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2.
  • Wang, Haidong, et al. (author)
  • Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015 : a systematic analysis for the Global Burden of Disease Study 2015
  • 2016
  • In: The Lancet. - 0140-6736 .- 1474-547X. ; 388:10053, s. 1459-1544
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Improving survival and extending the longevity of life for all populations requires timely, robust evidence on local mortality levels and trends. The Global Burden of Disease 2015 Study (GBD 2015) provides a comprehensive assessment of all-cause and cause-specific mortality for 249 causes in 195 countries and territories from 1980 to 2015. These results informed an in-depth investigation of observed and expected mortality patterns based on sociodemographic measures.METHODS: We estimated all-cause mortality by age, sex, geography, and year using an improved analytical approach originally developed for GBD 2013 and GBD 2010. Improvements included refinements to the estimation of child and adult mortality and corresponding uncertainty, parameter selection for under-5 mortality synthesis by spatiotemporal Gaussian process regression, and sibling history data processing. We also expanded the database of vital registration, survey, and census data to 14 294 geography-year datapoints. For GBD 2015, eight causes, including Ebola virus disease, were added to the previous GBD cause list for mortality. We used six modelling approaches to assess cause-specific mortality, with the Cause of Death Ensemble Model (CODEm) generating estimates for most causes. We used a series of novel analyses to systematically quantify the drivers of trends in mortality across geographies. First, we assessed observed and expected levels and trends of cause-specific mortality as they relate to the Socio-demographic Index (SDI), a summary indicator derived from measures of income per capita, educational attainment, and fertility. Second, we examined factors affecting total mortality patterns through a series of counterfactual scenarios, testing the magnitude by which population growth, population age structures, and epidemiological changes contributed to shifts in mortality. Finally, we attributed changes in life expectancy to changes in cause of death. We documented each step of the GBD 2015 estimation processes, as well as data sources, in accordance with Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER).FINDINGS: Globally, life expectancy from birth increased from 61·7 years (95% uncertainty interval 61·4-61·9) in 1980 to 71·8 years (71·5-72·2) in 2015. Several countries in sub-Saharan Africa had very large gains in life expectancy from 2005 to 2015, rebounding from an era of exceedingly high loss of life due to HIV/AIDS. At the same time, many geographies saw life expectancy stagnate or decline, particularly for men and in countries with rising mortality from war or interpersonal violence. From 2005 to 2015, male life expectancy in Syria dropped by 11·3 years (3·7-17·4), to 62·6 years (56·5-70·2). Total deaths increased by 4·1% (2·6-5·6) from 2005 to 2015, rising to 55·8 million (54·9 million to 56·6 million) in 2015, but age-standardised death rates fell by 17·0% (15·8-18·1) during this time, underscoring changes in population growth and shifts in global age structures. The result was similar for non-communicable diseases (NCDs), with total deaths from these causes increasing by 14·1% (12·6-16·0) to 39·8 million (39·2 million to 40·5 million) in 2015, whereas age-standardised rates decreased by 13·1% (11·9-14·3). Globally, this mortality pattern emerged for several NCDs, including several types of cancer, ischaemic heart disease, cirrhosis, and Alzheimer's disease and other dementias. By contrast, both total deaths and age-standardised death rates due to communicable, maternal, neonatal, and nutritional conditions significantly declined from 2005 to 2015, gains largely attributable to decreases in mortality rates due to HIV/AIDS (42·1%, 39·1-44·6), malaria (43·1%, 34·7-51·8), neonatal preterm birth complications (29·8%, 24·8-34·9), and maternal disorders (29·1%, 19·3-37·1). Progress was slower for several causes, such as lower respiratory infections and nutritional deficiencies, whereas deaths increased for others, including dengue and drug use disorders. Age-standardised death rates due to injuries significantly declined from 2005 to 2015, yet interpersonal violence and war claimed increasingly more lives in some regions, particularly in the Middle East. In 2015, rotaviral enteritis (rotavirus) was the leading cause of under-5 deaths due to diarrhoea (146 000 deaths, 118 000-183 000) and pneumococcal pneumonia was the leading cause of under-5 deaths due to lower respiratory infections (393 000 deaths, 228 000-532 000), although pathogen-specific mortality varied by region. Globally, the effects of population growth, ageing, and changes in age-standardised death rates substantially differed by cause. Our analyses on the expected associations between cause-specific mortality and SDI show the regular shifts in cause of death composition and population age structure with rising SDI. Country patterns of premature mortality (measured as years of life lost [YLLs]) and how they differ from the level expected on the basis of SDI alone revealed distinct but highly heterogeneous patterns by region and country or territory. Ischaemic heart disease, stroke, and diabetes were among the leading causes of YLLs in most regions, but in many cases, intraregional results sharply diverged for ratios of observed and expected YLLs based on SDI. Communicable, maternal, neonatal, and nutritional diseases caused the most YLLs throughout sub-Saharan Africa, with observed YLLs far exceeding expected YLLs for countries in which malaria or HIV/AIDS remained the leading causes of early death.INTERPRETATION: At the global scale, age-specific mortality has steadily improved over the past 35 years; this pattern of general progress continued in the past decade. Progress has been faster in most countries than expected on the basis of development measured by the SDI. Against this background of progress, some countries have seen falls in life expectancy, and age-standardised death rates for some causes are increasing. Despite progress in reducing age-standardised death rates, population growth and ageing mean that the number of deaths from most non-communicable causes are increasing in most countries, putting increased demands on health systems.
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  • 2019
  • Journal article (peer-reviewed)
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4.
  • Bentham, James, et al. (author)
  • A century of trends in adult human height
  • 2016
  • In: eLIFE. - 2050-084X. ; 5
  • Journal article (peer-reviewed)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. (author)
  • A century of trends in adult human height
  • 2016
  • In: eLIFE. - : eLife Sciences Publications Ltd. - 2050-084X. ; 5
  • Journal article (peer-reviewed)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. (author)
  • Effects of diabetes definition on global surveillance of diabetes prevalence and diagnosis: a pooled analysis of 96 population-based studies with 331288 participants
  • 2015
  • In: The Lancet Diabetes & Endocrinology. - 2213-8595 .- 2213-8587. ; 3:8, s. 624-637
  • Journal article (peer-reviewed)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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8.
  • Lahrouchi, Najim, et al. (author)
  • Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome
  • 2020
  • In: Circulation. - : Lippincott Williams & Wilkins. - 0009-7322 .- 1524-4539. ; 142:4, s. 324-338
  • Journal article (peer-reviewed)abstract
    • Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. Results: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (P<5x10(-8)) nearNOS1AP,KCNQ1, andKLF12, and 1 missense variant inKCNE1(p.Asp85Asn) at the suggestive threshold (P<10(-6)). Heritability analyses showed that approximate to 15% of variance in overall LQTS susceptibility was attributable to common genetic variation (h2SNP0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r(g)=0.40;P=3.2x10(-3)). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (P<10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (P<0.005). Conclusions: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.
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9.
  • Zhou, Bin, et al. (author)
  • Worldwide trends in diabetes since 1980: A pooled analysis of 751 population-based studies with 4.4 million participants
  • 2016
  • In: The Lancet. - : Elsevier B.V.. - 0140-6736 .- 1474-547X. ; 387:10027, s. 1513-1530
  • Journal article (peer-reviewed)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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10.
