| 1. |
- Estrada, Karol, et al.
(författare)
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Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.
- 2012
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:5, s. 491-501
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Tidskriftsartikel (refereegranskat)abstract
- Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
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| 2. |
- Lu, Yingchang, et al.
(författare)
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New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.
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| 3. |
- Zheng, Hou-Feng, et al.
(författare)
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Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 526:7571, s. 112-
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Tidskriftsartikel (refereegranskat)abstract
- The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF <= 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants(1-8), as well as rare, population specific, coding variants(9). Here we identify novel non-coding genetic variants with large effects on BMD (n(total) = 53,236) and fracture (n(total) = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD8 (rs11692564(T), MAF51.6%, replication effect size510.20 s.d., P-meta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size +10.41 s.d., P-meta = 1 x 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.
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| 4. |
- Bentham, James, et al.
(författare)
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A century of trends in adult human height
- 2016
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Ingår i: eLIFE. - 2050-084X. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.522.7) and 16.5 cm (13.319.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries.
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| 5. |
- Bentham, James, et al.
(författare)
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A century of trends in adult human height
- 2016
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Ingår i: eLIFE. - : eLife Sciences Publications Ltd. - 2050-084X. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.5–22.7) and 16.5 cm (13.3– 19.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8– 144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries.
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| 6. |
- Danaei, Goodarz, et al.
(författare)
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Effects of diabetes definition on global surveillance of diabetes prevalence and diagnosis: a pooled analysis of 96 population-based studies with 331288 participants
- 2015
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Ingår i: The Lancet Diabetes & Endocrinology. - 2213-8595 .- 2213-8587. ; 3:8, s. 624-637
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Tidskriftsartikel (refereegranskat)abstract
- Background Diabetes has been defined on the basis of different biomarkers, including fasting plasma glucose (FPG), 2-h plasma glucose in an oral glucose tolerance test (2hOGTT), and HbA(1c). We assessed the effect of different diagnostic definitions on both the population prevalence of diabetes and the classification of previously undiagnosed individuals as having diabetes versus not having diabetes in a pooled analysis of data from population-based health examination surveys in different regions. Methods We used data from 96 population-based health examination surveys that had measured at least two of the biomarkers used for defining diabetes. Diabetes was defined using HbA(1c) (HbA(1c) >= 6 . 5% or history of diabetes diagnosis or using insulin or oral hypoglycaemic drugs) compared with either FPG only or FPG-or-2hOGTT definitions (FPG >= 7 . 0 mmol/L or 2hOGTT >= 11 . 1 mmol/L or history of diabetes or using insulin or oral hypoglycaemic drugs). We calculated diabetes prevalence, taking into account complex survey design and survey sample weights. We compared the prevalences of diabetes using different definitions graphically and by regression analyses. We calculated sensitivity and specificity of diabetes diagnosis based on HbA1c compared with diagnosis based on glucose among previously undiagnosed individuals (ie, excluding those with history of diabetes or using insulin or oral hypoglycaemic drugs). We calculated sensitivity and specificity in each survey, and then pooled results using a random-effects model. We assessed the sources of heterogeneity of sensitivity by meta-regressions for study characteristics selected a priori. Findings Population prevalence of diabetes based on FPG- or-2hOGTT was correlated with prevalence based on FPG alone (r= 0 . 98), but was higher by 2-6 percentage points at different prevalence levels. Prevalence based on HbA(1c) was lower than prevalence based on FPG in 42 . 8% of age-sex-survey groups and higher in another 41 . 6%; in the other 15 . 6%, the two definitions provided similar prevalence estimates. The variation across studies in the relation between glucose-based and HbA(1c)-based prevalences was partly related to participants' age, followed by natural logarithm of per person gross domestic product, the year of survey, mean BMI, and whether the survey population was national, subnational, or from specific communities. Diabetes defined as HbA(1c) 6 . 5% or more had a pooled sensitivity of 52 . 8% (95% CI 51 . 3-54 . 3%) and a pooled specificity of 99 . 74% (99 . 71-99 . 78%) compared with FPG 7 . 0 mmol/L or more for diagnosing previously undiagnosed participants; sensitivity compared with diabetes defined based on FPG-or-2hOGTT was 30 . 5% (28 . 7-32 . 3%). None of the preselected study-level characteristics explained the heterogeneity in the sensitivity of HbA(1c) versus FPG. Interpretation Different biomarkers and definitions for diabetes can provide different estimates of population prevalence of diabetes, and differentially identify people without previous diagnosis as having diabetes. Using an HbA(1c)-based definition alone in health surveys will not identify a substantial proportion of previously undiagnosed people who would be considered as having diabetes using a glucose-based test.
