Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals

Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.</p

Global variation in diabetes diagnosis and prevalence based on fasting glucose and hemoglobin A1c

Fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) are both used to diagnose diabetes, but these measurements can identify different people as having diabetes. We used data from 117 population-based studies and quantified, in different world regions, the prevalence of diagnosed diabetes, and whether those who were previously undiagnosed and detected as having diabetes in survey screening, had elevated FPG, HbA1c or both. We developed prediction equations for estimating the probability that a person without previously diagnosed diabetes, and at a specific level of FPG, had elevated HbA1c, and vice versa. The age-standardized proportion of diabetes that was previously undiagnosed and detected in survey screening ranged from 30% in the high-income western region to 66% in south Asia. Among those with screen-detected diabetes with either test, the age-standardized proportion who had elevated levels of both FPG and HbA1c was 29-39% across regions; the remainder had discordant elevation of FPG or HbA1c. In most low- and middle-income regions, isolated elevated HbA1c was more common than isolated elevated FPG. In these regions, the use of FPG alone may delay diabetes diagnosis and underestimate diabetes prevalence. Our prediction equations help allocate finite resources for measuring HbA1c to reduce the global shortfall in diabetes diagnosis and surveillance

Worldwide trends in underweight and obesity from 1990 to 2022: a pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults

Background Underweight and obesity are associated with adverse health outcomes throughout the life course. We estimated the individual and combined prevalence of underweight or thinness and obesity, and their changes, from 1990 to 2022 for adults and school-aged children and adolescents in 200 countries and territories. Methods We used data from 3663 population-based studies with 222 million participants that measured height and weight in representative samples of the general population. We used a Bayesian hierarchical model to estimate trends in the prevalence of different BMI categories, separately for adults (age ≥20 years) and school-aged children and adolescents (age 5–19 years), from 1990 to 2022 for 200 countries and territories. For adults, we report the individual and combined prevalence of underweight (BMI &lt;18·5 kg/m2) and obesity (BMI ≥30 kg/m2). For school&#x2;aged children and adolescents, we report thinness (BMI &lt;2 SD below the median of the WHO growth reference) and obesity (BMI &gt;2 SD above the median). Findings From 1990 to 2022, the combined prevalence of underweight and obesity in adults decreased in 11 countries (6%) for women and 17 (9%) for men with a posterior probability of at least 0·80 that the observed changes were true decreases. The combined prevalence increased in 162 countries (81%) for women and 140 countries (70%) for men with a posterior probability of at least 0·80. In 2022, the combined prevalence of underweight and obesity was highest in island nations in the Caribbean and Polynesia and Micronesia, and countries in the Middle East and north Africa. Obesity prevalence was higher than underweight with posterior probability of at least 0·80 in 177 countries (89%) for women and 145 (73%) for men in 2022, whereas the converse was true in 16 countries (8%) for women, and 39 (20%) for men. From 1990 to 2022, the combined prevalence of thinness and obesity decreased among girls in five countries (3%) and among boys in 15 countries (8%) with a posterior probability of at least 0·80, and increased among girls in 140 countries (70%) and boys in 137 countries (69%) with a posterior probability of at least 0·80. The countries with highest combined prevalence of thinness and obesity in school-aged children and adolescents in 2022 were in Polynesia and Micronesia and the Caribbean for both sexes, and Chile and Qatar for boys. Combined prevalence was also high in some countries in south Asia, such as India and Pakistan, where thinness remained prevalent despite having declined. In 2022, obesity in school-aged children and adolescents was more prevalent than thinness with a posterior probability of at least 0·80 among girls in 133 countries (67%) and boys in 125 countries (63%), whereas the converse was true in 35 countries (18%) and 42 countries (21%), respectively. In almost all countries for both adults and school-aged children and adolescents, the increases in double burden were driven by increases in obesity, and decreases in double burden by declining underweight or thinness. Interpretation The combined burden of underweight and obesity has increased in most countries, driven by an increase in obesity, while underweight and thinness remain prevalent in south Asia and parts of Africa. A healthy nutrition transition that enhances access to nutritious foods is needed to address the remaining burden of underweight while curbing and reversing the increase in obesit

Worldwide trends in underweight and obesity from 1990 to 2022 : a pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults

