Pim Van Der Harst

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but...

Occupational exposures are important and possibly modifiable contributors to the global burden of chronic obstructive pulmonary disease (COPD). Exposure to vapours, gases, dusts and fumes (VGDF) has been associated with a two- to threefold higher COPD risk. Less is known about effects of occupational exposure to pesticides and solvents. In the current study, we assessed if VGDF, pesticides and solvents are associated with the level of lung function and the prevalence of airway obstruction in the general population. We included 11 851 subjects aged 18-89 years from the LifeLines cohort study. Regression models assessing associations between occupational exposures (no/low/high), level of lung function (prebronchodilator FEV(1), FEV(1)/FVC) and mild and moderate/severe airway obstruction were adjusted for sex, age, height, weight, current/ex-smoking and packyears. Additionally, we stratified by smoking status and gender and tested for interaction. A second general population cohort (n=2364) was used to verify our initial findings. Occupational exposure to VGDF and pesticides was associated with a lower level of FEV(1) and FEV(1)/FVC and with a higher prevalence of mild and moderate/severe airway obstruction in the two general populations investigated. There were no associations with exposure to solvents. Occupational exposure to both VGDF and pesticides is associated with airway obstruction in the general population.

Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determ...

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations w...