado/fisiologia , Pulmão/fisiologia , Pulmão/fisiopatologia , Menarca , Capacidade Vital/fisiologia , Adolescente , Adulto , Obstrução das Vias Respiratórias/diagnóstico , Obstrução das Vias Respiratórias/fisiopatologia , Feminino , Variação Genética , Humanos , Menarca/genética , Menarca/fisiologia , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único/genética , Valor Preditivo dos Testes , Puberdade/genética , Distribuição Aleatória , Testes de Função Respiratória , Maturidade Sexual
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