Maternal central obesity and birth size: a Mendelian randomization analysis

The correlation between obesity and primary open-angle glaucoma (POAG) has not yet been fully established. The aim of this study was to investigate the causal relationship between obesity and POAG by a two-sample Mendelian randomization (MR) study. In this study, body mass index (BMI), an index to evaluate general obesity, and waist and hip circumference, indices to evaluate abdominal obesity, were selected as exposures in MR analysis. Single-nucleotide polymorphisms (SNPs) were chosen as instrumental variables (IVs). Summary data from genome-wide association studies (GWASs) based on a European ancestry by Locke et al., with regard to BMI, and Shungin et al., with regard to waist and hip circumference, were used. Genetic predictors of POAG were obtained from public GWAS summary data. To assess the causal effect of obesity on POAG, the inverse variance-weighted (IVW) method was used as the primary method, and other methods, such as MR–Egger, weighted median, simple mode, and weighted mode, were also used as complementary analyses. Finally, we performed Cochran’s Q statistic to assess heterogeneity, and sensitivity analysis was performed to evaluate the reliability and stability of the MR results. MR analysis showed that BMI has a positive effect on the risk of POAG, with 1 standard deviation (SD) increase in BMI; the risk of POAG increases by approximately 90.9% [OR = 1.909; 95% CI= (1.225, 2.975); p = 0.0042)] (analyzed by IVW); there were no heterogeneity and pleiotropy in the result; and waist circumference also had a positive effect on the risk of POAG [OR = 2.319; 95% CI= (1.071, 5.018); p = 0.033)] analyzed by weighted median. As hip circumference increases, with 1 SD increase in hip circumference, the risk of POAG increases by approximately 119% [OR = 2.199; 95% CI= (1.306, 3.703); p = 0.00305)] estimated by IVW, there were not heterogeneity and pleiotropy as for the result. Our study for the first time confirms that obesity might increase the risk of POAG using two-sample MR analysis. These results might provide guidance on the prevention and treatment of POAG.

Preterm birth has been associated with an increased risk of myopia, but the causal relationship between these two factors remains unclear. Traditional epidemiological studies are limited by confounding factors and reverse causality. Mendelian randomization (MR) analysis, utilizing genetic variants as instrumental variables, provides a robust approach to investigate causal relationships. In this study, we aimed to explore the potential causal link between preterm birth and myopia risk using a two-sample MR analysis strategy. We conducted a Mendelian randomization study to investigate the causal relationship between preterm birth and myopia risk. Genetic variants (single nucleotide polymorphisms, SNPs) were used as instrumental variables, and summary data from genome-wide association studies (GWAS) were utilized. Four regression models, including MR-Egger regression, weighted median regression, inverse variance weighted regression, and Weighted mode regression, were employed to validate the causal relationship. Sensitivity analysis was performed using the leave-one-out method. At the same time, the funnel diagram and MR-Egger test were used to judge the stability of the research results. The MR analysis revealed a significant causal effect of preterm birth on myopia risk. Both the inverse variance weighted regression and weighted median regression models showed a p-value less than 0.05, indicating a robust association. The risk of myopia increased by approximately 30% for everyone standard deviation increase in preterm birth. Sensitivity analysis, funnel plot and MR-Egger test all confirm the stability of the research results. Our findings provide evidence supporting a causal relationship between preterm birth and myopia risk. Preterm infants are at a higher risk of developing myopia, and this association is not likely to be influenced by confounding factors or reverse causality. The SNP loci rs6699397, rs10871582, and rs2570497 should be closely monitored as they may lead to abnormal concentrations of intraocular cytokines, particularly vascular endothelial growth factor, potentially elucidating one of the pathogenic mechanisms contributing to the higher incidence of myopia in preterm infants. However the complex interconnections involved extend beyond these factors alone.

