ORCID Profile
0000-0001-7088-0777
Current Organisation
University of South Australia
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Publisher: Elsevier BV
Date: 05-2021
Publisher: Springer Science and Business Media LLC
Date: 09-10-2018
Publisher: Elsevier BV
Date: 09-2020
Publisher: Cambridge University Press (CUP)
Date: 29-11-2020
DOI: 10.1017/S0007114519003076
Abstract: Excessive Ca intakes have been proposed to associate with vascular calcification and a higher risk of prostate cancer. We investigated the associations of supplemental and dietary Ca intake with mortality using data from 497 828 UK Biobank participants. The average follow-up was 4·2 years and 14 255 participants died, 8297 from cancer, 2959 from CVD and 572 from respiratory disease. The use of Ca supplements and milk consumption were associated with differences in mortality in younger (≤65 years) but not in older participants ( years, P interaction ≤ 0·04 for all comparisons). Among participants years, there was an inverse association between Ca supplementation (OR 0·91, 95 % CI 0·83, 0·99) and milk consumption (OR 0·93, 95 % CI 0·86, 1·00) with respect to all-cause mortality. In the same age group, milk drinkers had lower odds of cancer mortality (OR 0·89, 95 % CI 0·80, 0·98) but Ca supplement use was associated with increased odds of respiratory mortality (OR 1·69, 95 % CI 1·16, 2·74). All associations in participants aged ≥65 years were null after full adjustment. In sensitivity analyses stratified by hormone replacement therapy, Ca supplement use was associated with decreased odds of cancer mortality in users but increased risk in other women (OR 0·81, 95 % CI 0·69, 0·94 v . OR 1·17, 95 % CI 1·01, 1·35, respectively). To conclude, we saw little evidence for harm with dietary or supplemental Ca. Further studies are required to confirm the proposed interaction with hormone replacement therapy and to exclude reverse causation as a determinant in the association between Ca supplements and increased risk of respiratory diseases.
Publisher: Springer Science and Business Media LLC
Date: 24-05-2021
DOI: 10.1038/S41366-021-00841-2
Abstract: High milk intake has been associated with cardio-metabolic risk. We conducted a Mendelian Randomization (MR) study to obtain evidence for the causal relationship between milk consumption and cardio-metabolic traits using the lactase persistence ( LCT -13910 C T, rs4988235) variant as an instrumental variable. We tested the association of LCT genotype with milk consumption (for validation) and with cardio-metabolic traits (for a possible causal association) in a meta-analysis of the data from three large-scale population-based studies (1958 British Birth Cohort, Health and Retirement study, and UK Biobank) with up to 417,236 participants and using summary statistics from consortia meta-analyses on intermediate traits ( N = 123,665–697,307) and extended to cover disease endpoints ( N = 86,995–149,821). In the UK Biobank, carriers of ‘T’ allele of LCT variant were more likely to consume milk ( P = 7.02 × 10 −14 ). In meta-analysis including UK Biobank, the 1958BC, the HRS, and consortia-based studies, under an additive model, ‘T’ allele was associated with higher body mass index (BMI) ( P meta-analysis = 4.68 × 10 −12 ) and lower total cholesterol (TC) ( P = 2.40 × 10 −36 ), low-density lipoprotein cholesterol (LDL-C) ( P = 2.08 × 10 −26 ) and high-density lipoprotein cholesterol (HDL-C) ( P = 9.40 × 10 −13 ). In consortia meta-analyses, ‘T’ allele was associated with a lower risk of coronary artery disease (OR:0.86, 95% CI:0.75–0.99) but not with type 2 diabetes (OR:1.06, 95% CI:0.97–1.16). Furthermore, the two-s le MR analysis showed a causal association between genetically instrumented milk intake and higher BMI ( P = 3.60 × 10 −5 ) and body fat (total body fat, leg fat, arm fat and trunk fat P 1.37 × 10 −6 ) and lower LDL-C ( P = 3.60 × 10 −6 ), TC ( P = 1.90 × 10 −6 ) and HDL-C ( P = 3.00 × 10 −5 ). Our large-scale MR study provides genetic evidence for the association of milk consumption with higher BMI but lower serum cholesterol levels. These data suggest no need to limit milk intakes with respect to cardiovascular disease risk, with the suggested benefits requiring confirmation in further studies.
