Meta-Analysis of Genomewide Association Studies Reveals Genetic Variants for Hip Bone Geometry

Hip geometry is an important predictor of fracture. We performed a meta-analysis of GWAS studies in adults to identify genetic variants that are associated with proximal femur geometry phenotypes. We analyzed four phenotypes: (i) femoral neck length; (ii) neck-shaft angle; (iii) femoral neck width, and (iv) femoral neck section modulus, estimated from DXA scans using algorithms of hip structure analysis. In the Discovery stage, 10 cohort studies were included in the fixed-effect meta-analysis, with up to 18,719 men and women ages 16 to 93 years. Association analyses were performed with ∼2.5 million polymorphisms under an additive model adjusted for age, body mass index, and height. Replication analyses of meta-GWAS significant loci (at adjusted genomewide significance [GWS], threshold p ≤ 2.6 × 10 –8 ) were performed in seven additional cohorts in silico. We looked up SNPs associated in our analysis, for association with height, bone mineral density (BMD), and fracture. In meta-analysis (combined Discovery and Replication stages), GWS associations were found at 5p15 (IRX1 and ADAMTS16); 5q35 near FGFR4; at 12p11 (in CCDC91); 11q13 (near LRP5 and PPP6R3 (rs7102273)). Several hip geometry signals overlapped with BMD, including LRP5 (chr. 11). Chr. 11 SNP rs7102273 was associated with any-type fracture (p = 7.5 × 10 –5 ). We used bone transcriptome data and discovered several significant eQTLs, including rs7102273 and PPP6R3 expression (p = 0.0007), and rs6556301 (intergenic, chr.5 near FGFR4) and PDLIM7 expression (p = 0.005). In conclusion, we found associations between several genes and hip geometry measures that explained 12% to 22% of heritability at different sites. The results provide a defined set of genes related to biological pathways relevant to BMD and etiology of bone fragility

Assessment of gene-by-sex interaction effect on bone mineral density

To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field.Sexual dimorphism in various bone phenotypes, including bone mineral density (BMD), is widely observed; however, the extent to which genes explain these sex differences is unclear. To identify variants with different effects by sex, we examined gene-by-sex autosomal interactions genome-wide, and performed expression quantitative trait loci (eQTL) analysis and bioinformatics network analysis. We conducted an autosomal genome-wide meta-analysis of gene-by-sex interaction on lumbar spine (LS) and femoral neck (FN) BMD in 25,353 individuals from 8 cohorts. In a second stage, we followed up the 12 top single-nucleotide polymorphisms (SNPs; p < 1 × 10(-5) ) in an additional set of 24,763 individuals. Gene-by-sex interaction and sex-specific effects were examined in these 12 SNPs. We detected one novel genome-wide significant interaction associated with LS-BMD at the Chr3p26.1-p25.1 locus, near the GRM7 gene (male effect = 0.02 and p = 3.0 × 10(-5) ; female effect = -0.007 and p = 3.3 × 10(-2) ), and 11 suggestive loci associated with either FN- or LS-BMD in discovery cohorts. However, there was no evidence for genome-wide significant (p < 5 × 10(-8) ) gene-by-sex interaction in the joint analysis of discovery and replication cohorts. Despite the large collaborative effort, no genome-wide significant evidence for gene-by-sex interaction was found to influence BMD variation in this screen of autosomal markers. If they exist, gene-by-sex interactions for BMD probably have weak effects, accounting for less than 0.08% of the variation in these traits per implicated SNP. © 2012 American Society for Bone and Mineral Research.Medtronic NIH R01 AG18728 R01HL088119 R01AR046838 U01 HL084756 R01 AR43351 P01-HL45522 R01-MH-078111 R01-MH-083824 Nutrition and Obesity Research Center of Maryland P30DK072488 NIAMS/NIH F32AR059469 Instituto de Salud Carlos III-FIS (Spanish Health Ministry) PI 06/0034 PI08/0183 Canadian Institutes of Health Research (CIHR) NHLBI HHSN268201200036C N01-HC-85239 N01-HC-85079 N01-HC-85086 N01-HC-35129 N01 HC15103 N01 HC-55222 N01-HC-75150 N01-HC-45133 HL080295 HL087652 HL105756 NIA AG-023629 AG-15928 AG-20098 AG-027058 N01AG62101 N01AG62103 N01AG62106 1R01AG032098-01A1 National Center of Advancing Translational Technologies CTSI UL1TR000124 National Institute of Diabetes and Digestive and Kidney Diseases DK063491 EUROSPAN (European Special Populations Research Network) European Commission FP6 STRP grant 018947 LSHG-CT-2006-01947 Netherlands Organisation for Scientific Research Erasmus MC Centre for Medical Systems Biology (CMSB) Netherlands Brain Foundation (HersenStichting Nederland) US National Institute for Arthritis, Musculoskeletal and Skin Diseases National Institute on Aging R01 AR/AG41398 R01 AR050066 R21 AR056405 National Heart, Lung, and Blood Institute's Framingham Heart Study N01-HC-25195 Affymetrix, Inc. N02-HL-6-4278 Canadian Institutes of Health Research from Institute of Aging 165446 Institute of Genetics 179433 Institute of Musculoskeletal health 221765 Intramural Research Program of the NIH, National Institute on Aging National Institutes of Health HHSN268200782096C Hong Kong Research Grant Council HKU 768610M Bone Health Fund of HKU Foundation KC Wong Education Foundation Small Project Funding 201007176237 Matching Grant CRCG Grant Osteoporosis and Endocrine Research Fund Genomics Strategic Research Theme of The University of Hong Kong Netherlands Organisation of Scientific Research NWO Investments 175.010.2005.011 911-03-012 Research Institute for Diseases in the Elderly 014-93-015 Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) 050-060-810 Erasmus Medical Center and Erasmus University, Rotterdam Netherlands Organization for the Health Research and Development (ZonMw) Research Institute for Diseases in the Elderly (RIDE) Ministry of Education, Culture and Science Ministry for Health, Welfare and Sports European Commission (DG XII) Municipality of Rotterdam German Bundesministerium fur Forschung und Technology 01 AK 803 A-H 01 IG 07015

