ORCID Profile
0000-0001-7785-4547
Current Organisation
University of Bristol
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Publisher: Cold Spring Harbor Laboratory
Date: 19-09-2020
DOI: 10.1101/2020.09.17.302208
Abstract: Higher birth weight is associated with higher adult body mass index (BMI). If genetic variants can be identified with alleles that predispose to both greater fetal growth and to greater adult adiposity, such shared genetic effects might indicate biological processes important in the early patterning of adiposity. However, variants identified in genome-wide association studies of adult BMI have overall been only weakly associated with birth weight. Genetic variants have recently been identified where one allele is associated with higher adult body fat percentage, but lower risk of metabolic disease, likely due to a favourable body fat distribution. The effect of these adult metabolically favourable adiposity alleles on an in idual’s own birth weight is unknown. We aimed to test the effect on birth weight of a fetal genetic predisposition to higher metabolically favourable adult adiposity and to compare this with the effects of a fetal genetic predisposition to higher adult BMI. We also aimed to examine the effects of a genetic predisposition to higher metabolically favourable adult adiposity or BMI on other birth anthropometric traits (length, ponderal index, head circumference and skinfold thickness) and on cord-blood insulin, leptin and adiponectin. We used published GWAS data from up to 406,063 in iduals to estimate the fetal effects on birth weight of alleles that are robustly associated with higher metabolically favourable adult adiposity or BMI. We additionally used 9,350 mother-child pairs from four cohorts to test the effects of the same alleles on other birth anthropometric traits and cord-blood markers. In all analyses, we adjusted for potential confounding due to the maternal genotype. We used inverse-variance weighted meta-analyses to combine summary data across SNPs. Fetal genetic predisposition to higher metabolically favourable adult adiposity was associated with higher birth weight (10 grams (95% CI: 7 to 13) higher mean birth weight per 1 SD pooled “genetic score”). Fetal genetic predisposition to higher adult BMI was also associated with higher birth weight, but with a smaller magnitude of effect (4 grams (95% CI: 0 to 8) higher mean birth weight per 1 SD pooled “genetic score”) and with higher heterogeneity across SNPs. Effects on other birth anthropometric outcomes were consistent with the effect on birth weight but with wider confidence intervals. There was no strong evidence for an effect on cord-blood markers. Some genetic variants previously linked to adult adiposity influence birth weight. Alleles that predispose to higher metabolically favourable adult adiposity collectively have a stronger effect on birth weight than those predisposing to higher BMI. This suggests that the early accumulation of a metabolically favourable fat distribution might underlie part of the observed association between higher birth weight and higher adult BMI. Larger s les are needed to clarify the effects on other birth anthropometric measures and cord-blood markers.
Publisher: Springer Science and Business Media LLC
Date: 02-09-2200
DOI: 10.1038/S41467-019-11881-8
Abstract: The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration the association is replicated in 9,291 additional infants (combined P = 3.96 × 10 −14 ). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.
Publisher: Springer Science and Business Media LLC
Date: 11-03-2022
DOI: 10.1007/S10552-022-01562-1
Abstract: Dietary factors are assumed to play an important role in cancer risk, apparent in consensus recommendations for cancer prevention that promote nutritional changes. However, the evidence in this field has been generated predominantly through observational studies, which may result in biased effect estimates because of confounding, exposure misclassification, and reverse causality. With major geographical differences and rapid changes in cancer incidence over time, it is crucial to establish which of the observational associations reflect causality and to identify novel risk factors as these may be modified to prevent the onset of cancer and reduce its progression. Mendelian randomization (MR) uses the special properties of germline genetic variation to strengthen causal inference regarding potentially modifiable exposures and disease risk. MR can be implemented through instrumental variable (IV) analysis and, when robustly performed, is generally less prone to confounding, reverse causation and measurement error than conventional observational methods and has different sources of bias (discussed in detail below). It is increasingly used to facilitate causal inference in epidemiology and provides an opportunity to explore the effects of nutritional exposures on cancer incidence and progression in a cost-effective and timely manner. Here, we introduce the concept of MR and discuss its current application in understanding the impact of nutritional factors (e.g., any measure of diet and nutritional intake, circulating biomarkers, patterns, preference or behaviour) on cancer aetiology and, thus, opportunities for MR to contribute to the development of nutritional recommendations and policies for cancer prevention. We provide applied ex les of MR studies examining the role of nutritional factors in cancer to illustrate how this method can be used to help prioritise or deprioritise the evaluation of specific nutritional factors as intervention targets in randomised controlled trials. We describe possible biases when using MR, and methodological developments aimed at investigating and potentially overcoming these biases when present. Lastly, we consider the use of MR in identifying causally relevant nutritional risk factors for various cancers in different regions across the world, given notable geographical differences in some cancers. We also discuss how MR results could be translated into further research and policy. We conclude that findings from MR studies, which corroborate those from other well-conducted studies with different and orthogonal biases, are poised to substantially improve our understanding of nutritional influences on cancer. For such corroboration, there is a requirement for an interdisciplinary and collaborative approach to investigate risk factors for cancer incidence and progression.