Publisher: American College of Physicians
Date: 11-2022
DOI: 10.7326/M21-3324
Publisher: Springer Science and Business Media LLC
Date: 22-05-2017
DOI: 10.1038/S41598-017-01977-W
Abstract: Observational studies on smoking and risk of hay fever and asthma have shown inconsistent results. However, observational studies may be biased by confounding and reverse causation. Mendelian randomization uses genetic variants as markers of exposures to examine causal effects. We examined the causal effect of smoking on hay fever and asthma by using the smoking-associated single nucleotide polymorphism (SNP) rs16969968/rs1051730. We included 231,020 participants from 22 population-based studies. Observational analyses showed that current vs never smokers had lower risk of hay fever (odds ratio (OR) = 0·68, 95% confidence interval (CI): 0·61, 0·76 P 0·001) and allergic sensitization (OR = 0·74, 95% CI: 0·64, 0·86 P 0·001), but similar asthma risk (OR = 1·00, 95% CI: 0·91, 1·09 P = 0·967). Mendelian randomization analyses in current smokers showed a slightly lower risk of hay fever (OR = 0·958, 95% CI: 0·920, 0·998 P = 0·041), a lower risk of allergic sensitization (OR = 0·92, 95% CI: 0·84, 1·02 P = 0·117), but higher risk of asthma (OR = 1·06, 95% CI: 1·01, 1·11 P = 0·020) per smoking-increasing allele. Our results suggest that smoking may be causally related to a higher risk of asthma and a slightly lower risk of hay fever. However, the adverse events associated with smoking limit its clinical significance.
Publisher: Springer Science and Business Media LLC
Date: 20-06-2013
DOI: 10.1038/JHH.2013.51
Abstract: There are fetal sex-specific differences in the balance between angiotensin (Ang) II and Ang-(1-7) in the maternal circulation during pregnancy. To determine whether at 15 weeks' gestation plasma levels of Ang II and Ang-(1-7), as well as levels of prorenin and Ang-converting enzyme (ACE), predicted the development of gestational hypertension (GH) or preecl sia (PreE) and were associated with estimates of fetal and maternal health, women who later developed GH (n=50) or PreE (n=50) were compared with body mass index-matched controls (n=100). Women who subsequently developed PreE or GH had increased Ang-(1-7) levels at 15 weeks' gestation compared with women with normal pregnancies. When separated by fetal sex, this difference was seen only in women carrying a female fetus. Prorenin and ACE concentrations were not useful biomarkers for the prediction of either PreE or GH at 15 weeks' gestation. Women with a male fetus who developed PreE and women who subsequently developed GH had increased blood pressures at 15 weeks' gestation compared with women with normal pregnancies, suggesting that these women were on an early trajectory for the development of hypertension. We propose that measurement of Ang-(1-7) during early gestation could be useful in predicting, those women who will go on to develop new-onset hypertension in pregnancy.
Publisher: Elsevier BV
Date: 09-2014
Publisher: Oxford University Press (OUP)
Date: 05-12-2021
DOI: 10.1093/EURHEARTJ/EHAB809
Abstract: Low vitamin D status is associated with a higher risk for cardiovascular diseases (CVDs). Although most existing linear Mendelian randomization (MR) studies reported a null effect of vitamin D on CVD risk, a non-linear effect cannot be excluded. Our aim was to apply the non-linear MR design to investigate the association of serum 25-hydroxyvitamin D [25(OH)D] concentration with CVD risk. The non-linear MR analysis was conducted in the UK Biobank with 44 519 CVD cases and 251 269 controls. Blood pressure (BP) and cardiac-imaging-derived phenotypes were included as secondary outcomes. Serum 25(OH)D concentration was instrumented using 35 confirmed genome-wide significant variants. We also estimated the potential reduction in CVD incidence attributable to correction of low vitamin D status. There was a L-shaped association between genetically predicted serum 25(OH)D and CVD risk (P non-linear = 0.007), where CVD risk initially decreased steeply with increasing concentrations and levelled off at around 50 nmol/L. A similar association was seen for systolic (P non-linear = 0.03) and diastolic (P non-linear = 0.07) BP. No evidence of association was seen for cardiac-imaging phenotypes (P = 0.05 for all). Correction of serum 25(OH)D level below 50 nmol/L was predicted to result in a 4.4% reduction in CVD incidence (95% confidence interval: 1.8– 7.3%). Vitamin D deficiency can increase the risk of CVD. Burden of CVD could be reduced by population-wide correction of low vitamin D status.
Publisher: Cold Spring Harbor Laboratory
Date: 05-06-2020
DOI: 10.1101/2020.06.04.20121061
Abstract: Substantial genetic correlations have been reported across psychiatric disorders and numerous cross-disorder genetic variants have been detected. To identify the genetic variants underlying general psychopathology in childhood, we performed a genome-wide association study using a total psychiatric problem score. We analyzed 6,844,199 common SNPs in 38,418 school-aged children from 20 population-based cohorts participating in the EArly Genetics and Lifecourse Epidemiology (EAGLE) consortium. The SNP heritability of total psychiatric problems was 5.4% (SE=0.01) and two loci reached genome-wide significance: rs10767094 and rs202005905. We also observed an association of SBF2 , a gene associated with neuroticism in previous GWAS, with total psychiatric problems. The genetic effects underlying the total psychiatric problem score were shared with known genetic variants for common psychiatric disorders only (attention-deficit/hyperactivity disorder, anxiety, depression, insomnia) (r G 0.49), but not with autism or the less common adult disorders (schizophrenia, bipolar disorder, or eating disorders) (r G 0.01). Importantly, the total psychiatric problem score also showed at least a moderate genetic correlation of with intelligence, educational attainment, wellbeing, smoking, and body fat (r G 0.29).The results suggest that many common genetic variants are associated with childhood psychiatric symptoms and related phenotypes in general instead of with specific symptoms. Further research is needed to establish causality and pleiotropic mechanisms between psychiatric disorders and related traits.