A list of authors and their affiliations appears online. A supplementary appendix is herewith attached.Background: Underweight and obesity are associated with adverse health outcomes throughout the life course. We estimated the individual and combined prevalence of underweight or thinness and obesity, and their changes, from 1990 to 2022 for adults and school-aged children and adolescents in 200 countries and territories. Methods: We used data from 3663 population-based studies with 222 million participants that measured height and weight in representative samples of the general population. We used a Bayesian hierarchical model to estimate trends in the prevalence of different BMI categories, separately for adults (age ≥20 years) and school-aged children and adolescents (age 5–19 years), from 1990 to 2022 for 200 countries and territories. For adults, we report the individual and combined prevalence of underweight (BMI 2 SD above the median). Findings: From 1990 to 2022, the combined prevalence of underweight and obesity in adults decreased in 11 countries (6%) for women and 17 (9%) for men with a posterior probability of at least 0·80 that the observed changes were true decreases. The combined prevalence increased in 162 countries (81%) for women and 140 countries (70%) for men with a posterior probability of at least 0·80. In 2022, the combined prevalence of underweight and obesity was highest in island nations in the Caribbean and Polynesia and Micronesia, and countries in the Middle East and north Africa. Obesity prevalence was higher than underweight with posterior probability of at least 0·80 in 177 countries (89%) for women and 145 (73%) for men in 2022, whereas the converse was true in 16 countries (8%) for women, and 39 (20%) for men. From 1990 to 2022, the combined prevalence of thinness and obesity decreased among girls in five countries (3%) and among boys in 15 countries (8%) with a posterior probability of at least 0·80, and increased among girls in 140 countries (70%) and boys in 137 countries (69%) with a posterior probability of at least 0·80. The countries with highest combined prevalence of thinness and obesity in school-aged children and adolescents in 2022 were in Polynesia and Micronesia and the Caribbean for both sexes, and Chile and Qatar for boys. Combined prevalence was also high in some countries in south Asia, such as India and Pakistan, where thinness remained prevalent despite having declined. In 2022, obesity in school-aged children and adolescents was more prevalent than thinness with a posterior probability of at least 0·80 among girls in 133 countries (67%) and boys in 125 countries (63%), whereas the converse was true in 35 countries (18%) and 42 countries (21%), respectively. In almost all countries for both adults and school-aged children and adolescents, the increases in double burden were driven by increases in obesity, and decreases in double burden by declining underweight or thinness. Interpretation: The combined burden of underweight and obesity has increased in most countries, driven by an increase in obesity, while underweight and thinness remain prevalent in south Asia and parts of Africa. A healthy nutrition transition that enhances access to nutritious foods is needed to address the remaining burden of underweight while curbing and reversing the increase in obesity.peer-reviewe

Testicular, Other Genital, and Breast Cancers in First-Degree Relatives of Testicular Cancer Patients and Controls

Abstract Previous studies showed an increased prevalence of testicular cancer among fathers and brothers of testicular cancer patients. We examined whether testicular, other genital, and breast cancers aggregate in parents and siblings of testicular cancer patients in a population-based case-control study, including males, ages 15 to 69 years at diagnosis, with primary malignant tumors of the testes or extragonadal germ cell tumors. Controls were ascertained through the mandatory registries of residents and frequency matched to the cases by age and region of residence. In a face-to-face interview, 269 cases and 797 controls provided health-related information on parents and siblings. We calculated odds ratios (OR) and corresponding 95% confidence intervals (95% CI) based on the generalized estimating equations technique, adjusting for the matching variables and relatives' age. Three (1.1%) fathers and eight (3.2%) brothers of cases were affected with testicular cancer compared with four (0.5%) fathers and two (0.2%) brothers of controls. The OR (95% CI) of familial testicular cancer was 6.6 (2.35-18.77). Only nonseminoma patients had fathers with testicular cancer, whereas the affected brothers were all related to seminoma patients. Overall, we found an increased risk for genital other than testicular cancers (OR 2.5, 95% CI 1.43-4.43). For breast cancer, we detected an increased risk in sisters (OR 9.5, 95% CI 2.01-45.16, adjusted for age of study participant and age of sister) but not in mothers. Our findings support the hypothesis that testicular and other genital cancers have a common familial component that may be due to genetic and shared exogenous factors such as estrogen exposure during fetal development.</jats:p

Prevalence of Monoclonal Gammopathy of Undetermined Significance (MGUS) and Light-Chain MGUS (LCMGUS) In a Metropolitan Area In Germany

