| 1. |
- Docherty, Anna R, et al.
(författare)
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GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.
- 2023
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Ingår i: The American journal of psychiatry. - : American Psychiatric Association Publishing. - 1535-7228 .- 0002-953X. ; 180:10, s. 723-738
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Tidskriftsartikel (refereegranskat)abstract
- Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures.This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses.Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors.This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.
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| 2. |
- Mullins, Niamh, et al.
(författare)
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Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors
- 2022
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Ingår i: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 91:3, s. 313-327
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged.CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.
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| 3. |
- Benyamin, Beben, et al.
(författare)
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Identification of novel loci affecting circulating chromogranins and related peptides
- 2017
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 26:1, s. 233-242
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Tidskriftsartikel (refereegranskat)abstract
- Chromogranins are pro-hormone secretory proteins released from neuroendocrine cells, with effects on control of blood pressure. We conducted a genome-wide association study for plasma catestatin, the catecholamine release inhibitory peptide derived from chromogranin A (CHGA), and other CHGA- or chromogranin B (CHGB)-related peptides, in 545 US and 1252 Australian subjects. This identified loci on chromosomes 4q35 and 5q34 affecting catestatin concentration (P = 3.40 × 10(-30) for rs4253311 and 1.85 × 10(-19) for rs2731672, respectively). Genes in these regions include the proteolytic enzymes kallikrein (KLKB1) and Factor XII (F12). In chromaffin cells, CHGA and KLKB1 proteins co-localized in catecholamine storage granules. In vitro, kallikrein cleaved recombinant human CHGA to catestatin, verified by mass spectrometry. The peptide identified from this digestion (CHGA360-373) selectively inhibited nicotinic cholinergic stimulated catecholamine release from chromaffin cells. A proteolytic cascade involving kallikrein and Factor XII cleaves chromogranins to active compounds both in vivo and in vitro.
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| 4. |
- Björklund, Jesper, et al.
(författare)
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Dendroclimatic potential of dendroanatomy in temperature-sensitive Pinus sylvestris
- 2020
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Ingår i: Dendrochronologia. - : Elsevier BV. - 1125-7865 .- 1612-0051. ; 60
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Tidskriftsartikel (refereegranskat)abstract
- © 2020 The Authors The most frequently and successfully used tree-ring parameters for the study of temperature variations are ring width and maximum latewood density (MXD). MXD is preferred over ring width due to a more prominent association with temperature. In this study we explore the dendroclimate potential of dendroanatomy based on the first truly well replicated dataset. Twenty-nine mature living Pinus sylvestris trees were sampled in North-eastern Finland at the cool and moist boreal forest zone, close to the latitudinal tree line, where ring width, X-ray MXD as well as the blue intensity counterpart MXBI were compared with dendroanatomical parameters. Maximum radial cell wall thickness as well as anatomical MXD and latewood density appeared to be the most promising parameters for temperature reconstruction. In fact, these parameters compare favorably to MXD derived from X-ray techniques as well as MXBI, in terms of shared variation and temperature correlations across frequencies and over time. The reasons for these results are thought to be the unprecedentedly high measurement resolution of the anatomical technique, which provide the optimal resolution – the cell – whereas X-ray techniques have a slightly lower resolution and BI techniques even lower. While the results of this study are encouraging, further tests on longer and multigenerational chronologies are required to more generally and fully assess the dendroclimate potential of anatomical parameters.
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| 5. |
- Björklund, Jesper, et al.
(författare)
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Fennoscandian tree-ring anatomy shows a warmer modern than medieval climate.
- 2023
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Ingår i: Nature. - 1476-4687 .- 0028-0836. ; 620:7972, s. 97-103
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Tidskriftsartikel (refereegranskat)abstract
- Earth system models and various climate proxy sources indicate global warming is unprecedented during at least the Common Era1. However, tree-ring proxies often estimate temperatures during the Medieval Climate Anomaly (950-1250CE) that are similar to, or exceed, those recorded for the past century2,3, in contrast tosimulation experiments at regional scales4. This not only calls into question the reliability of models and proxies but also contributes to uncertainty in future climate projections5. Here we show that the current climate of the Fennoscandian Peninsula is substantially warmer than that of the medieval period. This highlights the dominant role of anthropogenic forcing in climate warming even at the regional scale, thereby reconciling inconsistencies between reconstructions and model simulations. We used an annually resolved 1,170-year-long tree-ring record that relies exclusively on tracheid anatomical measurements from Pinus sylvestris trees, providing high-fidelity measurements of instrumental temperature variability during the warm season. We therefore call for the construction of more such millennia-long records to further improve our understanding and reduce uncertainties around historical and future climate change at inter-regional and eventually global scales.