Publisher: Hindawi Limited
Date: 14-10-2019
DOI: 10.1002/DA.22963
Abstract: This study aimed to explore the association between depression and body mass index (BMI), and to investigate whether genetic susceptibility to high BMI is different among in iduals with or without depression. We used data on 251,125 in iduals of white British ancestry from the UK Biobank. We conducted Mendelian randomization (MR) analysis to test for a causal association between depression and BMI using a major depressive disorder (MDD)-related genetic risk score (GRS We found observational and genetic evidence for an association between depression and BMI (MR beta: 0.09, 95% confidence interval [CI] 0.04-0.13). Further, the contribution of genetic risk to high BMI was higher among in iduals with depression compared to controls. Carrying 10 additional BMI increasing alleles was associated with 0.24 standard deviation (SD 95%CI 0.23-0.25) higher BMI among depressed in iduals compared to 0.20 SD (95%CI 0.19-0.21) higher in controls, which corresponds to 3.4 kg and 2.8 kg extra weight for an in idual of average height. Amongst the in idual loci, the evidence for interaction was most notable for a variant near MC4R, a gene known to affect both appetite regulation and the hypothalamic-pituitary adrenal axis (p Genetic predisposition to high BMI was higher among depressed than to nondepressed in iduals. This study provides support for a possible role of MC4R in the link between depression and obesity.
Publisher: Elsevier BV
Date: 06-2021
DOI: 10.1016/J.CLNU.2020.12.042
Abstract: There is evidence that long-term heavy coffee consumption may adversely affect in iduals' cardiovascular disease (CVD) risk. As hyperlipidemia is a well-established contributor to CVD risk, we investigated the association between habitual coffee intake and plasma lipid profile. We used data from up to 362,571 UK Biobank participants to examine phenotypic associations between self-reported coffee intake and plasma lipid profiles, including low-density-lipoproteins cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (total-C), triglycerides, and apolipoproteins A1 and B (ApoA1 and ApoB). Mendelian randomization (MR) analysis using genetically instrumented coffee intake was used to interrogate the causal nature of coffee-lipid associations. We observed a positive dose-dependent association between self-reported coffee intake and plasma concentration of LDL-C, ApoB and total-C, with the highest lipid levels seen among participants reported drinking >6 cups/day (P Our phenotypic and genetic analyses suggest that long-term heavy coffee consumption may lead to unfavourable lipid profile, which could potentially increase in iduals' risk for CVD. These findings may have clinical relevance for people with elevated LDL cholesterol.
Publisher: Elsevier BV
Date: 07-2019
Publisher: Springer Science and Business Media LLC
Date: 26-11-2021
DOI: 10.1038/S41598-021-02476-9
Abstract: We present a simple and efficient hypothesis-free machine learning pipeline for risk factor discovery that accounts for non-linearity and interaction in large biomedical databases with minimal variable pre-processing. In this study, mortality models were built using gradient boosting decision trees (GBDT) and important predictors were identified using a Shapley values-based feature attribution method, SHAP values. Cox models controlled for false discovery rate were used for confounder adjustment, interpretability, and further validation. The pipeline was tested using information from 502,506 UK Biobank participants, aged 37–73 years at recruitment and followed over seven years for mortality registrations. From the 11,639 predictors included in GBDT, 193 potential risk factors had SHAP values ≥ 0.05, passed the correlation test, and were selected for further modelling. Of the total variable importance summed up, 60% was directly health related, and baseline characteristics, sociodemographics, and lifestyle factors each contributed about 10%. Cox models adjusted for baseline characteristics, showed evidence for an association with mortality for 166 out of the 193 predictors. These included mostly well-known risk factors (e.g., age, sex, ethnicity, education, material deprivation, smoking, physical activity, self-rated health, BMI, and many disease outcomes). For 19 predictors we saw evidence for an association in the unadjusted but not adjusted analyses, suggesting bias by confounding. Our GBDT-SHAP pipeline was able to identify relevant predictors ‘hidden’ within thousands of variables, providing an efficient and pragmatic solution for the first stage of hypothesis free risk factor identification.