  • Allentoft, Morten E., et al. (author)
  • Population genomics of post-glacial western Eurasia
  • 2024
  • In: Nature. - 0028-0836 .- 1476-4687. ; 625:7994, s. 301-311
  • Journal article (peer-reviewed)abstract
    • Western Eurasia witnessed several large-scale human migrations during the Holocene1–5. Here, to investigate the cross-continental effects of these migrations, we shotgun-sequenced 317 genomes—mainly from the Mesolithic and Neolithic periods—from across northern and western Eurasia. These were imputed alongside published data to obtain diploid genotypes from more than 1,600 ancient humans. Our analyses revealed a ‘great divide’ genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers were highly genetically differentiated east and west of this zone, and the effect of the neolithization was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacement of hunter-gatherers in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness decreased in the west from the Neolithic transition onwards, whereas, east of the Urals, relatedness remained high until around 4,000 bp, consistent with the persistence of localized groups of hunter-gatherers. The boundary dissolved when Yamnaya-related ancestry spread across western Eurasia around 5,000 bp, resulting in a second major turnover that reached most parts of Europe within a 1,000-year span. The genetic origin and fate of the Yamnaya have remained elusive, but we show that hunter-gatherers from the Middle Don region contributed ancestry to them. Yamnaya groups later admixed with individuals associated with the Globular Amphora culture before expanding into Europe. Similar turnovers occurred in western Siberia, where we report new genomic data from a ‘Neolithic steppe’ cline spanning the Siberian forest steppe to Lake Baikal. These prehistoric migrations had profound and lasting effects on the genetic diversity of Eurasian populations.
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11.
  • Duncanson, Laura, et al. (author)
  • Aboveground biomass density models for NASA's Global Ecosystem Dynamics Investigation (GEDI) lidar mission
  • 2022
  • In: Remote Sensing of Environment. - : Elsevier BV. - 0034-4257 .- 1879-0704. ; 270
  • Journal article (peer-reviewed)abstract
    • NASA's Global Ecosystem Dynamics Investigation (GEDI) is collecting spaceborne full waveform lidar data with a primary science goal of producing accurate estimates of forest aboveground biomass density (AGBD). This paper presents the development of the models used to create GEDI's footprint-level (~25 m) AGBD (GEDI04_A) product, including a description of the datasets used and the procedure for final model selection. The data used to fit our models are from a compilation of globally distributed spatially and temporally coincident field and airborne lidar datasets, whereby we simulated GEDI-like waveforms from airborne lidar to build a calibration database. We used this database to expand the geographic extent of past waveform lidar studies, and divided the globe into four broad strata by Plant Functional Type (PFT) and six geographic regions. GEDI's waveform-to-biomass models take the form of parametric Ordinary Least Squares (OLS) models with simulated Relative Height (RH) metrics as predictor variables. From an exhaustive set of candidate models, we selected the best input predictor variables, and data transformations for each geographic stratum in the GEDI domain to produce a set of comprehensive predictive footprint-level models. We found that model selection frequently favored combinations of RH metrics at the 98th, 90th, 50th, and 10th height above ground-level percentiles (RH98, RH90, RH50, and RH10, respectively), but that inclusion of lower RH metrics (e.g. RH10) did not markedly improve model performance. Second, forced inclusion of RH98 in all models was important and did not degrade model performance, and the best performing models were parsimonious, typically having only 1-3 predictors. Third, stratification by geographic domain (PFT, geographic region) improved model performance in comparison to global models without stratification. Fourth, for the vast majority of strata, the best performing models were fit using square root transformation of field AGBD and/or height metrics. There was considerable variability in model performance across geographic strata, and areas with sparse training data and/or high AGBD values had the poorest performance. These models are used to produce global predictions of AGBD, but will be improved in the future as more and better training data become available.
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12.
  • Hop, Paul J., et al. (author)
  • Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS
  • 2022
  • In: Science Translational Medicine. - : American Association for the Advancement of Science. - 1946-6234 .- 1946-6242. ; 14:633
  • Journal article (peer-reviewed)abstract
    • Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study meta-analysis in 9706 samples passing stringent quality control (6763 patients, 2943 controls). We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We then tested 39 DNA methylation-based proxies of putative ALS risk factors and found that high-density lipoprotein cholesterol, body mass index, white blood cell proportions, and alcohol intake were independently associated with ALS. Integration of these results with our latest genome-wide association study showed that cholesterol biosynthesis was potentially causally related to ALS. Last, DNA methylation at several DMPs and blood cell proportion estimates derived from DNA methylation data were associated with survival rate in patients, suggesting that they might represent indicators of underlying disease processes potentially amenable to therapeutic interventions.
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13.
  • Pröbstel, Anne-Katrin, et al. (author)
  • Gut microbiota-specific IgA+ B cells traffic to the CNS in active multiple sclerosis
  • 2020
  • In: Science immunology. - : American Association for the Advancement of Science. - 2470-9468. ; 5:53
  • Journal article (peer-reviewed)abstract
    • Changes in gut microbiota composition and a diverse role of B cells have recently been implicated in multiple sclerosis (MS), a central nervous system (CNS) autoimmune disease. Immunoglobulin A (IgA) is a key regulator at the mucosal interface. However, whether gut microbiota shape IgA responses and what role IgA+ cells have in neuroinflammation are unknown. Here, we identify IgA-bound taxa in MS and show that IgA-producing cells specific for MS-associated taxa traffic to the inflamed CNS, resulting in a strong, compartmentalized IgA enrichment in active MS and other neuroinflammatory diseases. Unlike previously characterized polyreactive anti-commensal IgA responses, CNS IgA cross-reacts with surface structures on specific bacterial strains but not with brain tissue. These findings establish gut microbiota-specific IgA+ cells as a systemic mediator in MS and suggest a critical role of mucosal B cells during active neuroinflammation with broad implications for IgA as an informative biomarker and IgA-producing cells as an immune subset to harness for therapeutic interventions.
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14.
  • Smith, Bradley N., et al. (author)
  • The C9ORF72 expansion mutation is a common cause of ALS+/-FTD in Europe and has a single founder
  • 2013
  • In: European Journal of Human Genetics. - London : Nature Publishing Group. - 1018-4813 .- 1476-5438. ; 21:1, s. 102-108
  • Journal article (peer-reviewed)abstract
    • A massive hexanucleotide repeat expansion mutation (HREM) in C9ORF72 has recently been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we describe the frequency, origin and stability of this mutation in ALS+/-FTD from five European cohorts (total n = 1347). Single-nucleotide polymorphisms defining the risk haplotype in linked kindreds were genotyped in cases (n = 434) and controls (n = 856). Haplotypes were analysed using PLINK and aged using DMLE+. In a London clinic cohort, the HREM was the most common mutation in familial ALS+/-FTD: C9ORF72 29/112 (26%), SOD1 27/112 (24%), TARDBP 1/112 (1%) and FUS 4/112 (4%) and detected in 13/216 (6%) of unselected sporadic ALS cases but was rare in controls (3/856, 0.3%). HREM prevalence was high for familial ALS+/-FTD throughout Europe: Belgium 19/22 (86%), Sweden 30/41 (73%), the Netherlands 10/27 (37%) and Italy 4/20 (20%). The HREM did not affect the age at onset or survival of ALS patients. Haplotype analysis identified a common founder in all 137 HREM carriers that arose around 6300 years ago. The haplotype from which the HREM arose is intrinsically unstable with an increased number of repeats (average 8, compared with 2 for controls, P<10(-8)). We conclude that the HREM has a single founder and is the most common mutation in familial and sporadic ALS in Europe.
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15.
  • van Rheenen, Wouter, et al. (author)
  • Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis
  • 2016
  • In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:9, s. 1043-1048
  • Journal article (peer-reviewed)abstract
    • To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
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16.
  • Williamson, Alice, et al. (author)
  • Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake
  • 2023
  • In: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 55:6, s. 973-983
  • Journal article (peer-reviewed)abstract
    • Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in >55,000 participants from three ancestry groups. We identified ten new loci (P < 5 × 10-8) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits.
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17.
