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A catalog of genetic loci associated with kidney function from analyses of a million individuals
(2019)
Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 x 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 x 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height(1), their effects on infant head circumference were largely independent of height (P = 3.8 x 10(-7) for rs7980687 and P = 1.3 x 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 x 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume(2), Parkinson's disease and other neurodegenerative diseases(3-5), indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.
Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m(2)/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m(2) at follow-up among those with eGFRcrea 60 mL/min/1.73m(2) or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or (LARP4B). Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m(2)/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m(2) at follow-up among those with eGFRcrea 60 mL/min/1.73m(2) or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or (LARP4B). Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (P < 5 x 10(-8)) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 x 10(-11)), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 x 10(-12)), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 x 10(-3) for 6q22 and 1.2 x 10(-3) for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size.
Context. Over the past 20 yr, the quietest areas of the solar surface have revealed a weak but extremely dynamic magnetism occurring at small scales (<500 km), which may provide an important contribution to the dynamics and energetics of the outer layers of the atmosphere. Understanding this magnetism requires the inference of physical quantities from high-sensitivity spectro-polarimetric data with high spatio-temporal resolution. Aims. We present high-precision spectro-polarimetric data with high spatial resolution (0.4") of the very quiet Sun at 1.56 mu m obtained with the GREGOR telescope to shed some light on this complex magnetism. Methods. We used inversion techniques in two main approaches. First, we assumed that the observed profiles can be reproduced with a constant magnetic field atmosphere embedded in a field-free medium. Second, we assumed that the resolution element has a substructure with either two constant magnetic atmospheres or a single magnetic atmosphere with gradients of the physical quantities along the optical depth, both coexisting with a global stray-light component. Results. Half of our observed quiet-Sun region is better explained by magnetic substructure within the resolution element. However, we cannot distinguish whether this substructure comes from gradients of the physical parameters along the line of sight or from horizontal gradients (across the surface). In these pixels, a model with two magnetic components is preferred, and we find two distinct magnetic field populations. The population with the larger filling factor has very weak (similar to 150 G) horizontal fields similar to those obtained in previous works. We demonstrate that the field vector of this population is not constrained by the observations, given the spatial resolution and polarimetric accuracy of our data. The topology of the other component with the smaller filling factor is constrained by the observations for field strengths above 250 G: we infer hG fields with inclinations and azimuth values compatible with an isotropic distribution. The filling factors are typically below 30%. We also find that the flux of the two polarities is not balanced. From the other half of the observed quiet-Sun area similar to 50% are two-lobed Stokes V profiles, meaning that 23% of the field of view can be adequately explained with a single constant magnetic field embedded in a non-magnetic atmosphere. The magnetic field vector and filling factor are reliable inferred in only 50% based on the regular profiles. Therefore, 12% of the field of view harbour hG fields with filling factors typically below 30%. At our present spatial resolution, 70% of the pixels apparently are non-magnetised.
Introducing the CTA concept
(2013)
The Cherenkov Telescope Array (CTA) is a new observatory for very high-energy (VHE) gamma rays. CTA has ambitions science goals, for which it is necessary to achieve full-sky coverage, to improve the sensitivity by about an order of magnitude, to span about four decades of energy, from a few tens of GeV to above 100 TeV with enhanced angular and energy resolutions over existing VHE gamma-ray observatories. An international collaboration has formed with more than 1000 members from 27 countries in Europe, Asia, Africa and North and South America. In 2010 the CTA Consortium completed a Design Study and started a three-year Preparatory Phase which leads to production readiness of CTA in 2014. In this paper we introduce the science goals and the concept of CTA, and provide an overview of the project.
Context. The solar magnetic field is responsible for all aspects of solar activity. Thus, emergence of magnetic flux at the surface is the first manifestation of the ensuing solar activity. Aims. Combining high-resolution and synoptic observations aims to provide a comprehensive description of flux emergence at photospheric level and of the growth process that eventually leads to a mature active region. Methods. The small active region NOAA 12118 emerged on 2014 July 17 and was observed one day later with the 1.5-m GREGOR solar telescope on 2014 July 18. High-resolution time-series of blue continuum and G-band images acquired in the blue imaging channel (BIC) of the GREGOR Fabry-Perot Interferometer (GFPI) were complemented by synoptic line-of-sight magnetograms and continuum images obtained with the Helioseismic and Magnetic Imager (HMI) onboard the Solar Dynamics Observatory (SDO). Horizontal proper motions and horizontal plasma velocities were computed with local correlation tracking (LCT) and the differential affine velocity estimator (DAVE), respectively. Morphological image processing was employed to measure the photometric and magnetic area, magnetic flux, and the separation profile of the emerging flux region during its evolution. Results. The computed growth rates for photometric area, magnetic area, and magnetic flux are about twice as high as the respective decay rates. The space-time diagram using HMI magnetograms of five days provides a comprehensive view of growth and decay. It traces a leaf-like structure, which is determined by the initial separation of the two polarities, a rapid expansion phase, a time when the spread stalls, and a period when the region slowly shrinks again. The separation rate of 0.26 km s(-1) is highest in the initial stage, and it decreases when the separation comes to a halt. Horizontal plasma velocities computed at four evolutionary stages indicate a changing pattern of inflows. In LCT maps we find persistent flow patterns such as outward motions in the outer part of the two major pores, a diverging feature near the trailing pore marking the site of upwelling plasma and flux emergence, and low velocities in the interior of dark pores. We detected many elongated rapidly expanding granules between the two major polarities, with dimensions twice as large as the normal granules.