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| 6. |
- Brehm, Nicolas, et al.
(författare)
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Tree-rings reveal two strong solar proton events in 7176 and 5259 BCE
- 2022
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- The Sun sporadically produces eruptive events leading to intense fluxes of solar energetic particles (SEPs) that dramatically disrupt the near-Earth radiation environment. Such events have been directly studied for the last decades but little is known about the occurrence and magnitude of rare, extreme SEP events. Presently, a few events that produced measurable signals in cosmogenic radionuclides such as 14C, 10Be and 36Cl have been found. Analyzing annual 14C concentrations in tree-rings from Switzerland, Germany, Ireland, Russia, and the USA we discovered two spikes in atmospheric 14C occurring in 7176 and 5259 BCE. The ~2% increases of atmospheric 14C recorded for both events exceed all previously known 14C peaks but after correction for the geomagnetic field, they are comparable to the largest event of this type discovered so far at 775 CE. These strong events serve as accurate time markers for the synchronization with floating tree-ring and ice core records and provide critical information on the previous occurrence of extreme solar events which may threaten modern infrastructure.
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| 7. |
- Büntgen, Ulf, et al.
(författare)
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Tree-Ring Amplification of the Early Nineteenth-Century Summer Cooling in Central Europe
- 2015
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Ingår i: Journal of Climate. - 0894-8755 .- 1520-0442. ; 28:13, s. 5272-5288
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Forskningsöversikt (refereegranskat)abstract
- Annually resolved and absolutely dated tree-ring chronologies are the most important proxy archives to reconstruct climate variability over centuries to millennia. However, the suitability of tree-ring chronologies to reflect the “true” spectral properties of past changes in temperature and hydroclimate has recently been debated. At issue is the accurate quantification of temperature differences between early nineteenth-century cooling and recent warming. In this regard, central Europe (CEU) offers the unique opportunity to compare evidence from instrumental measurements, paleomodel simulations, and proxy reconstructions covering both the exceptionally hot summer of 2003 and the year without summer in 1816. This study uses 565 Swiss stone pine (Pinus cembra) ring width samples from high-elevation sites in the Slovakian Tatra Mountains and Austrian Alps to reconstruct CEU summer temperatures over the past three centuries. This new temperature history is compared to different sets of instrumental measurements and state-of-the-art climate model simulations. All records independently reveal the coolest conditions in the 1810s and warmest after 1996, but the ring width–based reconstruction overestimates the intensity and duration of the early nineteenth-century summer cooling by approximately 1.5°C at decadal scales. This proxy-specific deviation is most likely triggered by inflated biological memory in response to reduced warm season temperature, together with changes in radiation and precipitation following the Tambora eruption in April 1815. While suggesting there exists a specific limitation in ring width chronologies to capture abrupt climate perturbations with increased climate system inertia, the results underline the importance of alternative dendrochronological and wood anatomical parameters, including stable isotopes and maximum density, to assess the frequency and severity of climatic extremes.
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| 8. |
- Chen, Yuqing, et al.
(författare)
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Chromogranin A regulates renal function by triggering Weibel-Palade body exocytosis
- 2009
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Ingår i: Journal of the American Society of Nephrology. - 1046-6673 .- 1533-3450. ; 20:7, s. 1623-1632
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Tidskriftsartikel (refereegranskat)abstract
- Chromogranin A (CHGA), a protein released from secretory granules of chromaffin cells and sympathetic nerves, triggers endothelin-1 release from endothelial cells. CHGA polymorphisms associate with an increased risk for ESRD, but whether altered CHGA-endothelium interactions may explain this association is unknown. Here, CHGA led to the release of endothelin-1 and Weibel-Palade body exocytosis in cultured human umbilical vein endothelial cells. In addition, CHGA triggered secretion of endothelin-1 from glomerular endothelial cells and TGF-beta1 from mesangial cells cocultured with glomerular endothelial cells. In humans, plasma CHGA correlated positively with endothelin-1 and negatively with GFR. GFR was highly heritable in twin pairs, and common promoter haplotypes of CHGA predicted GFR. In patients with progressive hypertensive renal disease, a CHGA haplotype predicted rate of GFR decline. In conclusion, these data suggest that CHGA acts through the glomerular endothelium to regulate renal function.
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| 9. |
- Hightower, C. Makena, et al.
