Mendelian randomization study of maternal influences on birthweight and future cardiometabolic risk in the HUNT cohort.
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ABSTRACT:
SUBMITTER: Moen GH
PROVIDER: S-EPMC7588432 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundMaternal cardiovascular risk factors have been associated with adverse maternal and fetal outcomes. Given the difficulty in establishing causal relationships using epidemiological data, we applied Mendelian randomization to explore the role of cardiovascular risk factors on risk of developing preeclampsia or eclampsia, and low fetal birthweight.MethodsUncorrelated single-nucleotide polymorphisms associated systolic blood pressure (SBP), body mass index, type 2 diabetes, LDL (low-density lipoprotein) with cholesterol, smoking, urinary albumin-to-creatinine ratio, and estimated glomerular filtration rate at genome-wide significance in studies of 298 957 to 1 201 909 European ancestry participants were selected as instrumental variables. A 2-sample Mendelian randomization study was performed with primary outcome of preeclampsia or eclampsia (PET). Risk factors associated with PET were further investigated for their association with low birthweight.ResultsHigher genetically predicted SBP was associated increased risk of PET (odds ratio [OR] per 1-SD SBP increase 1.90 [95% CI=1.45-2.49]; P=3.23×10-6) and reduced birthweight (OR=0.83 [95% CI=0.79-0.86]; P=3.96×10-18), and this was not mediated by PET. Body mass index and type 2 diabetes were also associated with PET (respectively, OR per 1-SD body mass index increase =1.67 [95% CI=1.44-1.94]; P=7.45×10-12; and OR per logOR increase type 2 diabetes =1.11 [95% CI=1.04-1.19]; P=1.19×10-3), but not with reduced birthweight.ConclusionsOur results provide evidence for causal effects of SBP, body mass index, and type 2 diabetes on PET and identify that SBP is associated with reduced birthweight independently of PET. The results provide insight into the pathophysiological basis of PET and identify hypertension as a potentially modifiable risk factor amenable to therapeutic intervention.
| S-EPMC7612410 | biostudies-literature
Project description:BackgroundDisturbed one-carbon (1-C) metabolism in the mother is associated with poor fetal growth but causality of this relationship has not been established.MethodsWe studied the association between maternal total homocysteine and offspring birthweight in the Pune Maternal Nutrition Study (PMNS, Pune, India) and Parthenon Cohort Study (Mysore, India). We tested for evidence of causality within a Mendelian randomization framework, using a methylenetetrahydrofolatereductase (MTHFR) gene variant rs1801133 (earlier known as 677C→T) by instrumental variable and triangulation analysis, separately and using meta-analysis.ResultsMedian (IQR) homocysteine concentration and mean (SD) birthweight were 8.6 µmol/l (6.7,10.8) and 2642 g (379) in the PMNS and 6.0 µmol/l (5.1,7.1) and 2871 g (443) in the Parthenon study. Offspring birthweight was inversely related to maternal homocysteine concentration-PMNS: -22 g/SD [95% confidence interval (CI): (-50, 5), adjusted for gestational age and offspring gender]; Parthenon: -57 g (-92, -21); meta-analysis: -40 g (-62, -17)]. Maternal risk genotype at rs1801133 predicted higher homocysteine concentration [PMNS: 0.30 SD/allele (0.14, 0.46); Parthenon: 0.21 SD (0.02, 0.40); meta-analysis: 0.26 SD (0.14, 0.39)]; and lower birthweight [PMNS: -46 g (-102, 11, adjusted for gestational age, offspring gender and rs1801133 genotype); Parthenon: -78 g (-170, 15); meta-analysis: -61 g (-111, -10)]. Instrumental variable and triangulation analysis supported a causal association between maternal homocysteine concentration and offspring birthweight.ConclusionsOur findings suggest a causal role for maternal homocysteine (1-C metabolism) in fetal growth. Reducing maternal homocysteine concentrations may improve fetal growth.
