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1.
Int J Cardiol ; 2021 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-33592239

RESUMO

BACKGROUND: Observational data have reported that being overweight or obese, compared to being normal weight, is associated with a lower risk for death - the "obesity paradox". We used Mendelian randomization (MR) to estimate causal effects of body mass index (BMI) on mortality risks in people with coronary heart disease (CHD), type 2 diabetes mellitus (T2DM) or malignancy in whom this paradox has been often reported. METHODS: We studied 457,746 White British UK Biobank participants including three subgroups with T2DM (n = 19,737), CHD (n = 21,925) or cancer (n = 42,612) at baseline and used multivariable-adjusted Cox models and MR approaches to describe relationships between BMI and mortality risk. RESULTS: Observational Cox models showed J-shaped relationships between BMI and mortality risk including within disease subgroups in which the BMI values associated with minimum mortality risk were within overweight/obese ranges (26.5-32.5 kg/m2). In all participants, MR analyses showed a positive linear causal effect of BMI on mortality risk (HR for mortality per unit higher BMI: 1.05; 95% CI: 1.03-1.08), also evident in people with CHD (HR: 1.08; 95% CI: 1.01-1.14). Point estimates for hazard ratios across all BMI values in participants with T2DM and cancer were consistent with overall positive linear effects but confidence intervals included the null. CONCLUSION: These data support the idea that population efforts to promote intentional weight loss towards the normal BMI range would reduce, not enhance, mortality risk in the general population including, importantly, individuals with CHD.

3.
Obesity (Silver Spring) ; 29(2): 428-437, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33491305

RESUMO

OBJECTIVE: This study aimed to investigate the role of cytokines as intermediates in the pathway from increased adiposity to disease. METHODS: BMI and circulating levels of up to 41 cytokines were measured in individuals from three Finnish cohort studies (n = 8,293). Mendelian randomization (MR) was used to assess the impact of BMI on circulating cytokines and the impact of BMI-driven cytokines on risk of obesity-related diseases. RESULTS: Observationally, BMI was associated with 19 cytokines. For every SD increase in BMI, causal effect estimates were strongest for hepatocyte growth factor, monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and were as ratios of geometric means 1.13 (95% CI: 1.08-1.19), 1.08 (95% CI: 1.04-1.14), and 1.13 (95% CI: 1.04-1.21), respectively. TRAIL was associated with a small increase in the odds of coronary artery disease (odds ratio: 1.03; 95% CI: 1.00-1.06). There was inconsistent evidence for a protective role of MCP-1 against inflammatory bowel diseases. CONCLUSIONS: Observational and MR estimates of the effect of BMI on cytokine levels were generally concordant. There was little evidence for an effect of raised levels of BMI-driven cytokines on disease. These findings illustrate the challenges of MR when applied in the context of molecular mediation.

4.
Nat Commun ; 12(1): 24, 2021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-33402679

RESUMO

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


Assuntos
Anorexia Nervosa/genética , Glicemia/metabolismo , Intolerância à Glucose/genética , Proteínas Substratos do Receptor de Insulina/genética , Resistência à Insulina/genética , Insulina/sangue , Fatores de Transcrição Kruppel-Like/genética , Adulto , Anorexia Nervosa/sangue , Anorexia Nervosa/etnologia , Anorexia Nervosa/fisiopatologia , Grupo com Ancestrais do Continente Europeu , Jejum/sangue , Feminino , Expressão Gênica , Loci Gênicos , Estudo de Associação Genômica Ampla , Intolerância à Glucose/sangue , Intolerância à Glucose/etnologia , Intolerância à Glucose/fisiopatologia , Humanos , Proteínas Substratos do Receptor de Insulina/sangue , Fatores de Transcrição Kruppel-Like/sangue , Masculino , Pessoa de Meia-Idade , Fenótipo , Caracteres Sexuais , Fatores Sexuais , Relação Cintura-Quadril
5.
Pediatr Infect Dis J ; 40(3): 260-263, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33315747

RESUMO

Diarrhea is a major cause of infant mortality. Being a "nonsecretor" (having an inactive fucosyltransferase-2 gene) protects against diarrhea by inhibiting enteric infections. Breastfeeding also protects against diarrhea; however, the impact of maternal secretor status is unknown. In the ALSPAC cohort (N = 4971), we found that breastfeeding by nonsecretor mothers was especially protective against diarrhea, which could inform new prevention strategies.

