Dissect Relationships Between Gene Co-expression And Functional Connectivity In Human Brain

[Objective] The human brain is a complex network composed of interconnected brain regions with different structures and functions.The complexity of the human brain is characterized by the intra-and inter-network connections of the precise circuits,which are regulated by the transcriptome.Therefore,investigation of the association between gene transcription and brain connectivity will improve our understanding of the genetic mechanisms underlying abnormal connections in neuropsychiatric disorders.Although recent evidence indicates an association between gene co-expression and functional connectivity in human brain,specific association patterns remain largely unknown.There are at least three questions need to be further answered.Prior studies have identified genes associated with the averaged functional connectivity phenotypes derived from a group of subjects.It is still unknown that which expression-connectivity associations are consistently present in most individuals.Heritability analysis indicates that genetic and environmental factors influence functional connectivity architecture with different weights.It is an open question that which kinds of functional connectivity are prone to be affected by genetic factors(e.g.,gene expression).Inter-regional gene expression similarity within brain functional networks is much higher than those between networks,suggesting that the distributed brain functional networks may possess dissociable genetic signatures.However,we barely know which genes contribute generally to functional connectivity architecture of all functional networks,and which genes contribute specifically to a certain functional network.Answering these questions will largely improve our understanding on the molecular mechanisms of functional connectivity.Here,multiple comprehensive methods were applied to explore the brain coupling pattern between gene co-expression and functional connectivity in the whole brain and at sub-network level based on neuroimaging-based functional connectivity data of living brains and brain-wide gene expression data of postmortem brains.Part 1: We aimed to investigate the coupling pattern between functional connectivity and gene co-expression in the whole human brain through the non-negative tensor decomposition algorithm combined with permutation test and connectional coupling weight values seperately to find the reliable gene set highly associated with functional connectivity and functional connections highly related to gene expression.Part 2: At sub-network level,we compared the differences in the contribution of each gene among the 8 groups of intra-network connections from different functional networks by multiple comprehensive methods to identify connectivity-related genes common to all functional networks or specific to a certain network.[Materials and Methods] Based on f MRI data of 800 healthy adults and whole adult brain gene expression data from the Allen Institute of Brain Science,we screened connectivity-related genes at individual level for following investigations.Part 1: We investigated the coupling pattern between functional connectivity and gene co-expression in the whole brain.The non-negatively constrained tensor decomposition algorithm was combined with permutation test and connectional coupling weight values seperately to select reliable genes highly associated with functional connectivity and functional connections highly related to gene expression.Part 2: We investigated the coupling pattern between functional connectivity and gene co-expression at sub-network level.We compared the differences in the contribution of each gene among the 8 groups of intra-network connections from different functional networks by one-way analysis of variance to identify connectivity-related genes common to all functional networks.And then,we identified network-specific genes by tensor decomposition model,network-type specific analysis and comparing contributions of genes to different networks.[Results] Part 1: We identified 125 connectivity-related genes(20 novel genes)enriched for dendrite extension,signaling pathway and schizophrenia,and 179 gene-related functional connections mainly connecting intra-network regions,especially homologous cortical regions.Part 2: We identified that 51 genes were associated with connectivity in all brain functional networks and enriched for action potential and schizophrenia;in contrast,51 genes showed network-specific modulatory effects and enriched for ion transportation.[Conclusions] We confirmed that most of the previously identified connectivity-related genes can be detected in individual-level transcription-neuroimaging association analysis.Moreover,we found unequal influences of gene expression on functional connections and identified 179 functional connections linking more closely to gene expression than other connections.We also identified network-shared genes and network-specific genes for the first time,which are involved in different molecular processes.These findings provide new knowledge for the relationship between gene expression and functional connectivity in the human brain.