Direct targets ofMEF2Care enriched for genes associated with schizophrenia and cognitive function and are involved in neurogenesis and mitochondrial function
Authors: Ali Deema , Laighneach Aodán , Corley Emma , Patlola Saahithh Redddi , Holleran Laurena , McKernan Declan P. , Kelly John P. , Corvin Aiden P. , Hallahan Brian , McDonald Colm , Donohoe Gary , Morris Derek W. 
Published: December 2023

Myocyte Enhancer Factor 2C(MEF2C) is a transcription factor that plays a crucial role in neurogenesis and synapse development. Genetic studies have identifiedMEF2Cas a gene that influences cognition and risk for neuropsychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia (SCZ). Here, we investigated the involvement ofMEF2Cin these phenotypes using human-derived neural stem cells (NSCs) and induced neurons (iNs), which represented early and late neurodevelopmental stages. For these cellular models,MEF2Cfunction had previously been disrupted, either by direct or indirect mutation, and gene expression assayed using RNA-seq. We integrated these RNA-seq data withMEF2CChIP-seq data to identify dysregulated direct target genes ofMEF2Cin the NSCs and iNs models. SeveralMEF2Cdirect target gene-sets were enriched for SNP-based heritability for intelligence, educational attainment and SCZ, as well as being enriched for genes containing rarede novomutations reported in ASD and/or developmental disorders. These gene-sets are enriched in both excitatory and inhibitory neurons in the hippocampus and cortex and are involved in a wide range of biological processes including neurogenesis, metabolic processes, protein modifications, as well as mitochondrial function and energy production. We observed a trans expression quantitative trait locus (eQTL) effect of a single SNP atMEF2C(rs6893807, which is associated with IQ) on the expression of a target gene,BNIP3L.BNIP3Lis a prioritized risk gene from the largest genome-wide association study of SCZ and has a function in mitophagy in mitochondria. Overall, our analysis reveals that either direct or indirect disruption ofMEF2Cdysregulates sets of genes that contain multiple alleles associated with SCZ risk and cognitive function and implicates neurogenesis and mitochondrial function in the etiology of these phenotypes.

Author Summary

Schizophrenia is a complex disorder caused by many genes. Current drugs for schizophrenia are only partially effective and do not treat cognitive deficits, which are key factors for explaining disability, leading to unemployment, homelessness and social isolation. Genome-wide association studies of schizophrenia and cognitive function have been effective at identifying individual SNPs and genes that contribute to these phenotypes but have struggled to immediately uncover the bigger picture of the underlying biology of the disorder. Here we take an individual gene associated with schizophrenia and cognitive function calledMEF2C, which on its own is a very important regulator of brain development. We use functional genomics data from studies whereMEF2Chas been mutated to identify sets of other genes that are influenced byMEF2Cin developing and mature neurons. We show that several of these gene-sets are enriched for common variants associated with schizophrenia and cognitive function, and for rare variants that increase risk of various neurodevelopmental disorders. These gene-sets are involved in neurogenesis and mitochondrial function, providing evidence that these biological processes may be important in the context of the molecular mechanisms that underpin schizophrenia and cognitive function.