(författare)
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Genetic variation at the delta-sarcoglycan (SGCD) locus elevates heritable sympathetic nerve activity in human twin pairs
- 2013
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Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 127:6, s. 750-761
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Tidskriftsartikel (refereegranskat)abstract
- The Syrian Cardiomyopathic Hamster (BIO-14.6/53.58 strains) model of cardiac failure, resulting from naturally occurring deletion at the SGCD (delta-sarcoglycan) locus, displays widespread disturbances in catecholamine metabolism. Rare Mendelian myopathy disorders of human SGCD occur, although common naturally occurring SGCD genetic variation has not been evaluated for effects on human norepinephrine (NE) secretion. This study investigated the effect of SGCD genetic variation on control of NE secretion in healthy twin pairs. Genetic associations profiled SNPs across the SGCD locus. Trait heritability (h(2)) and genetic covariance (pleiotropy; shared h(2)) were evaluated. Sympathochromaffin exocytosis in vivo was probed in plasma by both catecholamines and Chromogranin B (CHGB). Plasma NE is substantially heritable (p=3.19E-16, at 65.2 +/- 5.0% of trait variance), sharing significant (p<0.05) genetic determination with circulating and urinary catecholamines, CHGB, eGFR, and several cardio-metabolic traits. Participants with higher pNE showed significant (p<0.05) differences in several traits, including increased BP and hypertension risk factors. Peak SGCD variant rs1835919 predicted elevated systemic vascular compliance, without changes in specifically myocardial traits. We used a chimeric-regulated secretory pathway photoprotein (CHGA-EAP) to evaluate the effect of SGCD on the exocytotic pathway in transfected PC12 cells; in transfected cells, expression of SGCD augmented CHGA trafficking into the exocytotic regulated secretory pathway. Thus, our investigation determined human NE secretion to be a highly heritable trait, influenced by common genetic variation within the SGCD locus. Circulating NE aggregates with BP and hypertension risk factors. In addition, coordinate NE and CHGB elevation by rs1835919 implicates exocytosis as the mechanism of release.
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| 10. |
- Hou, Liping, et al.
(författare)
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Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder.
- 2016
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Ingår i: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 25:15, s. 3383-94
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Tidskriftsartikel (refereegranskat)abstract
- Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behavior. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ∼2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, p=5.87×10(-9); odds ratio=1.12) and markers within ERBB2 (rs2517959, p=4.53×10(-9); odds ratio=1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.
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| 11. |
- Lendvay, Bertalan, et al.
(författare)
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Improved recovery of ancient DNA from subfossil wood - application to the world's oldest Late Glacial pine forest
- 2018
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Ingår i: New Phytologist. - : Wiley. - 0028-646X .- 1469-8137. ; 217:4, s. 1737-1748
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Tidskriftsartikel (refereegranskat)abstract
- Ancient DNA from historical and subfossil wood has a great potential to provide new insights into the history of tree populations. However, its extraction and analysis have not become routine, mainly because contamination of the wood with modern plant material can complicate the verification of genetic information. Here, we used sapwood tissue from 22 subfossil pines that were growing c. 13000yr bp in Zurich, Switzerland. We developed and evaluated protocols to eliminate surface contamination, and we tested ancient DNA authenticity based on plastid DNA metabarcoding and the assessment of post-mortem DNA damage. A novel approach using laser irradiation coupled with bleaching and surface removal was most efficient in eliminating contaminating DNA. DNA metabarcoding confirmed which ancient DNA samples repeatedly amplified pine DNA and were free of exogenous plant taxa. Pine DNA sequences of these samples showed a high degree of cytosine to thymine mismatches, typical of post-mortem damage. Stringent decontamination of wood surfaces combined with DNA metabarcoding and assessment of post-mortem DNA damage allowed us to authenticate ancient DNA retrieved from the oldest Late Glacial pine forest. These techniques can be applied to any subfossil wood and are likely to improve the accessibility of relict wood for genome-scale ancient DNA studies.
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| 12. |
- Opgenoorth, Lars, et al.