  • Zeggini, Eleftheria, et al. (author)
  • Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes
  • 2008
  • In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 40:5, s. 638-645
  • Journal article (peer-reviewed)abstract
    • Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D)(1-11). Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and similar to 2.2 million SNPs (directly genotyped and imputed), followed by replication testing in an independent sample with an effective sample size of up to 53,975. We detected at least six previously unknown loci with robust evidence for association, including the JAZF1 (P=5.0 x 10(-14)), CDC123-CAMK1D (P=1.2 x 10(-10)), TSPAN8-LGR5 (P=1.1 x 10(-9)), THADA (P=1.1 x 10(-9)), ADAMTS9 (P=1.2 x 10(-8)) and NOTCH2 (P=4.1 x 10(-8)) gene regions. Our results illustrate the value of large discovery and follow-up samples for gaining further insights into the inherited basis of T2D.
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18.
  • Allentoft, Morten E., et al. (author)
  • 100 ancient genomes show repeated population turnovers in Neolithic Denmark
  • 2024
  • In: Nature. - 0028-0836 .- 1476-4687. ; 625, s. 329-337
  • Journal article (peer-reviewed)abstract
    • Major migration events in Holocene Eurasia have been characterized genetically at broad regional scales1–4. However, insights into the population dynamics in the contact zones are hampered by a lack of ancient genomic data sampled at high spatiotemporal resolution5–7. Here, to address this, we analysed shotgun-sequenced genomes from 100 skeletons spanning 7,300 years of the Mesolithic period, Neolithic period and Early Bronze Age in Denmark and integrated these with proxies for diet (13C and 15N content), mobility (87Sr/86Sr ratio) and vegetation cover (pollen). We observe that Danish Mesolithic individuals of the Maglemose, Kongemose and Ertebølle cultures form a distinct genetic cluster related to other Western European hunter-gatherers. Despite shifts in material culture they displayed genetic homogeneity from around 10,500 to 5,900 calibrated years before present, when Neolithic farmers with Anatolian-derived ancestry arrived. Although the Neolithic transition was delayed by more than a millennium relative to Central Europe, it was very abrupt and resulted in a population turnover with limited genetic contribution from local hunter-gatherers. The succeeding Neolithic population, associated with the Funnel Beaker culture, persisted for only about 1,000 years before immigrants with eastern Steppe-derived ancestry arrived. This second and equally rapid population replacement gave rise to the Single Grave culture with an ancestry profile more similar to present-day Danes. In our multiproxy dataset, these major demographic events are manifested as parallel shifts in genotype, phenotype, diet and land use.
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19.
  • Andersen, Claire Swetman, et al. (author)
  • The combined CTA1-DD/ISCOMs vector is an effective intranasal adjuvant for boosting prior Mycobacterium bovis BCG immunity to Mycobacterium tuberculosis.
  • 2007
  • In: Infection and immunity. - 0019-9567. ; 75:1, s. 408-16
  • Journal article (peer-reviewed)abstract
    • Infection with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), remains one of the leading causes of mortality worldwide. The current "gold standard" vaccine Mycobacterium bovis BCG has a limited efficacy that wanes over time. The development of a vaccine to boost BCG-induced immunity is therefore a highly active area of research. Mucosal administration of vaccines is believed to provide better protection against pathogens, such as M. tuberculosis, that invade the host via mucosal surfaces. In this study we demonstrate that an intranasal vaccine, comprising the antigenic fusion protein Ag85B-ESAT-6 and the mucosal combined adjuvant vector CTA1-DD/ISCOMs, strongly promotes a Th1-specific immune response, dominated by gamma interferon-secreting CD4-positive T cells. Mucosal administration of Ag85B-ESAT-6 mixed with CTA1-DD/ISCOMs strongly boosted prior BCG immunity, leading to a highly increased recruitment of antigen-specific cells to the site of infection. Most importantly, we observed a significantly (P < 0.001) reduced bacterial burden in the lung compared to nonboosted control animals. Thus, the results demonstrate the effectiveness of mucosal vaccination with Ag85B-ESAT-6 mixed with CTA1-DD/ISCOMs as adjuvant for stimulating TB-specific protective immunity in the lung.
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20.
  • Andersen, Claus Yding, et al. (author)
  • Preovulatory progesterone concentration associates significantly to follicle number and LH concentration but not to pregnancy rate
  • 2011
  • In: Reproductive BioMedicine Online. - : Elsevier BV. - 1472-6491 .- 1472-6483. ; 23:2, s. 187-195
  • Journal article (peer-reviewed)abstract
    • Using data from a large prospective randomized controlled trial that evaluated the effect of recombinant LH (rLH) co-administration for ovarian stimulation, the present study assessed whether progesterone concentration on the day of human chorionic gonadotrophin (HCG) administration was associated with pregnancy outcome. Progesterone concentration was measured on stimulation day 1 and on the day of HCG administration in 475 patients who underwent IVF/intracytoplasmic sperm injection treatment following ovarian stimulation with gonadotrophin-releasing hormone (GnRH) agonist and recombinant FSH with or without rLH administration from day 6 of stimulation. There was no significant association between the late-follicular-phase progesterone concentration and the clinical pregnancy rate. However, progesterone concentration was strongly associated with the number of follicles and retrieved oocytes. Late-follicular-phase LH concentration also showed a significant positive association with progesterone concentration (P = 0.018). Administration of rLH during ovarian stimulation did not affect progesterone concentration. The present study does not support an association between progesterone concentration on the day of HCG administration and the probability of clinical pregnancy in women undergoing ovarian stimulation with GnRH agonists and gonadotrophins for assisted reproduction treatment. Instead, late-follicular-phase progesterone concentration appears to be governed by the number of preovulatory follicles and LH concentration. (C) 2011, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.
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21.
  • Andersen, Hans Estrup, et al. (author)
  • Identifying Hot Spots of Agricultural Nitrogen Loss Within the Baltic Sea Drainage Basin
  • 2016
  • In: Water, Air and Soil Pollution. - : Springer Science and Business Media LLC. - 0049-6979 .- 1573-2932. ; 227:1
  • Journal article (peer-reviewed)abstract
    • Agricultural management practices are among the major drivers of agricultural nitrogen (N) loss. Legislation and management incentives for measures to mitigate N loss should eventually be carried out at the individual farm level. Consequently, an appropriate scale to simulate N loss from a scientific perspective should be at the farm scale. A data set of more than 4000 agricultural fields with combinations of climate, soils and agricultural management which overall describes the variations found in the Baltic Sea drainage basin was constructed. The soil-vegetation-atmosphere model Daisy (Hansen et al. 2012) was used to simulate N loss from the root zone of all agricultural fields in the data set. From the data set of Daisy simulations, we identified the most important drivers for N loss by multiple regression statistics and developed a statistical N loss model. By applying this model to a basin-wide data set on climate, soils and agricultural management at a 10 x 10 km scale, we were able to calculate root-zone N losses from the entire Baltic Sea drainage basin and identify N loss hot spots in a consistent way and at a level of detail not hitherto seen for this area. Further, the root-zone N loss model was coupled to estimates of nitrogen retention in catchments separated into retention in groundwater and retention in surface waters allowing calculation of the coastal N loading.
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22.