Association of maternal arsenic exposure with birth size: A systematic review and meta-analysis

BackgroundThe scientific literature poses a perplexing dilemma for pregnant women with respect to the consumption of fish from natural bodies of water. On one hand, fish is a good source of protein, low in fat and a rich source of other nutrients all of which have presumably beneficial effects on developing embryos and fetuses. On the other hand, consumption of fish contaminated with environmental toxicants such as polychlorinated biphenyls (PCBs) has been associated with decrements in gestation and birth size.Methods2,716 infants born between 1986–1991 to participants of the New York State Angler Cohort Study were studied with respect to duration of maternal consumption of contaminated fish from Lake Ontario and its tributaries and gestation and birth size. Hospital delivery records (maternal and newborn) were obtained for 92% of infants for the ascertainment of gestation (weeks), birth size (weight, length, chest, and head circumference) and other known determinants of fetal growth (i.e., maternal parity, history of placental infarction, uterine bleeding, pregnancy loss or cigarette smoking and infant's race, sex and presence of birth defect). Duration of maternal fish consumption prior to the index infant's birth was categorized as: none; 1–2, 3–7, 8+ years, while birth weight (in grams), birth length (in centimeters), and head and chest circumference (in centimeters) were left as continuous variables in multiple linear regression models. Birth size percentiles, ponderal indices and head to chest circumference ratios were computed to further assess proportionality and birth size in relation to gestational age.ResultsAnalysis of variance failed to identify significant mean differences in gestation or any measure of birth size in relation to duration of maternal lifetime fish consumption. Multiple linear regressions identified gestational age, male sex, number of daily cigarettes, parity and placental infarction, as significant determinants of birth size.ConclusionsThe results support the absence of an adverse relation between Lake Ontario fish consumption and reduced birth size as measured by weight, length and head circumference. Biological determinants and maternal cigarette smoking during pregnancy remain important determinants of birth size.

Background: Adiposity is closely related to osteoarthritis, but the causal effects of different types of adiposity on osteoarthritis are indistinct. This study conducted a Mendelian Randomization (MR) analysis for the causal effects of general adiposity and abdominal adiposity on knee osteoarthritis (KOA) and hip osteoarthritis (HOA). Methods: The general adiposity was assessed by body mass index (BMI), while the abdominal adiposity was evaluated with waist circumference (WC), hip circumference (HC), and waist-to-hip ratio (WHR). The data used in this two-sample MR analysis originated from genome-wide association studies (GWAS). Significant (p < 5 × 10−8) and independent (r2 < 0.01) single-nucleotide polymorphisms were selected as instrumental variables for the MR analysis. Subsequently, this study used the inverse variance weighted, weighted median, and other methods for the causal inference, and the results were presented as odds ratios (OR). Moreover, sensitivity analyses were conducted to assess the stability and reliability of the results. Results: The MR results revealed positive causal effects of BMI on KOA (OR: 1.694; 95% CI: from 1.492 to 1.923; p = 3.96 × 10−16) and HOA (OR: 1.412; 95% CI: from 1.196 to 1.666; p = 4.58 × 10−5). Additionally, WC and HC both positively and causally related to KOA (WC: OR: 1.827; 95% CI: from 1.564 to 2.134; p = 2.68 × 10−14; HC: OR: 1.610; 95% CI: from 1.357 to 1.912; p = 5.03 × 10−8) and HOA (WC: OR: 1.491; 95% CI: from 1.254 to 1.772; p = 5.85 × 10−6; HC: OR: 1.439; 95% CI: from 1.205 to 1.719; p = 5.82 × 10−5). However, no causal relationship existed between WHR and obesity. These results were robust according to the sensitivity analyses. Conclusions: This study indicated that both general and abdominal obesity had positive causal effects on knee osteoarthritis and hip osteoarthritis.

