TWAS pathway method greatly enhances the number of leads for uncovering the molecular underpinnings of psychiatric disorders
Vladimir I Vladimirov,
Anna R. Docherty,
Bradley T. Webb,
Brien P. Riley,
Kenneth S Kendler,
Nikolaos P. Daskalakis,
Posted 20 Jul 2018
bioRxiv DOI: 10.1101/373050 (published DOI: 10.1002/ajmg.b.32823)
Posted 20 Jul 2018
Genetic signal detection in genome-wide association studies (GWAS) is enhanced by pooling small signals from multiple Single Nucleotide Polymorphism (SNP), e.g. across genes and pathways. Because genes are believed to influence traits via gene expression, it is of interest to combine information from expression Quantitative Trait Loci (eQTLs) in a gene or genes in the same pathway. Such methods, widely referred as transcriptomic wide association analysis (TWAS), already exist for gene analysis. Due to the possibility of eliminating most of the confounding effect of linkage disequilibrium (LD) from TWAS gene statistics, pathway TWAS methods would be very useful in uncovering the true molecular bases of psychiatric disorders. However, such methods are not yet available for arbitrarily large pathways/gene sets. This is possibly due to it quadratic (in the number of SNPs) computational burden for computing LD across large regions. To overcome this obstacle, we propose JEPEGMIX2-P, a novel TWAS pathway method that i) has a linear computational burden, ii) uses a large and diverse reference panel (33K subjects), iii) is competitive (adjusts for background enrichment in gene TWAS statistics) and iv) is applicable as-is to ethnically mixed cohorts. To underline its potential for increasing the power to uncover genetic signals over the state-of-the-art and commonly used non-transcriptomics methods, e.g. MAGMA, we applied JEPEGMIX2-P to summary statistics of most large meta-analyses from Psychiatric Genetics Consortium (PGC). While our work is just the very first step toward clinical translation of psychiatric disorders, PGC anorexia results suggest a possible avenue for treatment. ### Competing Interest Statement The authors have declared no competing interest.
- Downloaded 473 times
- Download rankings, all-time:
- Site-wide: 46,567 out of 119,003
- In bioinformatics: 4,958 out of 9,624
- Year to date:
- Site-wide: 29,211 out of 119,003
- Since beginning of last month:
- Site-wide: 48,553 out of 119,003
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!