  • Andersen, Mikkel Österheden, et al. (author)
  • Surgical Treatment of Degenerative Disk Disease in Three Scandinavian Countries : An International Register Study Based on Three Merged National Spine Registers
  • 2019
  • In: Global Spine Journal. - : SAGE PUBLICATIONS LTD. - 2192-5682 .- 2192-5690. ; 9:8, s. 850-858
  • Journal article (peer-reviewed)abstract
    • Study Design: Observational study of prospectively collected data.Objectives: Patients with chronic low back pain resistant to nonoperative treatment often face a poor prognosis for recovery. The aim of the current study was to compare the variation and outcome of surgical treatment of degenerative disc disease in the Scandinavian countries based on The International Consortium for Health Outcomes Measurement core spine data sets.Methods: Anonymized individual level data from 3 national registers were pooled into 1 database. At the time of surgery, the patient reports data on demographics, lifestyle topics, comorbidity, and data on health-related quality of life such as Oswestry Disability Index, Euro-Qol-5D, and back and leg pain scores. The surgeon records diagnosis, type of surgery performed, and complications. One-year follow-ups are obtained with questionnaires. Baseline and 1-year follow-up data were analyzed to expose any differences between the countries.Results: A total of 1893 patients were included. At 1-year follow-up, 1315 (72%) patients responded. There were statistically significant baseline differences in age, smoking, comorbidity, frequency of previous surgery and intensity of back and leg pain. Isolated fusion was the primary procedure in all the countries ranging from 84% in Denmark to 76% in Sweden. There was clinically relevant improvement in all outcome measures except leg pain.Conclusions: In homogenous populations with similar health care systems the treatment traditions can vary considerably. Despite variations in preoperative variables, patient reported outcomes improve significantly and clinically relevant with surgical treatment.
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23.
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24.
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25.
  • Bangsbo, Jens, et al. (author)
  • The Copenhagen Consensus Conference 2016 : children, youth, and physical activity in schools and during leisure time
  • 2016
  • In: British Journal of Sports Medicine. - : BMJ Publishing Group Ltd. - 0306-3674 .- 1473-0480. ; 50:19, s. 1177-1178
  • Journal article (other academic/artistic)abstract
    • From 4 to 7 April 2016, 24 researchers from 8 countries and from a variety of academic disciplines gathered in Snekkersten, Denmark, to reach evidence-based consensus about physical activity in children and youth, that is, individuals between 6 and 18 years. Physical activity is an overarching term that consists of many structured and unstructured forms within school and out-of-school-time contexts, including organised sport, physical education, outdoor recreation, motor skill development programmes, recess, and active transportation such as biking and walking. This consensus statement presents the accord on the effects of physical activity on children's and youth's fitness, health, cognitive functioning, engagement, motivation, psychological well-being and social inclusion, as well as presenting educational and physical activity implementation strategies. The consensus was obtained through an iterative process that began with presentation of the state-of-the art in each domain followed by plenary and group discussions. Ultimately, Consensus Conference participants reached agreement on the 21-item consensus statement.
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26.
  • Benzinou, Michael, et al. (author)
  • Common nonsynonymous variants in PCSK1 confer risk of obesity.
  • 2008
  • In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 40:8, s. 943-5
  • Journal article (peer-reviewed)abstract
    • Mutations in PCSK1 cause monogenic obesity. To assess the contribution of PCSK1 to polygenic obesity risk, we genotyped tag SNPs in a total of 13,659 individuals of European ancestry from eight independent case-control or family-based cohorts. The nonsynonymous variants rs6232, encoding N221D, and rs6234-rs6235, encoding the Q665E-S690T pair, were consistently associated with obesity in adults and children (P = 7.27 x 10(-8) and P = 2.31 x 10(-12), respectively). Functional analysis showed a significant impairment of the N221D-mutant PC1/3 protein catalytic activity.
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27.
  • Bjerregaard-Andersen, Morten, et al. (author)
  • Tuberculosis burden in an urban population: a cross sectional tuberculosis survey from Guinea Bissau
  • 2010
  • In: BMC Infectious Diseases. - : Springer Science and Business Media LLC. - 1471-2334. ; 10
  • Journal article (peer-reviewed)abstract
    • Background: Little is known about the prevalence of pulmonary tuberculosis (TB) in low income countries. We conducted a cross sectional survey for pulmonary TB and TB symptoms in Bissau, Guinea-Bissau, in an urban cohort with known HIV prevalence. TB surveillance in the area is routinely based on passive case finding. Methods: Two cohorts were selected based on a previous HIV survey, but only 52.5% of those enrolled in the adult cohort had participated in the HIV survey. One cohort included all adults living in 384 randomly selected houses; in this cohort 8% (135/1687) were HIV infected. The other included individuals 50 years or older from all other houses in the study area; of these 11% (62/571) were HIV infected. Symptom screening was done through household visits using a standardised questionnaire. TB suspects were investigated with sputum smear microscopy and X-ray. Results: In the adult cohort, we found 4 cases among 2989 individuals screened, giving a total TB prevalence of 134/100,000 (95% CI 36-342/100,000). In the >50 years cohort, we found 4 cases among 571 individuals screened, giving a total prevalence of 701/100,000 (191-1784/100.000). Two of the eight detected TB cases were unknown by the TB program. Of the total TB cases five were HIV uninfected while three had unknown HIV status. The prevalence of TB symptoms was 2.1% (63/2989) and 10.3% (59/571) in the two cohorts respectively. Conclusions: In conclusion we found a moderately high prevalence of pulmonary TB and TB symptoms in the general population, higher among elderly individuals. By active case finding unknown cases were detected. Better awareness of TB and its symptoms needs to be promoted in low income settings.
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28.
  • Blauw, Hylke M, et al. (author)
  • A large genome scan for rare CNVs in amyotrophic lateral sclerosis
  • 2010
  • In: Human Molecular Genetics. - : Oxford Journals. - 0964-6906 .- 1460-2083. ; 19:20, s. 4091-4099
  • Journal article (peer-reviewed)abstract
    • Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease selectively affecting motor neurons in the brain and spinal cord. Recent genome-wide association studies (GWASs) have identified several common variants which increase disease susceptibility. In contrast, rare copy-number variants (CNVs), which have been associated with several neuropsychiatric traits, have not been studied for ALS in well-powered study populations. To examine the role of rare CNVs in ALS susceptibility, we conducted a CNV association study including over 19,000 individuals. In a genome-wide screen of 1875 cases and 8731 controls, we did not find evidence for a difference in global CNV burden between cases and controls. In our association analyses, we identified two loci that met our criteria for follow-up: the DPP6 locus (OR = 3.59, P = 6.6 × 10(-3)), which has already been implicated in ALS pathogenesis, and the 15q11.2 locus, containing NIPA1 (OR = 12.46, P = 9.3 × 10(-5)), the gene causing hereditary spastic paraparesis type 6 (HSP 6). We tested these loci in a replication cohort of 2559 cases and 5887 controls. Again, results were suggestive of association, but did not meet our criteria for independent replication: DPP6 locus: OR = 1.92, P = 0.097, pooled results: OR = 2.64, P = 1.4 × 10(-3); NIPA1: OR = 3.23, P = 0.041, pooled results: OR = 6.20, P = 2.2 × 10(-5)). Our results highlight DPP6 and NIPA1 as candidates for more in-depth studies. Unlike other complex neurological and psychiatric traits, rare CNVs with high effect size do not play a major role in ALS pathogenesis.
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29.
  • Bogaert, Elke, et al. (author)
  • Polymorphisms in the GluR2 gene are not associated with amyotrophic lateral sclerosis
  • 2012
  • In: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 33:2, s. 418-420
  • Journal article (peer-reviewed)abstract
    • Excitotoxicity is thought to play a pathogenic role in amyotrophic lateral sclerosis (ALS). Excitotoxic motor neuron death is mediated through the Ca(2+)-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type of glutamate receptors and Ca(2+) permeability is determined by the GluR2 subunit. We investigated whether polymorphisms or mutations in the GluR2 gene (GRIA2) predispose patients to ALS. Upon sequencing 24 patients and 24 controls no nonsynonymous coding variants were observed but 24 polymorphisms were identified, 9 of which were novel. In a screening set of 310 Belgian ALS cases and 794 healthy controls and a replication set of 3157 cases and 5397 controls from 6 additional populations no association with susceptibility, age at onset, or disease duration was observed. We conclude that polymorphisms in the GluR2 gene (GRIA2) are not a major contributory factor in the pathogenesis of ALS.
