Here we present a Joint-Tissue Imputation (JTI) approach and a Mendelian Randomization (MR) framework for causal inference, MR-JTI. JTI borrows information across transcriptomes of different tissues, leveraging shared genetic regulation, to improve prediction performance in a tissue-dependent manner. Notably, JTI includes single-tissue imputation PrediXcan as a special case and outperforms other single-tissue approaches (BSLMM and Dirichlet Process Regression). MR-JTI models variant-level heterogeneity (primarily due to horizontal pleiotropy, addressing a major challenge of TWAS interpretation) and performs causal inference with type-I error control. We make explicit the connection between the genetic architecture of gene expression and of complex traits, and the suitability of MR as a causal inference strategy for TWAS. We provide a resource of imputation models generated from GTEx and PsychENCODE panels. Analysis of biobanks and meta-analysis data and extensive simulations show substantially improved statistical power, replication, and causal mapping rate for JTI relative to existing approaches.
Autism Spectrum Disorder (ASD) is a severe neurodevelopmental disorder. To enhance the understanding of the gut microbiota structure in ASD children at different ages as well as the relationship between gut microbiota and fecal metabolites, we first used the 16S rRNA sequencing to evaluate the gut microbial population in a cohort of 143 children aged 2-13 years old. We found that the α-diversity of ASD group showed no significant change with age, while the TD group showed increased α-diversity with age, which indicates that the compositional development of the gut microbiota in ASD varies at different ages in ways that are not consistent with TD group. Recent studies have shown that chronic constipation is one of the most commonly obvious gastrointestinal (GI) symptoms along with ASD core symptoms. To further investigate the potential interaction effects between ASD and GI symptoms, the 30 C-ASD and their aged-matched TD were picked out to perform metagenomics analysis. We observed that C-ASD group displayed decreased diversity, depletion of species of Sutterella, Prevotella, and Bacteroides as well as dysregulation of associated metabolism activities, which may involve in the pathogenesis of C-ASD. Consistent with metagenomic analysis, liquid chromatography-mass spectrometry (LC/ MS) revealed some of the differential metabolites between C-ASD and TD group were involved in the metabolic network of neurotransmitters including serotonin, dopamine, histidine, and GABA. Furthermore, we found these differences in metabolites were associated with altered abundance of specific bacteria. The study suggested possible future modalities for ASD intervention through targeting the specific bacteria associated with neurotransmitter metabolism.
The resources generated by the GTEx consortium offer unprecedented opportunities to advance our understanding of the biology of human diseases. Here, we present an in-depth examination of the phenotypic consequences of transcriptome regulation and a blueprint for the functional interpretation of genome-wide association study-discovered loci. Across a broad set of complex traits and diseases, we demonstrate widespread dose-dependent effects of RNA expression and splicing. We develop a data-driven framework to benchmark methods that prioritize causal genes and find no single approach outperforms the combination of multiple approaches. Using colocalization and association approaches that take into account the observed allelic heterogeneity of gene expression, we propose potential target genes for 47% (2519 out of 5385) of the GWAS loci examined.
DI d .pine receptor llization was examined by i unohistochemistry using a polyclonal anti-peptide antibody which (i) immunoprecipitated a protein frment encoded by a D1 receptor cDNA and (it) on Western blots of solubilized striatal and hippocampal membranes recognized two proteins ofapproimatey 50 kDa and 75 kDa, corresponding to reported sizes of DI receptor proteins. Immunreactiv overlapped with dopamine-containing pathways, patterns ofD1 receptor binding, and mRNA expression. Staning was concentrated in prefrontal, cigulate, parietal, piriform, entorhinal, and hippocampal cortical areas and subcorticafly in the basal ganglia, amygdala, septal area, substanti inomnta, thalamus, hypothalamus, and neurohypophysis. Prominent labeling was seen in the thalic reticular nucleus, a region known to integrate ascending basal forebrain inputs with thalamocortical and corticothalamic pathways and in fiber bundles interconnecting limbic areas. In striatal neuropil, staining appeared in spines (heads and necks), at postsynaptic sites in dendrites, and in axon terminals; in the pars reticulata of the substantia nigra, labeling was prevalent in myelinated and unmyelinated axons and dendrites. These data provide direct evidence for the regional and subcellular distribution of D1 receptor protein in the brain and for its pre-and postsynaptic localization in the basal ganglia. The prominent immunoreactivity seen in the limbic system and thalamic reticular nucleus supports an important role for this receptor subtype in mediating integrative processes involved with learning, memory, and cognition.Two classes of dopamine receptors, D1 and D2, are known to mediate the diverse functional effects of dopamine neurotransmission in the brain. These receptor classes are coupled to guanine nucleotide-binding proteins and have distinct properties based on pharmacological, biochemical, and electrophysiological data (1, 2). D1 receptors are more abundant in brain than D2 receptors, but the precise role of D1 receptor activation independent of D2 receptor actions has not been established (3). D1 receptor stimulation may modulate the activity of D2 receptors (4), mediate stereotypic behaviors (5), alter the release of neurotransmitters (6), affect electroencephalograph activity and behavioral arousal (7), and affect memory processes associated with the prefrontal cortex (8). D1 receptor activity shows age-dependent decreases in the human brain (9) and is altered in Huntington disease (10) and Alzheimer disease (11 11988The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
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