Genetic Sharing with Cardiovascular Disease Risk Factors and Diabetes Reveals Novel Bone Mineral Density Loci.

Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Probabilistic Models for Cyclic Straining of Saturated Clean Sands

A maximum likelihood framework for the probabilistic assessment of postcyclic straining of saturated clean sands is described. Databases consisting of cyclic laboratory test results including maximum shear and postcyclic volumetric strains in conjunction with relative density, number of stress (strain) cycles, and "index" test results were used for the development of probabilistically based postcyclic strain correlations. For this purpose, in addition to the compilation of existing data from literature, a series of stress-controlled cyclic triaxial and simple shear tests were performed on laboratory-constituted saturated clean sand specimens. The variabilities in testing conditions (i.e., type of test, consolidation procedure, confining pressure, rate of loading, etc.) were corrected through a series of correction schemes, the effectiveness of which were later confirmed by the discriminant analyses results. Volumetric and shear strain boundary curves were developed in the cyclic stress ratio versus N-1,N-60,N-CS or q(c,1) domain. In addition to being based on significantly extended and higher quality databases, contrary to the existing judgmentally derived deterministic ones, proposed correlations have formal probabilistic bases, and so provide insight regarding uncertainty of strain predictions or probability of exceeding a target strain value. Probabilistic uses of the proposed correlations were illustrated by three sets of examples. A companion paper applied and calibrated the proposed volumetric strain correlation to semiempirically evaluate postearthquake settlement of level, free-field sites. For the calibration, case history soil profiles, composed of a broad range of sand types and depositional characteristics, shaken by a number of earthquakes, were used. Superior predictions of field settlements by this laboratory data-based cyclic strain assessment approach were concluded to be strongly mutually supportive

Probabilistic Model for the Assessment of Cyclically Induced Reconsolidation (Volumetric) Settlements

A maximum likelihood framework for the probabilistic assessment of cyclically induced reconsolidation settlements of saturated cohesionless soil sites is described. For this purpose, over 200 case history sites were carefully studied. After screening for data quality and completeness, the resulting database is composed of 49 high-quality, cyclically induced ground settlement case histories from seven different earthquakes. For these case history sites, settlement predictions by currently available methods of Tokimatsu and Seed (1984), Ishihara and Yoshimine (1992), Shamoto (1998), and Wu and Seed (2004) are presented comparatively, along with the predictions of the proposed probabilistic model. As an integral part of the proposed model, the volumetric strain correlation presented in the companion paper is used. The accuracy of the mean predictions as well as their uncertainty is assessed by both linear regression and maximum likelihood methodologies. The analyses results revealed that (1) the predictions of Shamoto and Tokimatsu and Seed are smaller than the actual settlements and need to be calibrated by a factor of 1.93 and 1.45, respectively; and (2) Ishihara and Yoshimine, and Wu and Seed predictions are higher than the actual settlements and need to be calibrated by a factor of 0.90 and 0.98, respectively. The Wu and Seed procedure produced the most unbiased estimates of mean settlements [i.e., their calibration coefficient (0.98) is the closest to unity], but the uncertainty (scatter) of their predictions remains high as revealed by the second to last smaller R(2) value, or relatively higher standard deviation (sigma(epsilon)) of the model error. In addition to superior model predictions, the main advantage of the proposed methodology is the probabilistic nature of the calibration scheme, which enables incorporation of the model uncertainty into mean settlement predictions. To illustrate the potential use of the proposed model, the probability of cyclically induced reconsolidation settlement of a site after a scenario earthquake to be less than a threshold settlement level is assessed

Recent Advances in Soil Liquefaction Engineering: A Unified and Consistent Framework

Over the past decade, major advances have occurred in both understanding and practice with regard to assessment and mitigation of hazard associated with seismically induced soil liquefaction. Soil liquefaction engineering has evolved into a sub-field in its own right, and engineering assessment and mitigation of seismic soil liquefaction hazard is increasingly well addressed in both research and practice. This rapid evolution in the treatment of liquefaction has been pushed largely by a confluence of lessons and data provided by a series of major earthquakes over the past dozen years, as well as by the research and professional/political will engendered by these major seismic events. The overall field of soil liquefaction engineering is now beginning to coalesce into an internally consistent and comprehensive framework, and one in which the various elements are increasingly mutually supportive of each other. Although the rate of progress has been laudable, further advances are occurring, and more remains to be done. As we enter a “new millenium”, engineers are increasingly well able to deal with important aspects of soil liquefaction engineering. This paper will highlight a number of important recent and ongoing developments in soil liquefaction engineering, and will offer insights regarding research in progress, as well as suggestions regarding further advances needed