| S-EPMC4190518 | biostudies-literature
Project description:Women with small or large for gestational age offspring are at increased risk of cardiovascular disease later in life. How their cardiovascular risk factors develop across the life course is incompletely known. We linked data from the population-based HUNT Study (1984-2008) and the Medical Birth Registry of Norway (1967-2012) for 22,487 women. Mixed effect models were used to compare cardiovascular risk factor trajectories for women according to first offspring birthweight for gestational age. Women with small for gestational age (SGA) offspring had 1-2 mmHg higher systolic and diastolic blood pressure across the life course, but lower measures of adiposity, compared to women with offspring who were appropriate for gestational age (AGA). In contrast, women with large for gestational age (LGA) offspring had higher measures of adiposity, ~0.1 mmol/l higher non-HDL cholesterol and triglycerides and 0.2 mmol/l higher non-fasting glucose, compared with mothers of AGA offspring. These differences were broadly stable from prior to first pregnancy until 60 years of age. Our findings point to different cardiovascular risk profiles in mothers of SGA versus LGA offspring, where giving birth to SGA offspring might primarily reflect adverse maternal vascular health whereas LGA offspring might reflect the mother's metabolic health.
| S-EPMC7319986 | biostudies-literature
Project description:Observational evidence links higher blood levels of copper with higher risk of cardiovascular diseases. However, whether those associations reflect causal links or can be attributed to confounding is still not fully clear. We investigated causal effects of copper on the risk of cardiometabolic endpoints (stroke, coronary artery disease [CAD] and type 2 diabetes) and cardiometabolic risk factors in two-sample Mendelian randomization (MR) studies. The selection of genetic instruments for blood copper levels relied on meta-analysis of genome-wide association studies in three independent studies (European Prospective Investigation into Cancer and Nutrition-Potsdam study, Prospective investigation of the Vasculature in Uppsala Seniors study, Queensland Institute of Medical Research studies). For the selected instruments, outcome associations were drawn from large public genetic consortia on the respective disease endpoints (MEGASTROKE, Cardiogram, DIAGRAM) and cardiometabolic risk factors. MR results indicate an inverse association for genetically higher copper levels with risk of CAD (odds ratio [95% confidence interval] = 0.92 [0.86-0.99], P = 0.022) and systolic blood pressure (beta [standard error (SE)] = -0.238 [0.121]; P = 0.049). Multivariable MR incorporating copper and systolic blood pressure into one model suggested systolic blood pressure as mediating factor between copper and CAD risk. In contrast to previous observational evidence establishing higher blood copper levels as risk-increasing factor for cardiometabolic diseases, this study suggests that higher levels of genetically predicted copper might play a protective role for the development of CAD and systolic blood pressure.
| S-EPMC8895748 | biostudies-literature
Project description:BackgroundA lack of genetic data across generations makes transgenerational Mendelian randomization (MR) difficult. We used UK Biobank and a novel proxy gene-by-environment MR to investigate effects of maternal smoking heaviness in pregnancy on offspring health, using participants' (generation one: G1) genotype (rs16969968 in CHRNA5) as a proxy for their mothers' (G0) genotype.MethodsWe validated this approach by replicating an established effect of maternal smoking heaviness on offspring birthweight. Then we applied this approach to explore effects of maternal (G0) smoking heaviness on offspring (G1) later life outcomes and on birthweight of G1 women's children (G2).ResultsEach additional smoking-increasing allele in offspring (G1) was associated with a 0.018 [95% confidence interval (CI): -0.026, -0.009] kg lower G1 birthweight in maternal (G0) smoking stratum, but no meaningful effect (-0.002 kg; 95% CI: -0.008, 0.003) in maternal non-smoking stratum (interaction P-value = 0.004). The differences in associations of rs16969968 with grandchild's (G2) birthweight between grandmothers (G0) who did, versus did not, smoke were heterogeneous (interaction P-value = 0.042) among mothers (G1) who did (-0.020 kg/allele; 95% CI: -0.044, 0.003), versus did not (0.007 kg/allele; 95% CI: -0.005, 0.020), smoke in pregnancy.ConclusionsOur study demonstrated how offspring genotype can be used to proxy for the mother's genotype in gene-by-environment MR. We confirmed the causal effect of maternal (G0) smoking on offspring (G1) birthweight, but found little evidence of an effect on G1 longer-term health outcomes. For grandchild's (G2) birthweight, the effect of grandmother's (G0) smoking heaviness in pregnancy may be modulated by maternal (G1) smoking status in pregnancy.
