Characterising the loss-of-function impact of 5’ untranslated region variants in 15,708 individuals

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: May 27, 2020

Upstream open reading frames (uORFs) are tissue-specific cis-regulators of protein translation. Isolated reports have shown that variants create or disrupt uORFs can cause disease. Here, in a systematic genome-wide study using 15,708 whole genome sequences, we show new upstream start codons, and disrupting stop sites existing uORFs, under strong negative selection. This selection signal is significantly stronger for arising genes intolerant to loss-of-function variants. Furthermore, creating overlap the coding sequence signals equivalent missense Finally, identify specific where modification likely represents an important disease mechanism, report novel uORF frameshift variant NF2 neurofibromatosis. Our results highlight uORF-perturbing as under-recognised functional class contribute penetrant human disease, demonstrate power large-scale population sequencing data studying non-coding classes.

Language: Английский

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Genomic analyses implicate noncoding de novo variants in congenital heart disease

Nature Genetics, Journal Year: 2020, Volume and Issue: 52(8), P. 769 - 777

Published: June 29, 2020

Language: Английский

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A framework for an evidence-based gene list relevant to autism spectrum disorder

Nature Reviews Genetics, Journal Year: 2020, Volume and Issue: 21(6), P. 367 - 376

Published: April 21, 2020

Language: Английский

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Whole-Genome and RNA Sequencing Reveal Variation and Transcriptomic Coordination in the Developing Human Prefrontal Cortex

Cell Reports, Journal Year: 2020, Volume and Issue: 31(1), P. 107489 - 107489

Published: April 1, 2020

Gene expression levels vary across developmental stage, cell type, and region in the brain. Genomic variants also contribute to variation expression, some neuropsychiatric disorder loci may exert their effects through this mechanism. To investigate these relationships, we present BrainVar, a unique resource of paired whole-genome bulk tissue RNA sequencing from dorsolateral prefrontal cortex 176 individuals prenatal postnatal development. Here identify common that alter gene (expression quantitative trait [eQTLs]) constantly development or predominantly during stages. Both "constant" "temporal-predominant" eQTLs are enriched for associated with traits disorders colocalize specific variants. Expression more than 12,000 genes rise fall concerted late-fetal transition, transitional cell-type-specific risk loci, underscoring importance cataloging trajectories understanding cortical physiology pathology.

Language: Английский

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Autism Spectrum Disorder Genetics and the Search for Pathological Mechanisms

American Journal of Psychiatry, Journal Year: 2021, Volume and Issue: 178(1), P. 30 - 38

Published: Jan. 1, 2021

Recent progress in the identification of genes and genomic regions contributing to autism spectrum disorder (ASD) has had a broad impact on our understanding nature genetic risk for range psychiatric disorders, ASD biology, defining key challenges now facing field efforts translate gene discovery into an actionable pathology. While these advances have not yet transformative clinical practice, there is nonetheless cause real optimism: reliable lists are large growing rapidly; identified encoded proteins already begun point relatively small number areas where parallel neuroscience functional genomics yielding profound insights; strong evidence pointing mid-fetal prefrontal cortical development as one nexus vulnerability some largest-effect genes; multiple plausible paths forward toward rational therapeutics that, while admittedly challenging, constitute fundamental departures from what was possible prior era successful discovery.

Language: Английский

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