Arch filament systems occur in active sunspot groups, where a fibril structure connects areas of opposite magnetic polarity, in contrast to active region filaments that follow the polarity inversion line. We used the GREGOR Infrared Spectrograph (GRIS) to obtain the full Stokes vector in the spectral lines SiI lambda 1082.7 nm, He I lambda 1083.0 nm, and Ca I lambda 1083.9 nm. We focus on the near-infrared calcium line to investigate the photospheric magnetic field and velocities, and use the line core intensities and velocities of the helium line to study the chromospheric plasma. The individual fibrils of the arch filament system connect the sunspot with patches of magnetic polarity opposite to that of the spot. These patches do not necessarily coincide with pores, where the magnetic field is strongest. Instead, areas are preferred not far from the polarity inversion line. These areas exhibit photospheric downflows of moderate velocity, but significantly higher downflows of up to 30 km s(-1) in the chromospheric helium line. Our findings can be explained with new emerging flux where the matter flows downward along the field lines of rising flux tubes, in agreement with earlier results. (C) 2016 WILEY-VCH Verlag GmbH& Co. KGaA, Weinheim
The new generation of solar instruments provides better spectral, spatial, and temporal resolution for a better understanding of the physical processes that take place on the Sun. Multiple-component profiles are more commonly observed with these instruments. Particularly, the He i 10830 triplet presents such peculiar spectral profiles, which give information on the velocity and magnetic fine structure of the upper chromosphere. The purpose of this investigation is to describe a technique to efficiently fit the two blended components of the He i 10830 triplet, which are commonly observed when two atmospheric components are located within the same resolution element. The observations used in this study were taken on 2015 April 17 with the very fast spectroscopic mode of the GREGOR Infrared Spectrograph (GRIS) attached to the 1.5-m GREGOR solar telescope, located at the Observatorio del Teide, Tenerife, Spain. We apply a double-Lorentzian fitting technique using Levenberg-Marquardt least-squares minimization. This technique is very simple and much faster than inversion codes. Line-of-sight Doppler velocities can be inferred for a whole map of pixels within just a few minutes. Our results show sub-and supersonic downflow velocities of up to 32 km s(-1) for the fast component in the vicinity of footpoints of filamentary structures. The slow component presents velocities close to rest. (C) 2016 WILEY-VCH Verlag GmbH& Co. KGaA, Weinheim
Improved measurements of the photospheric and chromospheric three-dimensional magnetic and flow fields are crucial for a precise determination of the origin and evolution of active regions. We present an illustrative sample of multi-instrument data acquired during a two-week coordinated observing campaign in August 2015 involving, among others, the GREGOR solar telescope (imaging and near-infrared spectroscopy) and the space missions Solar Dynamics Observatory (SDO) and Interface Region Imaging Spectrograph (IRIS). The observations focused on the trailing part of active region NOAA 12396 with complex polarity inversion lines and strong intrusions of opposite polarity flux. The GREGOR Infrared Spectrograph (GRIS) provided Stokes IQUV spectral profiles in the photospheric Si i.1082.7 nm line, the chromospheric He I lambda 1083.0 nm triplet, and the photospheric Ca I lambda 1083.9 nm line. Carefully calibrated GRIS scans of the active region provided maps of Doppler velocity and magnetic field at different atmospheric heights. We compare quick-look maps with those obtained with the " Stokes Inversions based on Response functions" (SIR) code, which furnishes deeper insight into the magnetic properties of the region. We find supporting evidence that newly emerging flux and intruding opposite polarity flux are hampering the formation of penumbrae, i.e., a penumbra fully surrounding a sunspot is only expected after cessation of flux emergence in proximity to the sunspots. (C) 2016 WILEY-VCH Verlag GmbH& Co.KGaA, Weinheim
Ground-based gamma-ray astronomy has had a major breakthrough with the impressive results obtained using systems of imaging atmospheric Cherenkov telescopes. Ground-based gamma-ray astronomy has a huge potential in astrophysics, particle physics and cosmology. CTA is an international initiative to build the next generation instrument, with a factor of 5-10 improvement in sensitivity in the 100 GeV-10 TeV range and the extension to energies well below 100 GeV and above 100 TeV. CTA will consist of two arrays (one in the north, one in the south) for full sky coverage and will be operated as open observatory. The design of CTA is based on currently available technology. This document reports on the status and presents the major design concepts of CTA.
The Stardust mission returned cometary, interplanetary and (probably) interstellar dust in 2006 to Earth that have been analysed in Earth laboratories worldwide. Results of this mission have changed our view and knowledge on the early solar nebula. The Rosetta mission is on its way to land on comet 67P/Churyumov-Gerasimenko and will investigate for the first time in great detail the comet nucleus and its environment starting in 2014. Additional astronomy and planetary space missions will further contribute to our understanding of dust generation, evolution and destruction in interstellar and interplanetary space and provide constraints on solar system formation and processes that led to the origin of life on Earth. One of these missions, SARIM-PLUS, will provide a unique perspective by measuring interplanetary and interstellar dust with high accuracy and sensitivity in our inner solar system between 1 and 2 AU. SARIM-PLUS employs latest in-situ techniques for a full characterisation of individual micrometeoroids (flux, mass, charge, trajectory, composition()) and collects and returns these samples to Earth for a detailed analysis. The opportunity to visit again the target comet of the Rosetta mission 67P/Churyumov-Gerasimeenternko, and to investigate its dusty environment six years after Rosetta with complementary methods is unique and strongly enhances and supports the scientific exploration of this target and the entire Rosetta mission. Launch opportunities are in 2020 with a backup window starting early 2026. The comet encounter occurs in September 2021 and the reentry takes place in early 2024. An encounter speed of 6 km/s ensures comparable results to the Stardust mission.