Publisher: Springer Science and Business Media LLC
Date: 22-11-2017
Publisher: American Association for Cancer Research (AACR)
Date: 04-2020
DOI: 10.1158/1055-9965.EPI-19-0891
Abstract: Results from epidemiologic studies examining polyunsaturated fatty acids (PUFA) and colorectal cancer risk are inconsistent. Mendelian randomization may strengthen causal inference from observational studies. Given their shared metabolic pathway, examining the combined effects of aspirin/NSAID use with PUFAs could help elucidate an association between PUFAs and colorectal cancer risk. Information was leveraged from genome-wide association studies (GWAS) regarding PUFA-associated SNPs to create weighted genetic scores (wGS) representing genetically predicted circulating blood PUFAs for 11,016 non-Hispanic white colorectal cancer cases and 13,732 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Associations per SD increase in the wGS were estimated using unconditional logistic regression. Interactions between PUFA wGSs and aspirin/NSAID use on colorectal cancer risk were also examined. Modest colorectal cancer risk reductions were observed per SD increase in circulating linoleic acid [ORLA = 0.96 95% confidence interval (CI) = 0.93–0.98 P = 5.2 × 10−4] and α-linolenic acid (ORALA = 0.95 95% CI = 0.92–0.97 P = 5.4 × 10−5), whereas modest increased risks were observed for arachidonic (ORAA = 1.06 95% CI = 1.03–1.08 P = 3.3 × 10−5), eicosapentaenoic (OREPA = 1.04 95% CI = 1.01–1.07 P = 2.5 × 10−3), and docosapentaenoic acids (ORDPA = 1.03 95% CI = 1.01–1.06 P = 1.2 × 10−2). Each of these effects was stronger among aspirin/NSAID nonusers in the stratified analyses. Our study suggests that higher circulating shorter-chain PUFAs (i.e., LA and ALA) were associated with reduced colorectal cancer risk, whereas longer-chain PUFAs (i.e., AA, EPA, and DPA) were associated with an increased colorectal cancer risk. The interaction of PUFAs with aspirin/NSAID use indicates a shared colorectal cancer inflammatory pathway. Future research should continue to improve PUFA genetic instruments to elucidate the independent effects of PUFAs on colorectal cancer.
