| 1. |
- Young, William J., et al.
(author)
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Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways
- 2022
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 13
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Journal article (peer-reviewed)abstract
- The QT interval is a heritable electrocardiographic measure associated with arrhythmia risk when prolonged. Here, the authors used a series of genetic analyses to identify genetic loci, pathways, therapeutic targets, and relationships with cardiovascular disease. The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.
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| 2. |
- Marchant, Rob, et al.
(author)
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Drivers and trajectories of land cover change in East Africa : Human and environmental interactions from 6000 years ago to present
- 2018
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In: Earth-Science Reviews. - : Elsevier. - 0012-8252 .- 1872-6828. ; 178, s. 322-378
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Journal article (peer-reviewed)abstract
- East African landscapes today are the result of the cumulative effects of climate and land-use change over millennial timescales. In this review, we compile archaeological and palaeoenvironmental data from East Africa to document land-cover change, and environmental, subsistence and land-use transitions, over the past 6000 years. Throughout East Africa there have been a series of relatively rapid and high-magnitude environmental shifts characterised by changing hydrological budgets during the mid- to late Holocene. For example, pronounced environmental shifts that manifested as a marked change in the rainfall amount or seasonality and subsequent hydrological budget throughout East Africa occurred around 4000, 800 and 300 radiocarbon years before present (yr BP). The past 6000 years have also seen numerous shifts in human interactions with East African ecologies. From the mid-Holocene, land use has both diversified and increased exponentially, this has been associated with the arrival of new subsistence systems, crops, migrants and technologies, all giving rise to a sequence of significant phases of land-cover change. The first large-scale human influences began to occur around 4000 yr BP, associated with the introduction of domesticated livestock and the expansion of pastoral communities. The first widespread and intensive forest clearances were associated with the arrival of iron-using early farming communities around 2500 yr BP, particularly in productive and easily-cleared mid-altitudinal areas. Extensive and pervasive land-cover change has been associated with population growth, immigration and movement of people. The expansion of trading routes between the interior and the coast, starting around 1300 years ago and intensifying in the eighteenth and nineteenth centuries CE, was one such process. These caravan routes possibly acted as conduits for spreading New World crops such as maize (Zea mays), tobacco (Nicotiana spp.) and tomatoes (Solanum lycopersicum), although the processes and timings of their introductions remains poorly documented. The introduction of southeast Asian domesticates, especially banana (Musa spp.), rice (Oryza spp.), taro (Colocasia esculenta), and chicken (Gallus gallus), via transoceanic biological transfers around and across the Indian Ocean, from at least around 1300 yr BP, and potentially significantly earlier, also had profound social and ecological consequences across parts of the region. Through an interdisciplinary synthesis of information and metadatasets, we explore the different drivers and directions of changes in land-cover, and the associated environmental histories and interactions with various cultures, technologies, and subsistence strategies through time and across space in East Africa. This review suggests topics for targeted future research that focus on areas and/or time periods where our understanding of the interactions between people, the environment and land-cover change are most contentious and/or poorly resolved. The review also offers a perspective on how knowledge of regional land-use change can be used to inform and provide perspectives on contemporary issues such as climate and ecosystem change models, conservation strategies, and the achievement of nature-based solutions for development purposes.
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| 3. |
- Aragam, Krishna G., et al.
(author)
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Phenotypic Refinement of Heart Failure in a National Biobank Facilitates Genetic Discovery
- 2019
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In: Circulation. - 0009-7322. ; 139:4, s. 489-501
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Journal article (peer-reviewed)abstract
- Heart failure (HF) is a morbid and heritable disorder for which the biological mechanisms are incompletely understood. We therefore examined genetic associations with HF in a large national biobank, and assessed whether refined phenotypic classification would facilitate genetic discovery. Methods: We defined all-cause HF among 488 010 participants from the UK Biobank and performed a genome-wide association analysis. We refined the HF phenotype by classifying individuals with left ventricular dysfunction and without coronary artery disease as having nonischemic cardiomyopathy (NICM), and repeated a genetic association analysis. We then pursued replication of lead HF and NICM variants in independent cohorts, and performed adjusted association analyses to assess whether identified genetic associations were mediated through clinical HF risk factors. In addition, we tested rare, loss-of-function mutations in 24 known dilated cardiomyopathy genes for association with HF and NICM. Finally, we examined associations between lead variants and left ventricular structure and function among individuals without HF using cardiac magnetic resonance imaging (n=4158) and echocardiographic data (n=30 201). Results: We identified 7382 participants with all-cause HF in the UK Biobank. Genome-wide association analysis of all-cause HF identified several suggestive loci (P<1×10 -6 ), the majority linked to upstream HF risk factors, ie, coronary artery disease (CDKN2B-AS1 and MAP3K7CL) and atrial fibrillation (PITX2). Refining the HF phenotype yielded a subset of 2038 NICM cases. In contrast to all-cause HF, genetic analysis of NICM revealed suggestive loci that have been implicated in dilated cardiomyopathy (BAG3, CLCNKA-ZBTB17). Dilated cardiomyopathy signals arising from our NICM analysis replicated in independent cohorts, persisted after HF risk factor adjustment, and were associated with indices of left ventricular dysfunction in individuals without clinical HF. In addition, analyses of loss-of-function variants implicated BAG3 as a disease susceptibility gene for NICM (loss-of-function variant carrier frequency=0.01%; odds ratio,12.03; P=3.62×10 -5 ). Conclusions: We found several distinct genetic mechanisms of all-cause HF in a national biobank that reflect well-known HF risk factors. Phenotypic refinement to a NICM subtype appeared to facilitate the discovery of genetic signals that act independently of clinical HF risk facto rs and that are associated with subclinical left ventricular dysfunction.