Smoking, alcohol consumption, and age at onset of Huntington's disease: a Mendelian randomization study

Pernicious anaemia (PA) is characterised by vitamin B12 deficiency due to autoimmune-mediated destruction of gastric parietal cells and the consequent loss of intrinsic factor, a specific transporter for the intestinal uptake of vitamin B12. The aetiology of PA remains largely unknown, although genetic and environmental factors have been proposed to underpin the onset of PA(1). A significant proportion of PA patients exhibit iron deficiency, with approximately 50% of PA patients presenting with it before or at diagnosis and 61% subsequently, suggesting an association between the two(2). However, findings from traditional epidemiological studies are subject to confounding and reverse causality. For instance, these associations do not clarify whether iron deficiency contributes to the development of PA or is a consequence of the disease process. Given the profound prevalence of iron deficiency at diagnosis, we hypothesised that reduced iron levels may play a causal role in the onset of PA. We used a Mendelian randomisation (MR) approach to test the causal relationship between iron status and PA.MR leverages the naturally randomised allocation of genetic variants among the population as instrumental variables to gauge the causal effect of an exposure on an outcome of interest(3). We conducted two-sample MR analyses to assess the association between genetically predicted iron levels and PA risk. We obtained genetic association data on iron status from the deCODE study(4). PA genetic association data was sourced from the R10 release of Finngen as our main analysis. The participant data consisted of 3,694 cases of PA and 393,684 controls. Our primary MR analysis method was the inverse-variance weighted approach with additional sensitivity analyses, including leave-one-out, Egger and weighted median analyses.Four single nucleotide polymorphisms (SNPs) were strongly associated with systemic iron status and used as genetic instruments to proxy iron status in two-sample MR analyses. We found that genetically predicted higher iron status was not significantly associated with risk of PA (odds ratio per 1 standard deviation increase in serum iron: 1.12, 95% confidence interval 0.80 to 1.57, P = 0.49). Sensitivity analyses had consistent results, indicating that MR assumptions were not violated and that no single SNP drove the association.This is the first study to test the hypothesis that iron deficiency is causally associated with an increased risk of PA. Our results show that genetically predicted lower iron levels were not associated with an increased risk of PA among individuals of Finnish ancestry. Further investigation is required to understand the manifestation of iron deficiency in PA. Iron deficiency may only be a consequence of PA due to the loss of parietal cells, which produce hydrochloric acid necessary for iron absorption. The frequent presence of iron deficiency before or at diagnosis may also reflect delays in diagnosing PA.

To investigate the possible association between birth size and cord concentrations of some organochlorine compounds (OCs), including 4,4'-dichlorodiphenyltrichloroethane (DDT), 4,4'-1,1-dichloro-2,2-bis(p-dichlorodiphenyl)ethylene (DDE), hexachlorobenzene (HCB), β-hexachlorocyclohexane (β-HCH), 4 polychlorinated biphenyl (PCB) congeners (118, 138, 153, and 180), and their sum (ΣPCBs) in a birth cohort in Valencia, Spain. A total of 494 mothers and their newborns (born 2003-2006) participated in the study. Multivariate linear regression analyses were performed between birth weight, length, or head circumference and OC concentrations. Median concentrations of 4,4'-DDT, 4,4'-DDE, HCB, β-HCH, and ΣPCBs were 0.02, 0.46, 0.22, 0.09, and 0.35 ng/mL, respectively. For birth weight there was a significant decrease of 63 and 107 g for each 10-fold increase in cord serum 4,4'-DDT and 4,4'-DDE concentrations, and a marginally significant decrease of 79 and 53 g for each 10-fold increase in HCB and β-HCH concentrations. A significant decrease of 0.39 cm in birth length was found for each 10-fold increase in HCB concentrations. For newborns with cord 4,4'-DDT concentrations above the median there was a significant decrease of 0.26 cm in birth head circumference. These results reveal that prenatal exposure to some OCs could impair the anthropometric development of the fetus, reducing the birth weight, length, and head circumference.