Abstract Abstract 4037 Background: We utilized the biobank of the ongoing population-based, prospective Heinz Nixdorf Recall Study to determine the prevalence of monoclonal gammopathy of undetermined significance (MGUS) and a recently defined entity – light-chain MGUS (LCMGUS) – in the densely populated Ruhr area in Germany. Methods: The Heinz Nixdorf Recall study cohort comprises 4814 men and women from 3 large adjacent cities in Germany. Subjects were randomly selected from statutory lists of residence and gave informed consent. We screened serum samples from the baseline examination which took place from 2000 until 2003. Standard serum electrophoresis (SPE) was combined with parallel screening immunofixation electrophoresis (scIFE) using pentavalent antisera (Hydragel 12 IF, Penta-Kit, Sebia, Fulda, Germany). Where a monoclonal band was visible or suspected, confirmatory IFE followed. Free light-chain (FLC) κ and λ measurements were performed on a Dade Behring BNII automated nephelometer (Siemens, Germany) utilizing a commercially available kit (FREELITE, The Binding Site Ltd, Birmingham, UK). Definition of MGUS cases was based on common criteria including monoclonal protein concentration, laboratory results, and disease history. LCMGUS cases were defined as an abnormal FLC ratio, an increase in the FLC that caused the abnormal ratio and no detectable intact immunoglobulin (Dispenzieri et al. Lancet 2010: 1721-8). Age-standardization of prevalences was performed by direct standardization to the U.S. population 2000. Results: 165 MGUS cases were identified in a total of 4708 screened samples, translating into a prevalence of 3.5% (95% CI, 3.0 – 4.1). The median age of MGUS cases was 63 years (range 47 – 75), 103 (62%) were of male gender, and prevalence increased with age. The age-standardized prevalence was 3.9% (95% CI 3.2 – 4.5) which was significantly higher (p&lt;0.05) than previously reported (Kyle et al. NEJM 2006: 1362-9). Immunoglobulin isotypes were IgG 59%, IgA 17%, IgM 28%, biclonal 2.4%, kappa 55%, and lambda 44%. Concentrations of monoclonal proteins ranged from unmeasurable – 22.4 g/l with a median of 5.3 g/l. After a median observational time of 5 years, 3 MGUS cases had progressed to multiple myeloma and 1 case developed a diffuse large B-cell lymphoma, representing a progression rate of 0.5%/year (95% CI 0.13 – 1.3). An abnormal FLC ratio was detected in 222 samples. SPE + scIFE showed an intact immunoglobulin in 39 of these samples, thus representing conventional MGUS. A total of 34 (19%) of the 183 individuals with abnormal FLC ratios and no intact immunoglobulin had an increase in concentration of the FLC causing the abnormal ratio and thus met LCMGUS criteria. The overall prevalence of LCMGUS was 0.7% (95% CI 0.5 – 1.0) and the age-standardized prevalence was 0.8 (95% CI 0.5 – 1.1). None of the LCMGUS cases progressed during the observational period. Conclusion: The higher MGUS prevalence of 3.9% in the Heinz Nixdorf Recall cohort compared to previous reports can be explained by the combined SPE + scIFE screening approach. Re-evaluation of the gels without the pentavalent tracks resulted in a prevalence similar to that reported for Olmsted County, Minnesota, U.S. The prevalence of the recently defined entity LCMGUS in the Heinz Nixdorf Recall cohort also compares favourably with the recently reported prevalence. Further characterization of MGUS and LCMGUS cases in the well-defined Heinz Nixdorf Recall cohort is the focus of ongoing analyzes. Disclosures: Eisele: Celgene: Research Funding. Dürig:Celgene: Research Funding. </jats:sec

Polyclonal Free Light Chain Elevation and Mortality In the German Heinz Nixdorf Recall Study

