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Genes regulated by SATB2 during neurodevelopment contribute to schizophrenia and educational attainment.

ABSTRACT: SATB2 is associated with schizophrenia and is an important transcription factor regulating neocortical organization and circuitry. Rare mutations in SATB2 cause a syndrome that includes developmental delay, and mouse studies identify an important role for SATB2 in learning and memory. Interacting partners BCL11B and GATAD2A are also schizophrenia risk genes indicating that other genes interacting with or are regulated by SATB2 are making a contribution to schizophrenia and cognition. We used data from Satb2 mouse models to generate three gene-sets that contain genes either functionally related to SATB2 or targeted by SATB2 at different stages of development. Each was tested for enrichment using the largest available genome-wide association studies (GWAS) datasets for schizophrenia and educational attainment (EA) and enrichment analysis was also performed for schizophrenia and other neurodevelopmental disorders using data from rare variant sequencing studies. These SATB2 gene-sets were enriched for genes containing common variants associated with schizophrenia and EA, and were enriched for genes containing rare variants reported in studies of schizophrenia, autism and intellectual disability. In the developing cortex, genes targeted by SATB2 based on ChIP-seq data, and functionally affected when SATB2 is not expressed based on differential expression analysis using RNA-seq data, show strong enrichment for genes associated with EA. For genes expressed in the hippocampus or at the synapse, those targeted by SATB2 are more strongly enriched for genes associated EA than gene-sets not targeted by SATB2. This study demonstrates that single gene findings from GWAS can provide important insights to pathobiological processes. In this case we find evidence that genes influenced by SATB2 and involved in synaptic transmission, axon guidance and formation of the corpus callosum are contributing to schizophrenia and cognition.

SUBMITTER: Whitton L

PROVIDER: S-EPMC6097700 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Genes regulated by SATB2 during neurodevelopment contribute to schizophrenia and educational attainment.

Whitton Laura L Apostolova Galina G Rieder Dietmar D Dechant Georg G Rea Stephen S Donohoe Gary G Morris Derek W DW

PLoS genetics 20180724 7

SATB2 is associated with schizophrenia and is an important transcription factor regulating neocortical organization and circuitry. Rare mutations in SATB2 cause a syndrome that includes developmental delay, and mouse studies identify an important role for SATB2 in learning and memory. Interacting partners BCL11B and GATAD2A are also schizophrenia risk genes indicating that other genes interacting with or are regulated by SATB2 are making a contribution to schizophrenia and cognition. We used dat ...[more]

PMID: 30040823

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Project description:BackgroundIndividuals suffering from schizophrenia have a reduced life expectancy with cardiovascular disease (CVD) as a major contributor. Low educational attainment is associated with schizophrenia, as well as with all-cause and CVD mortality. However, it is unknown to what extent low educational attainment can explain the increased mortality in individuals with schizophrenia.AimHere, we quantify associations between educational attainment and all-cause and CVD mortality in individuals with schizophrenia, and compare them with the corresponding associations in the general population.MethodAll Norwegian citizens born between January 1, 1925, and December 31, 1959, were followed up from January 1, 1990, to December 31, 2014. The total sample included 1,852,113 individuals, of which 6548 were registered with schizophrenia. We estimated hazard ratios (HR) for all-cause and CVD mortality with Cox models, in addition to life years lost. Educational attainment for index persons and their parents were included in the models.ResultsIn the general population individuals with low educational attainment had higher risk of all-cause (HR: 1.48 [95% CI: 1.47-1.49]) and CVD (HR: 1.59 [95% CI: 1.57-1.61]) mortality. In individuals with schizophrenia these estimates were substantially lower (all-cause: HR: 1.13 [95% CI: 1.05-1.21] and CVD: HR: 1.12 [95% CI: 0.98-1.27]). Low educational attainment accounted for 3.28 (3.21-3.35) life years lost in males and 2.48 (2.42-2.55) years in females in the general population, but was not significantly associated with life years lost in individuals with schizophrenia. Results were similar for parental educational attainment.ConclusionsOur results indicate that while individuals with schizophrenia in general have lower educational attainment and higher mortality rates compared with the general population, the association between educational attainment and mortality is smaller in schizophrenia subjects than in the general population.

Project description:The brain is the organ of thought. The word thought is defined as the act of thinking about or considering something: an idea or opinion, or a set of ideas about a particular subject. It implicitly includes the processes of learning. Mental functions, including most if not all aspects of human behavior, such as those related to learning, arise from the activity of the brain. Neural connections that generate and support mental functions are formed throughout life, which enables lifelong learning of new concepts and skills. Both brain formation and function, as well as neural plasticity, are influenced by the activity of a variety of genes and also by epigenetic modifications, which contribute to the regulation of gene expression by adapting it to environmental conditions. In this review, aimed especially at education professionals, I discuss the genetic and epigenetic contributions to mental aspects related to learning processes in terms of heritability. I will argue that, despite most if not all aspects related to learning having a clear genetic background, innate abilities can be enhanced or diminished through educational processes. Thus, the importance of education, in the context of the inheritability of learning processes, will be discussed. The conclusion I draw is that, despite the relatively high genetic heritability shown in most brain processes associated with learning, educational practices are a key contributor to student development, allowing genetically based skills to be enhanced or alternatively diminished. Therefore one of the main goals of education in a changing an uncertain world should be to form adaptable and versatile people who can, and want to, make the most of their capabilities. Thus, knowledge derived from genetics and epigenetics, as well as from neuroscience, should be used to enhance education professionals' understanding of the biological origins of differences in mental capabilities, thereby empowering them with the possibility to adopt more respectful and flexible educational practices to attain the goal mentioned above.

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Genes regulated by SATB2 during neurodevelopment contribute to schizophrenia and educational attainment.

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Genes regulated by SATB2 during neurodevelopment contribute to schizophrenia and educational attainment.

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