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| 4. |
- Barrenäs, Fredrik, et al.
(author)
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Interleukin-15 response signature predicts RhCMV/SIV vaccine efficacy
- 2021
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In: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 17:7
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Journal article (peer-reviewed)abstract
- Simian immunodeficiency virus (SIV) challenge of rhesus macaques (RMs) vaccinated with strain 68-1 Rhesus Cytomegalovirus (RhCMV) vectors expressing SIV proteins (RhCMV/SIV) results in a binary outcome: stringent control and subsequent clearance of highly pathogenic SIV in similar to 55% of vaccinated RMs with no protection in the remaining 45%. Although previous work indicates that unconventionally restricted, SIV-specific, effector-memory (EM)-biased CD8(+) T cell responses are necessary for efficacy, the magnitude of these responses does not predict efficacy, and the basis of protection vs. non-protection in 68-1 RhCMV/SIV vector-vaccinated RMs has not been elucidated. Here, we report that 68-1 RhCMV/SIV vector administration strikingly alters the whole blood transcriptome of vaccinated RMs, with the sustained induction of specific immune-related pathways, including immune cell, toll-like receptor (TLR), inflammasome/cell death, and interleukin-15 (IL-15) signaling, significantly correlating with subsequent vaccine efficacy. Treatment of a separate RM cohort with IL-15 confirmed the central involvement of this cytokine in the protection signature, linking the major innate and adaptive immune gene expression networks that correlate with RhCMV/SIV vaccine efficacy. This change-from-baseline IL-15 response signature was also demonstrated to significantly correlate with vaccine efficacy in an independent validation cohort of vaccinated and challenged RMs. The differential IL-15 gene set response to vaccination strongly correlated with the pre-vaccination activity of this pathway, with reduced baseline expression of IL-15 response genes significantly correlating with higher vaccine-induced induction of IL-15 signaling and subsequent vaccine protection, suggesting that a robust de novo vaccine-induced IL-15 signaling response is needed to program vaccine efficacy. Thus, the RhCMV/SIV vaccine imparts a coordinated and persistent induction of innate and adaptive immune pathways featuring IL-15, a known regulator of CD8(+) T cell function, that support the ability of vaccine-elicited unconventionally restricted CD8(+) T cells to mediate protection against SIV challenge.
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| 5. |
- Githumbi, Esther N., et al.
(author)
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Pollen, People and Place : Multidisciplinary Perspectives on Ecosystem Change at Amboseli, Kenya
- 2018
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In: Frontiers in Earth Science. - : Frontiers Media S.A.. - 2296-6463. ; 5, s. 1-26
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Journal article (peer-reviewed)abstract
- This study presents a multidisciplinary perspective for understanding environmental change and emerging socio-ecological interactions across the Amboseli region of southwestern Kenya. We focus on late Holocene (<5,000 cal yr. BP) changes and continuities reconstructed from sedimentary, archeological, historical records and socio-ecological models. We utilize multi-disciplinary approaches to understand environmental-ecosystem-social interactions over the longue durée and use this to simulate different land use scenarios supporting conservation and sustainable livelihoods using a socio-ecological model. Today the semi-arid Amboseli landscape supports a large livestock and wildlife population, sustained by a wide variety of plants and extensive rangelands regulated by seasonal rainfall and human activity. Our data provide insight into how large-scale and long-term interactions of climate, people, livestock, wildlife and external connections have shaped the ecosystems across the Amboseli landscape. Environmental conditions were dry between ~5,000 and 2,000 cal yr. BP, followed by two wet periods at ~2,100–1,500 and 1,400–800 cal yr. BP with short dry periods; the most recent centuries were characterized by variable climate with alternative dry and wet phases with high spatial heterogeneity. Most evident in paleo and historical records is the changing woody to grass cover ratio, driven by changes in climate and fire regimes entwined with fluctuating elephant, cattle and wild ungulate populations moderated by human activity, including elephant ivory trade intensification. Archeological perspectives on the occupation of different groups (hunter-gatherers, pastoralists, and farmers) in Amboseli region and the relationships between them are discussed. An overview of the known history of humans and elephants, expanding networks of trade, and the arrival and integration of metallurgy, livestock and domesticated crops in the wider region is provided. In recent decades, increased runoff and flooding have resulted in the expansion of wetlands and a reduction of woody vegetation, compounding problems created by increased enclosure and privatization of these landscapes. However, most of the wetlands outside of the protected area are drying up because of the intensified water extraction by the communities surrounding the National Park and on the adjacent mountains areas, who have increased in numbers, become sedentary and diversified land use around the wetlands.