Publisher: Springer Science and Business Media LLC
Date: 20-09-2021
DOI: 10.1007/S00125-021-05570-9
Abstract: Higher maternal BMI during pregnancy is associated with higher offspring birthweight, but it is not known whether this is solely the result of adverse metabolic consequences of higher maternal adiposity, such as maternal insulin resistance and fetal exposure to higher glucose levels, or whether there is any effect of raised adiposity through non-metabolic (e.g. mechanical) factors. We aimed to use genetic variants known to predispose to higher adiposity, coupled with a favourable metabolic profile, in a Mendelian randomisation (MR) study comparing the effect of maternal ‘metabolically favourable adiposity’ on offspring birthweight with the effect of maternal general adiposity (as indexed by BMI). To test the causal effects of maternal metabolically favourable adiposity or general adiposity on offspring birthweight, we performed two-s le MR. We used variants identified in large, published genetic-association studies as being associated with either higher adiposity and a favourable metabolic profile, or higher BMI ( n = 442,278 and n = 322,154 for metabolically favourable adiposity and BMI, respectively). We then extracted data on the metabolically favourable adiposity and BMI variants from a large, published genetic-association study of maternal genotype and offspring birthweight controlling for fetal genetic effects ( n = 406,063 with maternal and/or fetal genotype effect estimates). We used several sensitivity analyses to test the reliability of the results. As secondary analyses, we used data from four cohorts (total n = 9323 mother–child pairs) to test the effects of maternal metabolically favourable adiposity or BMI on maternal gestational glucose, anthropometric components of birthweight and cord-blood biomarkers. Higher maternal adiposity with a favourable metabolic profile was associated with lower offspring birthweight (−94 [95% CI −150, −38] g per 1 SD [6.5%] higher maternal metabolically favourable adiposity, p = 0.001). By contrast, higher maternal BMI was associated with higher offspring birthweight (35 [95% CI 16, 53] g per 1 SD [4 kg/m 2 ] higher maternal BMI, p = 0.0002). Sensitivity analyses were broadly consistent with the main results. There was evidence of outlier SNPs for both exposures their removal slightly strengthened the metabolically favourable adiposity estimate and made no difference to the BMI estimate. Our secondary analyses found evidence to suggest that a higher maternal metabolically favourable adiposity decreases pregnancy fasting glucose levels while a higher maternal BMI increases them. The effects on neonatal anthropometric traits were consistent with the overall effect on birthweight but the smaller s le sizes for these analyses meant that the effects were imprecisely estimated. We also found evidence to suggest that higher maternal metabolically favourable adiposity decreases cord-blood leptin while higher maternal BMI increases it. Our results show that higher adiposity in mothers does not necessarily lead to higher offspring birthweight. Higher maternal adiposity can lead to lower offspring birthweight if accompanied by a favourable metabolic profile. The data for the genome-wide association studies (GWAS) of BMI are available at ollaboration/giant/index.php/GIANT_consortium_data_files . The data for the GWAS of body fat percentage are available at walker05.u.hpc.mssm.edu .
Publisher: Cold Spring Harbor Laboratory
Date: 25-05-2020
DOI: 10.1101/2020.05.25.20112441
Abstract: Higher maternal BMI during pregnancy results in higher offspring birth weight, but it is not known whether this is solely the result of adverse metabolic consequences of higher maternal adiposity, such as maternal insulin resistance and fetal exposure to higher glucose levels, or whether there is any effect of raised adiposity through non-metabolic (e.g. mechanical) factors. We aimed to use genetic variants known to predispose to higher adiposity coupled with a favourable metabolic profile, in a Mendelian Randomisation (MR) study comparing the effect of maternal “metabolically favourable adiposity” on offspring birth weight with the effect of maternal general adiposity (as indexed by BMI). To test the causal effects of maternal metabolically favourable adiposity or general adiposity on offspring birth weight, we performed two s le MR. We used variants identified in large genetic association studies as associated with either higher adiposity and a favourable metabolic profile, or higher BMI (N = 442,278 and N = 322,154 for metabolically favourable adiposity and BMI, respectively). We then used data from the same variants in a large genetic study of maternal genotype and offspring birth weight independent of fetal genetic effects (N = 406,063 with maternal and/or fetal genotype effect estimates). We used several sensitivity analyses to test the reliability of the results. As secondary analyses, we used data from four cohorts (total N = 9,323 mother-child pairs) to test the effects of maternal metabolically favourable adiposity or BMI on maternal gestational glucose, anthropometric components of birth weight and cord-blood biomarkers. Higher maternal adiposity with a favourable metabolic profile was associated with lower offspring birth weight (−94 (95% CI: −150 to −38) grams per 1 SD (6.5%) higher maternal metabolically favourable adiposity). By contrast, higher maternal BMI was associated with higher offspring birth weight (35 (95% CI: 16 to 53) grams per 1 SD (4 kg/m 2 ) higher maternal BMI). Sensitivity analyses were broadly consistent with the main results. There was evidence of outlier SNPs for both exposures and their removal slightly strengthened the metabolically favourable adiposity estimate and made no difference to the BMI estimate. Our secondary analyses found evidence to suggest that maternal