BackgroundAs the number of COVID-19 deaths continues to rise worldwide, the identification of risk factors for the disease is an urgent issue, and it remains controversial whether atherogenic lipid-related traits including serum apolipoprotein B, low-density lipoprotein (LDL)-cholesterol, and triglyceride levels, are risk factors. The aim of this study was to estimate causal effects of lipid-related traits on COVID-19 risk in the European population using a two-sample Mendelian randomization (MR) approach.MethodsWe used summary statistics from a genome-wide association study (GWAS) that included 441,016 participants from the UK Biobank as the exposure dataset of lipid-related traits and from COVID-19 Host Genetics Initiative GWAS meta-analyses of European ancestry as the outcome dataset for COVID-19 susceptibility (32,494 cases and 1,316,207 controls), hospitalization (8316 cases and 1,549,095 controls), and severity (4792 cases and 1,054,664 controls). We performed two-sample MR analyses using the inverse variance weighted (IVW) method. As sensitivity analyses, the MR-Egger regression, weighted median, and weighted mode methods were conducted as were leave-one-out sensitivity analysis, the MR-PRESSO global test, PhenoScanner searches, and IVW multivariable MR analyses. A P value below 0.0055 with Bonferroni correction was considered statistically significant.ResultsThis MR study suggested that serum apolipoprotein B or LDL-cholesterol levels were not significantly associated with COVID-19 risk. On the other hand, we inferred that higher serum triglyceride levels were suggestively associated with higher risks of COVID-19 susceptibility (odds ratio [OR] per standard deviation increase in lifelong triglyceride levels, 1.065; 95% confidence interval [CI], 1.001–1.13; P = 0.045) and hospitalization (OR, 1.174; 95% CI, 1.04–1.33; P = 0.012), and were significantly associated with COVID-19 severity (OR, 1.274; 95% CI, 1.08–1.50; P = 0.004). Sensitivity and bidirectional MR analyses suggested that horizontal pleiotropy and reverse causation were unlikely.ConclusionsOur MR study indicates a causal effect of higher serum triglyceride levels on a greater risk of COVID-19 severity in the European population using the latest and largest GWAS datasets to date. However, as the underlying mechanisms remain unclear and our study might be still biased due to possible horizontal pleiotropy, further studies are warranted to validate our findings and investigate underlying mechanisms.

Causal association between 25-Hydroxyvitamin D and risk of abnormal spermatozoa: A bidirectional Mendelian randomization study

BackgroundThe causal effects of plasma lipid concentrations and the risk of primary open angle glaucoma (POAG) are still unclear. Thus, the purpose of this study was to identify, applying a two-sample Mendelian randomization (MR) analysis, whether plasma lipid concentrations are causally associated with the risk of POAG.MethodsTwo-sample MR analysis of data from a genome-wide association study (GWAS) was performed to investigate the causal role of plasma lipid levels and POAG. A total of 185 independent single-nucleotide polymorphisms (SNPs) associated with plasma lipid levels were selected as instrumental variables (IVs). The SNPs were obtained from a meta-analysis of GWAS based on 188,577 European-ancestry individuals for MR analyses. Association with POAG for the SNPs was obtained from a GWAS conducted among the United Kingdom (UK) Biobank study participants with a total of 463,010 European-ancestry individuals. Four MR methods (inverse variance weighted [IVW], weighted mode, weighted median, and MR-Egger regression) were applied to obtain the overall causal estimate for multiple, instrumental SNPs.ResultsUsing the IVW analysis method, no evidence was found to support a causal association between plasma LDL-C level and POAG risk (β = − 0.00026; 95% CI = -0.00062, 0.00011; P = 0.165) with no significant heterogeneity among SNPs. The overall causal estimate between plasma LDL-C level and POAG was consistent using the other three MR methods. Using the four MR methods, no evidence of an association between plasma HDL-C (β = 0.00023; 95% CI = -0.00015, 0.00061; P = 0.238; IVW method) or TG levels (β = − 0.00028; 95% CI = -0.00071, 0.00015; P = 0.206; IVW method) and POAG risk was found. Sensitivity analyses did not reveal any sign of directional pleiotropy.ConclusionsThe present study did not find any evidence for a causal association between plasma lipid levels and POAG risk. Further research is needed to elucidate the potential biological mechanisms to provide a reasonable interpretation for these results.