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30.
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31.
  • Brockmann, Sarah J., et al. (author)
  • CHCHD10 mutations p.R15L and p.G66V cause motoneuron disease by haploinsufficiency
  • 2018
  • In: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 27:4, s. 706-715
  • Journal article (peer-reviewed)abstract
    • Mutations in the mitochondrially located protein CHCHD10 cause motoneuron disease by an unknown mechanism. In this study, we investigate the mutations p. R15L and p. G66V in comparison to wild-type CHCHD10 and the non-pathogenic variant p. P34S in vitro, in patient cells as well as in the vertebrate in vivo model zebrafish. We demonstrate a reduction of CHCHD10 protein levels in p. R15L and p. G66V mutant patient cells to approximately 50%. Quantitative real-time PCR revealed that expression of CHCHD10 p. R15L, but not of CHCHD10 p. G66V, is already abrogated at the mRNA level. Altered secondary structure and rapid protein degradation are observed with regard to the CHCHD10 p. G66V mutant. In contrast, no significant differences in expression, degradation rate or secondary structure of non-pathogenic CHCHD10 p. P34S are detected when compared with wild-type protein. Knockdown of CHCHD10 expression in zebrafish to about 50% causes motoneuron pathology, abnormal myofibrillar structure and motility deficits in vivo. Thus, our data show that the CHCHD10 mutations p. R15L and p. G66V cause motoneuron disease primarily based on haploinsufficiency of CHCHD10.
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32.
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33.
  • Burisch, Johan, et al. (author)
  • Disease course of inflammatory bowel disease unclassified in a European population-based inception cohort : an Epi-IBD study
  • 2019
  • In: Journal of Gastroenterology and Hepatology. - : John Wiley & Sons. - 0815-9319 .- 1440-1746. ; 34:6, s. 996-1003
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: A definitive diagnosis of Crohn's disease (CD) or ulcerative colitis (UC) is not always possible and a proportion of patients will be diagnosed as inflammatory bowel disease unclassified (IBDU). The aim of the study was to investigate the prognosis of patients initially diagnosed with IBDU and the disease course during the following five years.METHODS: The Epi-IBD study is a prospective population-based cohort of 1,289 IBD patients diagnosed in centres across Europe. Clinical data were captured prospectively throughout the follow-up period.RESULTS: Overall, 476 (37%) patients were initially diagnosed with CD, 701 (54%) with UC, and 112 (9%) with IBDU. During follow-up, 28 (25%) IBDU patients were changed diagnoses to either UC (n=20, 71%) or CD (n=8, 29%) after a median of six months (IQR: 4-12), while 84 (7% of the total cohort) remained IBDU. A total of 17 (15%) IBDU patients were hospitalized for their IBD during follow-up, while 8 (7%) patients underwent surgery. Most surgeries (n=6, 75%) were performed on patients whose diagnosis was later changed to UC; three of these colectomies led to a definitive diagnosis of UC. Most patients (n=107, 96%) received 5-aminosalicylic acid, while 11 (10%) patients received biologicals, of whom five remained classified as IBDU.CONCLUSIONS: In a population-based inception cohort, 7% of IBD patients were not given a definitive diagnosis of IBD after five years of follow-up. One in four patients with IBDU eventually were classified as CD or UC. Overall, the disease course and medication burden in IBDU patients were mild.
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34.
  • Burisch, Johan, et al. (author)
  • Natural Disease Course of Ulcerative Colitis During the First Five Years of Follow-up in a European Population-based Inception Cohort-An Epi-IBD Study
  • 2019
  • In: Journal of Crohn's & Colitis. - : Oxford University Press. - 1873-9946 .- 1876-4479. ; 13:2, s. 198-208
  • Journal article (peer-reviewed)abstract
    • Background and Aims: Few population-based cohort studies have assessed the disease course of ulcerative colitis [UC] in the era of biological therapy and widespread use of immunomodulators. The aim of this study was to assess the 5-year outcome and disease course of patients with UC in the Epi-IBD cohort.Methods: In a prospective, population-based inception cohort of unselected patients with UC, patients were followed up from the time of their diagnosis, which included the collection of their clinical data, demographics, disease activity, medical therapy, and rates of surgery, cancers, and deaths. Associations between outcomes and multiple covariates were analysed by Cox regression analysis.Results: A total of 717 patients were included in the study. During follow-up, 43 [6%] patients underwent a colectomy and 163 [23%] patients were hospitalised. Of patients with limited colitis [distal to the left flexure], 90 [21%] progressed to extensive colitis. In addition, 92 [27%] patients with extensive colitis experienced a regression in disease extent, which was associated with a reduced risk of hospitalisation (hazard ratio [HR]: 0.5 95% CI: 0.3-0.8]. Overall, patients were treated similarly in both geographical regions; 80 [11%] patients needed biological therapy and 210 [29%] patients received immunomodulators. Treatment with immunomodulators was found to reduce the risk of hospitalisation [HR: 0.5 95% CI: 0.3-0.8].Conclusions: Although patients in this population-based cohort were treated more aggressively with immunomodulators and biological therapy than in cohorts from the previous two decades, their disease outcomes, including colectomy rates, were no different. However, treatment with immunomodulators was found to reduce the risk of hospitalisation.
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35.
  • Calliari, Danilo, 1969, et al. (author)
  • Salinity modulates the energy balance and reproductive success of co-occurring copepods Acartia tonsa and A-clausi in different ways
  • 2006
  • In: Marine Ecology-Progress Series. - : Inter-Research Science Center. - 0171-8630 .- 1616-1599. ; 312, s. 177-188
  • Journal article (peer-reviewed)abstract
    • We assessed metabolic balance, RNA content, and egg hatching success (EHS) in Acartia tonsa and A. clausi over a wide salinity range (2 to 33 and 16 to 33, respectively). For A. tonsa, the energy partitioning between ingestion, production and respiration was relatively constant with small differences in gross growth efficiency (GGE) and cost of growth (CG). In contrast, A. clausi exhibited significantly reduced ingestion and GGE, and highly elevated CG at salinities <= 20. In both species, RNA levels mirrored egg production. EHS was generally high in both species, but decreased by 80% for A. clausi at 16. These results contribute to the understanding of distribution patterns of both species along salinity gradients. The observed responses would allow the dominance of A. tonsa at low salinities, although its higher energetic requirement and feeding activity subject it to stronger predation pressure than competing A. clausi.
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36.