metabolically favourable adiposity decreases pregnancy fasting glucose levels whilst maternal BMI increases them. The effects on neonatal anthropometric traits were consistent with the overall effect on birth weight, but the smaller s le sizes for these analyses meant the effects were imprecisely estimated. We also found evidence to suggest that maternal metabolically favourable adiposity decreases cord-blood leptin whilst maternal BMI increases it. Our results show that higher adiposity in mothers does not necessarily lead to higher offspring birth weight. Higher maternal adiposity can lead to lower offspring birth weight if accompanied by a favourable metabolic profile. Studies in non-pregnant people with obesity suggest many people can have a “metabolically healthy” form of obesity, but effects in pregnancy and on offspring are not known. Multiple lines of evidence show that higher maternal BMI is causally associated with higher offspring birth weight, and that this may be mediated by the fetal insulin response to higher maternal gestational glucose. Recently, genetic variants have been identified, where one allele is associated with higher adiposity but lower risk of type II diabetes and favourable metabolic profile, including lower insulin and glucose levels, so called “metabolically favourable adiposity” the mechanism is thought to be due to greater subcutaneous adipose storage capacity that leads to higher insulin sensitivity. What is the effect of maternal metabolically favourable adiposity on birth weight, and how does it compare with the effect of maternal BMI on birth weight? Higher maternal adiposity can lead to lower, not higher birth weight, if it is also associated with a metabolically favourable profile this contrasts with the effect of higher maternal general adiposity (BMI), on higher birth weight. Higher maternal metabolically favourable adiposity causes lower maternal fasting plasma glucose levels, most likely due to higher insulin sensitivity in contrast higher maternal general adiposity leads to higher maternal fasting plasma glucose levels, most likely due to lower insulin sensitivity. Identifying ways of stratifying overweight and obese pregnant women into those with and without metabolically favourable adiposity could allow for targeted management to obtain healthy fetal growth and birth weight.
Publisher: Center for Open Science
Date: 05-02-2019
Abstract: Mendelian randomization (MR) has been increasingly used to interrogate the causal effects of modifiable risk factors on human health and disease over the last 15 years. As MR becomes more commonplace in clinical guidelines and drug development, there is a need for researchers and practitioners from multiple disciplines to understand the existing and rapidly evolving ‘language’ of MR. The MR Dictionary provides useful definitions and descriptions for undertaking, understanding and interpreting MR studies to a wide, inter-disciplinary audience – both those new to MR and those who are experienced in its use but who want to remain up to date. The full searchable (with terms cross-referenced throughout) version of the MR Dictionary is provided on the journal website. In the first instance, we aim to update the MR Dictionary annually and encourage users of the Dictionary to help us in this endeavour. By the first update (August 2020), we aim to have moved to an open, collaborative and interactive online tool on the journal website that will support more rapid and extensive linked searches and more immediate updates and online discussion.
Publisher: Springer Science and Business Media LLC
Date: 13-06-2022
DOI: 10.1186/S12916-022-02399-W
Abstract: Despite early interest in the health effects of polyunsaturated fatty acids (PUFA), there is still substantial controversy and uncertainty on the evidence linking PUFA to cardiovascular diseases (CVDs). We investigated the effect of plasma concentration of omega-3 PUFA (i.e. docosahexaenoic acid (DHA) and total omega-3 PUFA) and omega-6 PUFA (i.e. linoleic acid and total omega-6 PUFA) on the risk of CVDs using Mendelian randomization. We conducted the largest genome-wide association study (GWAS) of circulating PUFA to date including a s le of 114,999 in iduals and incorporated these data in a two-s le Mendelian randomization framework to investigate the involvement of circulating PUFA on a wide range of CVDs in up to 1,153,768 in iduals of European ancestry (i.e. coronary artery disease, ischemic stroke, haemorrhagic stroke, heart failure, atrial fibrillation, peripheral arterial disease, aortic aneurysm, venous thromboembolism and aortic valve stenosis). GWAS identified between 46 and 64 SNPs for the four PUFA traits, explaining 4.8–7.9% of circulating PUFA variance and with mean F statistics . Higher genetically predicted DHA (and total omega-3 fatty acids) concentration was related to higher risk of some cardiovascular endpoints however, these findings did not pass our criteria for multiple testing correction and were attenuated when accounting for LDL-cholesterol through multivariable Mendelian randomization or excluding SNPs in the vicinity of the FADS locus. Estimates for the relation between higher genetically predicted linoleic acid (and total omega-6) concentration were inconsistent across different cardiovascular endpoints and Mendelian randomization methods. There was weak evidence of higher genetically predicted linoleic acid being related to lower risk of ischemic stroke and peripheral artery disease when accounting by LDL-cholesterol. We have conducted the largest GWAS of circulating PUFA to date and the most comprehensive Mendelian randomization analyses. Overall, our Mendelian randomization findings do not support a protective role of circulating PUFA concentration on the risk of CVDs. However, horizontal pleiotropy via lipoprotein-related traits could be a key source of bias in our analyses.