Iron levels imbalances are linked to cardiovascular outcomes. We aimed to assess the association between genetically predicted lifelong higher iron levels and cardiovascular outcomes, employing a two-sample Mendelian randomization (MR) approach to account for confounding biases. We used a study involving 257 953 subjects across six cohort studies that identified genetic variants consistently associated with iron biomarkers, including ferritin, serum iron, total iron binding capacity (TIBC), and transferrin saturation (TSAT). The UK Biobank study was used to investigate the association between the same genetic variants and left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), left ventricular ejection fraction (LVEF), left ventricular mass (LVM), and left ventricular mass-to-end-diastolic volume ratio (LVMVR). Two-sample MR approach was used in our main analysis. Heterogeneity, pleiotropy, bidirectional MR, MR-Egger, weighted median, and weighted mode were explored in the sensitivity analysis. One standard deviation (SD) increase in genetically predicted serum iron levels was associated with lower LVEDV (beta (95%CI): -0.11, (-0.19, -0.03), P-value = 0.006) and lower LVESV (-0.11 (-0.19, -0.03), P-value = 0.007). Moreover, one SD increase in genetically predicted TSAT was associated with higher LVMVR (0.09, (0.03, 0.15), P-value = 0.005). Heterogeneity, pleiotropy, and bidirectional effects were not observed. The identified associations were explained by HFE, TMPRSS6, TF, and TFR2 genes. No other associations were identified between iron biomarkers and cardiovascular outcomes. Our study provides MR evidence that iron status may alter cardiovascular function and structure. HFE, TMPRSS6, TF and TFR2 genes play a crucial role in the identified associations.

The influence of birth weight and length on bone mineral density and content later in life is unclear, especially in adolescence. This study evaluated the impact of birth weight and length on bone mineral density and content among adolescents. We included 961 participants from the population-based Fit Futures study (2010-2011). Dual-energy X-ray absorptiometry (DXA) was used to measure bone mineral density (BMD) and bone mineral content (BMC) at femoral neck (FN), total hip (TH) and total body (TB). BMD and BMC measures were linked with birth weight and length ascertained from the Medical Birth Registry of Norway. Linear regression models were used to investigate the influence of birth parameters on BMD and BMC. Birth weight was positively associated with BMD-TB and BMC at all sites among girls; standardized β coefficients [95% CI] were 0.11 [0.01, 0.20] for BMD-TB and 0.15 [0.06, 0.24], 0.18 [0.09, 0.28] and 0.29 [0.20, 0.38] for BMC-FN, TH and TB, respectively. In boys, birth weight was positively associated with BMC at all sites with estimates of 0.10 [0.01, 0.19], 0.12 [0.03, 0.21] and 0.15 [0.07, 0.24] for FN, TH and TB, respectively. Corresponding analyses using birth length as exposure gave significantly positive associations with BMC at all sites in both sexes. The significant positive association between birth weight and BMC-TB in girls, and birth length and BMC-TB in boys remained after multivariable adjustment. We found a positive association between birth size and BMC in adolescence. However, this association was attenuated after adjustment for weight, height and physical activity during adolescence.

