Abstract
Cognitive abilities, such as memory, learning, language, problem solving, and planning, involve the frontal lobe and other brain areas. Not much is known yet about the molecular basis of cognitive abilities, but it seems clear that cognitive abilities are determined by the interplay of many genes. One approach for analyzing the genetic networks involved in cognitive functions is to study the coexpression networks of genes with known importance for proper cognitive functions, such as genes that have been associated with cognitive disorders like intellectual disability (ID) or autism spectrum disorders (ASD). Because many of these genes are gene regulatory factors (GRFs) we aimed to provide insights into the gene regulatory networks active in the human frontal lobe. Using genome wide human frontal lobe expression data from 10 independent data sets, we first derived 10 individual coexpression networks for all GRFs including their potential target genes. We observed a high level of variability among these 10 independently derived networks, pointing out that relying on results from a single study can only provide limited biological insights. To instead focus on the most confident information from these 10 networks we developed a method for integrating such independently derived networks into a consensus network. This consensus network revealed robust GRF interactions that are conserved across the frontal lobes of different healthy human individuals. Within this network, we detected a strong central module that is enriched for 166 GRFs known to be involved in brain development and/or cognitive disorders. Interestingly, several hubs of the consensus network encode for GRFs that have not yet been associated with brain functions. Their central role in the network suggests them as excellent new candidates for playing an essential role in the regulatory network of the human frontal lobe, which should be investigated in future studies.
Highlights
Defined, cognition refers to the biological mechanisms through which animals perceive, learn and memorize information from the environment and decide to act upon them (Shettleworth, 2009)
Within this list of human gene regulatory factors (GRFs) we identified 676 GRFs that are involved in cognitive functions, brain development, and disorders by using different sources
Among the 401 genes implicated in intellectual disability (ID), we identified 106 genes coding for GRFs, which represents a highly significant enrichment of GRFs among all ID genes
Summary
Cognition refers to the biological mechanisms through which animals perceive, learn and memorize information from the environment and decide to act upon them (Shettleworth, 2009). Research on cognitive disorders such as Alzheimer’s disease (AD; Bullido et al, 1998), intellectual disability (ID; Kaufman et al, 2010), autism spectrum disorder (ASD; Bailey et al, 1996; Voineagu et al, 2011; Berg and Geschwind, 2012; Ecker et al, 2012), schizophrenia (SZ; Andreasen, 1995), circadian rhythm and bipolar disorder (BD; Akula et al, 2014, 2016; Takahashi, 2015), Parkinson’s disease (PD; Polymeropoulos, 2000), and several syndromes or disorders associated with ID or cognitive impairment (SY; Greydanus and Pratt, 2005) has already identified several candidate genes involved in cognition. These studies revealed that most cognitive disorders are complex and phenotypically and genetically heterogeneous (Sebat et al, 2007; Tsankova et al, 2007; Voineagu et al, 2011; Weyn-Vanhentenryck et al, 2014), creating challenges for studying these disorders
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