Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration

Despite significant progress in the identification of genetic loci for age-related macular degeneration (AMD), not all of the heritability has been explained. To identify variants which contribute to the remaining genetic susceptibility, we performed the largest meta-analysis of genome-wide association studies to date for advanced AMD. We imputed 6 036 699 single-nucleotide polymorphisms with the 1000 Genomes Project reference genotypes on 2594 cases and 4134 controls with follow-up replication of top signals in 5640 cases and 52 174 controls. We identified two new common susceptibility alleles, rs1999930 on 6q21-q22.3 near FRK/COL10A1 [odds ratio (OR) 0.87; P = 1.1 × 10−8] and rs4711751 on 6p12 near VEGFA (OR 1.15; P = 8.7 × 10−9). In addition to the two novel loci, 10 previously reported loci in ARMS2/HTRA1 (rs10490924), CFH (rs1061170, and rs1410996), CFB (rs641153), C3 (rs2230199), C2 (rs9332739), CFI (rs10033900), LIPC (rs10468017), TIMP3 (rs9621532) and CETP (rs3764261) were confirmed with genome-wide significant signals in this large study. Loci in the recently reported genes ABCA1 and COL8A1 were also detected with suggestive evidence of association with advanced AMD. The novel variants identified in this study suggest that angiogenesis (VEGFA) and extracellular collagen matrix (FRK/COL10A1) pathways contribute to the development of advanced AMD

Identification of common genetic risk variants for autism spectrum disorder

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.Peer reviewe

Improving Genetic Prediction by Leveraging Genetic Correlations Among Human Diseases and Traits

Genomic prediction has the potential to contribute to precision medicine. However, to date, the utility of such predictors is limited due to low accuracy for most traits. Here theory and simulation study are used to demonstrate that widespread pleiotropy among phenotypes can be utilised to improve genomic risk prediction. We show how a genetic predictor can be created as a weighted index that combines published genome-wide association study (GWAS) summary statistics across many different traits. We apply this framework to predict risk of schizophrenia and bipolar disorder in the Psychiatric Genomics consortium data, finding substantial heterogeneity in prediction accuracy increases across cohorts. For six additional phenotypes in the UK Biobank data, we find increases in prediction accuracy ranging from 0.7 for height to 47 for type 2 diabetes, when using a multi-trait predictor that combines published summary statistics from multiple traits, as compared to a predictor based only on one trait. © 2018 The Author(s)

Genome-wide association study identifies 30 Loci Associated with Bipolar Disorder

This paper is dedicated to the memory of Psychiatric Genomics Consortium (PGC) founding member and Bipolar disorder working group co-chair Pamela Sklar. We thank the participants who donated their time, experiences and DNA to this research, and to the clinical and scientific teams that worked with them. We are deeply indebted to the investigators who comprise the PGC. The views expressed are those of the authors and not necessarily those of any funding or regulatory body. Analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org ) hosted by SURFsara, and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu).Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P<1x10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (GWS, p < 5x10-8) in the discovery GWAS were not GWS in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis 30 loci were GWS including 20 novel loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene-sets including regulation of insulin secretion and endocannabinoid signaling. BDI is strongly genetically correlated with schizophrenia, driven by psychosis, whereas BDII is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential new biological mechanisms for BD.This work was funded in part by the Brain and Behavior Research Foundation, Stanley Medical Research Institute, University of Michigan, Pritzker Neuropsychiatric Disorders Research Fund L.L.C., Marriot Foundation and the Mayo Clinic Center for Individualized Medicine, the NIMH Intramural Research Program; Canadian Institutes of Health Research; the UK Maudsley NHS Foundation Trust, NIHR, NRS, MRC, Wellcome Trust; European Research Council; German Ministry for Education and Research, German Research Foundation IZKF of Münster, Deutsche Forschungsgemeinschaft, ImmunoSensation, the Dr. Lisa-Oehler Foundation, University of Bonn; the Swiss National Science Foundation; French Foundation FondaMental and ANR; Spanish Ministerio de Economía, CIBERSAM, Industria y Competitividad, European Regional Development Fund (ERDF), Generalitat de Catalunya, EU Horizon 2020 Research and Innovation Programme; BBMRI-NL; South-East Norway Regional Health Authority and Mrs. Throne-Holst; Swedish Research Council, Stockholm County Council, Söderström Foundation; Lundbeck Foundation, Aarhus University; Australia NHMRC, NSW Ministry of Health, Janette M O'Neil and Betty C Lynch

Age at first birth in women is genetically associated with increased risk of schizophrenia

Prof. Paunio on PGC:n jäsenPrevious studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is -0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health.Peer reviewe

The Role of Prosodic Sensitivity in Children's Reading Development

While the critical importance of phonological awareness (segmental phonology) to reading ability is well established, the potential role of prosody (suprasegmental phonology) in reading development has only recently been explored. This study examined the relationship between children’s prosodic skills and reading ability. Hierarchical multiple regression analyses examined the unique contribution of word-level and phrase-level prosodic skills to the prediction of three concurrent measures of reading ability in 81 fourth-grade children (mean age 9;3 years). After controlling for phonological awareness and general rhythmic sensitivity, children’s prosodic skills predicted unique variation in word-reading accuracy and in reading comprehension. Phrase-level prosodic skills, assessed by means of an reiterative speech task, predicted unique variance in reading comprehension, after controlling for word reading accuracy, phonological awareness, and general rhythmic sensitivity. These results add to the growing body of evidence of the importance of prosodic skills in reading development