Publisher: Oxford University Press (OUP)
Date: 11-11-2022
DOI: 10.1093/IJE/DYAC212
Abstract: Whether non-alcoholic fatty liver disease (NAFLD) causes cardiovascular disease (CVD) and type 2 diabetes (T2D) is unclear and possible differences between ethnicities have not been thoroughly explored. We used Mendelian randomization (MR) to assess the role of NAFLD in CVD and T2D risk in Europeans and East Asians. We conducted a MR study using genetic predictors of alanine aminotransferase (ALT), liability to NAFLD, aspartate transaminase (AST), liver magnetic resonance imaging corrected T1 and proton density fat fraction and combined them with genome-wide association studies (GWAS) summary statistics of CVD, T2D and glycaemic traits (s le size ranging from 14 400 to 977 320). Inverse-variance weighted analysis was used to assess the effect of NAFLD in these outcomes, with sensitivity analyses and replication in FinnGen. We conducted analyses in East Asians using ethnicity-specific genetic predictors of ALT and AST, and the respective outcome GWAS summary statistics. In Europeans, higher ALT was associated with higher T2D risk (odds ratio: 1.77 per standard deviation, 95% CI 1.5 to 2.08), with similar results for other exposures, across sensitivity analyses and in FinnGen. Although NAFLD proxies were related to higher coronary artery disease (CAD) and stroke risk, sensitivity analyses suggested possible bias by horizontal pleiotropy. In East Asians, higher ALT was possibly associated with higher T2D risk, and ALT and AST were inversely associated with CAD. NAFLD likely increases the risk of T2D in Europeans and East Asians. Potential differential effects on CAD between Europeans and East Asians require further investigation.
Publisher: Cold Spring Harbor Laboratory
Date: 18-04-2022
DOI: 10.1101/2022.04.15.22273911
Abstract: Amino acids are key to protein synthesis, energy metabolism, cell signaling and gene expression however, the contribution of specific maternal amino acids to fetal growth is unclear. We explored the effect of maternal circulating amino acids on fetal growth, proxied by birthweight, using two-s le Mendelian randomization and summary data from a genome-wide association study (GWAS) of serum amino acids levels (s le 1, n = 86,507) and a maternal GWAS of offspring birthweight, adjusting for fetal genotype effects (s le 2, n = 406,063 with maternal and/or fetal genotype effect estimates). A total of 106 independent single nucleotide polymorphisms (SNPs) robustly associated with 19 amino acids ( p 4.9 × 10 −10 ) were used as genetic instrumental variables. Our results provide evidence that maternal circulating glutamine (59 g offspring birthweight increase per SD increase in maternal amino acid level, 95% CI: 7, 110) and serine (27 g, 95% CI: 9, 46) raise, while leucine (−59 g, 95% CI: -106, -11) and phenylalanine (−25 g, 95% CI: -47, -4) lower offspring birthweight. Our findings strengthen evidence for key roles of maternal circulating amino acids in healthy fetal growth.
Publisher: FapUNIFESP (SciELO)
Date: 10-2007
DOI: 10.1590/S1517-86922007000500011
Abstract: As espécies reativas de oxigênio (ERO) são normalmente produzidas pelo metabolismo corporal. Todavia, ERO apresentam a capacidade de retirar elétrons de outros compostos celulares, sendo capazes de provocar lesões oxidativas em várias moléculas, fato que leva à perda total da função celular. A realização de exercícios físicos aumenta a síntese de ERO, além de promover lesão muscular e inflamação. Após uma sessão de exercícios físicos, inicia-se normalmente a fase de recuperação, quando são observados ersos efeitos positivos à saúde, incluindo o aumento da resistência a novas lesões induzidas ou não por exercícios, fato que é considerado como um processo "adaptativo". Diversos estudos, porém, relatam que essa recuperação não é alcançada por in íduos que se submetem a exercícios intensos e prolongados, ou, ainda, que possuem elevada freqüência de treinamento. Alternativas nutricionais têm sido muito estudadas, a fim de reduzir os efeitos promovidos pelo exercício extenuante, dentre as quais está a suplementação com vitamina E, vitamina C, creatina e glutamina. Esta revisão tem como objetivo abordar os aspectos atuais envolvendo a formação das ERO, os processos de lesão celular e inflamação, a adaptação aos tipos de exercício aeróbio e anaeróbio e possíveis intervenções nutricionais.