6.
PLoS Genet ; 16(12): e1009191, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33284794

RESUMO

Babies born clinically Small- or Large-for-Gestational-Age (SGA or LGA; sex- and gestational age-adjusted birth weight (BW) <10th or >90th percentile, respectively), are at higher risks of complications. SGA and LGA include babies who have experienced environment-related growth-restriction or overgrowth, respectively, and babies who are heritably small or large. However, the relative proportions within each group are unclear. We assessed the extent to which common genetic variants underlying variation in birth weight influence the probability of being SGA or LGA. We calculated independent fetal and maternal genetic scores (GS) for BW in 11,951 babies and 5,182 mothers. These scores capture the direct fetal and indirect maternal (via intrauterine environment) genetic contributions to BW, respectively. We also calculated maternal fasting glucose (FG) and systolic blood pressure (SBP) GS. We tested associations between each GS and probability of SGA or LGA. For the BW GS, we used simulations to assess evidence of deviation from an expected polygenic model. Higher BW GS were strongly associated with lower odds of SGA and higher odds of LGA (ORfetal = 0.75 (0.71,0.80) and 1.32 (1.26,1.39); ORmaternal = 0.81 (0.75,0.88) and 1.17 (1.09,1.25), respectively per 1 decile higher GS). We found evidence that the smallest 3% of babies had a higher BW GS, on average, than expected from their observed birth weight (assuming an additive polygenic model: Pfetal = 0.014, Pmaternal = 0.062). Higher maternal SBP GS was associated with higher odds of SGA P = 0.005. We conclude that common genetic variants contribute to risk of SGA and LGA, but that additional factors become more important for risk of SGA in the smallest 3% of babies.

7.
BMC Med ; 18(1): 396, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33327948

RESUMO

BACKGROUND: Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood. METHODS: We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models. RESULTS: In sex-specific MR analyses, higher BMI (per 4.2 kg/m2) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m2) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles. CONCLUSIONS: Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.

9.
Wellcome Open Res ; 5: 210, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32995559

RESUMO

The Avon Longitudinal Study of Parents and Children (ALSPAC) is a prospective population-based cohort study which recruited pregnant women in 1990-1992 and has followed these women, their partners and their offspring ever since. The study reacted rapidly to the coronavirus disease 2019 (COVID-19) pandemic, deploying an online questionnaire early on during lockdown (from 9 th April to 15 th May). In late May 2020, a second questionnaire was developed asking about physical and mental health, lifestyle and behaviours, employment and finances. The online questionnaire was deployed across the parent and offspring generations between the 26th May and 5 th July 2020. 6482 participants completed the questionnaire (2639 original mothers, 1039 original fathers/partners, 2711 offspring (mean age ~28 years) and 93 partners of offspring). 1039 new participants who did not respond to the first questionnaire deployed in April completed the second questionnaire.  A positive COVID-19 was reported by 36 (0.6%) participants (12 G0 and 24 G1), 91 (1.4%; 35 G0 and 56 G1) reported that they had been told by a doctor they likely had COVID-19 and 838 (13%; 422 G0 and 416 G1) suspected that they have had COVID-19.  Using algorithmically estimated cases based on symptoms, we estimate that the predicted prevalence of COVID-19 from mid-April to time of questionnaire completion was 3.1%. Data from both COVID questionnaires will be complemented with linkage to health records and results of biological testing as they become available. Data has been released as an update to the original dataset released in May 2020. It comprises: 1) a standard dataset containing all participant responses to both questionnaires with key sociodemographic factors and 2) as a composite release coordinating data from the existing resource, thus enabling bespoke research across all areas supported by the study. This data note describes the second questionnaire and the data obtained from it.