Publisher: American Medical Association (AMA)
Date: 20-09-2019
Publisher: Oxford University Press (OUP)
Date: 23-04-2013
Publisher: Informa UK Limited
Date: 24-06-2022
Publisher: Oxford University Press (OUP)
Date: 04-11-2022
DOI: 10.1093/PM/PNAC170
Abstract: Depression frequently coexists with chronic pain. Contemporary models suggest that these conditions share pathobiological mechanisms, prompting a need to investigate their temporal association. This investigation aimed to explore two distinctly different chronic pain conditions, and their cross-sectional and prospective associations with depression. Self-reported information was available on chronic widespread pain (CWP), chronic low back pain (CLBP) (45 years), and depression symptoms (45 and 50 years) from up to 9,377 participants in the 1958 British cohort. Depression symptom outcomes were derived by “Clinical Interview Schedule-Revised” (45 years) and “Short Form-36” (50 years). Relationships between both chronic pain conditions and depression symptoms were investigated by fitting four separate logistic regression models, each with varying levels of covariate adjustment, including depression at baseline. CWP was associated with depression symptoms cross-sectionally (odds ratio [OR] = 2.04, 95% confidence interval [CI] 1.65, 2.52 P & 0.001, n = 7,629), and prospectively when fully adjusted for baseline, sociodemographic, lifestyle, and health covariates (OR = 1.45, 95% CI 1.17, 1.80 P = & 0.001, n = 6,275). CLBP was associated with depression symptoms prospectively (full model: OR = 1.28, 95% CI 1.01, 1.61 P = 0.04, n = 6,288). In fully adjusted models the prospective association of CWP with depression symptoms was more heavily influenced by our covariates than CLBP with depression symptoms. Pain may be a stressor from which depression can arise. Development of depression may be differentially dependant upon the type of pain experienced. Screening for depression symptoms among in iduals with both chronic pain conditions is indicated and should be repeated over time.
Publisher: Springer Science and Business Media LLC
Date: 17-09-2018
Publisher: Springer Science and Business Media LLC
Date: 16-10-2017
DOI: 10.1038/S41598-017-13189-3
Abstract: The causal nature of the association between hypovitaminosis D and poor cognitive function in mid- to later-life is uncertain. Using a Mendelian randomisation(MR) approach, we examined the causal relationship between 25(OH)D and cognitive function. Data came from 172,349 participants from 17 cohorts. DHCR7 (rs12785878), CYP2R1 rs12794714) and their combined synthesis score were chosen to proxy 25(OH)D. Cognitive tests were standardised into global and memory scores. Analyses were stratified by 25(OH)D tertiles, sex and age. Random effects meta-analyses assessed associations between 25(OH)D and cognitive function. Associations of serum 25(OH)D with global and memory-related cognitive function were non-linear (lower cognitive scores for both low and high 25(OH)D, p curvature ≤ 0.006), with much of the curvature attributed to a single study. DHCR7 , CYP2R1 , and the synthesis score were associated with small reductions in 25(OH)D per vitamin D-decreasing allele. However, coefficients for associations with global or memory-related cognitive function were non-significant and in opposing directions for DHCR7 and CYP2R1 , with no overall association observed for the synthesis score . Coefficients for the synthesis score and global and memory cognition were similar when stratified by 25(OH)D tertiles, sex and age. We found no evidence for serum 25(OH)D concentration as a causal factor for cognitive performance in mid- to later life.
Publisher: Elsevier BV
Date: 11-2020
Publisher: MDPI AG
Date: 20-10-2022
DOI: 10.3390/NU14204408
Abstract: Twin studies suggest a considerable genetic contribution to the variability in 25-hydroxyvitamin D (25(OH)D) concentrations, reporting heritability estimates up to 80% in some studies. While genome-wide association studies (GWAS) suggest notably lower rates (13–16%), they have identified many independent variants that associate with serum 25(OH)D concentrations. These discoveries have provided some novel insight into the metabolic pathway, and in this review we outline findings from GWAS studies to date with a particular focus on 35 variants which have provided replicating evidence for an association with 25(OH)D across independent large-scale analyses. Some of the 25(OH)D associating variants are linked directly to the vitamin D metabolic pathway, while others may reflect differences in storage capacity, lipid metabolism, and pathways reflecting skin properties. By constructing a genetic score including these 25(OH)D associated variants we show that genetic differences in 25(OH)D concentrations persist across the seasons, and the odds of having low concentrations ( nmol/L) are about halved for in iduals in the highest 20% of vitamin D genetic score compared to the lowest quintile, an impact which may have notable influences on retaining adequate levels. We also discuss recent studies on personalized approaches to vitamin D supplementation and show how Mendelian randomization studies can help inform public health strategies to reduce adverse health impacts of vitamin D deficiency.