The “HPI Future SOC Lab” is a cooperation of the Hasso Plattner Institute (HPI) and industry partners. Its mission is to enable and promote exchange and interaction between the research community and the industry partners.
The HPI Future SOC Lab provides researchers with free of charge access to a complete infrastructure of state of the art hard and software. This infrastructure includes components, which might be too expensive for an ordinary research environment, such as servers with up to 64 cores and 2 TB main memory. The offerings address researchers particularly from but not limited to the areas of computer science and business information systems. Main areas of research include cloud computing, parallelization, and In-Memory technologies.
This technical report presents results of research projects executed in 2017. Selected projects have presented their results on April 25th and November 15th 2017 at the Future SOC Lab Day events.
During the summer of 2013, a 4-month spectroscopic campaign took place to observe the variabilities in three Wolf-Rayet stars. The spectroscopic data have been analysed for WR 134 (WN6b), to better understand its behaviour and long-term periodicity, which we interpret as arising from corotating interaction regions (CIRs) in the wind. By analysing the variability of the He ii lambda 5411 emission line, the previously identified period was refined to P = 2.255 +/- 0.008 (s.d.) d. The coherency time of the variability, which we associate with the lifetime of the CIRs in the wind, was deduced to be 40 +/- 6 d, or similar to 18 cycles, by cross-correlating the variability patterns as a function of time. When comparing the phased observational grey-scale difference images with theoretical grey-scales previously calculated from models including CIRs in an optically thin stellar wind, we find that two CIRs were likely present. A separation in longitude of Delta I center dot a parts per thousand integral 90A degrees was determined between the two CIRs and we suggest that the different maximum velocities that they reach indicate that they emerge from different latitudes. We have also been able to detect observational signatures of the CIRs in other spectral lines (C iv lambda lambda 5802,5812 and He i lambda 5876). Furthermore, a DAC was found to be present simultaneously with the CIR signatures detected in the He i lambda 5876 emission line which is consistent with the proposed geometry of the large-scale structures in the wind. Small-scale structures also show a presence in the wind, simultaneously with the larger scale structures, showing that they do in fact co-exist.
To address one of the central questions of plate tectonics-How do large transform systems work and what are their typical features?-seismic investigations across the Dead Sea Transform (DST), the boundary between the African and Arabian plates in the Middle East, were conducted for the first time. A major component of these investigations was a combined reflection/ refraction survey across the territories of Palestine, Israel and Jordan. The main results of this study are: (1) The seismic basement is offset by 3-5 km under the DST, (2) The DST cuts through the entire crust, broadening in the lower crust, (3) Strong lower crustal reflectors are imaged only on one side of the DST, (4) The seismic velocity sections show a steady increase in the depth of the crust-mantle transition (Moho) from 26 km at the Mediterranean to 39 km under the Jordan highlands, with only a small but visible, asymmetric topography of the Moho under the DST. These observations can be linked to the left-lateral movement of 105 km of the two plates in the last 17 Myr, accompanied by strong deformation within a narrow zone cutting through the entire crust. Comparing the DST and the San Andreas Fault (SAF) system, a strong asymmetry in subhorizontal lower crustal reflectors and a deep reaching deformation zone both occur around the DST and the SAF. The fact that such lower crustal reflectors and deep deformation zones are observed in such different transform systems suggests that these structures are possibly fundamental features of large transform plate boundaries
Recent studies have emphasized an important role for neurotrophins, such as brain-derived neurotrophic factor (BDNF), in regulating the plasticity of neural circuits involved in the pathophysiology of stress-related diseases. The aim of the present study was to examine the interplay of the BDNF Val(66)Met and the serotonin transporter promoter (5-HTTLPR) polymorphisms in moderating the impact of early-life adversity on BDNF plasma concentration and depressive symptoms. Participants were taken from an epidemiological cohort study following the long-term outcome of early risk factors from birth into young adulthood. In 259 individuals (119 males, 140 females), genotyped for the BDNF Val(66)Met and the 5-HTTLPR polymorphisms, plasma BDNF was assessed at the age of 19 years. In addition, participants completed the Beck Depression Inventory (BDI). Early adversity was determined according to a family adversity index assessed at 3 months of age. Results indicated that individuals homozygous for both the BDNF Val and the 5-HTTLPR L allele showed significantly reduced BDNF levels following exposure to high adversity. In contrast, BDNF levels appeared to be unaffected by early psychosocial adversity in carriers of the BDNF Met or the 5-HTTLPR S allele. While the former group appeared to be most susceptible to depressive symptoms, the impact of early adversity was less pronounced in the latter group. This is the first preliminary evidence indicating that early-life adverse experiences may have lasting sequelae for plasma BDNF levels in humans, highlighting that the susceptibility to this effect is moderated by BDNF Val(66)Met and 5-HTTLPR genotype.
