Genetic Determinants of Circulating Estrogen Levels and Evidence of a Causal Effect of Estradiol on Bone Density in Men

Context: Serum estradiol (E2) and estrone (E1) levels exhibit substantial heritability.Objective: To investigate the genetic regulation of serum E2 and E1 in men.Design, Setting, and Participants: Genome-wide association study in 11,097 men of European origin from nine epidemiological cohorts.Main Outcome Measures: Genetic determinants of serum E2 and E1 levels.Results: Variants in/near CYP19A1 demonstrated the strongest evidence for association with E2, resolving to three independent signals. Two additional independent signals were found on the X chromosome; FAMily with sequence similarity 9, member B (FAM9B), rs5934505 (P = 3.4 × 10-8) and Xq27.3, rs5951794 (P = 3.1 × 10-10). E1 signals were found in CYP19A1 (rs2899472, P = 5.5 × 10-23), in Tripartite motif containing 4 (TRIM4; rs17277546, P = 5.8 × 10-14), and CYP11B1/B2 (rs10093796, P = 1.2 × 10-8). E2 signals in CYP19A1 and FAM9B were associated with bone mineral density (BMD). Mendelian randomization analysis suggested a causal effect of serum E2 on BMD in men. A 1 pg/mL genetically increased E2 was associated with a 0.048 standard deviation increase in lumbar spine BMD (P = 2.8 × 10-12). In men and women combined, CYP19A1 alleles associated with higher E2 levels were associated with lower degrees of insulin resistance.Conclusions: Our findings confirm that CYP19A1 is an important genetic regulator of E2 and E1 levels and strengthen the causal importance of E2 for bone health in men. We also report two independent loci on the X-chromosome for E2, and one locus each in TRIM4 and CYP11B1/B2, for E1

London calling?: Preferred emigration destinations among Icelandic youth

Post-print (lokagerð höfundar)Preferred emigration destinations among adolescents reflect images and stereotypes of other countries that continuously emerge in a multitude of local and global discourses and from concrete experiences with other countries. The affinities of Icelandic adolescents are split between the islands of the Northern Atlantic, continental Nordic countries, European core countries, and North American countries. If they had to leave Iceland, however, the largest proportion of Icelandic adolescents would want to move to the United States. Girls are more likely to choose the Nordic countries, in particular Denmark, while boys are more likely to choose English-speaking countries with a reputation for economic and military power such as the United States and England. Adolescents are more likely to prefer migrating to Europe rather than North America if they are proud of their Icelandic nationality, live in cohesive communities, have more educated parents, and feel closer to Europe. Adolescents who want to move abroad are in contrast most likely to have North American destinations in mind. Recent geopolitical changes may however shift the attention of Icelandic adolescents eastward towards the European continent.This article has benefited greatly from extensive discussions with Atli Hafthorsson, Brynhildur Thorarinsdottir, Kjartan Olafsson and Michael S. Gibbons, and from the pioneering scholarship of Professor Thorbjorn Broddason. The data collection was in part made possible by a grant from the University of Akureyri Research Fund.Peer Reviewe

Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Peer reviewe