High-quality chromosome-scale assembly of the walnut (Juglans regia L.) reference genome

The release of the first reference genome of walnut (Juglans regia L.) enabled many achievements in the characterization of walnut genetic and functional variation. However, it is highly fragmented, preventing the integration of genetic, transcriptomic, and proteomic information to fully elucidate walnut biological processes. Findings: Here, we report the new chromosome-scale assembly of the walnut reference genome (Chandler v2.0) obtained by combining Oxford Nanopore long-read sequencing with chromosome conformation capture (Hi-C) technology. Relative to the previous reference genome, the new assembly features an 84.4-fold increase in N50 size, with the 16 chromosomal pseudomolecules assembled and representing 95% of its total length. Using full-length transcripts from single-molecule real-time sequencing, we predicted 37,554 gene models, with a mean gene length higher than the previous gene annotations. Most of the new protein-coding genes (90%) present both start and stop codons, which represents a significant improvement compared with Chandler v1.0 (only 48%). We then tested the potential impact of the new chromosome-level genome on different areas of walnut research. By studying the proteome changes occurring during male flower development, we observed that the virtual proteome obtained from Chandler v2.0 presents fewer artifacts than the previous reference genome, enabling the identification of a new potential pollen allergen in walnut. Also, the new chromosome-scale genome facilitates in-depth studies of intraspecies genetic diversity by revealing previously undetected autozygous regions in Chandler, likely resulting from inbreeding, and 195 genomic regions highly differentiated between Western and Eastern walnut cultivars. Conclusion: Overall, Chandler v2.0 will serve as a valuable resource to better understand and explore walnut biology

Effect-based monitoring of Danube river using mobile passive sampling approach

Surface waters are often polluted by complex mixtures of pollutants whose toxic properties are relatively difficult to describe. Effect-based monitoring with a battery of bioassays represents an efficient approach for toxicological profiling and identification of samples of major interest through providing data of the toxic potencies and mode of action of the extracted mixtures that cannot be evaluated by chemical analysis alone. In our work we used an “active” passive sampling system (APS) for temporally and spatially integrative sampling using silicone rubber and EMPORE disc based passive samplers, which efficiently preconcentrate a wide spectrum of polar and non-polar organic pollutants from the water column along a defined river stretch. This concept was employed during Joint Danube Survey 3 in summer 2013. Eight Danube river stretches were sampled to cover spatial distribution of the pollutants characterized through a set of bioassays investigating presence of contaminants with several non-specific and important specific toxic modes of action. Presence of contaminants with potentials for causing endocrine disruption (anti/estrogenic anti/androgenic), dioxin-like activities, potential to elicit adaptive stress responses associated with oxidative stress, p53-mediated apoptotic response and NF-κB-associated inflammatory response were characterized in samples from different river stretches. This wide range of assessed endpoints serves as a toxicological profiling tool to describe risks associated with fresh water pollutant mixtures. The obtained results also serve for spatial characterization of pollution gradients along the river and selecting hotspots for further studies. This research was supported by SOLUTIONS Project from the European Union Seventh Framework Programme (FP7-ENV-2013-two-stage Collaborative project) under grant agreement 603437

Mobile passive sampling as a tool for toxicological profiling

Many components of complex organic pollutant mixtures in waters are often present at very low levels, posing a challenge for current analytical methods. Passive sampling is one of the perspective methods that could address this problem. In our work, we used a mobile "active" passive sampling system with two types of sorbent (EMPORE discs, silicone rubbers), which preconcentrates a wide spectrum of polar and non-polar organic pollutants from the water column. Eight Danube river stretches were sampled and spatial distribution profiles were described for a comprehensive range of organic pollutants including pesticides, pharmaceuticals and industrial chemicals. Sampling rate and the original concentrations of the pollutants in water were estimated for pollutants with different physicochemical properties by a set of reference compounds. The employed mode of passive sampling with an active exchange of water in the sampling chamber proved to be about five-times more effective than static exposure and in relatively short sampling times allowed quantification of chemicals in pg.L-1 levels. Beside chemical analyses, samples were characterized with a battery of in vitro bioassays sensitive to chemicals with selected modes of action. Toxic potentials for causing endocrine disruption (anti/estrogenic, anti/androgenic), dioxin-like activity, pregnane X receptor (PXR)-mediated activity and oxidative stress-associated response showed spatial variation along the river. Polarity of chemicals played an important role, while AhR-mediated effects were associated mostly with non-polar compounds (sampled by the silicone rubber sampler) the rest of toxic potentials was associated mainly with more polar chemicals sampled by the EMPORE disc samplers. To link the toxic potentials with chemical analysis data, the detected pollutant levels and their relative effect potencies were used for calculation of bioanalytical equivalent concentrations (BEQs) using the concentration addition concept, with effect concentrations obtained from literature or US EPA ToxCast database. BEQs served for explaining the observed bioassay-derived toxic potentials and identification of the main drivers of toxicity. Our work demonstrates the utility of passive sampling for analysis of trace contaminants in river water as well as effect-based monitoring. The SOLUTIONS Project is supported by the Seventh Framework Programme (FP7-ENV-2013) of the European Union under grant agreement no. 603437