Koh, J. Y. | bioRxiv Science

bioRxiv2017

Genetic Architecture of Subcortical Brain Structures in Over 40,000 Individuals Worldwide

Subcortical brain structures are integral to motion, consciousness, emotions, and learning. We identified common genetic variation related to the volumes of nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen, and thalamus, using genome-wide association analyses in over 40,000 individuals from CHARGE, ENIGMA and the UK-Biobank. We show that variability in subcortical volumes is heritable, and identify 25 significantly associated loci (20 novel). Annotation of these loci utilizing gene expression, methylation, and neuropathological data identified 62 candidate genes implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

genetics↗

bioRxiv2017

ConsensusDriver Improves Upon Individual Algorithms For Predicting Driver Alterations In Different Cancer Types And Individual Patients -- A Toolbox For Precision Oncology

BackgroundIn recent years, several large-scale cancer genomics studies have helped generate detailed molecular profiling datasets for many cancer types and thousands of patients. These datasets provide a unique resource for studying cancer driver prediction methods and their utility for precision oncology, both to predict driver genetic alterations in patient subgroups (e.g. defined by histology or clinical phenotype) or even individual patients.\n\nMethodsWe performed the most comprehensive assessment to date of 18 driver gene prediction methods, on more than 3,400 tumour samples, from 15 cancer types, to determine their suitability in guiding precision medicine efforts. These methods have diverse approaches, which can be classified into five categories: functional impact on proteins in general (FI) or specific to cancer (FIC), cohort-based analysis for recurrent mutations (CBA), mutations with expression correlation (MEC) and methods that use gene interaction network-based analysis (INA).\n\nResultsThe performance of driver prediction methods varies considerably, with concordance with a gold-standard varying from 9% to 68%. FI methods show relatively poor performance (concordance <22%) while CBA methods provide conservative results, but require large sample sizes for high sensitivity. INA methods, through the integration of genomic and transcriptomic data, and FIC methods, by training cancer-specific models, provide the best trade-off between sensitivity and specificity. As the methods were found to predict different subsets of drivers, we propose a novel consensus-based approach, ConsensusDriver, which significantly improves the quality of predictions (20% increase in sensitivity). This tool can be applied to predict driver alterations in patient subgroups (e.g. defined by histology or clinical phenotype) or even individual patients.\n\nConclusionExisting cancer driver prediction methods are based on very different assumptions and each of them can only detect a particular subset of driver events. Consensus-based methods, like ConsensusDriver, are thus a promising approach to harness the strengths of different driver prediction paradigms.

bioinformatics↗