Context: Recent evidence suggests that gene X environment interactions could explain the inconsistent findings of association studies relating the dopamine transporter (DAT1) gene with attention-deficit/hyperactivity disorder (ADHD). 1bjective: To examine whether psychosocial adversity moderated the effect of genetic variation in DAT1 on ADHD symptoms in. adolescents from a high-risk community sample. Design: Prospective cohort study. Setting: Data were taken from the Mannheim Study of Children at Risk, an ongoing longitudinal study of the long-term outcomes of early risk factors followed up from birth on. Participants: Three hundred five adolescents (146 boys, 159 girls) participated in a follow-up assessment at age 15 years. Main Outcome Measures: Measures of ADHD symptoms according to DSM-IV were obtained using standardized structural interviews with adolescents and their parents. Psychosocial adversity was determined according to an "enriched" family adversity index as proposed by Rutter and Quinton. DNA was genotyped for the common DAT1 40-base pair (bp) variable number of tandem repeats (VNTR) polymorphism in the 3' untranslated region; 3 previously described single nucleotide polymorphisms in exon 15, intron 9, and exon 9; and a novel 30-bp VNTR polymorphism in intron 8. Results: Adolescents homozygous for the 10-repeat allele of the 40-bp VNTR polymorphism who grew up in greater psychosocial adversity exhibited significantly more inattention and hyperactivity-impulsivity than adolescents with other genotypes or who lived in less adverse family conditions (significant interaction, P=.013-017). This gene X environment interaction was also observed in individuals homozygous for the 6-repeat allele of the 30-bp VNTR polymorphism and the haplotype comprising both markers. Conclusions: These findings provide initial evidence that environmental risks as described by the Rutter Family Adversity Index moderate the impact of the DAT1 gene on ADHD symptoms, suggesting a DAT1 effect only in those individuals exposed to psychosocial adversity.
Interindividual variability in the regulation of the human stress system accounts for a part of the individual's liability to stress-related diseases. These differences are influenced by environmental and genetic factors. Early childhood adversity is a well-studied environmental factor affecting an individual's stress response which has been shown to be modulated by gene environment interaction (GxE). Neuropeptide Y (NPY) plays a role in stress regulation and genetic variation in NPY may influence stress responses. In this study, we analyzed the association of a common variant in the NPY gene promoter, rs16147, with cortisol and ACTH responses to acute psychosocial stress in young adults from the Mannheim Study of Children at Risk (MARS), an ongoing epidemiological cohort study following the outcome of early adversity from birth into adulthood. We found evidence of a GxE interaction between rs16147 and early adversity significantly affecting HPA axis responses to acute psychosocial stress. These findings suggest that the neurobiological mechanisms linking early adverse experience and later neuroendocrine stress regulation are modulated by a gene variant whose functional relevance is documented by increasing convergent evidence from in vitro, animal and human studies.
Epigenetic modulations are a hypothesized link between environmental factors and the development of psychiatric disorders. Research has suggested that patients with depression or bipolar disorder exhibit higher methylation levels in the glucocorticoid receptor gene NR3C1. We aimed to investigate whether NR3C1 methylation changes are similarly associated with externalizing disorders such as aggressive behavior and conduct disorder. NR3C1 exon 1F methylation was analyzed in young adults with a lifetime diagnosis of an externalizing disorder (N = 68) or a depressive disorder (N = 27) and healthy controls (N = 124) from the Mannheim Study of Children at Risk. The externalizing disorders group had significantly lower NR3C1 methylation levels than the lifetime depressive disorder group (p = 0.009) and healthy controls (p = 0.001) This report of lower methylation levels in NR3C1 in externalizing disorders may indicate a mechanism through which the differential development of externalizing disorders as opposed to depressive disorders might occur.
Objective: To investigate the association of the neuropeptide Y (NPY) promoter polymorphism rs16147 with body mass index (BMI) during the course of development from infancy to adulthood.
Design: Longitudinal, prospective study of a German community sample.
Subjects: n = 306 young adults (139 males, 167 females).
Measurements: Participants' body weight and height were assessed at the ages of 3 months and 2, 4.5, 8, 11, 15 and 19 years. NPY rs16147 was genotyped.
Results: Controlling for a number of possible confounders, homozygote carriers of the rs16147 C allele exhibited significantly lower BMI scores when compared with individuals carrying the T allele. In addition, a significant genotype by age interaction emerged, indicating that the genotype effect increased during the course of development.
Conclusions: This is the first longitudinal study to report an association between rs16147 and BMI during childhood and adolescence. The finding that this effect increased during the course of development may either be due to age-dependent alterations in gene expression or to maturation processes within the weight regulation circuits of the central nervous system.
Recent research suggests an important role of FKBP5, a glucocorticoid receptor regulating co-chaperone, in the development of stress-related diseases such as depression and anxiety disorders. The present study aimed to replicate and extend previous evidence indicating that FKBP5 polymorphisms moderate hypothalamus-pituitary-adrenal (HPA) function by examining whether FKBP5 rs1360780 genotype and different measures of childhood adversity interact to predict stress-induced cortisol secretion. At age 19 years, 195 young adults (90 males, 105 females) participating in an epidemiological cohort study completed the Trier Social Stress Test (TSST) to assess cortisol stress responsiveness and were genotyped for the FKBP5 rs1360780. Childhood adversity was assessed using the Childhood Trauma Questionnaire (CTQ) and by a standardized parent interview yielding an index of family adversity. A significant interaction between genotype and childhood adversity on cortisol response to stress was demonstrated for exposure to childhood maltreatment as assessed by retrospective self-report (CTQ), but not for prospectively ascertained objective family adversity. Severity of childhood maltreatment was significantly associated with attenuated cortisol levels among carriers of the rs1360780 CC genotype, while no such effect emerged in carriers of the T allele. These findings point towards the functional involvement of FKBP5 in long-term alterations of neuroendocrine stress regulation related to childhood maltreatment, which have been suggested to represent a premorbid risk or resilience factor in the context of stress-related disorders. (C) 2013 Elsevier B.V. and ECNR This is an open access article under the CC BY-NC-ND license.
