Using multiple Mendelian randomization approaches and genetic correlations to understand obesity, urate, and gout

Observational studies suggest relationships between obesity, urate, and gout but are possibly confounded. We assessed whether genetically determined obesity, higher urate (and related traits), and gout were causal using multiple Mendelian randomization (MR) approaches and linkage disequilibrium score regression for genetic correlations (rg). For data, we used genome-wide association study summary statistics available through MR-Base. We observed that obesity increased urate (beta = 0.127; 95% CI = 0.098, 0.157; P-value = 1.2E−17; rg = 0.25 [P-value = 0.001]) and triglycerides (beta = 0.082; 95% CI = 0.065, 0.099; P-value = 1.2E−21; rg = 0.23 [P-value = 8.8E−12]) and decreased high-density lipoprotein cholesterol (HDL) (beta = − 0.083; 95% CI = − 0.101, − 0.065; P-value = 2.5E−19; rg = − 0.28; [P-value = 5.2E−24]). Higher triglycerides increased urate (beta = 0.198; 95% CI = 0.146, 0.251; P-value = 8.9E−14; rg = 0.29 [P-value = 0.001]) and higher HDL decreased urate (beta = − 0.109; 95% CI = − 0.148, − 0.071; P-value = 2.7E− 08; rg = − 0.21 [P-value = 9.8E−05]). Higher urate (OR = 1.030; 95% CI = 1.028, 1.032; P-value = 1.1E−130; rg = 0.89 [P-value = 1.7E−55]) and obesity caused gout (OR = 1.003; 95% CI = 1.001, 1.004; P-value = 1.3E−04; rg = 0.23 [P-value = 2.7E−05]). Obesity on gout with urate as a mediator revealed all the effect of obesity on gout occurred through urate. Obesity on low-density lipoprotein cholesterol (LDL) was null (beta = −0.011; 95% CI = −0.030, 0.008; P-value = 2.6E−01; rg = 0.03 [P-value = 0.369]). A multivariable MR of obesity, HDL, and triglycerides on urate showed obesity influenced urate when accounting for HDL and triglycerides. Obesity’s impact on urate was exacerbated by it decreasing HDL

A Mendelian randomization study of telomere length and blood-cell traits

© 2020, The Author(s). Whether telomere attrition reducing proliferative reserve in blood-cell progenitors is causal has important public-health implications. Mendelian randomization (MR) is an analytic technique using germline genetic variants as instrumental variables. If certain assumptions are met, estimates from MR should be free from most environmental sources of confounding and reverse causation. Here, two-sample MR is performed to test whether longer telomeres cause changes to hematological traits. Summary statistics for genetic variants strongly associated with telomere length were extracted from a genome-wide association (GWA) study for telomere length in individuals of European ancestry (n = 9190) and from GWA studies of blood-cell traits, also in those of European ancestry (n ~ 173,000 participants). A standard deviation increase in genetically influenced telomere length increased red blood cell and white blood cell counts, decreased mean corpuscular hemoglobinand mean cell volume, and had no observable impact on mean corpuscular hemoglobin concentration, red cell distribution width, hematocrit, or hemoglobin. Sensitivity tests for pleiotropic distortion were mostly inconsistent with glaring violations to the MR assumptions. Similar to germline mutations in telomere biology genes leading to bone-marrow failure, these data provide evidence that genetically influenced common variation in telomere length impacts hematologic traits in the population

Can increasing years of schooling reduce type 2 diabetes (T2D)?: Evidence from a Mendelian randomization of T2D and 10 of its risk factors

© 2020, The Author(s). A focus in recent decades has involved examining the potential causal impact of educational attainment (schooling years) on a variety of disease and life-expectancy outcomes. Numerous studies have broadly revealed a link suggesting that as years of formal schooling increase so too does health and wellbeing; however, it is unclear whether the associations are causal. Here we use Mendelian randomization, an instrumental variables technique, with a two-sample design, to probe whether more years of schooling are causally linked to type 2 diabetes (T2D) and 10 of its attendant risk factors. The results revealed a protective effect of more schooling years against T2D (odds ratio = 0.39; 95% confidence interval: 0.26, 0.58; P = 3.89 × 10–06), which in turn might be partly mediated by more years of schooling being protective against the following: having a father with T2D, being overweight, having higher blood pressure and higher levels of circulating triglycerides, and having lower levels of HDL cholesterol. More schooling years had no effect on risk for gestational diabetes or polycystic ovarian syndrome and was associated with a decreased likelihood of moderate physical activity. These findings imply that strategies to retain adults in higher education may help reduce the risk for a major source of metabolic morbidity and mortality

