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Sökning: WFRF:(Schumann Gunter) > (2015-2019)

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1.
  • Bloeschl, Gunter, et al. (författare)
  • Twenty-three unsolved problems in hydrology (UPH) - a community perspective
  • 2019
  • Ingår i: Hydrological Sciences Journal. - : TAYLOR & FRANCIS LTD. - 0262-6667 .- 2150-3435. ; 64:10, s. 1141-1158
  • Tidskriftsartikel (refereegranskat)abstract
    • This paper is the outcome of a community initiative to identify major unsolved scientific problems in hydrology motivated by a need for stronger harmonisation of research efforts. The procedure involved a public consultation through online media, followed by two workshops through which a large number of potential science questions were collated, prioritised, and synthesised. In spite of the diversity of the participants (230 scientists in total), the process revealed much about community priorities and the state of our science: a preference for continuity in research questions rather than radical departures or redirections from past and current work. Questions remain focused on the process-based understanding of hydrological variability and causality at all space and time scales. Increased attention to environmental change drives a new emphasis on understanding how change propagates across interfaces within the hydrological system and across disciplinary boundaries. In particular, the expansion of the human footprint raises a new set of questions related to human interactions with nature and water cycle feedbacks in the context of complex water management problems. We hope that this reflection and synthesis of the 23 unsolved problems in hydrology will help guide research efforts for some years to come.
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2.
  • Adams, Hieab H. H., et al. (författare)
  • Novel genetic loci underlying human intracranial volume identified through genome-wide association
  • 2016
  • Ingår i: Nature Neuroscience. - 1097-6256 .- 1546-1726. ; 19:12, s. 1569-1582
  • Tidskriftsartikel (refereegranskat)abstract
    • Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (rho(genetic) = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (N-combined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.
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3.
  • Hibar, Derrek P., et al. (författare)
  • Common genetic variants influence human subcortical brain structures
  • 2015
  • Ingår i: ; 520:7546, s. 224-U216
  • Tidskriftsartikel (refereegranskat)abstract
    • The highly complex structure of the human brain is strongly shaped by genetic influences(1). Subcortical brain regions form circuits with cortical areas to coordinate movement(2), learning, memory(3) and motivation(4), and altered circuits can lead to abnormal behaviour and disease(5). To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume(5) and intracranial volume(6). These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 X 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.
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4.
  • Hibar, Derrek P., et al. (författare)
  • Novel genetic loci associated with hippocampal volume
  • 2017
  • Ingår i: Nature Communications. - 2041-1723 .- 2041-1723. ; 8
  • Tidskriftsartikel (refereegranskat)abstract
    • The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r(g) = -0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
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5.
  • Jia, Tianye, et al. (författare)
  • Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes : findings from the ENIGMA Epigenetics Working Group.
  • 2019
  • Ingår i: Molecular Psychiatry. - 1359-4184 .- 1476-5578.
  • Tidskriftsartikel (refereegranskat)abstract
    • DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc)-three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.
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6.
  • Meng, Weida, et al. (författare)
  • Genotype-dependent epigenetic regulation of DLGAP2 in alcohol use and dependence.
  • 2019
  • Ingår i: Molecular Psychiatry. - 1359-4184 .- 1476-5578.
  • Tidskriftsartikel (refereegranskat)abstract
    • Alcohol misuse is a major public health problem originating from genetic and environmental risk factors. Alterations in the brain epigenome may orchestrate changes in gene expression that lead to alcohol misuse and dependence. Through epigenome-wide association analysis of DNA methylation from human brain tissues, we identified a differentially methylated region, DMR-DLGAP2, associated with alcohol dependence. Methylation within DMR-DLGAP2 was found to be genotype-dependent, allele-specific and associated with reward processing in brain. Methylation at the DMR-DLGAP2 regulated expression of DLGAP2 in vitro, and Dlgap2-deficient mice showed reduced alcohol consumption compared with wild-type controls. These results suggest that DLGAP2 may be an interface for genetic and epigenetic factors controlling alcohol use and dependence.
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7.