| S-EPMC7660158 | biostudies-literature
Project description:BackgroundEpidemiological studies report associations of diverse cardiometabolic conditions including obesity with COVID-19 illness, but causality has not been established. We sought to evaluate the associations of 17 cardiometabolic traits with COVID-19 susceptibility and severity using 2-sample Mendelian randomization (MR) analyses.Methods and findingsWe selected genetic variants associated with each exposure, including body mass index (BMI), at p < 5 × 10-8 from genome-wide association studies (GWASs). We then calculated inverse-variance-weighted averages of variant-specific estimates using summary statistics for susceptibility and severity from the COVID-19 Host Genetics Initiative GWAS meta-analyses of population-based cohorts and hospital registries comprising individuals with self-reported or genetically inferred European ancestry. Susceptibility was defined as testing positive for COVID-19 and severity was defined as hospitalization with COVID-19 versus population controls (anyone not a case in contributing cohorts). We repeated the analysis for BMI with effect estimates from the UK Biobank and performed pairwise multivariable MR to estimate the direct effects and indirect effects of BMI through obesity-related cardiometabolic diseases. Using p < 0.05/34 tests = 0.0015 to declare statistical significance, we found a nonsignificant association of genetically higher BMI with testing positive for COVID-19 (14,134 COVID-19 cases/1,284,876 controls, p = 0.002; UK Biobank: odds ratio 1.06 [95% CI 1.02, 1.10] per kg/m2; p = 0.004]) and a statistically significant association with higher risk of COVID-19 hospitalization (6,406 hospitalized COVID-19 cases/902,088 controls, p = 4.3 × 10-5; UK Biobank: odds ratio 1.14 [95% CI 1.07, 1.21] per kg/m2, p = 2.1 × 10-5). The implied direct effect of BMI was abolished upon conditioning on the effect on type 2 diabetes, coronary artery disease, stroke, and chronic kidney disease. No other cardiometabolic exposures tested were associated with a higher risk of poorer COVID-19 outcomes. Small study samples and weak genetic instruments could have limited the detection of modest associations, and pleiotropy may have biased effect estimates away from the null.ConclusionsIn this study, we found genetic evidence to support higher BMI as a causal risk factor for COVID-19 susceptibility and severity. These results raise the possibility that obesity could amplify COVID-19 disease burden independently or through its cardiometabolic consequences and suggest that targeting obesity may be a strategy to reduce the risk of severe COVID-19 outcomes.
| S-EPMC7971850 | biostudies-literature
Project description:Observational studies suggest alcohol use promotes the development of some adverse cardiometabolic traits but protects against others including outcomes related to coronary artery disease. We used Mendelian randomization (MR) to explore causal relationships between the degree of alcohol consumption and several cardiometabolic traits in the UK Biobank. Using the well-established ADH1B Arg47His variant (rs1229984) and up to 24 additional SNPs recently found to be associated with alcohol consumption in an independent dataset as instruments, we conducted two-stage least squares and inverse weighted variance MR analyses, both as one-sample analyses in the UK Biobank and as two-sample analyses in external consortia. In the UK Biobank inverse variance weighted analyses, we found that one additional drink of alcohol per day was positively associated with systolic blood pressure (beta = 2.65 mmHg [1.40, 3.89]), hemorrhagic stroke (OR = 2.25 [1.41, 3.60]), and atrial fibrillation (OR = 1.26 [1.07, 1.48]), which were replicated in multivariable analyses. Alcohol was also associated with all cardiovascular disease and all-cause death. A positive association with myocardial infarction did not replicate in multivariable analysis, with suggestive mediation through blood pressure; similarly, a positive association between alcohol use with type 2 diabetes was mitigated by BMI in multivariable analysis. Findings were generally null in replication with two-sample analyses. Alcohol was not protective for any disease outcome with any analysis method, dataset, or strata. Stratifications by sex and smoking in the UK Biobank revealed higher point estimates of risk for several outcomes for men and mixed results for smoking strata, but no statistically significant heterogeneity. Our results are consistent with an overall harmful and/or null effect of alcohol on cardiometabolic health at all levels of use and suggest that even moderate alcohol use should not be promoted as a part of a healthy diet and lifestyle.
