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

Abstract

The 1.6Mb 3q29 deletion (3q29Del) confers >40-fold increased risk for schizophrenia (SZ) and is also a risk factor for intellectual disability (ID) and autism spectrum disorders (ASD). No single gene in this interval is definitively associated with SZ, ID, or ASD, prompting the hypothesis that neurodevelopmental sequelae emerge upon loss of multiple functionally-connected genes. However, 3q29 interval genes are unevenly annotated and the impact of the 3q29Del on the human neural transcriptome is not known. To formulate unbiased hypotheses, we engaged a systems-level approach using the adult human cortical transcriptome to predict novel biological roles, functional inter-relations and disease associations for individual 3q29 genes. Weighted gene co-expression network analysis showed that the 21 protein-coding genes located in the 3q29 interval segregate into seven clusters, demonstrating both convergent and distributed effects across the transcriptomic landscape. Analysis of 3q29 gene-containing clusters revealed nervous-system specific functions, such as regulation and organization of synaptic signaling, as well as core aspects of cell biology, including transcriptional regulation, chromatin remodeling, protein modifications, and mitochondrial metabolism. Top network neighbors of 3q29 interval genes show significant overlap with known SZ, ASD and ID-risk genes, suggesting that 3q29Del biology is relevant to idiopathic disease. By leveraging “guilt by association”, we propose nine 3q29 genes, including one hub gene, as prioritized drivers of neuropsychiatric risk. To test these predictions, we generated the first human cellular model of 3q29Del syndrome and show that neural progenitor cell (NPC) lines derived from 3q29Del carriers empirically validate network-derived targets, highlighting both the biological relevance of this in silico analysis and this novel NPC model of 3q29Del. These results provide foundational information to formulate testable hypotheses on causal drivers and mechanisms of the largest known genetic risk factor for SZ.

Metabolic effects of the schizophrenia-associated 3q29 deletion are sex-specific and uncoupled from behavioral phenotypes

“…The present study was the first to identify metabolic deficits in the context of the 3q29 deletion. Furthermore, we found pervasive sex-specific effects of the 3q29 deletion; these findings are supported by transcriptome network analysis by our team that identified a module enriched for estrogen-related signaling (Sefik et al, 2020). These results have important implications, both for the 3q29 deletion specifically and for metabolic and mechanistic studies more generally.…”

“…Data from animal models have revealed pervasive roles for estrogen and estrogen-related signaling in metabolic processes including fat metabolism and storage (Faulds et al, 2012). An independent study by our group using transcriptome network analysis identified a co-expression module significantly enriched for estrogen-dependent signaling (p=5.08E-06) that contained the 3q29 deletion interval gene PAK2 (Sefik et al, 2020). Together with the existing literature on sex differences in fat metabolism and our finding that male and female B6.Del16 +/ Bdh1-Tfrc mice are differentially affected by 3q29 deletion-associated metabolic phenotypes, this finding suggests that sex is an important consideration in defining the biological mechanisms underscoring phenotypes in 3q29del.…”

Psychosis spectrum symptoms among individuals with schizophrenia-associated copy number variants and evidence of cerebellar correlates of symptom severity

“…The association that we identified between cerebellar cortex volume and positive symptom severity in 3q29Del may help elucidate one part of this question, as this finding suggests that one or more genes affected by the hemizygous deletion of the 3q29 interval modulate the link between cerebellar development and psychosis-risk. In fact, many genes located in this interval, including DLG1 and BDH1, which have been proposed as drivers of neuropsychiatric phenotypes (133,134), show medium-high expression in the cerebellum (https://www.proteinatlas.org/). Its protracted development may increase the cerebellum's susceptibility to perturbations of these genes (135,136).…”