Multiscale Imaging Genetics Studies

[Purpose] The human brain is a complex system of neural components working at different levels of scales.Bridging the data of different scales to investigate the phenotypic interaction is help to understand the macroscale brain reagions and connectivity more clearly at celluler and molecular levels.We investigated the following three parts using multiscale imaging genetics methods.Part1: The biological function of ZNF804 A rs1344706,the first genome-wide supported risk variant of schizophrenia,remains largely unknown.Based on the upregulating effect of ZNF804 A on the expression of COMT,we hypothesize that ZNF804 A may affect grey matter volume(GMV)by interacting with COMT.Part2: In Chinese Han population,COMT rs4633 is found to be associated with impaired cognitive process.We aimed to investigate the association between COMT rs4633 and verbal intelligence and the underlying neural mechanisms in Chinese Han healthy young adults.Part3: Neuroticism increases the risk for mental disorders with unknown biological mechanisms.Cross-scale correlation analyses may provide new insights on biological correlates of human neuroticism.[Methods] Part1: Voxel-based morphometry was applied to analyze the main and interaction effects of ZNF804 A rs1344706 and COMT rs4680 on brain GMV in 274 healthy young human subjects.Part2: In 256 Chinese Han healthy young adults,we explored the modulatory effects of COMT rs4633 on verbal intelligence quotient(VIQ)and functional connectivity density(FCD)of the brain and the mediation effect of FCD on the association between COMT and VIQ.We further investigated the association between the expression patterns of dopamine receptor genes and the effect of COMT on FCD in the human brain.Part3: To explore the biological correlates of human neuroticism,we performed two cross-scale correlation analyses.In 274 healthy Chinese Han young adults,we performed voxel-wise imaging behavior correlation analyses to investigate associations of functional connectivity density and grey matter volume with neuroticism scores.Then,we performed genome-wide transcription-imaging correlation analysis to identify genes whose transcriptional profiles were spatially correlated with neuroticism-related imaging properties.To further characterize transcriptional profiles of genes related to neuroticism-related imaging properties,half of genes with high spatial expression stability were fed into weighted genes co-expression network analysis(WGCNA)to categorize these genes into different modules.And then WGCNA and cell-type specific expression analysis(CSEA)were used to identify the module specifically expressed in neuroticism-related brain regions.Finally,CSEA was used to identify the cell-specific expression of the module and spatiotemporal expression analysis was used to show developmental stages when the module was specifically expressed in neuroticism-related regions.[Results] Part1: The GMV of the left dorsolateral prefrontal cortex(DLPFC)showed a significant COMT rs4680 × ZNF804 A rs1344706 interaction,manifesting as an inverted U-shape modulation by the presumed dopamine signaling.In COMT Met-allele carriers,the ZNF804 A TG heterozygotes showed greater GMV in the left DLPFC than both GG and TT homozygotes.In COMT Val/Val homozygotes,however,the ZNF804 A TG heterozygotes exhibited smaller GMV in the left DLPFC than GG homozygotes and comparable GMV with TT homozygotes.Part2: COMT rs4633 TT homozygotes exhibited lower VIQ than CC homozygotes and TC heterozygotes,higher long-range FCD(lrFCD)than CC homozygotes and TC heterozygotes in the left superior frontal gyrus.TT homozygotes and TC heterozygotes showed higher lrFCD than CC homozygotes in the left inferior parietal lobule.The lrFCD differences across genotypic subgroups were negatively associated with the expression of DRD2 and DRD3 genes.The left parietal lrFCD mediated the association between COMT rs4633 and VIQ.Part3: The voxel-wise imaging-behavior correlation analyses consistently showed an association between neuroticism and striatal functional connectivity rather than volume.Genome-wide transcription-imaging correlation analysis showed significant spatial correlations between 7050 gene expression and neuroticism-related functional connectivity.The weighted genes co-expression network analysis categorized 3525/7050 genes with high spatial expression stability into 15 modules.Genes of one module(191 genes)consistently showed the highest gene expression in the striatum across donors.Cell-type specific expression analysis in mouse brain also confirmed the striatal specific expression of this module and further revealed that this module was specifically expressed in medium spiny neurons of the striatum.The top three hub genes of this module were adenosine A2 a receptor(ADORA2A),regulator of G protein signaling 9(RGS9),and synapse differentiation inducing 1 like(SYNDIG1L),which are functionally related to dopamine signal transmission.Spatiotemporal expression analysis in human brain revealed that this module showed highly specific expression in the striatum,especially in mid-late childhood and young adulthood.These spatiotemporal expression-specific genes are functionally linked to potassium channel and G-protein coupled receptor.[Summary] Part1: These findings suggest that ZNF804 A affects the GMV of the prefrontal cortex by interacting with COMT,which may improve our understanding of neurobiological effect of ZNF804 A and its association with schizophrenia.Part2: These findings provide a biological pathway that COMT rs4633 affects verbal intelligence via modulating the lrFCD of the left inferior parietal lobule.Part3: By combining multiscale correlation analyses and functional annotations,this study advances our understanding of the genetic and neural substrates of human neuroticism and emphasizes the importance of the striatal functional properties in human neuroticism.Overrally,our studies help us to understand the cellular and molecular mechanism of macroscale brain structure and function at micro-and mesoscales levels,which would deepen our understandings about the pathogenesis of neuropsychiatric disorders.