  • Chaitanya, Lakshmi, et al. (author)
  • Collaborative EDNAP exercise on the IrisPlex system for DNA based prediction of human eye colour
  • 2014
  • In: Forensic Science International. - : Elsevier. - 1872-4973 .- 1878-0326. ; 11, s. 241-251
  • Journal article (peer-reviewed)abstract
    • The IrisPlex system is a DNA-based test system for the prediction of human eye colour from biological samples and consists of a single forensically validated multiplex genotyping assay together with a statistical prediction model that is based on genotypes and phenotypes from thousands of individuals. IrisPlex predicts blue and brown human eye colour with, on average, >94% precision accuracy using six of the currently most eye colour informative single nucleotide polymorphisms (HERC2 rs12913832, OCA2 rs1800407, SLC24A4 rs12896399, SLC45A2 (MATP) rs16891982, TYR rs1393350, and IRF4 rs12203592) according to a previous study, while the accuracy in predicting non-blue and non-brown eye colours is considerably lower. In an effort to vigorously assess the IrisPlex system at the international level, testing was performed by 21 laboratories in the context of a collaborative exercise divided into three tasks and organised by the European DNA Profiling (EDNAP) Group of the International Society of Forensic Genetics (ISFG). Task 1 involved the assessment of 10 blood and saliva samples provided on FTA cards by the organising laboratory together with eye colour phenotypes; 99.4% of the genotypes were correctly reported and 99% of the eye colour phenotypes were correctly predicted. Task 2 involved the assessment of 5 DNA samples extracted by the host laboratory from simulated casework samples, artificially degraded, and provided to the participants in varying DNA concentrations. For this task, 98.7% of the genotypes were correctly determined and 96.2% of eye colour phenotypes were correctly inferred. For Tasks 1 and 2 together, 99.2% (1875) of the 1890 genotypes were correctly generated and of the 15 (0.8%) incorrect genotype calls, only 2 (0.1%) resulted in incorrect eye colour phenotypes. The voluntary Task 3 involved participants choosing their own test subjects for IrisPlex genotyping and eye colour phenotype inference, while eye photographs were provided to the organising laboratory and judged; 96% of the eye colour phenotypes were inferred correctly across 100 samples and 19 laboratories. The high success rates in genotyping and eye colour phenotyping clearly demonstrate the reproducibility and the robustness of the IrisPlex assay as well as the accuracy of the IrisPlex model to predict blue and brown eye colour from DNA. Additionally, this study demonstrates the ease with which the IrisPlex system is implementable and applicable across forensic laboratories around the world with varying pre-existing experiences.
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37.
  • Cheng, Haynes P. H., et al. (author)
  • Autofluorescence of pigmented skin lesions using a pulsed UV laser
  • 2010
  • In: Proceedings of SPIE. - : SPIE. ; 7715, s. 1-77151
  • Conference paper (peer-reviewed)abstract
    • We report preliminary clinical results of autofluorescence imaging of malignant and benign skin lesions, using pulsed 355 nm laser excitation with synchronized detection. The novel synchronized detection system allows high signal-tonoise ratio to be achieved in the resulting autofluorescence signal, which may in turn produce high contrast images that improve diagnosis, even in the presence of ambient room light. The synchronized set-up utilizes a compact, diode pumped, pulsed UV laser at 355 nm which is coupled to a CCD camera and a liquid crystal tunable filter. The excitation and image capture is sampled at 5 kHz and the resulting autofluorescence is captured with the liquid crystal filter cycling through seven wavelengths between 420 nm and 580 nm. The clinical study targets pigmented skin lesions and evaluates the prospects of using autofluorescence as a possible means in differentiating malignant and benign skin tumors. Up to now, sixteen patients have participated in the clinical study. The autofluorescence images, averaged over the exposure time of one second, will be presented along with histopathological results. Initial survey of the images show good contrast and diagnostic results show promising agreement based on the histopathological results.
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38.
  • Chiang, Huei-Hsin, et al. (author)
  • Novel TARDBP mutations in Nordic ALS patients
  • 2012
  • In: Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1434-5161 .- 1435-232X. ; 57:5, s. 316-319
  • Journal article (peer-reviewed)abstract
    • Amyotrophic lateral sclerosis (ALS) is a neurodegenerative syndrome primarily affecting the upper and lower motor neurons. A characteristic neuropathological finding in ALS patients is neuronal inclusions positive for TAR DNA-binding protein 43 (TDP-43). Subsequently, mutations in the gene encoding TDP-43, TARDBP, proved to be involved in the development of ALS. We thus sequenced TARDBP in 177 Nordic ALS patients and found two previously reported (p.A90V and p.S379P) and two novel (p.G357R and p.R361T) missense variations in three familial ALS patients. The p.A90V and p.G357R variations were detected in the same patient and p.R361T was present in a family with both ALS and frontotemporal dementia-ALS. None of the missense variations were present in 200 neurologically healthy controls. However, p.A90V has also been reported in healthy individuals by others. Thus, the data suggest that these variations are rare and p.G357R, p.R361T and p.S379P are likely pathogenic but further functional characterization is needed to prove their pathogenicity. The mutation frequency in TARDBP in Nordic ALS patients was 1.7%. The ALS cohort was highly selected for a positive family history suggesting that mutations in TARDBP generally are a rare cause of ALS in Nordic countries.
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39.
  • Czell, David, et al. (author)
  • Further analysis of KIFAP3 gene in ALS patients from Switzerland and Sweden
  • 2017
  • In: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. - : TAYLOR & FRANCIS LTD. - 2167-8421 .- 2167-9223. ; 18:3-4, s. 302-304
  • Journal article (peer-reviewed)abstract
    • A series of studies suggests that susceptibility to ALS may be influenced by variants in multiple genes. While analyses of the 10% of cases of familial origin have identified more than 33 monogenic ALS-causing genetic defects, little is known about genetic factors that influence susceptibility or phenotype in sporadic ALS (SALS). We and others conducted a genome-wide association study (GWAS) in a cohort of 1014 ALS cases from Western Europe, England and the United States, and identified an intronic single nucleotide polymorphism (SNP) rs1541160 in the KIFAP3 gene that was statistically associated with improved survival. We have now completed an additional survival analysis examining the impact of the rs1541160 genotype in a cohort of 264 ALS and progressive bulbar palsy (PBP) cases. In the combined cohort of 264 patients, the CC, CT and TT genotypes for rs1541160 were detected, respectively, in 8.3% (22), 41.7% (110) and 50.0% (132). This study does not show an influence of KIFAP3 variants on survival in the studied Swiss and Swedish cohort. There was a difference in survival between the US and English patients and the patients from the Netherlands. The effect of KIFAP3 variants may be population specific, or the rs1541160 association reported previously may have been a false-positive.
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40.
  • Diekstra, Frank P., et al. (author)
  • C9orf72 and UNC13A Are Shared Risk Loci for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia : A Genome-Wide Meta-Analysis
  • 2014
  • In: Annals of Neurology. - : John Wiley & Sons. - 0364-5134 .- 1531-8249. ; 76:1, s. 120-133
  • Journal article (peer-reviewed)abstract
    • Objective: Substantial clinical, pathological, and genetic overlap exists between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 inclusions have been found in both ALS and FTD cases (FTD-TDP). Recently, a repeat expansion in C9orf72 was identified as the causal variant in a proportion of ALS and FTD cases. We sought to identify additional evidence for a common genetic basis for the spectrum of ALS-FTD. Methods: We used published genome-wide association studies data for 4,377 ALS patients and 13,017 controls, and 435 pathology-proven FTD-TDP cases and 1,414 controls for genotype imputation. Data were analyzed in a joint meta-analysis, by replicating topmost associated hits of one disease in the other, and by using a conservative rank products analysis, allocating equal weight to ALS and FTD-TDP sample sizes. Results: Meta-analysis identified 19 genome-wide significant single nucleotide polymorphisms (SNPs) in C9orf72 on chromosome 9p21.2 (lowest p = 2.6 x 10(-12)) and 1 SNP in UNC13A on chromosome 19p13.11 (p = 1.0 x 10(-11)) as shared susceptibility loci for ALS and FTD-TDP. Conditioning on the 9p21.2 genotype increased statistical significance at UNC13A. A third signal, on chromosome 8q24.13 at the SPG8 locus coding for strumpellin (p = 3.91 x 10(-7)) was replicated in an independent cohort of 4,056 ALS patients and 3,958 controls (p = 0.026; combined analysis p = 1.01 x 10(-7)). Interpretation: We identified common genetic variants in C9orf72, but in addition in UNC13A that are shared between ALS and FTD. UNC13A provides a novel link between ALS and FTD-TDP, and identifies changes in neurotransmitter release and synaptic function as a converging mechanism in the pathogenesis of ALS and FTD-TDP.
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41.
