A combined pathway and regional heritability analysis indicates NETRIN1 pathway is associated with major depressive disorder

Zeng, Y. et al. (2017) A combined pathway and regional heritability analysis indicates NETRIN1 pathway is associated with major depressive disorder. Biological Psychiatry, 81(4), pp. 336-346. (doi: 10.1016/j.biopsych.2016.04.017) (PMID:27422368) (PMCID:PMC5262437)

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Background: Genome-wide association studies (GWASs) of major depressive disorder (MDD) have identified few significant associations. Testing the aggregation of genetic variants, in particular biological pathways, may be more powerful. Regional heritability analysis can be used to detect genomic regions that contribute to disease risk. Methods: We integrated pathway analysis and multilevel regional heritability analyses in a pipeline designed to identify MDD-associated pathways. The pipeline was applied to two independent GWAS samples [Generation Scotland: The Scottish Family Health Study (GS:SFHS, N = 6455) and Psychiatric Genomics Consortium (PGC:MDD) (N = 18,759)]. A polygenic risk score (PRS) composed of single nucleotide polymorphisms from the pathway most consistently associated with MDD was created, and its accuracy to predict MDD, using area under the curve, logistic regression, and linear mixed model analyses, was tested. Results: In GS:SFHS, four pathways were significantly associated with MDD, and two of these explained a significant amount of pathway-level regional heritability. In PGC:MDD, one pathway was significantly associated with MDD. Pathway-level regional heritability was significant in this pathway in one subset of PGC:MDD. For both samples the regional heritabilities were further localized to the gene and subregion levels. The NETRIN1 signaling pathway showed the most consistent association with MDD across the two samples. PRSs from this pathway showed competitive predictive accuracy compared with the whole-genome PRSs when using area under the curve statistics, logistic regression, and linear mixed model. Conclusions: These post-GWAS analyses highlight the value of combining multiple methods on multiple GWAS data for the identification of risk pathways for MDD. The NETRIN1 signaling pathway is identified as a candidate pathway for MDD and should be explored in further large population studies.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Padmanabhan, Professor Sandosh
Authors: Zeng, Y., Navarro, P., Fernandez-Pujals, A. M., Hall, L. S., Clarke, T.-K., Thomson, P. A., Smith, B. H., Hocking, L. J., Padmanabhan, S., Hayward, C., MacIntyre, D. J., Wray, N. R., Deary, I. J., Porteous, D. J., Haley, C. S., and McIntosh, A. M.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:Biological Psychiatry
ISSN (Online):1873-2402
Published Online:02 May 2016
Copyright Holders:Copyright © 2016 Society of Biological Psychiatry
First Published:First published in Biological Psychiatry 81(4): 336-346
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
381721Generation ScotlandAnna DominiczakScottish Executive Health Department (SEHHD-CSO)CZD/16/6RI CARDIOVASCULAR & MEDICAL SCIENCES