10.
Eur J Hum Genet ; 2020 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-33011735

RESUMO

Hypothesis-free Mendelian randomization studies provide a way to assess the causal relevance of a trait across the human phenome but can be limited by statistical power, sample overlap or complicated by horizontal pleiotropy. The recently described latent causal variable (LCV) approach provides an alternative method for causal inference which might be useful in hypothesis-free experiments across human phenome. We developed an automated pipeline for phenome-wide tests using the LCV approach including steps to estimate partial genetic causality, filter to a meaningful set of estimates, apply correction for multiple testing and then present the findings in a graphical summary termed causal architecture plot. We apply this pipeline to body mass index (BMI) and lipid traits as exemplars of traits where there is strong prior expectation for causal effects, and to dental caries and periodontitis as exemplars of traits where there is a need for causal inference. The results for lipids and BMI suggest that these traits are best viewed as contributing factors on a multitude of traits and conditions, thus providing additional evidence that supports viewing these traits as targets for interventions to improve health. On the other hand, caries and periodontitis are best viewed as a downstream consequence of other traits and diseases rather than a cause of ill health. The automated pipeline is implemented in the Complex-Traits Genetics Virtual Lab ( https://vl.genoma.io ) and results are available in https://view.genoma.io . We propose causal architecture plots based on phenome-wide partial genetic causality estimates as a new way visualizing the overall causal map of the human phenome.

11.
Metabolomics ; 16(6): 69, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32494907

RESUMO

INTRODUCTION: High plasma triacylglyceride levels are known to be associated with increased risk of atherosclerotic cardiovascular disease. Apolipoprotein C-III (apoC-III) is a key regulator of plasma triacylglyceride levels and is associated with hypertriglyceridemia via a number of pathways. There is consistent evidence for an association of cardiovascular events with blood apoC-III level, with support from human genetic studies of APOC3 variants. As such, apoC-III has been recognised as a potential therapeutic target for patients with severe hypertriglyceridaemia with one of the most promising apoC-III-targeting drugs, volanesorsen, having recently progressed through Phase III trials. OBJECTIVES: To exploit a rare loss of function variant in APOC3 (rs138326449) to characterise the potential long-term treatment effects of apoC-III targeting interventions on the metabolome. METHODS: In a recall-by-genotype study, 115 plasma samples were analysed by UHPLC-MS to acquire non-targeted metabolomics data. The study included samples from 57 adolescents and 33 adults. Overall, 12 985 metabolic features were tested for an association with APOC3 genotype. RESULTS: 161 uniquely annotated metabolites were found to be associated with rs138326449(APOC3). The highest proportion of associated metabolites belonged to the acyl-acyl glycerophospholipid and triacylglyceride metabolite classes. In addition to the anticipated (on-target) reduction of metabolites in the triacylglyceride and related classes, carriers of the rare variant exhibited previously unreported increases in levels of a number of metabolites from the acyl-alkyl glycerophospholipid class. CONCLUSION: Overall, our results suggest that therapies targeting apoC-III may potentially achieve a broad shift in lipid profile that favours better metabolic health.

