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

Cardiovascular disease, chronic kidney disease, and diabetes mortality burden of cardiometabolic risk factors from 1980 to 2010: A comparative risk assessment

Background: High blood pressure, blood glucose, serum cholesterol, and BMI are risk factors for cardiovascular diseases and some of these factors also increase the risk of chronic kidney disease and diabetes. We estimated mortality from cardiovascular diseases, chronic kidney disease, and diabetes that was attributable to these four cardiometabolic risk factors for all countries and regions from 1980 to 2010. Methods: We used data for exposure to risk factors by country, age group, and sex from pooled analyses of population-based health surveys. We obtained relative risks for the effects of risk factors on cause-specific mortality from meta-analyses of large prospective studies. We calculated the population attributable fractions for each risk factor alone, and for the combination of all risk factors, accounting for multicausality and for mediation of the effects of BMI by the other three risks. We calculated attributable deaths by multiplying the cause-specific population attributable fractions by the number of disease-specific deaths. We obtained cause-specific mortality from the Global Burden of Diseases, Injuries, and Risk Factors 2010 Study. We propagated the uncertainties of all the inputs to the final estimates. Findings: In 2010, high blood pressure was the leading risk factor for deaths due to cardiovascular diseases, chronic kidney disease, and diabetes in every region, causing more than 40% of worldwide deaths from these diseases; high BMI and glucose were each responsible for about 15% of deaths, and high cholesterol for more than 10%. After accounting for multicausality, 63% (10·8 million deaths, 95% CI 10·1-11·5) of deaths from these diseases in 2010 were attributable to the combined effect of these four metabolic risk factors, compared with 67% (7·1 million deaths, 6·6-7·6) in 1980. The mortality burden of high BMI and glucose nearly doubled from 1980 to 2010. At the country level, age-standardised death rates from these diseases attributable to the combined effects of these four risk factors surpassed 925 deaths per 100 000 for men in Belarus, Kazakhstan, and Mongolia, but were less than 130 deaths per 100 000 for women and less than 200 for men in some high-income countries including Australia, Canada, France, Japan, the Netherlands, Singapore, South Korea, and Spain. Interpretation: The salient features of the cardiometabolic disease and risk factor epidemic at the beginning of the 21st century are high blood pressure and an increasing effect of obesity and diabetes. The mortality burden of cardiometabolic risk factors has shifted from high-income to low-income and middle-income countries. Lowering cardiometabolic risks through dietary, behavioural, and pharmacological interventions should be a part of the global response to non-communicable diseases. Funding: UK Medical Research Council, US National Institutes of Health. © 2014 Elsevier Ltd

The role of Gdf5 regulatory regions in development of hip morphology.

Given GDF5 involvement in hip development, and osteoarthritis (OA) and developmental hip dysplasia (DDH) risk, here we sought to assess the role(s) of GDF5 and its regulatory sequence on the development of hip morphology linked to injury risk. The brachypodism (bp) mouse, which harbors a Gdf5 inactivating mutation, was used to survey how Gdf5 loss of function impacts the development of hip morphology. Two transgenic Gdf5 reporter BAC lines were used to assess the spatiotemporal expression of Gdf5 regulatory sequences. Each BAC line was also used to assess the functional roles of upstream and downstream sequence on hip morphology. bp/bp mice had shorter femora with smaller femoral heads and necks as well as larger alpha angles, smaller anterior offsets, and smaller acetabula, compared to bp/+ mice (p<0.04). Regulatory sequences downstream of Gdf5 drove strong prenatal (E17) expression and low postnatal (6 months) expression across regions of femoral head and acetabulum. Conversely, upstream regulatory sequences drove very low expression at E17 and no detectable expression at 6 months. Importantly, downstream, but not upstream Gdf5 regulatory sequences fully restored all the key morphologic features disrupted in bp/bp mice. Hip morphology is profoundly affected by Gdf5 absence, and downstream regulatory sequences mediate its effects by controlling Gdf5 expression during development. This downstream region contains numerous enhancers harboring risk variants related to hip OA, DDH, and dislocation. We posit that subtle alterations to morphology driven by changes in downstream regulatory sequence underlie this locus' role in hip injury risk

Aggression and second-to-fourth digit ratio (2D:4D) among second year students of DLSHSI College of Medicine, S.Y. 2014-2015

This cross-sectional study investigates the relationship of aggression and second-to-fourth digit ratio (2D:4D) among randomly selected second year medical students of DLSHSI. Ninety (90) male and ninety-four (94) female respondents aged 18-26 were assessed to determine the relationship between aggression, assessed using the Buss and Perry Aggression Questionnaire, and second-to-fourth digit ration (2D:4D), taken from digital measurement of hand scans. There was no association found between 2D:4D and BPAQ scores upon Pearson correlation coefficient analysis. It was found that there was a significant difference in the level of physical aggression in both genders but no significant difference in level of aggression of males and females in terms of physical, verbal, hostility, and anger traits as well as the total level of aggression. It was also noted that left and right 2D:4D was significantly different among the genders (p=0.0003;0.004)

The developmental impacts of natural selection on human pelvic morphology

Evolutionary responses to selection for bipedalism and childbirth have shaped the human pelvis, a structure that differs substantially from that in apes. Morphology related to these factors is present by birth, yet the developmental-genetic mechanisms governing pelvic shape remain largely unknown. Here, we pinpoint and characterize a key gestational window when human-specific pelvic morphology becomes recognizable, as the ilium and the entire pelvis acquire traits essential for human walking and birth. We next use functional genomics to molecularly characterize chondrocytes from different pelvic subelements during this window to reveal their developmental-genetic architectures. We then find notable evidence of ancient selection and genetic constraint on regulatory sequences involved in ilium expansion and growth, findings complemented by our phenotypic analyses showing that variation in iliac traits is reduced in humans compared to African apes. Our datasets provide important resources for musculoskeletal biology and begin to elucidate developmental mechanisms that shape human-specific morphology