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.
Highlights
Copy number variants (CNVs) offer tractable entry points to investigate the genetic contributions to complex neuropsychiatric diseases
Unbiased gene co-expression network analysis reveals convergent and distributed effects of 3q29 interval genes across the adult human cortical transcriptome Applying an unsupervised weighted gene co-expression network analysis (WGCNA) approach [29,42,] to publicly available data from the Genotype Tissue Expression Project (GTEx) Project [58] revealed that the protein-coding transcriptome of the healthy adult human prefrontal cortex (PFC) can be organized into a gene co-expression network of 19 modules (Fig. 1d and Table S1.2)
Nine 3q29 interval genes form transcriptomic subnetworks enriched for known SZ, Autism spectrum disorders (ASD), and intellectual disability/developmental delay (IDD)-risk genes We identified a refined subset of target genes that co-cluster based on Topological overlap measures (TOM) and have a strong pairwise correlation with 3q29 genes (Fig. 3a)
Summary
Copy number variants (CNVs) offer tractable entry points to investigate the genetic contributions to complex neuropsychiatric diseases. The recurrent 1.6 Mb deletion of the 3q29 interval (3q29Del) is robustly associated with schizophrenia spectrum and other non-affective psychotic disorders (SZ) [1,2,3,4] and is the strongest known risk allele for the disease with an estimated odds ratio >40 [5]. Autism spectrum disorders (ASD) and intellectual disability/developmental delay (IDD) are enriched in 3q29Del carriers [7,9,10,]. It is not currently known which genes within the interval are responsible for the increased neuropsychiatric risk. No transcriptomic investigation of 3q29Del in humans has been reported, and it is unclear what impact hemizygous loss of these genes might have in the nervous system
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