Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium

Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 × 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 × 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 × 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology

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

Large meta-analysis of genome-wide association studies identifies five loci for lean body mass

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 x 10(-8)) or suggestively genome wide (p < 2.3 x 10(-6)). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/ near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/ near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass

Economic impacts of overweight and obesity: current and future estimates for eight countries

BackgroundObesity is a growing public health challenge worldwide with significant health and economic impacts. However, much of what is known about the economic impacts of obesity comes from high-income countries and studies are not readily comparable due to methodological differences. Our objective is to demonstrate a method for estimating current and future national economic impacts of obesity and apply it across a sample of heterogeneous contexts globally.MethodsWe estimated economic impacts of overweight and obesity for eight countries using a cost-of-illness approach. Direct and indirect costs of obesity from 2019 to 2060 were estimated from a societal perspective as well as the effect of two hypothetical scenarios of obesity prevalence projections. Country-specific data were sourced from published studies and global databases.ResultsIn per capita terms, costs of obesity in 2019 ranged from US$17 in India to US$940 in Australia. These economic costs are comparable to 1.8% of gross domestic product (GDP) on average across the eight countries, ranging from 0.8% of GDP in India to 2.4% in Saudi Arabia. By 2060, with no significant changes to the status quo, the economic impacts from obesity are projected to grow to 3.6% of GDP on average ranging from 2.4% of GDP in Spain to 4.9% of GDP in Thailand. Reducing obesity prevalence by 5% from projected levels or keeping it at 2019 levels will translate into an average annual reduction of 5.2% and 13.2% in economic costs, respectively, between 2020 and 2060 across the eight countries.ConclusionOur findings demonstrate that the economic impacts of obesity are substantial across countries, irrespective of economic or geographical context and will increase over time if current trends continue. These findings strongly point to the need for advocacy to increase awareness of the societal impacts of obesity, and for policy actions to address the systemic roots of obesity.</jats:sec

Economic impacts of overweight and obesity: current and future estimates for 161 countries

IntroductionThe scope of the challenge of overweight and obesity (OAO) has not been fully realised globally, in part because much of what is known about the economic impacts of OAO come from high-income countries (HICs) and are not readily comparable due to methodological differences. Our objective is to estimate the current and future national economic impacts of OAO globally.MethodsWe estimated economic impacts of OAO for 161 countries using a cost-of-illness approach. Direct and indirect costs of OAO between 2019 and 2060 were estimated from a societal perspective. We assessed the effect of two hypothetical scenarios of OAO prevalence projections. Country-specific data were sourced from published studies and global databases.ResultsThe economic impact of OAO in 2019 is estimated at 2.19% of global gross domestic product (GDP) ranging on average from US$20 per capita in Africa to US$872 per capita in the Americas and from US$6 in low-income countries to US$1110 in HICs.If current trends continue, by 2060, the economic impacts from OAO are projected to rise to 3.29% of GDP globally. The biggest increase will be concentrated in lower resource countries with total economic costs increasing by fourfold between 2019 and 2060 in HICs, whereas they increase 12–25 times in low and middle-income countries. Reducing projected OAO prevalence by 5% annually from current trends or keeping it at 2019 levels will translate into average annual reductions of US$429 billion or US$2201 billion in costs, respectively, between 2020 and 2060 globally.ConclusionThis study provides novel evidence on the economic impact of OAO across different economic and geographic contexts. Our findings highlight the need for concerted and holistic action to address the global rise in OAO prevalence, to avert the significant risks of inaction and achieve the promise of whole-of-society gains in population well-being.</jats:sec