Publisher: Oxford University Press (OUP)
Date: 12-04-2023
DOI: 10.1093/IJE/DYAD018
Publisher: Elsevier BV
Date: 05-2023
Publisher: MDPI AG
Date: 27-07-2022
DOI: 10.3390/JCDD9080237
Abstract: Background: It is plausible that maternal pregnancy metabolism influences the risk of offspring congenital heart disease (CHD). We sought to explore this through a systematic approach using different methods and data. Methods: We undertook multivariable logistic regression of the odds of CHD for 923 mass spectrometry (MS)-derived metabolites in a sub-s le of a UK birth cohort (Born in Bradford (BiB) N = 2605, 46 CHD cases). We considered metabolites reaching a p-value threshold .05 to be suggestively associated with CHD. We sought validation of our findings, by repeating the multivariable regression analysis within the BiB cohort for any suggestively associated metabolite that was measured by nuclear magnetic resonance (NMR) or clinical chemistry (N = 7296, 87 CHD cases), and by using genetic risk scores (GRS: weighted genetic risk scores of single nucleotide polymorphisms (SNPs) that were associated with any suggestive metabolite) in Mendelian randomization (MR) analyses. The MR analyses were performed in BiB and two additional European birth cohorts (N = 38,662, 319 CHD cases). Results: In the main multivariable analyses, we identified 44 metabolites suggestively associated with CHD, including those from the following super pathways: amino acids, lipids, co-factors and vitamins, xenobiotics, nucleotides, energy, and several unknown molecules. Of these 44, isoleucine and leucine were available in the larger BiB cohort (NMR), and for these the results were validated. The MR analyses were possible for 27/44 metabolites and for 11 there was consistency with the multivariable regression results. Conclusions: In summary, we have used complimentary data sources and statistical techniques to construct layers of evidence. We found that pregnancy amino acid metabolism, androgenic steroid lipids, and levels of succinylcarnitine could be important contributing factors for CHD.
Publisher: Oxford University Press (OUP)
Date: 07-07-2022
DOI: 10.1093/HMG/DDAC153
Abstract: Despite early interest, the evidence linking fatty acids to cardiovascular diseases (CVDs) remains controversial. We used Mendelian randomization to explore the involvement of polyunsaturated (PUFA) and monounsaturated (MUFA) fatty acids biosynthesis in the etiology of several CVD endpoints in up to 1 153 768 European (maximum 123 668 cases) and 212 453 East Asian (maximum 29 319 cases) ancestry in iduals. As instruments, we selected single nucleotide polymorphisms mapping to genes with well-known roles in PUFA (i.e. FADS1/2 and ELOVL2) and MUFA (i.e. SCD) biosynthesis. Our findings suggest that higher PUFA biosynthesis rate (proxied by rs174576 near FADS1/2) is related to higher odds of multiple CVDs, particularly ischemic stroke, peripheral artery disease and venous thromboembolism, whereas higher MUFA biosynthesis rate (proxied by rs603424 near SCD) is related to lower odds of coronary artery disease among Europeans. Results were unclear for East Asians as most effect estimates were imprecise. By triangulating multiple approaches (i.e. uni-/multi-variable Mendelian randomization, a phenome-wide scan, genetic colocalization and within-sibling analyses), our results are compatible with higher low-density lipoprotein (LDL) cholesterol (and possibly glucose) being a downstream effect of higher PUFA biosynthesis rate. Our findings indicate that PUFA and MUFA biosynthesis are involved in the etiology of CVDs and suggest LDL cholesterol as a potential mediating trait between PUFA biosynthesis and CVDs risk.