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| 6. |
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| 7. |
- Kariuki, Rebecca W., et al.
(author)
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Integrating stakeholders' perspectives and spatial modelling to develop scenarios of future land use and land cover change in northern Tanzania
- 2021
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 16:2
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Journal article (peer-reviewed)abstract
- Rapid rates of land use and land cover change (LULCC) in eastern Africa and limited instances of genuinely equal partnerships involving scientists, communities and decision makers challenge the development of robust pathways toward future environmental and socioeconomic sustainability. We use a participatory modelling tool, Kesho, to assess the biophysical, socioeconomic, cultural and governance factors that influenced past (1959-1999) and present (2000-2018) LULCC in northern Tanzania and to simulate four scenarios of land cover change to the year 2030. Simulations of the scenarios used spatial modelling to integrate stakeholders' perceptions of future environmental change with social and environmental data on recent trends in LULCC. From stakeholders' perspectives, between 1959 and 2018, LULCC was influenced by climate variability, availability of natural resources, agriculture expansion, urbanization, tourism growth and legislation governing land access and natural resource management. Among other socio-environmental-political LULCC drivers, the stakeholders envisioned that from 2018 to 2030 LULCC will largely be influenced by land health, natural and economic capital, and political will in implementing land use plans and policies. The projected scenarios suggest that by 2030 agricultural land will have expanded by 8-20% under different scenarios and herbaceous vegetation and forest land cover will be reduced by 2.5-5% and 10-19% respectively. Stakeholder discussions further identified desirable futures in 2030 as those with improved infrastructure, restored degraded landscapes, effective wildlife conservation, and better farming techniques. The undesirable futures in 2030 were those characterized by land degradation, poverty, and cultural loss. Insights from our work identify the implications of future LULCC scenarios on wildlife and cultural conservation and in meeting the Sustainable Development Goals (SDGs) and targets by 2030. The Kesho approach capitalizes on knowledge exchanges among diverse stakeholders, and in the process promotes social learning, provides a sense of ownership of outputs generated, democratizes scientific understanding, and improves the quality and relevance of the outputs.
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| 8. |
- Kariuki, Rebecca W., et al.
(author)
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Serengeti's futures : Exploring land use and land cover change scenarios to craft pathways for meeting conservation and development goals
- 2022
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In: Frontiers in Conservation Science. - : Frontiers Media SA. - 2673-611X. ; 3
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Journal article (peer-reviewed)abstract
- Rapid land use transformations and increased climatic uncertainties challenge potential sustainable development pathways for communities and wildlife in regions with strong economic reliance on natural resources. In response to the complex causes and consequences of land use change, participatory scenario development approaches have emerged as key tools for analyzing drivers of change to help chart the future of socio-ecological systems. We assess stakeholder perspectives of land use and land cover change (LULCC) and integrate co-produced scenarios of future land cover change with spatial modeling to evaluate how future LULCC in the wider Serengeti ecosystem might align or diverge with the United Nations' Sustainable Development Goals and the African Union's Agenda 2063. Across the wider Serengeti ecosystem, population growth, infrastructural development, agricultural economy, and political will in support of climate change management strategies were perceived to be the key drivers of future LULCC. Under eight scenarios, declines in forest area as a proportion of total land area ranged from 0.1% to 4% in 2030 and from 0.1% to 6% in 2063, with the preservation of forest cover linked to the level of protection provided. Futures with well-demarcated protected areas, sound land use plans, and stable governance were highly desired. In contrast, futures with severe climate change impacts and encroached and degazetted protected areas were considered undesirable. Insights gained from our study are important for guiding pathways toward achieving sustainability goals while recognizing societies' relationship with nature. The results highlight the usefulness of multi-stakeholder engagement, perspective sharing, and consensus building toward shared socio-ecological goals.
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| 9. |
- Ntalla, Ioanna, et al.
(author)
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Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction
- 2020
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Journal article (peer-reviewed)abstract
- The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N=293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.
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| 10. |
- Roselli, Carolina, et al.
(author)
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Multi-ethnic genome-wide association study for atrial fibrillation
- 2018
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:9, s. 1225-1233
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Journal article (peer-reviewed)abstract
- Atrial fibrillation (AF) affects more than 33 million individuals worldwide(1) and has a complex heritability(2). We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.
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