Refining the role of de novo protein truncating variants in neurodevelopmental disorders using population reference samples
Jack A. Kosmicki,
Kaitlin E Samocha,
Daniel P Howrigan,
Stephan J. Sanders,
David J. Cutler,
Joseph D. Buxbaum,
Benjamin M Neale,
Daniel G MacArthur,
Dennis P. Wall,
Elise B Robinson,
Mark J Daly
Posted 12 May 2016
bioRxiv DOI: 10.1101/052886 (published DOI: 10.1038/ng.3789)
Posted 12 May 2016
Recent research has uncovered an important role for de novo variation in neurodevelopmental disorders. Using aggregated data from 9246 families with autism spectrum disorder, intellectual disability, or developmental delay, we show ~1/3 of de novo variants are independently observed as standing variation in the Exome Aggregation Consortium's cohort of 60,706 adults, and these de novo variants do not contribute to neurodevelopmental risk. We further use a loss-of-function (LoF)-intolerance metric, pLI, to identify a subset of LoF-intolerant genes that contain the observed signal of associated de novo protein truncating variants (PTVs) in neurodevelopmental disorders. LoF-intolerant genes also carry a modest excess of inherited PTVs; though the strongest de novo impacted genes contribute little to this, suggesting the excess of inherited risk resides lower-penetrant genes. These findings illustrate the importance of population-based reference cohorts for the interpretation of candidate pathogenic variants, even for analyses of complex diseases and de novo variation.
- Downloaded 1,547 times
- Download rankings, all-time:
- Site-wide: 15,440
- In genetics: 667
- Year to date:
- Site-wide: 87,837
- Since beginning of last month:
- Site-wide: 68,676
Downloads over time
Distribution of downloads per paper, site-wide
- 27 Nov 2020: The website and API now include results pulled from medRxiv as well as bioRxiv.
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!