  • Felbecker, Ansgar, et al. (author)
  • Four familial ALS pedigrees discordant for two SOD1 mutations : are all SOD1 mutations pathogenic?
  • 2010
  • In: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 81:5, s. 572-577
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: 153 mutations in the Cu/Zn superoxide dismutase (SOD1) gene have been claimed to be associated with amyotrophic lateral sclerosis (ALS) in familial and sporadic ALS in an autosomal dominant or autosomal recessive pattern with complete or reduced penetrance. The authors now report four ALS pedigrees from Finland, France, Germany and Sweden with either the D90A or E100K SOD1 mutations in some but not all affected members. After re-collecting DNA, the non-segregation of the SOD1 mutations with disease was confirmed by three independent laboratories using different PCR primers: while some of the affected patients carry SOD1 mutations, other affected family members have two wildtype/normal SOD1 genes. In addition, some unaffected members within the same families are carriers of SOD1 gene mutations. To exclude other known genetic causes, the authors ruled out mutations within the genes coding for VAPB, ANG, TDP43, FUS and DCTN1 in affected individuals in the four pedigrees. CONCLUSIONS: The authors find that the D90A and E100K SOD1 gene mutations found in some patients are not the exclusive cause of ALS in these pedigrees. Whether this is also the case for the other 151 SOD1 mutations reported in ALS pedigrees is unknown. The findings have consequences for genetic testing in clinical practice when diagnosing ALS and for genetic counselling in ALS. Some SOD1 mutations may be part of an oligo- or epigentic pattern of inheritance. Such a pattern of inheritance may model other oligo- or polygenetic traits responsible for other forms of ALS.
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42.
  • Freischmidt, Axel, et al. (author)
  • A serum microRNA sequence reveals fragile X protein pathology in amyotrophic lateral sclerosis
  • 2021
  • In: Brain. - : Oxford University Press. - 0006-8950 .- 1460-2156. ; 144:4, s. 1214-1229
  • Journal article (peer-reviewed)abstract
    • Knowledge about converging disease mechanisms in the heterogeneous syndrome amyotrophic lateral sclerosis (ALS) is rare, but may lead to therapies effective in most ALS cases. Previously, we identified serum microRNAs downregulated in familial ALS, the majority of sporadic ALS patients, but also in presymptomatic mutation carriers. A 5-nucleotide sequence motif (GDCGG; D = G, A or U) was strongly enriched in these ALS-related microRNAs. We hypothesized that deregulation of protein(s) binding predominantly to this consensus motif was responsible for the ALS-linked microRNA fingerprint. Using microRNA pull-down assays combined with mass spectrometry followed by extensive biochemical validation, all members of the fragile X protein family, FMR1, FXR1 and FXR2, were identified to directly and predominantly interact with GDCGG microRNAs through their structurally disordered RGG/RG domains. Preferential association of this protein family with ALS-related microRNAs was confirmed by in vitro binding studies on a transcriptome-wide scale. Immunohistochemistry of lumbar spinal cord revealed aberrant expression level and aggregation of FXR1 and FXR2 in C9orf72- and FUS-linked familial ALS, but also patients with sporadic ALS. Further analysis of ALS autopsies and induced pluripotent stem cell-derived motor neurons with FUS mutations showed co-aggregation of FXR1 with FUS. Hence, our translational approach was able to take advantage of blood microRNAs to reveal CNS pathology, and suggests an involvement of the fragile X-related proteins in familial and sporadic ALS already at a presymptomatic stage. The findings may uncover disease mechanisms relevant to many patients with ALS. They furthermore underscore the systemic, extra-CNS aspect of ALS.
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43.
  • Freischmidt, Axel, et al. (author)
  • Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia
  • 2015
  • In: Nature Neuroscience. - : Springer Science and Business Media LLC. - 1097-6256 .- 1546-1726. ; 18:5, s. 631-
  • Journal article (peer-reviewed)abstract
    • Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative syndrome hallmarked by adult-onset loss of motor neurons. We performed exome sequencing of 252 familial ALS (fALS) and 827 control individuals. Gene-based rare variant analysis identified an exome-wide significant enrichment of eight loss-of-function (LoF) mutations in TBK1 (encoding TANK-binding kinase 1) in 13 fALS pedigrees. No enrichment of LoF mutations was observed in a targeted mutation screen of 1,010 sporadic ALS and 650 additional control individuals. Linkage analysis in four families gave an aggregate LOD score of 4.6. In vitro experiments confirmed the loss of expression of TBK1 LoF mutant alleles, or loss of interaction of the C-terminal TBK1 coiled-coil domain (CCD2) mutants with the TBK1 adaptor protein optineurin, which has been shown to be involved in ALS pathogenesis. We conclude that haploinsufficiency of TBK1 causes ALS and fronto-temporal dementia.
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44.
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45.
  • Gimsing, Peter, et al. (author)
  • Effect of pamidronate 30 mg versus 90 mg on physical function in patients with newly diagnosed multiple myeloma (Nordic Myeloma Study Group): a double-blind, randomised controlled trial
  • 2010
  • In: LANCET ONCOLOGY. - : Elsevier Science B.V., Amsterdam.. - 1470-2045 .- 1474-5488. ; 11:10, s. 973-982
  • Journal article (peer-reviewed)abstract
    • Background Compared with placebo, prophylactic treatment with bisphosphonates reduces risk of skeletal events in patients with multiple myeloma. However, because of toxicity associated with long-term bisphosphonate treatment, establishing the lowest effective dose is important. This study compared the effect of two doses of pamidronate on health-related quality of life and skeletal morbidity in patients with newly diagnosed multiple myeloma. Methods This double-blind, randomised, phase 3 trial was undertaken at 37 clinics in Denmark, Norway, and Sweden. Patients with multiple myeloma who were starting antimyeloma treatment were randomly assigned in a 1:1 ratio to receive one of two doses of pamidronate (30 mg or 90 mg) given by intravenous infusion once a month for at least 3 years. Randomisation was done by use of a central, computerised minimisation system. Primary outcome was physical function after 12 months estimated by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire (scale 0-100). All patients who returned questionnaires at 12 months and were still on study treatment were included in the analysis of the primary endpoint. This study is registered with ClinicalTrials. gov, number NCT00376883. Findings From January, 2001, until August, 2005, 504 patients were randomly assigned to pamidronate 30 mg or 90 mg (252 in each group). 157 patients in the 90 mg group and 156 in the 30 mg group were included in the primary analysis. Mean physical function at 12 months was 66 points (95% CI 62.9-70.0) in the 90 mg group and 68 points (64.6-71.4) in the 30 mg group (95% CI of difference -6.6 to 3.3; p=0.52). Median time to first skeletal-related event in patients who had such an event was 9.2 months (8.1-10.7) in the 90 mg group and 10-2 months (7.3-14.0) in the 30 mg group (p=0.63). In a retrospective analysis, eight patients in the pamidronate 90 mg group developed osteonecrosis of the jaw compared with two patients in the 30 mg group. Interpretation Monthly infusion of pamidronate 30 mg should be the recommended dose for prevention of bone disease in patients with multiple myeloma.
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46.