Abstract Abstract 3903 Abnormalities of the κ:λ free light chain (FLC) ratio can detect monoclonal FLC elevations and are a valuable tool in the diagnosis and follow-up of plasma cell dyscrasias. However, due to their generation in active cells of the immune system and their renal metabolism, polyclonal FLC elevations might also provide valuable hints to other pathologic conditions. Recent reports suggest e.g. a role in predicting outcome in chronic viral infectious diseases. In a previous study, we screened the cohort of the German Heinz Nixdorf Recall Study for monoclonal gammopathies by combined serum protein electrophoresis and screening immunofixation (Eisele et al. EHA 2010, Abstract #0949) and also measured FLC concentration by nephelometric immunoassays (FREELITE, The Binding Site, UK) in all available samples. We here report our first preliminary results of the analysis of polyclonal FLC elevation with regard to all-cause mortality in the Heinz Nixdorf Recall cohort. The Heinz Nixdorf Recall Study cohort comprises 4814 men and women from 3 large adjacent cities in Germany. Subjects were randomly selected from statutory lists of residence and gave informed consent. We screened serum samples from the baseline examination which took place from 2000 until 2003. After exclusion of samples with monoclonal FLC elevation, laboratory results together with clinical information of 4350 study subjects (2180 male, 2170 female) were available for analysis. We used summated FLC (total FLC, tFLC) as a measure for polyclonal elevation. tFLC ranged from 2.7 to 275 mg/l with a median of 30.2 mg/l. High levels of tFLC were associated with high-sensitive CRP (hsCRP) and chronic kidney disease (CKD). Both quintiles of tFLC and CKD stage were associated with shorter survival in univariate analysis. Using the median as cutoff, tFLC still separated groups with different survival within CKD stages 0 and 1. tFLC remained an independent predictor of survival in multivariable cox regression analysis adjusted for sex, age, hsCRP and CKD stage (HR 1.13 (95%CI 1.03 – 1.24 per quintile, p=0.0068). For the 274 deaths that occurred during a median observational time of 5 years we had information available from death certificates. Causes of death were categorized into cardiopulmonary, infectious, cancer, and other. The number of deaths increased from the lowest to the highest tFLC quintile (34 vs. 98), however we found no associations of tFLC with categorized causes of death. Polyclonal FLC measurements are affected by a variety of health conditions and may thus be subject to fluctuations over time. We are currently measuring FLC in the 5-year follow-up samples of the Heinz Nixdorf Recall study. This will provide us with a more precise estimate of polyclonal FLC elevation and will help us to further define their role in predicting mortality. These results will also be reported at the conference. Disclosures: Eisele: Celgene: Research Funding. Dürig:Celgene: Research Funding. </jats:sec

Abstract 1847: Prognostic Impact Of Previous Percutaneous Coronary Interventions On Coronary Artery Bypass Graft Surgery: A Multicentric Analysis FromThe German Federal State North-Rhine-Westphalia

Background: We have previously shown that multiple prior percutaneous coronary intervention (PCI) procedures adversely affect outcome after subsequent coronary artery bypass grafting (CABG). We were now interested to investigate this effect on a multicentric basis. Methods: Eight cardiac surgical centers from the German Federal State of North-Rhine-Westphalia provided outcome data of 37140 consecutive patients having undergone isolated first-time CABG between 01/2000 and 12/2005. Twenty-two patient characteristics and outcome variables, which are part of a collection of data claimed by the national medical quality-control commission, were retrieved from the individual databases. Three groups of patients were analyzed for overall in-hospital mortality and major adverse cardiac events (MACE): Patients without a previous PCI procedure, patients with 1 previous PCI procedure and patients with ≥2 previous PCI procedures before surgery. Unadjusted univariable and risk-adjusted multivariable logistic regression analysis were applied. Computed propensity-score matching was performed based on 15 patient major risk factors to correct for and minimize selection bias. Results: A total of 10.3% of patients had 1 previous PCI procedure, and 3.7% of patients had ≥2 previous PCI procedures. Risk-adjusted multivariable logistic regression analysis of ≥2 previous PCI significantly correlated with in-hospital mortality (odds ratio [OR], 2.0; confidence interval [CI], 1.4–3.0; P &lt;0.0005) and MACE (OR, 1.5; CI, 1.2–1.9; P &lt;0.0013). After propensity score matching, conditional logistic regression analysis confirmed the results of adjusted analysis. A history of ≥2 previous PCI procedures was significantly associated with in-hospital mortality (OR, 1.9; CI, 1.3–2.7; P =0.0016) and MACE (OR, 1.5; CI, 1.2–1.9; P =0.0019). Conclusions: This large multicentric trial supports earlier results of our single-center analysis, multiple previous PCI procedures significantly increased the event of in-hospital mortality and MACE after subsequent CABG. </jats:p