Truncating Variant Burden in High Functioning Autism and Pleiotropic Effects of LRP1 Across Psychiatric Phenotypes
Alex D. Shaw,
Janice M. Fullerton,
Posted 28 Sep 2018
bioRxiv DOI: 10.1101/429779 (published DOI: 10.1503/jpn.180184)
Posted 28 Sep 2018
Previous research has implicated de novo (DN) and inherited truncating mutations in autism spectrum disorder (ASD). We aim to investigate whether the load of inherited truncating mutations contribute similarly to high functioning autism (HFA), and to characterise genes harbouring DN variants in HFA. We performed whole-exome sequencing (WES) in 20 HFA families (average IQ=100). No difference was observed in the number of transmitted versus non-transmitted truncating alleles to HFA (117 vs 130, P=0.32). Transmitted truncating and DN variants in HFA were not enriched in GO or KEGG categories, nor autism-related gene sets. However, in a HFA patient we identified a DN variant in a canonical splice site of LRP1, a post-synaptic density gene that is a target for the FMRP. This DN leads to in-frame skipping of exon-29, removing 2 of 6 blades of the β-propeller domain-4 of LRP1, with putative functional consequences. Results using large datasets implicate LRP1 across psychiatric diseases: i) DN are associated with ASD (P=0.039) and schizophrenia (P=0.008) from combined sequencing projects; ii) Common variants using Psychiatric Genomics Consortium GWAS datasets show gene-based association in schizophrenia (P=6.6E-07) and across six psychiatric diseases (meta-analysis P=8.1E-05); and iii) burden of ultra-rare pathogenic variants is higher in ASD (P=1.2E-05), using WES from 6,135 schizophrenia patients, 1,778 ASD patients and 6,245 controls. Previous and current studies suggest an impact of truncating mutations restricted to severe ASD phenotypes associated with intellectual disability. We provide evidence for pleiotropic effects of common and rare variants in the LRP1 gene across psychiatric phenotypes.
- Downloaded 374 times
- Download rankings, all-time:
- Site-wide: 71,085
- In genomics: 4,920
- Year to date:
- Site-wide: 90,887
- Since beginning of last month:
- Site-wide: 73,184
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!