Publisher: Springer Science and Business Media LLC
Date: 27-07-2021
DOI: 10.1186/S12937-021-00725-1
Abstract: Multiple observational studies have reported an inverse relationship between 25-hydroxyvitamin D concentrations (25(OH)D) and type 2 diabetes (T2D). However, the results of short- and long-term interventional trials concerning the relationship between 25(OH)D and T2D risk have been inconsistent. To evaluate the causal role of reduced blood 25(OH)D in T2D, here we have performed a bidirectional Mendelian randomization study using 59,890 in iduals (5,862 T2D cases and 54,028 controls) from European and Asian Indian ancestries. We used six known SNPs, including three T2D SNPs and three vitamin D pathway SNPs, as a genetic instrument to evaluate the causality and direction of the association between T2D and circulating 25(OH)D concentration. Results of the combined meta-analysis of eight participating studies showed that a composite score of three T2D SNPs would significantly increase T2D risk by an odds ratio (OR) of 1.24, p = 1.82 × 10 –32 Z score 11.86, which, however, had no significant association with 25(OH)D status (Beta -0.02nmol/L ± SE 0.01nmol/L p = 0.83 Z score -0.21). Likewise, the genetically instrumented composite score of 25(OH)D lowering alleles significantly decreased 25(OH)D concentrations (-2.1nmol/L ± SE 0.1nmol/L, p = 7.92 × 10 –78 Z score -18.68) but was not associated with increased risk for T2D (OR 1.00, p = 0.12 Z score 1.54). However, using 25(OH)D synthesis SNP (DHCR7 rs12785878) as an in idual genetic instrument, a per allele reduction of 25(OH)D concentration (-4.2nmol/L ± SE 0.3nmol/L) was predicted to increase T2D risk by 5%, p = 0.004 Z score 2.84. This effect, however, was not seen in other 25(OH)D SNPs (GC rs2282679, CYP2R1 rs12794714) when used as an in idual instrument. Our new data on this bidirectional Mendelian randomization study suggests that genetically instrumented T2D risk does not cause changes in 25(OH)D levels. However, genetically regulated 25(OH)D deficiency due to vitamin D synthesis gene (DHCR7) may influence the risk of T2D.
Publisher: MDPI AG
Date: 26-11-2021
DOI: 10.3390/NU13124260
Abstract: Several observational studies have examined vitamin D pathway polymorphisms and their association with type 1 diabetes (T1D) susceptibility, with inconclusive results. We aimed to perform a systematic review and meta-analysis assessing associations between selected variants affecting 25-hydroxyvitamin D [25(OH)D] and T1D risk. We conducted a systematic search of Medline, Embase, Web of Science and OpenGWAS updated in April 2021. The following keywords “vitamin D” and/or “single nucleotide polymorphisms (SNPs)” and “T1D” were selected to identify relevant articles. Seven SNPs (or their proxies) in six genes were analysed: CYP2R1 rs10741657, CYP2R1 (low frequency) rs117913124, DHCR7/NADSYN1 rs12785878, GC rs3755967, CYP24A1 rs17216707, AMDHD1 rs10745742 and SEC23A rs8018720. Seven case-control and three cohort studies were eligible for quantitative synthesis (n = 10). Meta-analysis results suggested no association with T1D (range of pooled ORs for all SNPs: 0.97–1.02 p 0.01). Heterogeneity was found in DHCR7/NADSYN1 rs12785878 (I2: 64.8%, p = 0.02). Sensitivity analysis showed exclusion of any single study did not alter the overall pooled effect. No association with T1D was observed among a Caucasian subgroup. In conclusion, the evidence from the meta-analysis indicates a null association between selected variants affecting serum 25(OH)D concentrations and T1D.
Publisher: Elsevier BV
Date: 2012
DOI: 10.1016/J.PLACENTA.2012.10.007
Abstract: This study aimed to determine the association of AGTR1 and AGTR2 polymorphisms with preecl sia and whether these are affected by environmental factors and fetal sex. Overall 3234 healthy nulliparous women, their partners and babies were recruited prospectively to the SCOPE study in Adelaide and Auckland. Data analyses were confined to 2121 Caucasian parent-infant trios, among whom 123 had preecl tic pregnancies. 1185 uncomplicated pregnancies served as controls. DNA was extracted from buffy coats and genotyped by utilizing the Sequenom MassARRAY system. Doppler sonography on the uterine arteries was performed at 20 weeks' gestation. Four polymorphisms in AGTR1 and AGTR2 genes, including AGTR1 A1166C, AGTR2 C4599A, AGTR2 A1675G and AGTR2 T1134C, were selected and significant associations were predominately observed for AGTR2 C4599A. When the cohort was stratified by maternal BMI, in women with BMI ≥ 25 kg/m(2), the AGTR2 C4599A AA genotype in mothers and neonates was associated with an increased risk for preecl sia compared with the CC genotype [adjusted OR 2.1 (95% CI 1.0-4.2) and adjusted OR 3.0 (95% CI 1.4-6.4), respectively]. In the same subset of women, paternal AGTR2 C4599A A allele was associated with an increased risk for preecl sia and uterine artery bilateral notching at 20 weeks' gestation compared with the C allele [adjusted OR 1.9 (95% CI 1.1-3.3) and adjusted OR 2.1 (95% CI 1.3-3.4), respectively]. AGTR2 C4599A in mothers, fathers and babies was associated with preecl sia and this association was only apparent in pregnancies in which the women had a BMI ≥ 25 kg/m(2), suggesting a gene-environment interaction.