(författare)
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The GenTree Platform : growth traits and tree-level environmental data in 12 European forest tree species
- 2021
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Ingår i: GigaScience. - : Oxford University Press. - 2047-217X. ; 10:3
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Tidskriftsartikel (refereegranskat)abstract
- Background: Progress in the field of evolutionary forest ecology has been hampered by the huge challenge of phenotyping trees across their ranges in their natural environments, and the limitation in high-resolution environmental information.Findings: The GenTree Platform contains phenotypic and environmental data from 4,959 trees from 12 ecologically and economically important European forest tree species: Abies alba Mill. (silver fir), Betula pendula Roth. (silver birch), Fagus sylvatica L. (European beech), Picea abies (L.) H. Karst (Norway spruce), Pinus cembra L. (Swiss stone pine), Pinus halepensis Mill. (Aleppo pine), Pinus nigra Arnold (European black pine), Pinus pinaster Aiton (maritime pine), Pinus sylvestris L. (Scots pine), Populus nigra L. (European black poplar), Taxus baccata L. (English yew), and Quercus petraea (Matt.) Liebl. (sessile oak). Phenotypic (height, diameter at breast height, crown size, bark thickness, biomass, straightness, forking, branch angle, fructification), regeneration, environmental in situ measurements (soil depth, vegetation cover, competition indices), and environmental modeling data extracted by using bilinear interpolation accounting for surrounding conditions of each tree (precipitation, temperature, insolation, drought indices) were obtained from trees in 194 sites covering the species' geographic ranges and reflecting local environmental gradients.Conclusion: The GenTree Platform is a new resource for investigating ecological and evolutionary processes in forest trees. The coherent phenotyping and environmental characterization across 12 species in their European ranges allow for a wide range of analyses from forest ecologists, conservationists, and macro-ecologists. Also, the data here presented can be linked to the GenTree Dendroecological collection, the GenTree Leaf Trait collection, and the GenTree Genomic collection presented elsewhere, which together build the largest evolutionary forest ecology data collection available.
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| 13. |
- Zhang, Kuixing, et al.
(författare)
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Neuropeptide Y (NPY) : Genetic Variation in the Human Promoter Alters Glucocorticoid Signaling, Yielding Increased NPY Secretion and Stress Responses
- 2012
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 60:17, s. 1678-1689
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivesThis study sought to understand whether genetic variation at the Neuropeptide Y (NPY) locus governs secretion and stress responses in vivo as well as NPY gene expression in sympathochromaffin cells.BackgroundThe NPY is a potent pressor peptide co-released with catecholamines during stress by sympathetic axons. Genome-wide linkage on NPY secretion identified a LOD (logarithm of the odds ratio) peak spanning the NPY locus on chromosome 7p15.MethodsOur approach began with genomics (linkage and polymorphism determination), extended into NPY genetic control of heritable stress traits in twin pairs, established transcriptional mechanisms in transfected chromaffin cells, and concluded with observations on blood pressure (BP) in the population.ResultsSystematic polymorphism tabulation at NPY (by re-sequencing across the locus: promoter, 4 exons, exon/intron borders, and untranslated regions; on 2n = 160 chromosomes of diverse biogeographic ancestries) identified 16 variants, of which 5 were common. We then studied healthy twin/sibling pairs (n = 399 individuals), typing 6 polymorphisms spanning the locus. Haplotype and single nucleotide polymorphism analyses indicated that proximal promoter variant ∇−880Δ (2-bp TG/—, Ins/Del, rs3037354) minor/Δ allele was associated with several heritable (h2) stress traits: higher NPY secretion (h2 = 73 ± 4%) as well as greater BP response to environmental (cold) stress, and higher basal systemic vascular resistance. Association of ∇−880Δ and plasma NPY was replicated in an independent sample of 361 healthy young men, with consistent allelic effects; genetic variation at NPY also associated with plasma NPY in another independent series of 2,212 individuals derived from Australia twin pairs. Effects of allele −880Δ to increase NPY expression were directionally coordinate in vivo (on human traits) and in cells (transfected NPY promoter/luciferase reporter activity). Promoter −880Δ interrupts a novel glucocorticoid response element motif, an effect confirmed in chromaffin cells by site-directed mutagenesis on the transfected promoter, with differential glucocorticoid stimulation of the motif as well as alterations in electrophoretic mobility shifts. The same −880Δ allele also conferred risk for hypertension and accounted for approximately 4.5/approximately 2.1 mm Hg systolic BP/diastolic BP in a population sample from BP extremes.ConclusionsWe conclude that common genetic variation at the NPY locus, especially in proximal promoter ∇−880Δ, disrupts glucocorticoid signaling to influence NPY transcription and secretion, raising systemic vascular resistance and early heritable responses to environmental stress, eventuating in elevated resting BP in the population. The results point to new molecular strategies for probing autonomic control of the human circulation and ultimately susceptibility to and pathogenesis of cardiovascular and neuropsychiatric disease states.
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