Abstract. This paper establishes a framework of a multi-risk context for analyzing acceptable risk beyond single-risk context and empirically examines how other risks affects flood risk acceptability based on Rational Action Paradigm (RAP) by using a survey conducted in the Toki-Shonai River region of Japan. The main findings obtained by cross-sectional analysis and covariance structure analysis within a multi-risk context can be summarized as follows. – Nearly half of the respondents accept no flood risk at all. – Flood risk acceptability depends on not only on the factors of flood risk itself (e.g. frequency, consequence, and characteristics), but also other types of risks involved in our technological society. – Flood risk acceptability is associated with a multi-risk context. Whether a risk is accepted depends on its perceived importance relative to others as well as the balance of its cost and benefit. Providing budget information and ensuring preparedness for flood risk may also affect the acceptability.
Background: Osteoporosis is diagnosed by the measurement of bone mineral density, which is a highly heritable and multifactorial trait. We aimed to identify genetic loci that are associated with bone mineral density. Methods: In this genome-wide association study, we identified the most promising of 314 075 single nucleotide polymorphisms (SNPs) in 2094 women in a UK study. We then tested these SNPs for replication in 6463 people from three other cohorts in western Europe. We also investigated allelic expression in lymphoblast cell lines. We tested the association between the replicated SNPs and osteoporotic fractures with data from two studies. Findings: We identified genome-wide evidence for an association between bone mineral density and two SNPs (p<5×10-8). The SNPs were rs4355801, on chromosome 8, near to the TNFRSF11B (osteoprotegerin) gene, and rs3736228, on chromosome 11 in the LRP5 (lipoprotein-receptor-related protein) gene. A non-synonymous SNP in the LRP5 gene was associated with decreased bone mineral density (rs3736228, p=6·3×10-12for lumbar spine and p=1·9×10-4for femoral neck) and an increased risk of both osteoporotic fractures (odds ratio [OR] 1·3, 95% CI 1·09-1·52, p=0·002) and osteoporosis (OR 1·3, 1·08-1·63, p=0·008). Three SNPs near the TNFRSF11B gene were associated with decreased bone mineral density (top SNP, rs4355801: p=7·6×10-10for lumbar spine and p=3·3×10-8for femoral neck) and increased risk of osteoporosis (OR 1·2, 95% CI 1·01-1·42, p=0·038). For carriers of the risk allele at rs4355801, expression of TNFRSF11B in lymphoblast cell lines was halved (p=3·0×10-6). 1883 (22%) of 8557 people were at least heterozygous for these risk alleles, and these alleles had a cumulative association with bone mineral density (trend p=2·3×10-17). The presence of both risk alleles increased the risk of osteoporotic fractures (OR 1·3, 1·08-1·63, p=0·006) and this effect was independent of bone mineral density. Interpretation: Two gene variants of key biological proteins increase the risk of osteoporosis and osteoporotic fracture. The combined effect of these risk alleles on fractures is similar to that of most well-replicated environmental risk factors, and they are present in more than one in five white people, suggesting a potential role in screening. Funding: Wellcome Trust, European Commission, NWO Investments, Arthritis Research Campaign, Chronic Disease Research Foundation, Canadian Institutes of Health Research, European Society for Clinical and Economic Aspects of Osteoporosis, Genome Canada, Genome Quebéc, Canada Research Chairs, National Health and Medical Research Council of Australia, and European Union.
Published ; Journal Article ; Meta-Analysis ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism. ; Intramural Research Program of the NIH ; NCRR ; NHLBI ; MedStar Research Institute ; NINDS ; National Center of Advancing Translational Technologies CTSI ; National Institute of Diabetes and Digestive and Kidney Diseases ; Robert Dawson Evans Endowment ; Italian Ministry of Health ; University and Research of the Autonomous Province of Bolzano ; European Union's Seventh Framework Programme ; ENGAGE project ; EPIGENESYS ; BLUEPRINT ; Dutch Innovation-Oriented Research Program on Genomics ; Netherlands Organization for Scientific Research (NWO) ; South Tyrolean Sparkasse Foundation ; Radboud University Nijmegen Medical Centre ; University of Maryland General Clinical Research Center ; Johns Hopkins University General Clinical Research Center ; Baltimore Veterans Administration Geriatric Research and Education Clinical Center (GRECC) ; Netherlands Research Institute for Diseases in the Elderly ; Erasmus Medical Center and Erasmus University, Rotterdam ; Netherlands Organization for the Health Research and Development (ZonMw) ; Dutch Ministry for Health, Welfare and Sports ; European Commission ; Municipality of Rotterdam ; German Bundesministerium fuer Forschung und Technology ; Wellcome Trust ; English Department of Health, National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre ; Canadian Institutes of Health Research, Canadian Foundation for Innovation ; Fonds de la Recherche en Santé Québec, Ministère du Développement Économique, de l'Innovation et de l'Exportation ; Lady Davis Institute of the Jewish General Hospital (JBR) ; Australian National Health and Medical Research Council ; Sir Charles Gairdner Hospital Research Fund ; Italian "Compagnia di San Paolo" ; Italian "Fondazione Cariplo" ; Leiden University Medical Centre ; Dutch Arthritis Association ; Pfizer, Groton, CT, USA ; Dutch Centre of Medical System Biology ; Netherlands Genomics Initiative (NGI), Netherlands Consortium of Healthy Aging ; Academy of Finland ; Finnish Diabetes Research Society ; Folkhälsan Research Foundation ; Novo Nordisk Foundation ; Finska Läkaresällskapet, Signe and Ane Gyllenberg Foundation ; University of Helsinki ; European Science Foundation (EUROSTRESS) ; Finnish Ministry of Education ; Ahokas Foundation ; Emil Aaltonen Foundation ; Juho Vainio Foundation ; BBSRC ; EPSRC ; ESRC ; MRC ; AXA Research Fund ; Help the Aged/Research Into Ageing (Disconnected Mind) ; Economic Structure Enhancing Fund (FES) of the Dutch government ; Dutch Ministry of Economic Affairs ; Dutch Ministry of Education, Culture and Science ; Northern Netherlands Collaboration of Provinces (SNN) ; Province of Groningen ; University of Groningen ; Dutch Kidney Foundation ; Dutch Diabetes Research Foundation ; Bristol-Myers Squibb ; Netherlands Heart Foundation ; National Computing Facilities Foundation (NCF), Netherlands ; Endocrine Research Fund
