Convergent and distributed effects of the 3q29 deletion on the human neural transcriptome

• Type of Material: Article
• Authors: Esra Sefik, Emory University; Ryan Purcell, Emory University; Elaine Walker, Emory University; Gary Bassell, Emory University; Jennifer Mulle, Emory University
• Language: English
• Date: 2021-06-15
• Publisher: Nature Publishing Group
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2021
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41398-021-01435-2
• Title of Journal or Parent Work: Translational Psychiatry
• Volume: 11
• Grant/Funding Information: This study was supported by NIH R01 MH110701 (J.G.M. and G.J.B.), F32 MH124273 (R.H.P.), and the Emory University School of Medicine.
• Keywords: Psychiatric disorders; Genomics
• Research Categories: Psychology, Clinical; Biology, Genetics

Abstract

The 3q29 deletion (3q29Del) confers high risk for schizophrenia and other neurodevelopmental and psychiatric disorders. However, no single gene in this interval is definitively associated with disease, prompting the hypothesis that neuropsychiatric sequelae emerge upon loss of multiple functionally-connected genes. 3q29 genes are unevenly annotated and the impact of 3q29Del on the human neural transcriptome is unknown. To systematically formulate unbiased hypotheses about molecular mechanisms linking 3q29Del to neuropsychiatric illness, we conducted a systems-level network analysis of the non-pathological adult human cortical transcriptome and generated evidence-based predictions that relate 3q29 genes to novel functions and disease associations. The 21 protein-coding genes located in the interval segregated into seven clusters of highly co-expressed genes, demonstrating both convergent and distributed effects of 3q29Del across the interrogated transcriptomic landscape. Pathway analysis of these clusters indicated involvement in nervous-system functions, including synaptic signaling and organization, as well as core cellular functions, including transcriptional regulation, posttranslational modifications, chromatin remodeling, and mitochondrial metabolism. Top network-neighbors of 3q29 genes showed significant overlap with known schizophrenia, autism, and intellectual disability-risk genes, suggesting that 3q29Del biology is relevant to idiopathic disease. Leveraging “guilt by association”, we propose nine 3q29 genes, including one hub gene, as prioritized drivers of neuropsychiatric risk. These results provide testable hypotheses for experimental analysis on causal drivers and mechanisms of the largest known genetic risk factor for schizophrenia and highlight the study of normal function in non-pathological postmortem tissue to further our understanding of psychiatric genetics, especially for rare syndromes like 3q29Del, where access to neural tissue from carriers is unavailable or limited.