Publisher: Springer Science and Business Media LLC
Date: 07-05-2020
Publisher: MDPI AG
Date: 09-06-2023
DOI: 10.3390/NU15122703
Abstract: (1) Background: Observational studies associate vitamin D deficiency with muscle disorders, while some clinical trial data support a minor association between the vitamin and skeletal muscle performance in healthy subjects. Vitamin D receptor knockout mice studies confirm the relationship between vitamin D and skeletal muscle however, causal inference in humans is challenging due to the ethical implications of including vitamin D-deficient participants in randomized trials. This study uses genetic methods to safely explore causal underpinnings for the relationship between 25(OH)D concentrations and skeletal muscle-related traits, including grip strength and combined arm skeletal muscle mass, and extends this analysis to suspected pathophysiology in the form of probable sarcopenia and sarcopenic obesity. (2) Methods: We conducted Mendelian randomization (MR) analyses in up to 307,281 participants from the UK Biobank of whom 25,414 had probable sarcopenia and 16,520 had sarcopenic obesity. In total, 35 variants were used to instrument 25(OH)D and MR analyses conducted using multiple approaches. (3) Results: Genetic analyses provided support for a relationship between genetically predicted higher 25(OH)D and skeletal muscle traits, with linear MR analyses for grip strength showing 0.11 kg (95% CI 0.04, 0.19) greater contractile force per 10 unit higher 25(OH)D, while there was a modest association with skeletal muscle mass (0.01 kg (95% CI 0.003, 0.02) greater muscle mass). For probable sarcopenia risk, there was suggestive evidence for lower odds by higher 25(OH)D (OR 0.96 (95% CI 0.92, 1.00)) however, this did not reflect an association with sarcopenic obesity (OR 0.97 (95% CI 0.93, 1.02)), but was seen in probable sarcopenia cases who were not obese (OR 0.92 (95% CI 0.86, 0.98)). Results were similar across multiple MR approaches. (4) Conclusions: Our study supports a causal relationship between 25(OH)D and skeletal muscle health. While evidence for benefit did not extend to lower risk of sarcopenic obesity, effective vitamin D-deficiency prevention strategies may help reduce age-related muscle weakness.
Publisher: Elsevier BV
Date: 07-2021
DOI: 10.1093/AJCN/NQAB014
Abstract: Excessive coffee consumption can lead to unpleasant sensations such as tachycardia and heart palpitations. Our aim was to investigate if cardiovascular symptoms can lead to alterations in habitual patterns of coffee consumption. We used information from up to 390,435 European ancestry participants in the UK Biobank, aged 39-73 y. Habitual coffee consumption was self-reported, and systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate were measured at baseline. Cardiovascular symptoms at baseline were based on hospital diagnoses, primary care records, and/or self-report. Mendelian randomization (MR) was used to examine genetic evidence for a causal association between SBP, DBP, and heart rate with habitual coffee consumption. Participants with essential hypertension, angina, or heart arrhythmia were all more likely to drink less caffeinated coffee and to be non-habitual or decaffeinated coffee drinkers compared with those who did not report related symptoms (P ≤ 3.5 × 10-8 for all comparisons). Higher SBP and DBP were associated with lower caffeinated coffee consumption at baseline, with consistent genetic evidence to support a causal explanation across all methods [MR-Egger regression (MREggr) β: -0.21 cups/d (95% CI: -0.34, -0.07) per 10 mm Hg higher SBP and -0.33 (-0.61, -0.07) per 10 mm Hg higher DBP)]. In genetic analyses, higher resting heart rate was associated with a greater odds of being a decaffeinated coffee drinker (MREggr OR: 1.71 95% CI: 1.31, 2.21) per 10 beats/min). We provide causal genetic evidence for cardiovascular system-driven influences on habitual coffee intakes, suggesting that people tend to naturally regulate their coffee consumption based on blood pressure levels and heart rate. These findings suggest that observational studies of habitual coffee intakes are prone to influences by reverse causation, and caution is required when inferred health benefits result from comparisons with coffee abstainers or decaffeinated coffee drinkers.
Publisher: Springer Science and Business Media LLC
Date: 08-08-2019
DOI: 10.1007/S00198-019-05118-Z
Abstract: We conducted a phenome-wide Mendelian randomization analysis (MR-PheWAS) to survey health effects associated with high normal serum calcium. We found causal evidence for conditions related to renal function, bone and joint health, and cardiovascular risk. These conditions collectively suggest that tissue calcification may be a key mechanism through which serum calcium influences health. Calcium is essential for the normal functioning of the cardiovascular system, muscles, and nerves. In this MR-PheWAS study, we sought to capture the totality of health effects associated with high normal serum calcium. We used data from up to 337,535 UK Biobank participants, and tested for associations between calcium genetic score (calcium-GS) and 925 disease outcomes, with follow-up analyses using complementary MR methods. Calcium-GS was robustly associated with serum calcium concentration (F statistics = 349). After multiple testing correction (P < 1.62E-4), we saw genetic evidence for an association between high serum calcium and urinary calculus (OR per 1 mg/dl 3.5, 95%CI 1.3-9.2), renal colic (9.1, 95%CI 2.5-33.5), and allergy/adverse effect of penicillin (2.2, 95%CI 1.5-3.3). Secondary analyses with independent replication from consortia meta-analyses suggested further effects on myocardial infarction and osteoarthrosis. We found causal evidence for effects of high normal serum calcium with conditions related to renal function, bone and joint health, and cardiovascular risk, which may collectively reflect influences on tissue calcification and immune function.