Publisher: Springer Science and Business Media LLC
Date: 02-2022
DOI: 10.1186/S12916-021-02216-W
Abstract: Greater maternal adiposity before or during pregnancy is associated with greater offspring adiposity throughout childhood, but the extent to which this is due to causal intrauterine or periconceptional mechanisms remains unclear. Here, we use Mendelian randomisation (MR) with polygenic risk scores (PRS) to investigate whether associations between maternal pre-/early pregnancy body mass index (BMI) and offspring adiposity from birth to adolescence are causal. We undertook confounder adjusted multivariable (MV) regression and MR using mother-offspring pairs from two UK cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC) and Born in Bradford (BiB). In ALSPAC and BiB, the outcomes were birthweight (BW N = 9339) and BMI at age 1 and 4 years ( N = 8659 to 7575). In ALSPAC only we investigated BMI at 10 and 15 years ( N = 4476 to 4112) and dual-energy X-ray absorptiometry (DXA) determined fat mass index (FMI) from age 10–18 years ( N = 2659 to 3855). We compared MR results from several PRS, calculated from maternal non-transmitted alleles at between 29 and 80,939 single nucleotide polymorphisms (SNPs). MV and MR consistently showed a positive association between maternal BMI and BW, supporting a moderate causal effect. For adiposity at most older ages, although MV estimates indicated a strong positive association, MR estimates did not support a causal effect. For the PRS with few SNPs, MR estimates were statistically consistent with the null, but had wide confidence intervals so were often also statistically consistent with the MV estimates. In contrast, the largest PRS yielded MR estimates with narrower confidence intervals, providing strong evidence that the true causal effect on adolescent adiposity is smaller than the MV estimates ( P difference = 0.001 for 15-year BMI). This suggests that the MV estimates are affected by residual confounding, therefore do not provide an accurate indication of the causal effect size. Our results suggest that higher maternal pre-/early-pregnancy BMI is not a key driver of higher adiposity in the next generation. Thus, they support interventions that target the whole population for reducing overweight and obesity, rather than a specific focus on women of reproductive age.
Publisher: Oxford University Press (OUP)
Date: 09-06-2022
DOI: 10.1093/IJE/DYAC121
Abstract: Coffee consumption has been associated with several adverse pregnancy outcomes, although data from randomized–controlled trials are lacking. We investigate whether there is a causal relationship between coffee consumption and miscarriage, stillbirth, birthweight, gestational age and pre-term birth using Mendelian randomization (MR). A two-s le MR study was performed using summary results data from a genome-wide association meta-analysis of coffee consumption (N = 91 462) from the Coffee and Caffeine Genetics Consortium. Outcomes included self-reported miscarriage (N = 49 996 cases and 174 109 controls from a large meta-analysis) the number of stillbirths [N = 60 453 from UK Biobank (UKBB)] gestational age and pre-term birth (N = 43 568 from the 23andMe, Inc cohort) and birthweight (N = 297 356 reporting own birthweight and N = 210 248 reporting offspring’s birthweight from UKBB and the Early Growth Genetics Consortium). Additionally, a one-s le genetic risk score (GRS) analysis of coffee consumption in UKBB women (N up to 194 196) and the Avon Longitudinal Study of Parents and Children (N up to 6845 mothers and 4510 children) and its relationship with offspring outcomes was performed. Both the two-s le MR and one-s le GRS analyses showed no change in risk of sporadic miscarriages, stillbirths, pre-term birth or effect on gestational age connected to coffee consumption. Although both analyses showed an association between increased coffee consumption and higher birthweight, the magnitude of the effect was inconsistent. Our results suggest that coffee consumption during pregnancy might not itself contribute to adverse outcomes such as stillbirth, sporadic miscarriages and pre-term birth or lower gestational age or birthweight of the offspring.
Publisher: Springer Science and Business Media LLC
Date: 25-11-2020
DOI: 10.1038/S41467-020-19733-6
Abstract: Preecl sia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preecl sia in the maternal genome at ZNF831 /20q13 and FTO /16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM /3q26, FGF5 /4q21 and SH2B3 /12q24 also associate with preecl sia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preecl sia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preecl sia.
Publisher: Wiley
Date: 12-03-2020
DOI: 10.1002/JBMR.3989
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Maria Carolina Borges.