  • Gispert, Suzana, et al. (author)
  • The modulation of Amyotrophic Lateral Sclerosis risk by Ataxin-2 intermediate polyglutamine expansions is a specific effect
  • 2012
  • In: Neurobiology of Disease. - : Elsevier. - 0969-9961 .- 1095-953X. ; 45:1, s. 356-361
  • Journal article (peer-reviewed)abstract
    • Full expansions of the polyglutamine domain (polyQ >= 34) within the polysome-associated protein ataxin-2 (ATXN2) are the cause of a multi-system neurodegenerative disorder, which usually presents as a Spino-Cerebellar Ataxia and is therefore known as SCA2, but may rarely manifest as Levodopa-responsive Parkinson syndrome or as motor neuron disease. Intermediate expansions (27 <= polyQ <= 33) were reported to modify the risk of Amyotrophic Lateral Sclerosis (ALS). We have now tested the reproducibility and the specificity of this observation. In 559 independent ALS patients from Central Europe, the association of ATXN2 expansions (30 <= polyQ <= 35) with ALS was highly significant. The study of 1490 patients with Parkinson's disease (PD) showed an enrichment of ATXN2 alleles 27/28 in a subgroup with familial cases, but the overall risk of sporadic PD was unchanged. No association was found between polyQ expansions in Ataxin-3 (ATXN3) and ALS risk. These data indicate a specific interaction between ATXN2 expansions and the causes of ALS, possibly through altered RNA-processing as a common pathogenic factor. (C) 2011 Elsevier Inc. All rights reserved.
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47.
  • Gron, Kurt J., et al. (author)
  • Archaeological cereals as an isotope record of long-term soil health and anthropogenic amendment in southern Scandinavia
  • 2021
  • In: Quaternary Science Reviews. - : Elsevier BV. - 0277-3791. ; 253
  • Journal article (peer-reviewed)abstract
    • Maintaining soil health is integral to agricultural production, and the archaeological record contains multiple lines of palaeoclimatic and palaeoenvironmental proxy evidence that can contribute to the understanding and analysis of long-term trajectories of change that are key for contextualizing 21st century global environmental challenges. Soil is a capital resource and its nutrient balance is modified by agricultural activities, making it necessary to ensure soil productivity is maintained and managed through human choices and actions. Since prehistory this has always been the case; soil is a non-renewable resource within a human lifetime. Here, we present and interpret carbon and nitrogen isotope analysis of charred cereals from southern Scandinavia. Anthropogenic effects on soils are evident from the initiation of farming 6000 years ago, as is amendment to counteract its effects. The earliest cereals were planted on pristine soils, and by the late Neolithic, agriculture extensified. By the Iron Age it was necessary to significantly amend depleted soils to maintain crop yields. We propose that these data provide a record of soil water retention, net precipitation and amendment. From the start of the Neolithic there is a concurrent decrease in both Δ13C and δ15N, mitigated only by the replacement of soil organic content in the form of manure in the Iron Age. The cereal isotopes provide a record of trajectories of agricultural sustainability and anthropogenic adaptation for nearly the entire history of farming in the region.
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48.
  • Hansen, Eline P., et al. (author)
  • Exploration of extracellular vesicles from Ascaris suum provides evidence of parasite-host cross talk
  • 2019
  • In: Journal of Extracellular Vesicles. - : Wiley. - 2001-3078. ; 8:1
  • Journal article (peer-reviewed)abstract
    • The prevalent porcine helminth, Ascaris suum, compromises pig health and reduces farm productivity worldwide. The closely related human parasite, A. lumbricoides, infects more than 800 million people representing a disease burden of 1.31 million disability-adjusted life years. The infections are often chronic in nature, and the parasites have a profound ability to modulate their hosts' immune responses. This study provides the first in-depth characterisation of extracellular vesicles (EVs) from different developmental stages and body parts of A. suum and proposes the role of these vesicles in the host-parasite interplay. The release of EVs from the third- (L3) and fourth-stage (L4) larvae and adults was demonstrated by transmission electron microscopy (TEM), and sequencing of EV-derived RNA identified a number of microRNAs (miRNAs) and transcripts of potential host immune targets, such as IL-13, IL-25 and IL-33, were identified. Furthermore, proteomics of EVs identified several proteins with immunomodulatory properties and other proteins previously shown to be associated with parasite EVs. Taken together, these results suggest that A. suum EVs and their cargo may play a role in host-parasite interactions. This knowledge may pave the way to novel strategies for helminth infection control and knowledge of their immune modulatory potential.
  •  
49.
  • Hudson, Lawrence N, et al. (author)
  • The database of the PREDICTS (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems) project
  • 2017
  • In: Ecology and Evolution. - : John Wiley & Sons. - 2045-7758. ; 7:1, s. 145-188
  • Journal article (peer-reviewed)abstract
    • The PREDICTS project-Projecting Responses of Ecological Diversity In Changing Terrestrial Systems (www.predicts.org.uk)-has collated from published studies a large, reasonably representative database of comparable samples of biodiversity from multiple sites that differ in the nature or intensity of human impacts relating to land use. We have used this evidence base to develop global and regional statistical models of how local biodiversity responds to these measures. We describe and make freely available this 2016 release of the database, containing more than 3.2 million records sampled at over 26,000 locations and representing over 47,000 species. We outline how the database can help in answering a range of questions in ecology and conservation biology. To our knowledge, this is the largest and most geographically and taxonomically representative database of spatial comparisons of biodiversity that has been collated to date; it will be useful to researchers and international efforts wishing to model and understand the global status of biodiversity.
  •  
50.
  • Jons, Daniel, et al. (author)
  • Epstein-Barr virus seroreactivity, putative autoimmunity and axonal injury in pre-symptomatic multiple sclerosis
  • 2023
  • In: Multiple Sclerosis Journal. - : Sage Publications. - 1352-4585 .- 1477-0970. ; 29:Suppl. 3, s. 39-40
  • Journal article (other academic/artistic)abstract
    • Introduction: Multiple sclerosis (MS) and presymptomatic axonal injury appears to develop only after an Epstein-Barr virus (EBV) infection. Anoctamin2 (ANO2), a chloride channel expressed in glial cells and neurons, was identified as a possible MS autoantigen. We here examine serum neurofilament (sNfL), a comprehensive EBV seroreactivity and antibodies against ANO2 in pre-symptomatic MS.Objectives/Aims: To study whether the appearance of EBV seroreactivity in the pre-symptomatic phase of MS precedes cumulating MS-induced neuroaxonal damage and whether it is associated with an incipient autoreactivity against a reported MS autoantigen (ANO2).Methods: We performed a case-control study with presymptomatic serum samples identified through cross-linkage of the Swedish MS register and Swedish biobanks. We assayed serum antibodies against EBV nuclear antigen 1 (EBNA1), viral capsid antigen p18 (VCAp18), EBV glycoprotein 350 (gp350), anoctamin 2 (ANO2), and serum neurofilament light (sNfL) in 669 pre-MS cases and matched controls.Results: EBNA1 seroreactivity increased in the pre-MS group from 20–15 years before MS onset, followed by gp350 seroreactivity (p=0.001–0.002, 15–10 years before onset). This appeared before the elevation of sNfL in EBV seropositive pre-MS cases (p=8⋅10-5, 10–5 years before onset). No significant sNfL increase was observed in the EBV seronegative group (p=0.95). Pre-MS cases with the highest sNfL levels cumulated in the EBV seropositive group (p=0.038). ANO2 seropositivity appeared virtually only in the EBNA1 seropositive group, in 16.7 % of EBNA1 seropositive pre-MS samples and in 10.0 % of corresponding controls (p=0.001). Combined EBNA1 and ANO2 seropositivity showed a higher association with subsequent MS than EBNA1 independent of ANO2 (p=0.002–0.028). In the EBNA1 seropositive stratum, ANO2 seropositivity was associated with 26% higher sNfL.Conclusion: In presymptomatic MS an antibody response against EBV, associated with ANO2 autoimmunity, was detectable before elevated sNfL, which cumulated in the EBV seropositive group. ANO2 seropositivity was associated with higher sNfL. An increase in ANO2 seroreactivity did not appear until after EBV seroconversion, limited to a subgroup of the EBV seropositive stratum. Thus, this specific cross-reaction could contribute to MS pathogenesis in a subgroup. This further implicates EBV in the pathogenesis of MS.
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