Publisher: Springer Science and Business Media LLC
Date: 14-05-2018
DOI: 10.1038/S41598-018-25919-2
Abstract: Coffee’s long-term effect on cognitive function remains unclear with studies suggesting both benefits and adverse effects. We used Mendelian randomization to investigate the causal relationship between habitual coffee consumption and cognitive function in mid- to later life. This included up to 415,530 participants and 300,760 coffee drinkers from 10 meta-analysed European ancestry cohorts. In each cohort, composite cognitive scores that capture global cognition and memory were computed using available tests. A genetic score derived using CYP1A1/2 (rs2472297) and AHR (rs6968865) was chosen as a proxy for habitual coffee consumption. Null associations were observed when examining the associations of the genetic score with global and memory cognition (β = −0.0007, 95% C.I. −0.009 to 0.008, P = 0.87 β = −0.001, 95% C.I. −0.005 to 0.002, P = 0.51, respectively), with high consistency between studies (P heterogeneity 0.4 for both). Domain specific analyses using available cognitive measures in the UK Biobank also did not support effects by habitual coffee intake for reaction time, pairs matching, reasoning or prospective memory (P ≥ 0.05 for all). Despite the power to detect very small effects, our meta-analysis provided no evidence for causal long-term effects of habitual coffee consumption on global cognition or memory.
Publisher: Elsevier BV
Date: 08-2022
DOI: 10.1093/AJCN/NQAC107
Publisher: Elsevier BV
Date: 07-2022
DOI: 10.1016/J.JAAC.2021.11.035
Abstract: To investigate the genetic architecture of internalizing symptoms in childhood and adolescence. In 22 cohorts, multiple univariate genome-wide association studies (GWASs) were performed using repeated assessments of internalizing symptoms, in a total of 64,561 children and adolescents between 3 and 18 years of age. Results were aggregated in meta-analyses that accounted for s le overlap, first using all available data, and then using subsets of measurements grouped by rater, age, and instrument. The meta-analysis of overall internalizing symptoms (INT Genetic correlations indicate that childhood and adolescent internalizing symptoms share substantial genetic vulnerabilities with adult internalizing disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalizing symptoms over time and the high comorbidity among childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood s les will be key in paving the way to future GWAS success.
Publisher: Springer Science and Business Media LLC
Date: 17-01-2018
DOI: 10.1038/S41467-017-02662-2
Abstract: Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci ( GC, NADSYN1/DHCR7, CYP2R1, CYP24A1 ). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery s le size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants ( P = 4.7×10 −9 at rs8018720 in SEC23A , and P = 1.9×10 −14 at rs10745742 in AMDHD1 ). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene–gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.
Publisher: Public Library of Science (PLoS)
Date: 20-06-2019
Publisher: Public Library of Science (PLoS)
Date: 22-08-2022
DOI: 10.1371/JOURNAL.PONE.0273116
Abstract: Substantial genetic correlations have been reported across psychiatric disorders and numerous cross-disorder genetic variants have been detected. To identify the genetic variants underlying general psychopathology in childhood, we performed a genome-wide association study using a total psychiatric problem score. We analyzed 6,844,199 common SNPs in 38,418 school-aged children from 20 population-based cohorts participating in the EAGLE consortium. The SNP heritability of total psychiatric problems was 5.4% (SE = 0.01) and two loci reached genome-wide significance: rs10767094 and rs202005905. We also observed an association of SBF2 , a gene associated with neuroticism in previous GWAS, with total psychiatric problems. The genetic effects underlying the total score were shared with common psychiatric disorders only (attention-deficit/hyperactivity disorder, anxiety, depression, insomnia) (rG 0.49), but not with autism or the less common adult disorders (schizophrenia, bipolar disorder, or eating disorders) (rG 0.01). Importantly, the total psychiatric problem score also showed at least a moderate genetic correlation with intelligence, educational attainment, wellbeing, smoking, and body fat (rG 0.29). The results suggest that many common genetic variants are associated with childhood psychiatric symptoms and related phenotypes in general instead of with specific symptoms. Further research is needed to establish causality and pleiotropic mechanisms between related traits.