12.
Nat Microbiol ; 5(9): 1079-1087, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32572223

RESUMO

Recent population-based1-4 and clinical studies5 have identified a range of factors associated with human gut microbiome variation. Murine quantitative trait loci6, human twin studies7 and microbiome genome-wide association studies1,3,8-12 have provided evidence for genetic contributions to microbiome composition. Despite this, there is still poor overlap in genetic association across human studies. Using appropriate taxon-specific models, along with support from independent cohorts, we show an association between human host genotype and gut microbiome variation. We also suggest that interpretation of applied analyses using genetic associations is complicated by the probable overlap between genetic contributions and heritable components of host environment. Using faecal 16S ribosomal RNA gene sequences and host genotype data from the Flemish Gut Flora Project (n = 2,223) and two German cohorts (FoCus, n = 950; PopGen, n = 717), we identify genetic associations involving multiple microbial traits. Two of these associations achieved a study-level threshold of P = 1.57 × 10-10; an association between Ruminococcus and rs150018970 near RAPGEF1 on chromosome 9, and between Coprococcus and rs561177583 within LINC01787 on chromosome 1. Exploratory analyses were undertaken using 11 other genome-wide associations with strong evidence for association (P < 2.5 × 10-8) and a previously reported signal of association between rs4988235 (MCM6/LCT) and Bifidobacterium. Across these 14 single-nucleotide polymorphisms there was evidence of signal overlap with other genome-wide association studies, including those for age at menarche and cardiometabolic traits. Mendelian randomization analysis was able to estimate associations between microbial traits and disease (including Bifidobacterium and body composition); however, in the absence of clear microbiome-driven effects, caution is needed in interpretation. Overall, this work marks a growing catalogue of genetic associations that will provide insight into the contribution of host genotype to gut microbiome. Despite this, the uncertain origin of association signals will likely complicate future work looking to dissect function or use associations for causal inference analysis.


Assuntos
Microbioma Gastrointestinal/genética , Estudo de Associação Genômica Ampla , Microbiota/genética , Animais , Bifidobacterium/genética , Fezes/microbiologia , Genótipo , Humanos , Camundongos , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , RNA Ribossômico 16S/genética
13.
Diabetes Care ; 43(7): 1537-1545, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32345654

RESUMO

OBJECTIVE: Type 2 diabetes develops for many years before diagnosis. We aimed to reveal early metabolic features characterizing liability to adult disease by examining genetic liability to adult type 2 diabetes in relation to metabolomic traits across early life. RESEARCH DESIGN AND METHODS: Up to 4,761 offspring from the Avon Longitudinal Study of Parents and Children were studied. Linear models were used to examine effects of a genetic risk score (162 variants) for adult type 2 diabetes on 229 metabolomic traits (lipoprotein subclass-specific cholesterol and triglycerides, amino acids, glycoprotein acetyls, and others) measured at age 8 years, 16 years, 18 years, and 25 years. Two-sample Mendelian randomization (MR) was also conducted using genome-wide association study data on metabolomic traits in an independent sample of 24,925 adults. RESULTS: At age 8 years, associations were most evident for type 2 diabetes liability (per SD higher) with lower lipids in HDL subtypes (e.g., -0.03 SD [95% CI -0.06, -0.003] for total lipids in very large HDL). At 16 years, associations were stronger with preglycemic traits, including citrate and with glycoprotein acetyls (0.05 SD; 95% CI 0.01, 0.08), and at 18 years, associations were stronger with branched-chain amino acids. At 25 years, associations had strengthened with VLDL lipids and remained consistent with previously altered traits, including HDL lipids. Two-sample MR estimates among adults indicated persistent patterns of effect of disease liability. CONCLUSIONS: Our results support perturbed HDL lipid metabolism as one of the earliest features of type 2 diabetes liability, alongside higher branched-chain amino acid and inflammatory levels. Several features are apparent in childhood as early as age 8 years, decades before the clinical onset of disease.

14.
J Invest Dermatol ; 140(12): 2380-2385, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32339537

RESUMO

Failure of dermal protection or repair mechanisms might lead to visibly aged skin. The study aimed to identify genetic associations with perceived age. A genome-wide association study was undertaken in 423,992 adult participants of UK Biobank, using questionnaire data on perceived age and genetic data imputed to the Haplotype Reference Consortium imputation panel. The study identified 74 independently associated genetic loci, to our knowledge previously unreported (P < 5 × 10-8), which were enriched for cell signaling pathways, including the NEK6 and SMAD2 subnetworks. Common genetic variation was estimated to account for 14% of variation in perceived age, and the heritability of perceived age was partially shared with that of 75 other traits, including multiple traits representing adiposity, suggesting that perceived age may be a useful proxy trait in genetic association studies.

