Summary of the two loci associated with SCD.

<p>Chr, chromosome; SE, standard error; OR, odds ratio.</p

Regional association plots for the two associated SNPs with SCD.

<p>Each SNP is plotted with respect to its chromosomal location (x-axis) and –log₁₀P-value (y-axis on the left). The spikes indicate the recombination rate (y-axis on the right) at that region of the chromosome.</p

Manhattan plot of associated findings.

<p>Data is displayed as –log₁₀P values against chromosomal location for the 119,117 SNPs that were included in the statistical analysis. The dotted line represents the conservative significance threshold of P = 4.2×10⁻⁷. The two loci that showed an association at this level are plotted in red.</p

Effects of calcium, magnesium, and potassium concentrations on ventricular repolarization in unselected individuals.

Background: Subclinical changes on the electrocardiogram are risk factors for cardiovascular mortality. Recognition and knowledge of electrolyte associations in cardiac electrophysiology are based on only in vitro models and observations in patients with severe medical conditions.Objectives: This study sought to investigate associations between serum electrolyte concentrations and changes in cardiac electrophysiology in the general population.Methods: Summary results collected from 153,014 individuals (54.4% women; mean age 55.1 ± 12.1 years) from 33 studies (of 5 ancestries) were meta-analyzed. Linear regression analyses examining associations between electrolyte concentrations (mmol/l of calcium, potassium, sodium, and magnesium), and electrocardiographic intervals (RR, QT, QRS, JT, and PR intervals) were performed. The study adjusted for potential confounders and also stratified by ancestry, sex, and use of antihypertensive drugs.Results: Lower calcium was associated with longer QT intervals (-11.5 ms; 99.75% confidence interval [CI]: -13.7 to -9.3) and JT duration, with sex-specific effects. In contrast, higher magnesium was associated with longer QT intervals (7.2 ms; 99.75% CI: 1.3 to 13.1) and JT. Lower potassium was associated with longer QT intervals (-2.8 ms; 99.75% CI: -3.5 to -2.0), JT, QRS, and PR durations, but all potassium associations were driven by use of antihypertensive drugs. No physiologically relevant associations were observed for sodium or RR intervals.Conclusions: The study identified physiologically relevant associations between electrolytes and electrocardiographic intervals in a large-scale analysis combining cohorts from different settings. The results provide insights for further cardiac electrophysiology research and could potentially influence clinical practice, especially the association between calcium and QT duration, by which calcium levels at the bottom 2% of the population distribution led to clinically relevant QT prolongation by >5 ms.</p

Meta-analysis results of Mendelian randomization analyses on effect of <i>FTO</i>-derived adiposity on cardiovascular and metabolic disease: quantitative phenotypes.

a<p>Beta coefficient corresponds to one-unit increase in BMI (kg/m²).</p>b<p>Beta coefficient corresponds to per-allele change.</p>c<p>Values were transformed to natural logarithm scale prior to analysis.</p

Comparison of our study with previous Mendelian randomization studies of adiposity on cardiometabolic phenotypes.

a<p>No formal MR study, although the association of <i>FTO</i> and T2D is well known.</p><p>N.A, not applicable.</p

Meta-analysis results of Mendelian randomization analyses on effect of <i>FTO</i>-derived adiposity on cardiovascular and metabolic disease: dichotomous outcomes.

a<p>OR/HR corresponds to one-unit increase in BMI (kg/m²).</p>b<p>OR/HR corresponds to per-allele change.</p>c<p>Only one study; meta-analysis not performed.</p><p>HR, hazard ratio.</p

In a Mendelian randomization framework, genotype–phenotype association is assumed to be independent of confounding factors.

<p>(A) In an example from our study, the IV estimator is calculated as the beta coefficient from the association of <i>FTO</i> with systolic blood pressure divided by the beta coefficient from the association of <i>FTO</i> with BMI (IV estimator = 0.32/0.36 = 0.89 mm Hg/BMI unit). The IV estimator is equivalent to what is seen when systolic blood pressure is regressed on BMI. These results are supportive of a causal, non-confounded relationship. For binary traits, the calculation of the IV estimator is done on the log-odds scale. (B) The relationship of BMI with T2D, where the IV estimator is ln(OR_IV) = ln(1.12)/0.36, which equals a causal OR of BMI for T2D of 1.37. This is larger than what is seen in the standard age- and sex-adjusted logistic regression of T2D on BMI (<i>p</i> = 0.001), indicating that confounding or reverse causation may be present or that BMI measured once in adulthood does not fully reflect the effect of lifetime adiposity.</p

Association between <i>FTO</i> and incident heart failure in 2,863 cases and 44,400 controls.

<p>Estimates (ES) are shown on a hazard ratio scale per number of effect alleles. The assigned weight for each study in the meta-analysis is shown in percent (% Weight). For cohort abbreviations and references, see <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001474#pmed.1001474.s003" target="_blank">Table S1</a>.</p

Association between <i>FTO</i> variant rs9939609 and BMI in 198,502 individuals.

<p>The assigned weight for each study in the meta-analysis is shown in percent (% Weight). ES, estimate. For cohort abbreviations and references, see <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001474#pmed.1001474.s003" target="_blank">Table S1</a>.</p