Mendelian randomization integrating GWAS and eQTL data reveals genetic determinants of complex and clinical traits

Genome-wide association studies (GWAS) have identified thousands of variants associated with complex traits, but their biological interpretation often remains unclear. Most of these variants overlap with expression QTLs, indicating their potential involvement in regulation of gene expression. Here, we propose a transcriptome-wide summary statistics-based Mendelian Randomization approach (TWMR) that uses multiple SNPs as instruments and multiple gene expression traits as exposures, simultaneously. Applied to 43 human phenotypes, it uncovers 3,913 putatively causal gene-trait associations, 36% of which have no genome-wide significant SNP nearby in previous GWAS. Using independent association summary statistics, we find that the majority of these loci were missed by GWAS due to power issues. Noteworthy among these links is educational attainment-associated BSCL2, known to carry mutations leading to a Mendelian form of encephalopathy. We also find pleiotropic causal effects suggestive of mechanistic connections. TWMR better accounts for pleiotropy and has the potential to identify biological mechanisms underlying complex traits

Refining Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder Genetic Loci by Integrating Summary Data From Genome-wide Association, Gene Expression, and DNA Methylation Studies

Background: Recent genome-wide association studies (GWASs) identified the first genetic loci associated with attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). The next step is to use these results to increase our understanding of the biological mechanisms involved. Most of the identified variants likely influence gene regulation. The aim of the current study is to shed light on the mechanisms underlying the genetic signals and prioritize genes by integrating GWAS results with gene expression and DNA methylation (DNAm) levels. Methods: We applied summary-data–based Mendelian randomization to integrate ADHD and ASD GWAS data with fetal brain expression and methylation quantitative trait loci, given the early onset of these disorders. We also analyzed expression and methylation quantitative trait loci datasets of adult brain and blood, as these provide increased statistical power. We subsequently used summary-data–based Mendelian randomization to investigate if the same variant influences both DNAm and gene expression levels. Results: We identified multiple gene expression and DNAm levels in fetal brain at chromosomes 1 and 17 that were associated with ADHD and ASD, respectively, through pleiotropy at shared genetic variants. The analyses in brain and blood showed additional associated gene expression and DNAm levels at the same and additional loci, likely because of increased statistical power. Several of the associated genes have not been identified in ADHD and ASD GWASs before. Conclusions: Our findings identified the genetic variants associated with ADHD and ASD that likely act through gene regulation. This facilitates prioritization of candidate genes for functional follow-up studies

Prophets of old and the day of the end: Zechariah, the book of watchers and apocalyptic

De onderzoeksvraag luidt of we na een beschrijving van deze teksten, waarbij niet uitgegaan wordt van een specifieke opvatting van apocalyptiek, ontwikkelingslijnen kunnen trekken die licht kunnen werpen op het vraagstuk van de oorsprongen van de apocalyptiek. ... Zie: Samenvatting

Creando mi profesión : una propuesta para el desarrollo profesional del profesorado

Resumen basado en el de la publicaciónSe presentan algunas propuestas para mejorar el desarrollo profesional del profesorado. Se persiguen dos objetivos: por un lado, mostrar instrumentos que ayuden a los estudiantes durante su proceso de construcción de un conocimiento práctico propio y paralelamente fomentar en ellos el aprendizaje de por vida; por otro, mostrar acciones pedagógicas basadas en la formación realista y el aprendizaje reflexivo. Se pretende ofrecer un abanico amplio de las distintas posibilidades que puede ofrecer esta metodología en su experimentación y puesta en escena durante la formación inicial del profesorado y a la vez ofrecer un modelo para la adquisición de competencias profesionales.CataluñaBiblioteca de Educación del Ministerio de Educación, Cultura y Deporte; Calle San Agustín, 5 - 3 planta; 28014 Madrid; Tel. +34917748000; [email protected]

Phylogeny and distribution of Y-chromosomal haplotypes in domestic, ancient and wild goats