15.
Hum Mol Genet ; 29(12): 2098-2106, 2020 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-32227112

RESUMO

Glycosuria is a condition where glucose is detected in urine at higher concentrations than normal (i.e. not detectable). Glycosuria at some point during pregnancy has an estimated prevalence of 50% and is associated with adverse outcomes in both mothers and offspring. Little is currently known about the genetic contribution to this trait or the extent to which it overlaps with other seemingly related traits, e.g. diabetes. We performed a genome-wide association study (GWAS) for self-reported glycosuria in pregnant mothers from the Avon Longitudinal Study of Parents and Children (cases/controls = 1249/5140). We identified two loci, one of which (lead SNP = rs13337037; chromosome 16; odds ratio of glycosuria per effect allele: 1.42; 95% CI: 1.30, 1.56; P = 1.97 × 10-13) was then validated using an obstetric measure of glycosuria measured in the same cohort (227/6639). We performed a secondary GWAS in the 1986 Northern Finland Birth Cohort (NFBC1986; 747/2991) using midwife-reported glycosuria and offspring genotype as a proxy for maternal genotype. The combined results revealed evidence for a consistent effect on glycosuria at the chromosome 16 locus. In follow-up analyses, we saw little evidence of shared genetic underpinnings with the exception of urinary albumin-to-creatinine ratio (Rg = 0.64; SE = 0.22; P = 0.0042), a biomarker of kidney disease. In conclusion, we identified a genetic association with self-reported glycosuria during pregnancy, with the lead SNP located 15kB upstream of SLC5A2, a target of antidiabetic drugs. The lack of strong genetic correlation with seemingly related traits such as type 2 diabetes suggests different genetic risk factors exist for glycosuria during pregnancy.

16.
Alcohol Clin Exp Res ; 44(5): 1132-1140, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32315093

RESUMO

BACKGROUND: Previous research has suggested that intrauterine alcohol exposure is associated with a variety of adverse outcomes in offspring. However, few studies have investigated its association with offspring internalizing disorders in late adolescence. METHODS: Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), we investigated the associations of maternal drinking in pregnancy with offspring depression at age 18 and 24 (n = 13,480). We also examined partner drinking as a negative control for intrauterine exposure for comparison. RESULTS: Offspring of mothers that consumed any alcohol at 18 weeks gestation were at increased risk of having a diagnosis of depression (fully adjusted model: OR 1.17, 95% CI 1.02 to 1.34), but there was no clear evidence of association between partners' alcohol consumption at 18 weeks gestation during pregnancy and increased risk of offspring depression (fully adjusted model: OR 0.87, 95% CI 0.74 to 1.01). Postestimation tests found a positive difference between the association of maternal and partner alcohol use on offspring depression, showing a stronger association for maternal compared with partner alcohol use (OR 1.41, CI 1.07 to 1.84). CONCLUSIONS: Maternal drinking in pregnancy was associated with increased risk of offspring depression at age 18. Residual confounding may explain this association, but the negative control comparison of paternal drinking provides some evidence that it may be causal, and this warrants further investigation.

17.
Nat Commun ; 11(1): 1536, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32210231

RESUMO

The timing of puberty is highly variable and is associated with long-term health outcomes. To date, understanding of the genetic control of puberty timing is based largely on studies in women. Here, we report a multi-trait genome-wide association study for male puberty timing with an effective sample size of 205,354 men. We find moderately strong genomic correlation in puberty timing between sexes (rg = 0.68) and identify 76 independent signals for male puberty timing. Implicated mechanisms include an unexpected link between puberty timing and natural hair colour, possibly reflecting common effects of pituitary hormones on puberty and pigmentation. Earlier male puberty timing is genetically correlated with several adverse health outcomes and Mendelian randomization analyses show a genetic association between male puberty timing and shorter lifespan. These findings highlight the relationships between puberty timing and health outcomes, and demonstrate the value of genetic studies of puberty timing in both sexes.