IntroductionAppropriate levels of physical activity (PA) can help prevent osteoarthritis (OA) and alleviate its symptoms. However, excessive or prolonged PA has been identified as a potential risk factor for OA. Despite these observations, the genetic causal relationship between PA and OA remains unclear. Therefore, this study aimed to clarify the causal link between PA and OA by investigating their shared genetic factors.Material and methodsThe study utilized genome-wide association study (GWAS) summary data to investigate the relationship between three types of PA – moderate to vigorous physical activity (MVPA), vigorous physical activity (VPA) and strenuous sports or other exercises (SSOE) – and knee osteoarthritis (KOA). A two-sample Mendelian randomization (MR) analysis was conducted using the TwoSampleMR and MRPRESSO packages in R. Sensitivity analyses were performed. Cochran’s Q statistic and Rucker’s Q statistic were employed to assess heterogeneity. The MR-Egger intercept test was used to evaluate horizontal pleiotropy. Additionally, the MR pleiotropy residual sum and outlier (MR-PRESSO) method was applied to detect horizontal pleiotropy and identify outlier SNPs. A leave-one-out analysis was conducted to determine whether the genetic associations were influenced by any single nucleotide polymorphism (SNP). The MR robust adjusted profile score (MR-RAPS) method was further used to validate the normal distribution of the MR analysis.ResultsThe results of the MR analysis indicate that MVPA (p = 0.436, odds ratio [OR] = 1.814, 95% confidence interval [CI] [0.405–8.119]), VPA (p = 0.995, OR = 1.011, 95% CI [0.040–25.224]) and SSOE (p = 0.266, OR = 0.258, 95% CI [0.024–2.812]) have no significant genetic causal relationship with KOA. We did not detect any heterogeneity or horizontal pleiotropy (p > 0.05), nor were there any outliers in our MR analysis. Our MR results were not driven by a single SNP and were normally distributed (p > 0.05).ConclusionsThe results of this study provide evidence against a genetic causal relationship between PA and KOA, thereby contributing to the understanding of their correlation. However, the study does not rule out the possibility of a relationship through non-genetic mechanisms.

BackgroundVenous thromboembolism (VTE) is still one of the most severe health issues, increasing mortality and lengthening hospital stays. Different abundances of gut microbiota have been clinically linked to VTE and coagulopathy. However, whether gut microbiota affected VTE formation remained uncertain.MethodsThe causative links between VTE and 211 gut microbiota at phylum, class, order, family and genus level were separately investigated using two-sample Mendelian Randomization (MR) analysis. Firstly, single nucleotide polymorphisms (SNPs) locus-wide significantly (P < 1.0 × 10− 5) related with gut microbiome abundance were extracted from large genome-wide analysis (GWAS) meta-analysis summary data. Instrumental variables (IVs) without pleiotropy were selected using the PhenoScanner and MR PRESSO test. Then, the MR analysis was implemented using the inverse variance weighted (IVW) method. Moreover, weighted median method, MR Egger method, simple median method and MR PRESSO were conducted to validate the causal associations. The reliability of the results was also assessed utilizing various sensitivity analyses, reverse MR analysis and multivariate Mendelian Randomization analysis (MVMR).ResultsWe found the phylum Firmicutes was robustly protective against VTE with MR analysis. Moreover, five taxa of Actinobacteria phylum (Bifidobacteriales order, Actinomycetales order, Bifidobacteriaceae family, Actinomycetaceae family, Slackia genus) and two taxa of Firmicutes phylum (Bacillales order, Lachnospiraceae UCG-010 genus) were suggestively protective for VTE. While three taxa of Firmicutes phylum (Bacilli class, Lactobacillales order and Lactococcus genus) might suggestively increase the risk of VTE. Sensitivity analyses indicated no significant horizontal pleiotropy, heterogeneity, or reverse causal associations. Furthermore, MVMR analysis unveiled independently positive causal association of Firmicutes phylum and Lachnospiraceae UCG-010 genus with risk of VTE.ConclusionTwo taxa of gut microbes (Firmicutes phylum and Lachnospiraceae UCG-010 genus) were independently protective against VTE, which suggests a potential avenue for developing new cost-effective strategies with minor side effects for VTE prevention and treatment.