7 research outputs found
Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence
Intelligence is highly heritable(1) and a major determinant of human health and well-being(2). Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence3-7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.Peer reviewe
Correlation between microbial community and granule conductivity in anaerobic bioreactors for brewery wastewater treatment
Discovery of PF-5190457, a Potent, Selective, and Orally Bioavailable Ghrelin Receptor Inverse Agonist Clinical Candidate
https://researchrepository.wvu.edu/wvu_herbwvfern/2465/thumbnail.jp
Evaluation and Synthesis of Polar Aryl- and Heteroaryl Spiroazetidine-Piperidine Acetamides as Ghrelin Inverse Agonists
Several polar heteroaromatic acetic
acids and their piperidine
amides were synthesized and evaluated as ghrelin or type 1a growth
hormone secretagogue receptor (GHS-R1a) inverse agonists. Efforts
to improve pharmacokinetic and safety profile was achieved by modulating
physicochemical properties and, more specifically, emphasizing increased
polarity of our chemical series. <i>ortho</i>-Carboxamide
containing compounds provided optimal physicochemical, pharmacologic,
and safety profile. pH-dependent chemical stability was also assessed
with our series
Discovery of PF-5190457, a Potent, Selective, and Orally Bioavailable Ghrelin Receptor Inverse Agonist Clinical Candidate
The identification of potent, highly
selective orally bioavailable
ghrelin receptor inverse agonists from a spiro-azetidino-piperidine
series is described. Examples from this series have promising in vivo
pharmacokinetics and increase glucose-stimulated insulin secretion
in human whole and dispersed islets. A physicochemistry-based strategy
to increase lipophilic efficiency for ghrelin receptor potency and
retain low clearance and satisfactory permeability while reducing
off-target pharmacology led to the discovery of <b>16h</b>.
Compound <b>16h</b> has a superior balance of ghrelin receptor
pharmacology and off-target selectivity. On the basis of its promising
pharmacological and safety profile, <b>16h</b> was advanced
to human clinical trials