| S-EPMC8357114 | biostudies-literature
Project description:Background: Individuals with a diagnosis of schizophrenia are known to be at high risk of premature mortality due to poor physical health, especially cardiovascular disease, diabetes, and obesity. The reasons for these physical health outcomes within this patient population are complex. Despite well-documented cardiometabolic adverse effects of certain antipsychotic drugs and lifestyle factors, schizophrenia may have an independent effect. Aims: To investigate if there is evidence that schizophrenia is causally related to cardiometabolic traits (blood lipids, anthropometric traits, glycaemic traits, blood pressure) and vice versa using bi-directional two-sample Mendelian randomization (MR) analysis. Methods: We used 185 genetic variants associated with schizophrenia from the latest Psychiatric Genomics Consortium GWAS (n = 130,644) in the forward analysis (schizophrenia to cardiometabolic traits) and genetic variants associated with the cardiometabolic traits from various consortia in the reverse analysis (cardiometabolic traits to schizophrenia), both at genome-wide significance (5 × 10-8). The primary method was inverse-variance weighted MR, supported by supplementary methods such as MR-Egger, as well as median and mode-based methods. Results: In the forward analysis, schizophrenia was associated with slightly higher low-density lipoprotein (LDL) cholesterol levels (0.013 SD change in LDL per log odds increase in schizophrenia risk, 95% CI, 0.001-0.024 SD; p = 0.027) and total cholesterol levels (0.013 SD change in total cholesterol per log odds increase in schizophrenia risk, 95% CI, 0.002-0.025 SD; p = 0.023). However, these associations did not survive multiple testing corrections. There was no evidence of a causal effect of cardiometabolic traits on schizophrenia in the reverse analysis. Discussion: Dyslipidemia and obesity in schizophrenia patients are unlikely to be driven primarily by schizophrenia itself. Therefore, lifestyle, diet, antipsychotic drugs side effects, as well as shared mechanisms for metabolic dysfunction and schizophrenia such as low-grade systemic inflammation could be possible reasons for the apparent increased risk of metabolic disease in people with schizophrenia. Further research is needed to examine the shared immune mechanism hypothesis.
| S-EPMC10115959 | biostudies-literature
Project description:Studies suggest that adiposity in childhood may reduce the risk of breast cancer in later life. The biological mechanism underlying this effect is unclear but is likely to be independent of body size in adulthood. Using a Mendelian randomization framework, we investigate 18 hypothesised mediators of the protective effect of childhood adiposity on later-life breast cancer, including hormonal, reproductive, physical, and glycaemic traits. Our results indicate that, while most of the hypothesised mediators are affected by childhood adiposity, only IGF-1 (OR: 1.08 [1.03: 1.15]), testosterone (total/free/bioavailable ~ OR: 1.12 [1.05: 1.20]), age at menopause (OR: 1.05 [1.03: 1.07]), and age at menarche (OR: 0.92 [0.86: 0.99], direct effect) influence breast cancer risk. However, multivariable Mendelian randomization analysis shows that the protective effect of childhood body size remains unaffected when accounting for these traits (ORs: 0.59-0.67). This suggests that none of the investigated potential mediators strongly contribute to the protective effect of childhood adiposity on breast cancer risk individually. It is plausible, however, that several related traits could collectively mediate the effect when analysed together, and this work provides a compelling foundation for investigating other mediating pathways in future studies.
| S-EPMC8993830 | biostudies-literature
Project description:BackgroundAtrial fibrillation is a common cardiovascular disorder, characterized by irregular electrical activity in the upper chambers of the heart. Both chronic cardiometabolic risk factors and genetics have been shown to contribute to the development of atrial fibrillation. Birthweight has also been associated with risk of atrial fibrillation.MethodsIn the current study, we utilized a genetic approach to study the effect of birthweight on atrial fibrillation. We used 2-sample Mendelian randomization to consider the impact of birthweight on incident atrial fibrillation using summary data from the Early Growth Genetics Consortium GWAS of birthweight and a large biobank-based GWAS of atrial fibrillation.ResultsUsing the framework of 2-sample Mendelian randomization, we found that a 1-SD genetic elevation of birthweight was associated with increased risk of atrial fibrillation (odds ratio, 1.27 [95% CI, 1.14-1.41]; P=1×10-5) with sensitivity analyses demonstrating robustness of this result.ConclusionsOur findings clarify the directionality of the relationship between birthweight and atrial fibrillation, supporting the growing body of evidence that intrauterine growth has a lifelong impact on cardiovascular health.
| S-EPMC7299774 | biostudies-literature