Converging evidence emphasizes the role of an interaction between monoamine oxidase A (MAOA) genotype, environmental adversity, and sex in the pathophysiology of aggression. The present study aimed to clarify the impact of this interaction on neural activity in aggression-related brain systems. Functional magnetic resonance imaging was performed in 125 healthy adults from a high-risk community sample followed since birth. DNA was genotyped for the MAOA-VNTR (variable number of tandem repeats). Exposure to childhood life stress (CLS) between the ages of 4 and 11 years was assessed using a standardized parent interview, aggression by the Youth/Young Adult Self-Report between the ages of 15 and 25 years, and the VIRA-R (Vragenlijst Instrumentele En Reactieve Agressie) at the age of 15 years. Significant interactions were obtained between MAOA genotype, CLS, and sex relating to amygdala, hippocampus, and anterior cingulate cortex (ACC) response, respectively. Activity in the amygdala and hippocampus during emotional face-matching increased with the level of CLS in male MAOA-L, while decreasing in male MAOA-H, with the reverse pattern present in females. Findings in the opposite direction in the ACC during a flanker NoGo task suggested that increased emotional activity coincided with decreased inhibitory control. Moreover, increasing amygdala activity was associated with higher Y(A)SR aggression in male MAOA-L and female MAOA-H carriers. Likewise, a significant association between amygdala activity and reactive aggression was detected in female MAOA-H carriers. The results point to a moderating role of sex in the MAOAx CLS interaction for intermediate phenotypes of emotional and inhibitory processing, suggesting a possible mechanism in conferring susceptibility to violence-related disorders.
Findings on the etiology of aggressive behavior have provided evidence for an effect both of genetic factors, such as variation in the monoamine oxidase A (MAOA) gene, and adverse environmental factors. Recent studies have supported the existence of gene × environment interactions, with early experiences playing a key role. In the present study, the effects of prenatal nicotine exposure, MAOA genotype and their interaction on aggressive behavior during young adulthood were examined. In a sample of 272 young adults (129 males, 143 females) from an epidemiological cohort study, smoking during pregnancy was measured with a standardized parent interview at the offspring’s age of 3 months. Aggressive behavior was assessed between the ages of 19 and 25 years using the Young Adult Self-Report. DNA was genotyped for the MAOA 5′ untranslated region variable number of tandem repeats polymorphism (VNTR). Results revealed a significant interaction between MAOA and smoking during pregnancy, indicating higher levels of aggressive behavior in young adults carrying the MAOA low-expressing genotype who had experienced prenatal nicotine exposure (n = 8, p = .025). In contrast, in carriers of the MAOA high-expressing genotype, maternal smoking during pregnancy had no effect on aggressive behavior during young adulthood (n = 20, p = .145). This study extends earlier findings demonstrating an interaction between MAOA genotype and prenatal nicotine exposure on aggressive behavior into young adulthood. The results point to the long-term adverse effects of smoking during pregnancy on the offspring’s mental health, possibly underlining the importance of smoking cessation during pregnancy. According to the nature of the study (particularly sample size and power), analyses are exploratory and results need to be interpreted cautiously.
Enhanced endocannabinoid signaling has been implicated in typically adolescent behavioral features such as increased risk-taking, impulsivity and novelty seeking. Research investigating the impact of genetic variants in the cannabinoid receptor 1 gene (CNR1) and of early rearing conditions has demonstrated that both factors contribute to the prediction of impulsivity-related phenotypes. The present study aimed to test the hypothesis of an interaction of the two most studied CNR1 polymorphisms rs806379 and rs1049353 with early psychosocial adversity in terms of affecting impulsivity in 15-year-olds from an epidemiological cohort sample followed since birth. In 323 adolescents (170 girls, 153 boys), problems of impulse control and novelty seeking were assessed using parent-report and self-report, respectively. Exposure to early psychosocial adversity was determined in a parent interview conducted at the age of 3 months. The results indicated that impulsivity increased following exposure to early psychosocial adversity, with this increase being dependent on CNR1 genotype. In contrast, while individuals exposed to early adversity scored higher on novelty seeking, no significant impact of genotype or the interaction thereof was detected. This is the first evidence to suggest that the interaction of CNR1 gene variants with the experience of early life adversity may play a role in determining adolescent impulsive behavior. However, given that the reported findings are obtained in a high-risk community sample, results are restricted in terms of interpretation and generalization. Future research is needed to replicate these findings and to identify the mediating mechanisms underlying this effect.
Objective: To clarify the nature of the association between dopamine genes and smoking by examining whether genetic variability in components of the dopamine pathway could explain refined phenotypes in adolescent smoking progression. Method: Data are from an ongoing prospective study of the long-term outcome of early risk factors studied since birth. At age 15 years, 220 participants (108 males, 112 females) completed a self-report questionnaire measuring smoking behavior and were genotyped for five dopamine gene variants. Results: Smoking initiation was related to allelic variation in the dopamine D-4 receptor gene (DRD4), whereas smoking continuation and dependence showed association with the dopamine D-2 receptor gene (DRD2). Adolescents with the seven-repeat allele of the common DRD4 exon 3 polymorphism had rates of ever smoking that were significantly higher than in those with other genotypes. Once smoking started, carriers of the T allele of a single nucleotide polymorphism of DRD2 (rs4648317) reported higher rates of current smoking and scored higher on nicotine dependence than their allelic counterparts. Among current smokers, intention to quit was significantly lower in adolescents homozygous for the 10-repeat allele of the common dopamine transporter 3 untranslated region polymorphism. Conclusions: Our results provide preliminary evidence of genetic influences on different stages of smoking and suggest the importance of specific dopamine genes in smoking progression in adolescence.
