Genome-wide association analyses of risk tolerance and risky behaviors in over 1 million individuals identify hundreds of loci and shared genetic influences.

Humans vary substantially in their willingness to take risks. In a combined sample of over 1 million individuals, we conducted genome-wide association studies (GWAS) of general risk tolerance, adventurousness, and risky behaviors in the driving, drinking, smoking, and sexual domains. Across all GWAS, we identified hundreds of associated loci, including 99 loci associated with general risk tolerance.

Generalization and fine mapping of red blood cell trait genetic associations to multi-ethnic populations: The PAGE Study.

Red blood cell (RBC) traits provide insight into a wide range of physiological states and exhibit moderate to high heritability, making them excellent candidates for genetic studies to inform underlying biologic mechanisms. Previous RBC trait genome-wide association studies were performed primarily in European- or Asian-ancestry populations, missing opportunities to inform understanding of RBC genetic architecture in diverse populations and reduce intervals surrounding putative functional SNPs through fine-mapping. Here, we report the first fine-mapping of six correlated (Pearson's r range: |0.

Physical activity types and atrial fibrillation risk in the middle-aged and elderly: The Rotterdam Study.

Background The association between physical activity and atrial fibrillation remains controversial. Physical activity has been associated with a higher and lower atrial fibrillation risk. These inconsistent results might be related to the type of physical activity.

Physical activity derived from questionnaires and wrist-worn accelerometers: comparability and the role of demographic, lifestyle, and health factors among a population-based sample of older adults.

Background: Agreement between questionnaires and accelerometers to measure physical activity (PA) differs between studies and might be related to demographic, lifestyle, and health characteristics, including disability and depressive symptoms.

Methods: We included 1,410 individuals aged 51-94 years from the population-based Rotterdam Study. Participants completed the LASA Physical Activity Questionnaire and wore a wrist-worn accelerometer on the nondominant wrist for 1 week thereafter.

Osteoporotic Vertebral Fracture Prevalence Varies Widely Between Qualitative and Quantitative Radiological Assessment Methods: The Rotterdam Study.

Accurate diagnosis of vertebral osteoporotic fractures is crucial for the identification of individuals at high risk of future fractures. Different methods for radiological assessment of vertebral fractures exist, but a gold standard is lacking. The aim of our study was to estimate statistical measures of agreement and prevalence of osteoporotic vertebral fractures in the population-based Rotterdam Study, across two assessment methods.

Meta-GWAS Accuracy and Power (MetaGAP) Calculator Shows that Hiding Heritability Is Partially Due to Imperfect Genetic Correlations across Studies.

Large-scale genome-wide association results are typically obtained from a fixed-effects meta-analysis of GWAS summary statistics from multiple studies spanning different regions and/or time periods. This approach averages the estimated effects of genetic variants across studies. In case genetic effects are heterogeneous across studies, the statistical power of a GWAS and the predictive accuracy of polygenic scores are attenuated, contributing to the so-called 'missing heritability'.

Sedentary time assessed by actigraphy and mortality: The Rotterdam Study.

Research suggests that sedentary behavior is a risk factor for mortality. However, most studies rely on questionnaires, which are prone to reporting error. We examined the association between sedentary time assessed by actigraphy and mortality among 1839 participants, aged 45-98years, from the prospective population-based Rotterdam Study, enrolled between 2004 and 2007.

Whole-Exome Sequencing Identifies Loci Associated with Blood Cell Traits and Reveals a Role for Alternative GFI1B Splice Variants in Human Hematopoiesis.

Circulating blood cell counts and indices are important indicators of hematopoietic function and a number of clinical parameters, such as blood oxygen-carrying capacity, inflammation, and hemostasis. By performing whole-exome sequence association analyses of hematologic quantitative traits in 15,459 community-dwelling individuals, followed by in silico replication in up to 52,024 independent samples, we identified two previously undescribed coding variants associated with lower platelet count: a common missense variant in CPS1 (rs1047891, MAF = 0.33, discovery + replication p = 6.

Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases.

White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of ∼157,622 individuals from 25 studies.

Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals.

Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV).

Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits.

Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants.

Physical Activity Types and Coronary Heart Disease Risk in Middle-Aged and Elderly Persons: The Rotterdam Study.

Physical activity is associated with decreased risk of coronary heart disease (CHD). The specific physical activity types that provide beneficial effects in an older population remain unclear. We assessed the association of total physical activity, walking, cycling, domestic work, sports, and gardening with CHD by using Cox proportional hazard models among 5,901 participants aged >55 (median age, 67) years from the prospective population-based Rotterdam Study, enrolled between 1997 and 2001.

Consumption of meat is associated with higher fasting glucose and insulin concentrations regardless of glucose and insulin genetic risk scores: a meta-analysis of 50,345 Caucasians.

Background: Recent studies suggest that meat intake is associated with diabetes-related phenotypes. However, whether the associations of meat intake and glucose and insulin homeostasis are modified by genes related to glucose and insulin is unknown.

Objective: We investigated the associations of meat intake and the interaction of meat with genotype on fasting glucose and insulin concentrations in Caucasians free of diabetes mellitus.

Polygenic risk scores for schizophrenia and bipolar disorder predict creativity.

We tested whether polygenic risk scores for schizophrenia and bipolar disorder would predict creativity. Higher scores were associated with artistic society membership or creative profession in both Icelandic (P = 5.2 × 10(-6) and 3.

Gene × dietary pattern interactions in obesity: analysis of up to 68 317 adults of European ancestry.

Obesity is highly heritable. Genetic variants showing robust associations with obesity traits have been identified through genome-wide association studies. We investigated whether a composite score representing healthy diet modifies associations of these variants with obesity traits.

Risk factors for inguinal hernia in middle-aged and elderly men: results from the Rotterdam Study.

Background: Prospective data on risk factors and the incidence of inguinal hernia are sparse, especially in an elderly population. The aim of this study was to determine the incidence of and risk factors for inguinal hernia.

Methods: We analyzed data from the Rotterdam Study, a prospective cohort study that observed the general population aged ≥45 years of Ommoord, a district in Rotterdam, from baseline (1990) over a period of >20 years.

Dairy products and the risk of stroke and coronary heart disease: the Rotterdam Study.

Purpose: We examined whether consumption of total dairy and dairy subgroups was related to incident stroke and coronary heart disease (CHD) in a general older Dutch population.

Methods: The study involved 4,235 participants of the Rotterdam Study aged 55 and over who were free of cardiovascular disease (CVD) and diabetes at baseline (1990-1993). Multivariable Cox proportional hazards models were used to calculate hazard ratios (HRs) for the intake of total dairy and dairy subgroups in relation to incident CVD events.

Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption.

Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91,462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in ~30 062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis.

FTO genetic variants, dietary intake and body mass index: insights from 177,330 individuals.

FTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent.

Trans-ethnic meta-analysis of white blood cell phenotypes.

White blood cell (WBC) count is a common clinical measure used as a predictor of certain aspects of human health, including immunity and infection status. WBC count is also a complex trait that varies among individuals and ancestry groups. Differences in linkage disequilibrium structure and heterogeneity in allelic effects are expected to play a role in the associations observed between populations.

Multiple nonglycemic genomic loci are newly associated with blood level of glycated hemoglobin in East Asians.

Glycated hemoglobin A1c (HbA1c) is used as a measure of glycemic control and also as a diagnostic criterion for diabetes. To discover novel loci harboring common variants associated with HbA1c in East Asians, we conducted a meta-analysis of 13 genome-wide association studies (GWAS; N = 21,026). We replicated our findings in three additional studies comprising 11,576 individuals of East Asian ancestry.

Multi-functionality of computer-aided quantitative vertebral fracture morphometry analyses.

Osteoporotic vertebral fractures are an increasingly active area of research. Oftentimes assessments are performed by software-assisted quantitative morphometry. Here, we will discuss multi-functionality of these data for research purposes.