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

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.

Structural deviations of the posterior fossa and the cerebellum and their cognitive links in a neurodevelopmental deletion syndrome

“…BDH1 and PCYT1A are involved in ketone body metabolism (106) and phosphatidylcholine biosynthesis (107), which are important regulators of bioenergetic homeostasis. Coincidently, both DLG1 and BDH1 were previously proposed as drivers of psychiatric and neurodevelopmental phenotypes in this CNV (43,44). We conjecture that dosage alterations in these genes may be especially detrimental for cerebellar cortex development and function.…”

“…3q29Del has a prevalence of approximately 1 in 30,000 and usually arises de novo during parental meiosis due to the hemizygous deletion of a 1.6-Mb locus, spanning 21 protein-coding genes (39, 42). Although several genes within the interval have been proposed as putative drivers (43, 44), it is not currently known which genes or biological mechanisms contribute to the emergence of abnormal neurodevelopmental phenotypes in 3q29Del.…”

Metabolic effects of the schizophrenia-associated 3q29 deletion

“…Bulk RNAseq on liver tissue from STD-treated WT and B6.Del16 +/ Bdh1-Tfrc mice were performed as previously described [ 49 ] (Fig. S1 ).…”

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).…”