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| 7. |
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| 8. |
- Schmidt, Amand F., et al.
(författare)
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Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9
- 2019
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Ingår i: BMC Cardiovascular Disorders. - : BMC. - 1471-2261 .- 1471-2261. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.
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| 9. |
- Zhou, Bin, et al.
(författare)
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Worldwide trends in diabetes since 1980: A pooled analysis of 751 population-based studies with 4.4 million participants
- 2016
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Ingår i: The Lancet. - : Elsevier B.V.. - 0140-6736 .- 1474-547X. ; 387:10027, s. 1513-1530
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Tidskriftsartikel (refereegranskat)abstract
- Background: One of the global targets for non-communicable diseases is to halt, by 2025, the rise in the age standardised adult prevalence of diabetes at its 2010 levels. We aimed to estimate worldwide trends in diabetes, how likely it is for countries to achieve the global target, and how changes in prevalence, together with population growth and ageing, are aff ecting the number of adults with diabetes.Methods: We pooled data from population-based studies that had collected data on diabetes through measurement of its biomarkers. We used a Bayesian hierarchical model to estimate trends in diabetes prevalence-defined as fasting plasma glucose of 7.0 mmol/L or higher, or history of diagnosis with diabetes, or use of insulin or oral hypoglycaemic drugs-in 200 countries and territories in 21 regions, by sex and from 1980 to 2014. We also calculated the posterior probability of meeting the global diabetes target if post-2000 trends continue.Findings: We used data from 751 studies including 4372000 adults from 146 of the 200 countries we make estimates for. Global age-standardised diabetes prevalence increased from 4.3% (95% credible interval 2.4-17.0) in 1980 to 9.0% (7.2-11.1) in 2014 in men, and from 5.0% (2.9-7.9) to 7.9% (6.4-9.7) in women. The number of adults with diabetes in the world increased from 108 million in 1980 to 422 million in 2014 (28.5% due to the rise in prevalence, 39.7% due to population growth and ageing, and 31.8% due to interaction of these two factors). Age-standardised adult diabetes prevalence in 2014 was lowest in northwestern Europe, and highest in Polynesia and Micronesia, at nearly 25%, followed by Melanesia and the Middle East and north Africa. Between 1980 and 2014 there was little change in age-standardised diabetes prevalence in adult women in continental western Europe, although crude prevalence rose because of ageing of the population. By contrast, age-standardised adult prevalence rose by 15 percentage points in men and women in Polynesia and Micronesia. In 2014, American Samoa had the highest national prevalence of diabetes (>30% in both sexes), with age-standardised adult prevalence also higher than 25% in some other islands in Polynesia and Micronesia. If post-2000 trends continue, the probability of meeting the global target of halting the rise in the prevalence of diabetes by 2025 at the 2010 level worldwide is lower than 1% for men and is 1% for women. Only nine countries for men and 29 countries for women, mostly in western Europe, have a 50% or higher probability of meeting the global target.Interpretation: Since 1980, age-standardised diabetes prevalence in adults has increased, or at best remained unchanged, in every country. Together with population growth and ageing, this rise has led to a near quadrupling of the number of adults with diabetes worldwide. The burden of diabetes, both in terms of prevalence and number of adults aff ected, has increased faster in low-income and middle-income countries than in high-income countries.
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