Shared genomic architectures of COVID-19 and antisocial behavior

Little is known about the genetics of norm violation and aggression in relation to coronavirus disease 2019 (COVID-19). To investigate this, we used summary statistics from genome-wide association studies and linkage disequilibrium score regression to calculate a matrix of genetic correlations (rgs) for antisocial behavior (ASB), COVID-19, and various health and behavioral traits. After false-discovery rate correction, ASB was genetically correlated with COVID-19 (rg = 0.51; P = 1.54E-02) and 19 other traits. ASB and COVID-19 were both positively genetically correlated with having a noisy workplace, doing heavy manual labor, chronic obstructive pulmonary disease, and genitourinary diseases. ASB and COVID-19 were both inversely genetically correlated with average income, education years, healthspan, verbal reasoning, lifespan, cheese intake, and being breastfed as a baby. But keep in mind that rgs are not necessarily causal. And, if causal, their prevailing directions of effect (which causes which) are indiscernible from rgs alone. Moreover, the SNP-heritability (hg2) estimates for two measures of COVID-19 were very small, restricting the overlap of genetic variance in absolute terms between ASB and COVID-19. Nonetheless, our findings suggest that those with antisocial tendencies possibly have a higher risk of exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) than those without antisocial tendencies. This may have been especially true early in the pandemic before vaccines against SARS-CoV-2 were available and before the emergence of the highly transmissible Omicron variant

Модель професійної культури юриста: критерії та підходи

В статті визначається модель професійної культури

Mendelian randomization reveals apolipoprotein B shortens healthspan and possibly increases risk for Alzheimer’s disease

Abstract Apolipoprotein B-100 (APOB) is a component of fat- and cholesterol-transporting molecules in the bloodstream. It is the main lipoprotein in low-density lipoprotein cholesterol (LDL) and has been implicated in conditions that end healthspan (the interval between birth and onset of chronic disease). However, APOB’s direct relationship with healthspan remains uncertain. With Mendelian randomization, we show that higher levels of APOB and LDL shorten healthspan in humans. Multivariable Mendelian randomization of APOB and LDL on healthspan suggests that the predominant trait accounting for the relationship is APOB. In addition, we provide preliminary evidence that APOB increases risk for Alzheimer’s disease, a condition that ends healthspan. If these relationships are causal, they suggest that interventions to improve healthspan in aging populations could include strategies targeting APOB. Ultimately, given that more than 44 million people currently suffer from Alzheimer’s disease worldwide, such interventions are needed

Lifestyle interventions to reduce endocrine-disrupting phthalate and phenol exposures among reproductive age men and women: A review and future steps

Non-persistent endocrine-disrupting chemicals (EDCs), including phthalates and phenols, are ubiquitous in both the environment and human body. A growing body of epidemiologic studies have identified concerning links between EDCs and adverse reproductive and developmental health effects. Despite consistent evidence, risk assessments and policy interventions often arrive late. This presents an urgent need to identify evidence-based interventions for implementation at both clinical and community levels to reduce EDC exposure, especially in susceptible populations. The reproductive life cycle (menarche to menopause for females and after pubertal onset for males) includes some of the most vulnerable periods to environmental exposures, such as the preconception and perinatal stages, representing a key window of opportunity to intervene and prevent unfavorable health outcomes. This review aims to synthesize and assess behavioral, dietary, and residential EDC-driven interventions to develop recommendations for subsequent, larger-scale studies that address knowledge-gaps in current interventions during the reproductive life cycle. We selected 21 primary interventions for evaluation, in addition to four supplemental interventions. Among these, accessible (web-based) educational resources, targeted replacement of (known) toxic products, and personalization of the intervention through meetings and support groups, were the most promising strategies for reducing EDC concentrations. However, we document a paucity of interventions to prevent phthalate and phenol exposures during the reproductive years, especially among men. Accordingly, we recommend additional, larger clinical and community-based intervention studies to reduce EDC exposure. Specifically, future intervention studies should focus on short-term, mid-, and long-term exposure reduction to phthalates and phenols. The latter, especially, is required for the development of clinical and public health guidelines to promote reproductive and developmental health globally