Moving in the Anthropocene
(2018)
Animal movement is fundamental for ecosystem functioning and species survival, yet the effects of the anthropogenic footprint on animal movements have not been estimated across species. Using a unique GPS-tracking database of 803 individuals across 57 species, we found that movements of mammals in areas with a comparatively high human footprint were on average one-half to one-third the extent of their movements in areas with a low human footprint. We attribute this reduction to behavioral changes of individual animals and to the exclusion of species with long-range movements from areas with higher human impact. Global loss of vagility alters a key ecological trait of animals that affects not only population persistence but also ecosystem processes such as predator-prey interactions, nutrient cycling, and disease transmission.
Association between pubertal stage at first drink and neural reward processing in early adulthood
(2017)
Puberty is a critical time period during human development. It is characterized by high levels of risk-taking behavior, such as increased alcohol consumption, and is accompanied by various neurobiological changes. Recent studies in animals and humans have revealed that the pubertal stage at first drink (PSFD) significantly impacts drinking behavior in adulthood. Moreover, neuronal alterations of the dopaminergic reward system have been associated with alcohol abuse or addiction. This study aimed to clarify the impact of PSFD on neuronal characteristics of reward processing linked to alcohol-related problems. One hundred sixty-eight healthy young adults from a prospective study covering 25 years participated in a monetary incentive delay task measured with simultaneous EEG-fMRI. PSFD was determined according to the age at menarche or Tanner stage of pubertal development, respectively. Alcohol-related problems in early adulthood were assessed with the Alcohol Use Disorder Identification Test (AUDIT). During reward anticipation, decreased fMRI activation of the frontal cortex and increased preparatory EEG activity (contingent negative variation) occurred with pubertal compared to postpubertal first alcohol intake. Moreover, alcohol-related problems during early adulthood were increased in pubertal compared to postpubertal beginners, which was mediated by neuronal activation of the right medial frontal gyrus. At reward delivery, increased fMRI activation of the left caudate and higher feedback-related EEG negativity were detected in pubertal compared to postpubertal beginners. Together with animal findings, these results implicate PSFD as a potential modulator of psychopathology, involving altered reward anticipation. Both PSFD timing and reward processing might thus be potential targets for early prevention and intervention.
Postpartale Depressionen sind häufige und schwerwiegende psychische Erkrankungen mit ungünstigem Einfluss auf die kindliche Entwicklung. Als Haupttransmissionsweg gilt die frühe Mutter-Kind-Interaktion. Über die langfristigen Auswirkungen auf die Kinder im Erwachsenenalter und die Rolle der Interaktion liegen kaum Ergebnisse vor. Im Rahmen der Mannheimer Risikokinderstudie wurden postpartale Depressionen bis zwei Jahre nach der Geburt erfasst. Die kindliche Entwicklung wurde fortlaufend und die Mutter-Kind-Interaktion im Alter von 3 Monaten standardisiert erhoben. 28 Kinder postpartal depressiver und 107 Kinder gesunder Mütter konnten mit 25 Jahren untersucht werden. Beeinträchtigungen der kognitiven und psychischen Entwicklung bei Kindern postpartal depressiver Mütter waren bis ins Erwachsenenalter nachweisbar. Responsives bzw. sensitives mütterliches Verhalten wirkte der negativen Entwicklung entgegen. Dies betont die Bedeutung einer hohen Qualität der Mutter-Kind-Interaktion für die Entwicklung von Risikokindern.
Die langfristigen Auswirkungen von Frühgeburtlichkeit auf kognitive Entwicklung und Schulerfolg
(2017)
In einer prospektiven Längsschnittstudie wurde der Zusammenhang zwischen früher Responsivität der Mutter und kognitiver Entwicklung ihrer früh- bzw. reifgeborenen Kinder untersucht. Im Alter von drei Monaten wurde dafür die Mutter-Kind-Interaktion mittels Verhaltensbeobachtung erfasst. Bei n=351 der teilnehmenden Kinder (101 frühgeboren) wurde die allgemeine Intelligenz (IQ) im Alter von 11 Jahren und bei n=313 (85 frühgeboren) zusätzlich der höchste erreichte Schulabschluss bis 25 Jahren erhoben. Frühgeborene wiesen mit 11 Jahren einen signifikant niedrigeren IQ als Reifgeborene auf, nachdem für mögliche konfundierende Faktoren kontrolliert worden war. Nur bei Früh-, nicht aber bei Reifgeborenen zeigte sich ein signifikanter positiver Zusammenhang zwischen mütterlicher Responsivität und IQ. Für die Wahrscheinlichkeit einen höheren Schulabschluss (mind. Fachabitur) zu erreichen, fand sich weder ein signifikanter Effekt von Frühgeburtlichkeit noch von mütterlicher Responsivität.
