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Delineating the Genetic Component of Gene Expression in Major Depression

Lorenza Dall’Aglio, Cathryn M. Lewis, View ORCID ProfileOliver Pain
doi: https://doi.org/10.1101/2020.03.24.004903
Lorenza Dall’Aglio
1Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
2Department of Child and Adolescent Psychiatry, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
3The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
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Cathryn M. Lewis
1Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
4Department of Medical and Molecular Genetics, Faculty of Life Sciences and Medicine, King’s College London
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Oliver Pain
1Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
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  • ORCID record for Oliver Pain
  • For correspondence: oliver.pain@kcl.ac.uk
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Abstract

Background Major Depression (MD) is determined by a multitude of factors including genetic risk variants which regulate gene expression (GE). Here, we examined the genetic component of GE in MD by performing a Transcriptome-Wide Association Study (TWAS), inferring GE-trait relationships from genetic, transcriptomic and phenotypic information.

Method Genes differentially expressed in depression were identified with the TWAS FUSION method, based on summary statistics from the largest genome-wide association analysis of MD (Ncases = 135,458) and GE levels from 20 tissue datasets. Follow-up analyses were performed to extensively characterize the identified associations: colocalization, conditional, and fine-mapping analyses together with functionally-enriched pathway investigations.

Results Transcriptome-wide significant GE differences between cases and controls were found at 91 genes, 50 of which were not found in previous MD TWASs. Of the 91 significant genes, eight represented strong, colocalized, and potentially causal associations with depression, which were independent from the effect of nearby genes. Such “high-confidence associations” include NEGR1, CTC-467M3.3, TMEM106B, CTD-2298J14.2, CCDC175, ESR2, PROX2, ZC3H7B. Lastly, TWAS-based enrichment analysis highlighted dysregulation of gene sets for long term potentiation, dendritic shaft, and memory processes in MD.

Conclusion This study has shed light on the genetic component of GE in depression by characterizing the identified associations, unravelling novel risk genes, and determining which associations are congruent with a causal model. These findings can be used as a resource for prioritizing and designing subsequent functional studies of MD.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted March 25, 2020.
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Delineating the Genetic Component of Gene Expression in Major Depression
Lorenza Dall’Aglio, Cathryn M. Lewis, Oliver Pain
bioRxiv 2020.03.24.004903; doi: https://doi.org/10.1101/2020.03.24.004903
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Delineating the Genetic Component of Gene Expression in Major Depression
Lorenza Dall’Aglio, Cathryn M. Lewis, Oliver Pain
bioRxiv 2020.03.24.004903; doi: https://doi.org/10.1101/2020.03.24.004903

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