  • Ruggeri, Barbara, et al. (författare)
  • Association of Protein Phosphatase PPM1G With Alcohol Use Disorder and Brain Activity During Behavioral Control in a Genome-Wide Methylation Analysis
  • 2015
  • Ingår i: American Journal of Psychiatry. - 0002-953X .- 1535-7228. ; 172:6, s. 543-552
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: The genetic component of alcohol use disorder is substantial, but monozygotic twin discordance indicates a role for nonheritable differences that could be mediated by epigenetics. Despite growing evidence associating epigenetics and psychiatric disorders, it is unclear how epigenetics, particularly DNA methylation, relate to brain function and behavior, including drinking behavior. Method: The authors carried out a genome-wide analysis of DNA methylation of 18 monozygotic twin pairs discordant for alcohol use disorder and validated differentially methylated regions. After validation, the authors characterized these differentially methylated regions using personality trait assessment and functional MRI in a sample of 499 adolescents. Results: Hypermethylation in the 3'-protein-phosphatase-1G (PPM1G) gene locus was associated with alcohol use disorder. The authors found association of PPM1G hypermethylation with early escalation of alcohol use and increased impulsiveness. They also observed association of PPM1G hypermethylation with increased blood-oxygen-level-dependent response in the right subthalamic nucleus during an impulsiveness task. Conclusions: Overall, the authors provide first evidence for an epigenetic marker associated with alcohol consumption and its underlying neurobehavioral phenotype.
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8.
  • Satizabal, Claudia L., et al. (författare)
  • Genetic architecture of subcortical brain structures in 38,851 individuals
  • 2019
  • Ingår i: ; 51:11, s. 1624-
  • Tidskriftsartikel (refereegranskat)abstract
    • Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
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9.
  • Tay, Nicole, et al. (författare)
  • Allele-Specific Methylation of SPDEF : A Novel Moderator of Psychosocial Stress and Substance Abuse
  • 2019
  • Ingår i: ; 176:2, s. 146-155
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: Psychosocial stress is a key risk factor for substance abuse among adolescents. Recently, epigenetic processes such as DNA methylation have emerged as potential mechanisms that could mediate this relationship. The authors conducted a genome-wide methylation analysis to investigate whether differentially methylated regions are associated with psychosocial stress in an adolescent population.Methods: A methylome-wide analysis of differentially methylated regions was used to examine a sample of 1,287 14-year-old adolescents (50.7% of them female) from the European IMAGEN study. The Illumina 450k array was used to assess DNA methylation, pyrosequencing was used for technical replication, and linear regression analyses were used to identify associations with psychosocial stress and substance use (alcohol and tobacco). Findings were replicated by pyrosequencing a test sample of 413 participants from the IMAGEN study.Results: Hypermethylation in the sterile alpha motif/pointed domain containing the ETS transcription factor (SPDEF) gene locus was associated with a greater number of stressful life events in an allele-dependent way. Among individuals with the minor G-allele, SPDEF methylation moderated the association between psychosocial stress and substance abuse. SPDEF methylation interacted with lifetime stress in gray matter volume in the right cuneus, which in turn was associated with the frequency of alcohol and tobacco use. SPDEF was involved in the regulation of trans-genes linked to substance use.Conclusions: Taken together, the study findings describe a novel epigenetic mechanism that helps explain how psychosocial stress exposure influences adolescent substance abuse.
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10.
  • Mueller, Christian P., et al. (författare)
  • The Cortical Neuroimmune Regulator TANK Affects Emotional Processing and Enhances Alcohol Drinking : A Translational Study
  • 2019
  • Ingår i: ; 29:4, s. 1736-1751
  • Tidskriftsartikel (refereegranskat)abstract
    • Alcohol abuse is a major public health problem worldwide. Understanding the molecular mechanisms that control regular drinking may help to reduce hazards of alcohol consumption. While immunological mechanisms have been related to alcohol drinking, most studies reported changes in immune function that are secondary to alcohol use. In this report, we analyse how the gene "TRAF family member-associated NF-kappa B activator" (TANK) affects alcohol drinking behavior. Based on our recent discovery in a large GWAS dataset that suggested an association of TANK, SNP rs197273, with alcohol drinking, we report that SNP rs197273 in TANK is associated both with gene expression (P = 1.16 x 10(-19)) and regional methylation (P = 5.90 x 10(-25)). A tank knock out mouse model suggests a role of TANK in alcohol drinking, anxiety-related behavior, as well as alcohol exposure induced activation of insular cortex NF-kappa B. Functional and structural neuroimaging studies among up to 1896 adolescents reveal that TANK is involved in the control of brain activity in areas of aversive interoceptive processing, including the insular cortex, but not in areas related to reinforcement, reward processing or impulsiveness. Our findings suggest that the cortical neuroimmune regulator TANK is associated with enhanced aversive emotional processing that better protects from the establishment of alcohol drinking behavior.
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