(5R,6S)-6-Acetoxy-5-hexadecanolide (MOP) is the oviposition pheromone of the mosquito Cx. quinquefasciatus, a vector of pathogens causing a variety of tropical diseases. We describe and evaluate herein three syntheses of MOP starting from mannitol-derived (3R,4R)-hexa-1,5-diene-3,4-diol. This C-2-symmetric building block is elaborated through bidirectional olefin metathesis reactions into 6-epi-MOP, which was converted into MOP via Mitsunobu inversion. The shortest of the three routes makes use of two sequential cross-metathesis reactions and an assisted tandem catalytic olefin reduction, induced by an in situ conversion of a Ru-carbene to a Ru-hydride.
Anhand von Daten der Mannheimer Risikokinderstudie, die sich mit der langfristigen Entwicklung von Kindern mit unterschiedlichen Risikobelastungen beschäftigt, wird gezeigt, wie Schutzfaktoren aufseiten des Kindes und seines familiären Umfelds im Verlauf der Entwicklung wirksam werden und zur Entstehung von Resilienz beitragen können. Eine besondere Rolle kommt dabei positiven frühen Eltern-Kind-Beziehungen zu (sowohl Mutter- als auch Vater-Kind-Interaktionen). Daneben spielen auch Interaktionserfahrungen im Alter von zwei Jahren des Kindes eine bedeutsame Rolle; diese schützen Risikokinder davor, eine ungünstige Entwicklung zu nehmen und tragen dazu bei, dass sich Kinder, die in psychosozialen Hochrisikofamilien aufwachsen, trotz ungünstiger „Startbedingungen“ positiv entwickeln. Neben Merkmalen der sozialen Umwelt nehmen auch sprachliche, sozial-emotionale und internale Kompetenzen des Kindes im Entwicklungsverlauf eine wichtige Rolle ein. Diese Kompetenzen ermöglichen es Risikokindern auch unter widrigen Lebensumständen (psychosoziale Hochrisikofamilien, Aufwachsen in Armutsverhältnissen) erfolgreich zu bestehen. Darüber hinaus zeigt die Arbeit, dass Resilienz ein Persönlichkeitsmerkmal ist, das ab dem frühen Erwachsenenalter eine hohe Stabilität besitzt. Mit diesen Befunden verweist die Arbeit auf die große Bedeutung der Resilienz bei der Vorhersage der langfristigen Entwicklung von Risikokindern.
Postpartale Depressionen sind häufige und schwerwiegende psychische Erkrankungen mit ungünstigem Einfluss auf die kindliche Entwicklung. Als Haupttransmissionsweg gilt die frühe Mutter-Kind-Interaktion. Über die langfristigen Auswirkungen auf die Kinder im Erwachsenenalter und die Rolle der Interaktion liegen kaum Ergebnisse vor. Im Rahmen der Mannheimer Risikokinderstudie wurden postpartale Depressionen bis zwei Jahre nach der Geburt erfasst. Die kindliche Entwicklung wurde fortlaufend und die Mutter-Kind-Interaktion im Alter von 3 Monaten standardisiert erhoben. 28 Kinder postpartal depressiver und 107 Kinder gesunder Mütter konnten mit 25 Jahren untersucht werden. Beeinträchtigungen der kognitiven und psychischen Entwicklung bei Kindern postpartal depressiver Mütter waren bis ins Erwachsenenalter nachweisbar. Responsives bzw. sensitives mütterliches Verhalten wirkte der negativen Entwicklung entgegen. Dies betont die Bedeutung einer hohen Qualität der Mutter-Kind-Interaktion für die Entwicklung von Risikokindern.
In einer prospektiven Längsschnittstudie wurden Auswirkungen früher psychosozialer Risiken bis ins junge Erwachsenenalter untersucht und dabei die Rolle von affektiver und behavioraler Dysregulation im Kindesalter als vermittelndem Faktor überprüft. Drei Monate nach der Geburt wurde das Vorliegen von 11 psychosozialen Belastungsfaktoren erfasst. Im Alter von 8 – 15 Jahren wurde dreimal das Child Behavior Checklist-Dysregulationsprofil (CBCL-DP) erhoben. Mit 25 Jahren wurde ein Strukturiertes Klinisches Interview durchgeführt und 309 der Teilnehmer füllten den Young Adult Self-Report aus. Frühe psychosoziale Risiken gingen mit einem erhöhten Risiko für das Vorliegen eines Substanzmissbrauchs im jungen Erwachsenenalter sowie mit erhöhtem externalisierendem und internalisierendem Problemverhalten einher. Der Zusammenhang zwischen frühen psychosozialen Risiken und späterem externalisierendem bzw. internalisierendem Problemverhalten wurde durch das CBCL-DP vermittelt.
Anhand von Daten der Mannheimer Risikokinderstudie, die sich mit der langfristigen Entwicklung von Kindern mit unterschiedlichen Risikobelastungen beschäftigt, wird gezeigt, wie Schutzfaktoren aufseiten des Kindes und seines familiären Umfelds im Verlauf der Entwicklung wirksam werden und zur Entstehung von Resilienz beitragen können. Eine besondere Rolle kommt dabei positiven frühen Eltern-Kind-Beziehungen zu (sowohl Mutter- als auch Vater-Kind-Interaktionen). Daneben spielen auch Interaktionserfahrungen im Alter von zwei Jahren des Kindes eine bedeutsame Rolle; diese schützen Risikokinder davor, eine ungünstige Entwicklung zu nehmen und tragen dazu bei, dass sich Kinder, die in psychosozialen Hochrisikofamilien aufwachsen, trotz ungünstiger „Startbedingungen“ positiv entwickeln. Neben Merkmalen der sozialen Umwelt nehmen auch sprachliche, sozial-emotionale und internale Kompetenzen des Kindes im Entwicklungsverlauf eine wichtige Rolle ein. Diese Kompetenzen ermöglichen es Risikokindern auch unter widrigen Lebensumständen (psychosoziale Hochrisikofamilien, Aufwachsen in Armutsverhältnissen) erfolgreich zu bestehen. Darüber hinaus zeigt die Arbeit, dass Resilienz ein Persönlichkeitsmerkmal ist, das ab dem frühen Erwachsenenalter eine hohe Stabilität besitzt. Mit diesen Befunden verweist die Arbeit auf die große Bedeutung der Resilienz bei der Vorhersage der langfristigen Entwicklung von Risikokindern.