Assuntos
Cor de Cabelo/genética , Longevidade/genética , Puberdade/genética , Maturidade Sexual/genética , Adulto , Fatores Etários , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Menarca/genética , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Fatores de Tempo , Adulto Jovem
18.
Am J Hum Genet ; 106(3): 327-337, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32059762

RESUMO

We aimed to increase our understanding of the genetic determinants of vitamin D levels by undertaking a large-scale genome-wide association study (GWAS) of serum 25 hydroxyvitamin D (25OHD). To do so, we used imputed genotypes from 401,460 white British UK Biobank participants with available 25OHD levels, retaining single-nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) > 0.1% and imputation quality score > 0.3. We performed a linear mixed model GWAS on standardized log-transformed 25OHD, adjusting for age, sex, season of measurement, and vitamin D supplementation. These results were combined with those from a previous GWAS including 42,274 Europeans. In silico functional follow-up of the GWAS results was undertaken to identify enrichment in gene sets, pathways, and expression in tissues, and to investigate the partitioned heritability of 25OHD and its shared heritability with other traits. Using this approach, the SNP heritability of 25OHD was estimated to 16.1%. 138 conditionally independent SNPs were detected (p value < 6.6 × 10-9) among which 53 had MAF < 5%. Single variant association signals mapped to 69 distinct loci, among which 63 were previously unreported. We identified enrichment in hepatic and lipid metabolism gene pathways and enriched expression of the 25OHD genes in liver, skin, and gastrointestinal tissues. We observed partially shared heritability between 25OHD and socio-economic traits, a feature which may be mediated through time spent outdoors. Therefore, through a large 25OHD GWAS, we identified 63 loci that underline the contribution of genes outside the vitamin D canonical metabolic pathway to the genetic architecture of 25OHD.


Assuntos
Estudo de Associação Genômica Ampla , Vitamina D/análogos & derivados , Feminino , Interação Gene-Ambiente , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Vitamina D/sangue
19.
Sci Adv ; 5(9): eaaw3095, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31840077

RESUMO

Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.


Assuntos
Índice de Massa Corporal , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas , Característica Quantitativa Herdável , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Criança , Feminino , Predisposição Genética para Doença , Genômica , Gráficos de Crescimento , Humanos , Lactente , Estudos Longitudinais , Masculino , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Receptores para Leptina/genética
20.
Wellcome Open Res ; 4: 107, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31681855

RESUMO

Background: Intimate partner violence (IPV) is a risk factor for developmental problems in offspring. Despite a high prevalence of IPV in the UK and elsewhere, the longer-term outcomes of offspring born to exposed mothers remain under-researched. Methods: Population-based cohort study. We assessed IPV prevalence by type and timing for 3,153 mother-child pairs with complete data within our study population and examined associations between IPV and offspring IQ. We used multiple-imputation to evaluate bias due to our exclusion of observations with missing covariate data. Results: Nearly one in five mothers reported IPV during the study period, with 17.6% reporting emotional violence and 6.8% reporting physical violence. Taking into account potential confounders, the IQ scores of children born to mothers exposed to physical violence remained lower than those of maternally unexposed children (full-scale IQ = -2.8 points [95%CI -4.9 to -0.7], verbal IQ = -2.2 [95%CI -4.4 to -0.1], performance IQ = -2.7 [95%CI  -5.0 to -0.5]) and odds of below-average intelligence (IQ<90) remained increased for full-scale (OR 1.48 [95%CI 1.03 to 2.14] and performance IQ (OR 1.48 [95%CI 1.08 to 2.04]) but not verbal IQ (OR 1.06 [95%CI 0.69 to 1.64]). Most physical violence occurred postnatally, and relative odds were most substantial when mothers were exposed to violence across pre-/perinatal and postnatal study periods (OR performance IQ<90 = 2.97 [95%CI 1.30 to 6.82]). Conclusions: Maternal exposure to physical IPV is associated with lower offspring IQ at age 8. Associations persisted after adjusting for potential confounders and were driven by violence occurring postnatally.

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