Publisher: Elsevier BV
Date: 03-2019
DOI: 10.1093/AJCN/NQY297
Abstract: Coffee is one of the most widely consumed stimulants worldwide and is generally considered to be safe or even beneficial for health. However, increased risk of myocardial infarction and hypertension has been suggested for in iduals who carry a functional variant at cytochrome P450 1A2 (CYP1A2), which makes them less effective at metabolizing caffeine. The aim of this study was to examine if the CYP1A2 genotype or a genetic score for caffeine metabolism (caffeine-GS) modifies the association between habitual coffee consumption and the risk of cardiovascular disease (CVD). Genetic data and information on habitual coffee intake and relevant covariates were available for 347,077 in iduals in the UK Biobank, including 8368 incident CVD cases. We used logistic regression to test for the association between coffee intake and CVD risk, and whether the association varies with CYP1A2 genotype or caffeine-GS. The association between habitual coffee intake and CVD risk was nonlinear, and, compared with participants drinking 1-2 cups/day, the risk of CVD was elevated for nondrinkers, drinkers of decaffeinated coffee, and those who reported drinking >6 cups/day (increase in odds by 11%, 7%, and 22%, respectively, P-curvature = 0.013). CYP1A2 genotype and caffeine-GS were not associated with CVD (P ≥ 0.22 for all comparisons). There was no evidence for an interaction between the CYP1A2 genotype or caffeine-GS and coffee intake with respect to risk of CVD (P ≥ 0.53). Heavy coffee consumption was associated with a modest increase in CVD risk, but this association was unaffected by genetic variants influencing caffeine metabolism.
Publisher: Oxford University Press (OUP)
Date: 17-05-2023
DOI: 10.1093/IJE/DYAC087
Abstract: Low vitamin D status is often associated with systemic low-grade inflammation as reflected by elevated C-reactive protein (CRP) levels. We investigated the causality and direction of the association between vitamin D status and CRP using linear and non-linear Mendelian randomization (MR) analyses. MR analyses were conducted using data from 294 970 unrelated participants of White-British ancestry from the UK Biobank. Serum 25-hydroxyvitamin D [25(OH)D] and CRP concentrations were instrumented using 35 and 46 genome-wide significant variants, respectively. In non-linear MR analysis, genetically predicted serum 25(OH)D had an L-shaped association with serum CRP, where CRP levels decreased sharply with increasing 25(OH)D concentration for participants within the deficiency range (& nmol/L) and levelled off at ∼50 nmol/L of 25(OH)D (Pnon-linear = 1.49E-4). Analyses using several pleiotropy-robust methods provided consistent results in stratified MR analyses, confirming the inverse association between 25(OH)D and CRP in the deficiency range (P = 1.10E-05) but not with higher concentrations. Neither linear or non-linear MR analysis supported a causal effect of serum CRP level on 25(OH)D concentration (Plinear = 0.32 and Pnon-linear = 0.76). The observed association between 25(OH)D and CRP is likely to be caused by vitamin D deficiency. Correction of low vitamin D status may reduce chronic inflammation.
Publisher: Springer Science and Business Media LLC
Date: 19-08-2020
DOI: 10.1038/S41380-019-0486-1
Abstract: Depression affects all aspects of an in idual's life but evidence relating to the causal effects on health is limited. We used information from 337,536 UK Biobank participants and performed hypothesis-free phenome-wide association analyses between major depressive disorder (MDD) genetic risk score (GRS) and 925 disease outcomes. GRS-disease outcome associations passing the multiple-testing corrected significance threshold (P < 1.9 × 10
Publisher: Elsevier BV
Date: 09-2020
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/C9QI01262A
Abstract: A Zn-MOF was constructed by a F-decorated ligand and bipyridyl linkers, displaying selective adsorption for CO 2 , C 2 H 6 , C 2 H 2 over CH 4 , catalysis for CO 2 conversion and selective adsorption for methyl blue.
Publisher: Wiley
Date: 30-10-2018
DOI: 10.1111/ADD.14438
Abstract: To use the rs1229984 variant associated with alcohol consumption as an instrument for alcohol consumption to test the causality of the association of alcohol consumption with hay fever, asthma, allergic sensitization and serum total immunoglobulin (Ig)E. Observational and Mendelian randomization analyses using genetic variants as unbiased markers of exposure to estimate causal effects, subject to certain assumptions. Europe. We included a total of 466 434 people aged 15-82 years from 17 population-based studies conducted from 1997 to 2015. The rs1229984 (ADH1B) was genotyped alcohol consumption, hay fever and asthma were self-reported. Specific and total IgE were measured from serum s les. Observational analyses showed that ever-drinking versus non-drinking, but not amount of alcohol intake, was positively associated with hay fever and inversely associated with asthma but not with allergic sensitization or serum total immunoglobulin (Ig)E. However, Mendelian randomization analyses did not suggest that the observational associations are causal. The causal odds ratio (OR) per genetically assessed unit of alcohol/week was an OR = 0.907 [95% confidence interval (CI) = 0.806, 1.019 P = 0.101] for hay fever, an OR = 0.897 (95% CI = 0.790, 1.019 P = 0.095) for asthma, an OR = 0.971 (95% CI = 0.804, 1.174 P = 0.763) for allergic sensitization and a 4.7% change (95% CI = -5.5%, 14.9% P = 0.366) for total IgE. In observational analyses, ever-drinking versus not drinking was positively associated with hay fever and negatively associated with asthma. However, the Mendelian randomization results were not consistent with these associations being causal.
No related grants have been discovered for Ang Zhou.