Die langfristigen Auswirkungen von Frühgeburtlichkeit auf kognitive Entwicklung und Schulerfolg
(2017)
In einer prospektiven Längsschnittstudie wurde der Zusammenhang zwischen früher Responsivität der Mutter und kognitiver Entwicklung ihrer früh- bzw. reifgeborenen Kinder untersucht. Im Alter von drei Monaten wurde dafür die Mutter-Kind-Interaktion mittels Verhaltensbeobachtung erfasst. Bei n=351 der teilnehmenden Kinder (101 frühgeboren) wurde die allgemeine Intelligenz (IQ) im Alter von 11 Jahren und bei n=313 (85 frühgeboren) zusätzlich der höchste erreichte Schulabschluss bis 25 Jahren erhoben. Frühgeborene wiesen mit 11 Jahren einen signifikant niedrigeren IQ als Reifgeborene auf, nachdem für mögliche konfundierende Faktoren kontrolliert worden war. Nur bei Früh-, nicht aber bei Reifgeborenen zeigte sich ein signifikanter positiver Zusammenhang zwischen mütterlicher Responsivität und IQ. Für die Wahrscheinlichkeit einen höheren Schulabschluss (mind. Fachabitur) zu erreichen, fand sich weder ein signifikanter Effekt von Frühgeburtlichkeit noch von mütterlicher Responsivität.
Saturn’s main rings are composed of >95% water ice, and the nature of the remaining few percent has remained unclear. The Cassini spacecraft’s traversals between Saturn and its innermost D ring allowed its cosmic dust analyzer (CDA) to collect material released from the main rings and to characterize the ring material infall into Saturn. We report the direct in situ detection of material from Saturn’s dense rings by the CDA impact mass spectrometer. Most detected grains are a few tens of nanometers in size and dynamically associated with the previously inferred “ring rain.” Silicate and water-ice grains were identified, in proportions that vary with latitude. Silicate grains constitute up to 30% of infalling grains, a higher percentage than the bulk silicate content of the rings.
Lower P300 amplitude in eight-year-old offspring of alcoholic fathers with a delinquent history
(2006)
The aim of the present study was to investigate the P300 amplitude as a possible vulnerability marker in children of alcoholic (COA) fathers with and without paternal delinquency. Event-related potentials (ERPs) of 122 children aged 8 years (63 boys, 59 girls) were compared depending on father's alcoholism subtype: 30 COAs without paternal delinquency, 10 COAs with paternal delinquency, and 82 children of non-alcoholic and non-delinquent fathers. ERPs were recorded from Fz, Cz, and Pz, using an auditory oddball paradigm. Sinus tones of 60 dB HL were presented binaurally at 1,000 Hz (standard stimulus) and 2,000 Hz (target stimulus), at a relative frequency ratio of 80:20. Two trial blocks of 250 stimuli each were collected. Results indicated that only COAs with paternal delinquency displayed significant differences from the control group, characterized by reduced P300 amplitude at frontal site and in the second trial block. Thus, the combination of fathers' alcoholism and delinquency was more likely to relate to attenuated P300 amplitude in the offspring than paternal alcoholism alone. Our results suggest that both alcoholic and delinquent family history appear to play a role in P300 amplitude reduction in the offspring.
The present study aimed to examine the extent to which the co-occurrence of ADHD and smoking in adolescents could be attributed to common genetic, environmental and psychopathological factors. Data are from an ongoing prospective study of the outcome of early risk factors. At age 15 years, 305 adolescents completed self-report questionnaires measuring tobacco consumption and deviant peer affiliations. Lifetime psychiatric diagnoses were obtained using standardized interviews. DNA was genotyped for the dopamine D4 receptor (DRD4) gene exon III polymorphism. Adolescents with a lifetime diagnosis of ADHD displayed significantly higher smoking activity than non-ADHD controls. A major component of this association could be accounted for by deviant peer affiliations and the comorbidity with oppositional-defiant and conduct disorder, while a minor part was attributable to DRD4 in males but not in females. These findings suggest that the association of ADHD with smoking relies on risk factors shared by the two behaviors.
Background: Several studies have reported higher smoking rates among adolescents with externalizing disorders (attention-deficit hyperactivity disorder and conduct disorder) as compared to healthy controls. Objective: To follow the association between childhood externalizing disorders and smoking during development, to determine the type of problems most strongly related to later tobacco use, and to control for the influence of covarying factors. Methods: Participants were from a longitudinal study of a birth cohort of 384 children born with different perinatal and psychosocial risks. Standardized assessments of behavioral disorders between 2 and 11 years and of tobacco use at age 15 were obtained. Results: 15-year-olds with externalizing disorders between 2 and 11 years reported higher tobacco use than those without a history of disorder. This association could be followed back into early childhood and held up even after controlling for covariates. Conclusions: The findings suggest that childhood externalizing disorders may represent an independent risk factor for elevated tobacco use in adolescence