Background: Varicose veins are a common problem with no approved medical therapies. While it is believed that varicose vein pathogenesis is multifactorial, there is a limited understanding of the genetic and environmental factors that contribute to their formation. Large-scale studies of risk factors for varicose veins may highlight important aspects of pathophysiology and identify groups at increased risk for disease. Methods: We applied machine learning to agnostically search for risk factors of varicose veins in 493,519 individuals in the UK Biobank. Predictors were further studied using univariable and multivariable Cox regression analysis (2,441 incident events). A genome-wide association study (GWAS) of varicose veins was also performed among 337,536 unrelated individuals (9,577 cases) of white British descent, followed by eQTL and pathway analyses. Because height emerged as a new candidate risk factor, we performed Mendelian randomization analyses to assess a potential causal role for height in varicose vein development. Results: Machine learning confirmed several known (age, sex, obesity, pregnancy, history of deep vein thrombosis) and identified several new risk factors for varicose vein disease, including height. After adjusting for traditional risk factors in Cox regression, greater height remained independently associated with varicose veins (HR for upper vs. lower quartile: 1·74; 95% CI: 1·51–2·01, P<0·0001). A GWAS identified 30 new genome-wide significant loci, identifying pathways involved in vascular development and skeletal/limb biology. Mendelian randomization analysis provided evidence that increased height is causally related to varicose veins (Inverse-variance weighted: OR=1·26; P=2·07×10−16). Conclusions: Using data from nearly half a million individuals, we present a comprehensive genetic and epidemiological study of varicose veins. We identified novel clinical and genetic risk factors which provide pathophysiological insights and could help future improvements of treatment of varicose vein disease.

BACKGROUND: Low birthweight has been associated with a higher risk of hypertension, type 2 diabetes mellitus (T2D), and cardiovascular disease. The Barker hypothesis posits that intrauterine growth restriction resulting in lower birthweight is causal for these diseases, but causality is difficult to infer from observational studies. METHODS: We performed regression analyses to assess associations of birthweight with cardiovascular disease and T2D in 237 631 individuals from the UK Biobank. Further, we assessed the causal relationship of such associations using Mendelian randomization. RESULTS: In the observational analyses, birthweight showed inverse associations with systolic and diastolic blood pressure (β, −0.83 and −0.26; per raw unit in outcomes and SD change in birthweight; 95% confidence interval [CI], −0.90 to −0.75 and −0.31 to −0.22, respectively), T2D (odds ratio, 0.83; 95% CI, 0.79−0.87), lipid-lowering treatment (odds ratio, 0.84; 95% CI, 0.81−0.86), and coronary artery disease (hazard ratio, 0.85; 95% CI, 0.78−0.94), whereas the associations with adult body mass index and body fat (β, 0.04 and 0.02; per SD change in outcomes and birthweight; 95% CI, 0.03−0.04 and 0.01−0.02, respectively) were positive. The Mendelian randomization analyses indicated inverse causal associations of birthweight with low-density lipoprotein cholesterol, 2-hour glucose, coronary artery disease, and T2D and positive causal association with body mass index but no associations with blood pressure. CONCLUSIONS: Our study indicates that lower birthweight, used as a proxy for intrauterine growth retardation, is causally related with increased susceptibility to coronary artery disease and T2D. This causal relationship is not mediated by adult obesity or hypertension.

Word count: 9,315 (main text); 318 (abstract) peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/208629 doi: bioRxiv preprint first posted online Oct. 25, 2017; Abstract Background: Low birthweight (BW) has been associated with a higher risk of

This study tries to find detectable signals of gene flow of Sub-Saharan origin into the Mediterranean in four genomic regions previously associated with coronary artery disease. A total of 366 single-nucleotide polymorphisms were genotyped in 772 individuals from 10 Mediterranean countries. Population structure analyses were performed, in which a noticeable Sub-Saharan component was found in the studied samples. The overall percentage of this Sub-Saharan component presents differences between the two Mediterranean coasts. D-statistics suggest possible Sub-Saharan introgression into one of the studied genomic regions (10q11). We also found differences in linkage disequilibrium patterns between the two Mediterranean coasts, possibly attributable to differential Sub-Saharan admixture. Our results confirm the potentially important role of human demographic history when performing epidemiological studies.