The male-specific part of the Y-chromosome is in mammalian and many other species the longest haplotype that is inherited without recombination. By its paternal transmission it has a small effective population size in species with dominant males. In several species, Y-chromosomal haplotypes are sensitive markers of population history and introgression. Previous studies have identified in domestic goats four major Y-chromosomal haplotypes Y1A, Y1B, Y2A and Y2B with a marked geographic differentiation and several regional variants. In this study we used published whole-genome sequences of 70 male goats from 16 modern breeds, 11 ancient-DNA samples and 29 samples from seven wild goat species. We identified single-copy male-specific SNPs in four scaffolds, containing SRY, ZFY, DBY with SSX3Y and UTY, and USP9Y with UMN2001, respectively. Phylogenetic analyses indicated haplogroups corresponding to the haplotypes Y1B, Y2A and Y2B, respectively, but Y1A was split into Y1AA and Y1AB. All haplogroups were detected in ancient DNA samples from southeast Europe and, with the exception of Y1AB, in the bezoar goat, which is the wild ancestor of the domestic goats. Combining these data with those of previous studies and with genotypes obtained by Sanger sequencing or the KASP assay yielded haplogroup distributions for 132 domestic breeds or populations. The phylogeographic differentiation indicated paternal population bottlenecks on all three continents. This possibly occurred during the Neolithic introductions of domestic goats to those continents with a particularly strong influence in Europe along the Danubian route. This study illustrates the power of the Y-chromosomal haplotype for the reconstructing the history of mammalian species with a wide geographic range

Dead Sea Scrolls data collection (images, labels, prediction plots) for dating ancient manuscripts using radiocarbon and AI-based writing style analysis

The dataset is associated with the following article: Title: Dating ancient manuscripts using radiocarbon and AI-based writing style analysis Authors: Mladen Popović, Maruf A. Dhali, Lambert Schomaker, Johannes van der Plicht, Kaare Lund Rasmussen, Jacopo La Nasa, Ilaria Degano, Maria Perla Colombini, and Eibert Tigchelaar (Under review) This data set is collected for the ERC project: The Hands that Wrote the Bible: Digital Palaeography and Scribal Culture of the Dead Sea Scrolls PI: Mladen Popović Grant agreement ID: 640497 Project website: https://cordis.europa.eu/project/id/640497 Copyright (c) University of Groningen, 2023. All rights reserved. Disclaimer and copyright notice for all data contained on the *.tar.gz files: 1) permission is hereby granted to use the data for research purposes. It is not allowed to distribute this data for commercial purposes. 2) provider gives no express or implied warranty of any kind, and any implied warranties of merchantability and fitness for purpose are disclaimed. 3) provider shall not be liable for any direct, indirect, special, incidental, or consequential damages arising out of any use of this data. 4) the user should refer to the first public article mentioned above on this data set. 5) the recipient should refrain from proliferating the data set to third parties external to his/her local research group. Please refer interested researchers to this site to obtain their own copy. Organization of the data: There are four *.tar.gz files: C14-Oxcal-data.tar.gz contains radiocarbon data (OxCal [1] raw data) for all 30 manuscripts. Please refer to the original article for details about OxCal data and the manuscripts. These raw OxCal data are used (after the selection of significant ranges) as the training labels during the training of Enoch, the date prediction model. train-images-c14.tar.gz contains the clean and preprocessed (binarized, aligned, and arrangement corrected) training images for the 25 radiocarbon-dated training manuscripts (including 4Q52; 64 images in total). test-images-all.tar.gz contains the clean and preprocessed test images for 135 previously undated manuscripts (359 images in total). Enoch-predictions.tar.gz contains the date prediction plots for each of the 135 test images. There are four directories inside the *.tar.gz file: - Enoch-predictions-c14wo4Q52-balanced05: Prediction plots with data balancing threshold of 0.05. These plots are used by expert palaeographers' evaluation of Enoch's style-based date predictions of 135 previously undated manuscripts. - Enoch-predictions-c14wo4Q52-balanced10: Prediction plots with data balancing threshold of 0.1. - Enoch-predictions-c14wo4Q52-unbalanced: Unbalanced raw predictions. - Enoch-predictions-c14wo4Q52-combined: Combined plots with all three prediction plots (unbalanced, 0.05, 0.1). Please refer to the original article for more details. The code to run the plot is available here: https://doi.org/10.5281/zenodo.8168930 If you have any questions, please get in touch with us: Mladen Popović Maruf A. Dhali Lambert Schomaker References: 1. Bronk Ramsey, C. (2001). Development of the radiocarbon calibration program. Radiocarbon, 43(2A), 355-363

Y-chromosomal haplotypes in domestic and wild goats reveal ancient paternal bottlenecks and recent introgressions

International audienc