Biology subjects

Akula, N.

Publications and source records attributed to Akula, N..

6 recordsLinked to original sources

bioRxiv2025

A neuro-immune axis of transcriptomic dysregulation within the subgenual anterior cingulate cortex in schizophrenia

Many genes are linked to psychiatric disorders, but genome-wide association studies (GWAS) and differential gene expression (DGE) analyses in post-mortem brain tissue often implicate distinct gene sets. This disconnect impedes therapeutic development, which relies on integrating genetic and genomic insights. We address this issue using a novel multivariate technique that reduces DGE bias by leveraging gene co-expression networks and controlling for confounds such as drug exposure. Deep RNA sequencing was performed in bulk post-mortem sgACC from individuals with bipolar disorder (BD; N=35), major depression (MDD; N=51), schizophrenia (SCZ; N=44), and controls (N=55). Toxicology data dimensionality was reduced using multiple correspondence analysis; case-control gene expression was then analyzed using 1) traditional DGE and 2) group regularized canonical correlation analysis (GRCCA) - a multivariate regression method that accounts for feature interdependence. Gene set enrichment analyses compared results with established neuropsychiatric risk genes, gene ontology pathways, and cell type enrichments. GRCCA revealed a significant association with SCZ (Pperm=0.001; no significant BD or MDD association), and the resulting gene weight vector correlated with DGE SCZ-control t-statistics (R=0.53; P<0.05). Both methods indicated down-regulation of immune and microglial genes and upregulation of ion transport and excitatory neuron genes. However, GRCCA - at both the gene and transcript level - showed stronger enrichments (FDR<0.05). Notably, GRCCA results were enriched for SCZ GWAS-implicated genes (FDR<0.05), while DGE results were not. These findings identify a SCZ-specific sgACC gene expression pattern that highlights SCZ risk genes and implicates neuro-immune pathways, thus demonstrating the utility of multivariate approaches to integrate genetic and genomic signals.

neuroscience↗

bioRxiv2024

High-risk neuropsychiatric copy number variants are associated with convergent transcriptomic changes in human brain cells

Large, recurrent copy number variants (CNVs) are among the strongest risk factors for neuropsychiatric conditions, contributing to multiple phenotypes with overlapping psychiatric and cognitive symptoms. However, the molecular basis of this convergent risk remains unknown. We evaluated the human brain transcriptome in carriers of nine high-risk neuropsychiatric CNVs and matched non-carriers using single nucleus RNA-sequencing. Brain tissue from carriers displayed widespread disruptions of gene expression, with thousands of differentially expressed genes, mostly located outside of the respective CNV regions. There were greater changes in deletions compared to reciprocal duplications. Functional enrichment analysis revealed changes in mitochondrial energy metabolism and synaptic function that converged across CNVs and cell types. For mirror CNVs, the direction of effects was often reversed between deletions and duplications and showed correlation with CNV gene dosage. These findings suggest that a shared pathophysiology underlies risk for convergent brain phenotypes across CNVs and point toward promising therapeutic targets.

genetics↗

bioRxiv2024

A conserved cell-type gradient across the human mediodorsal and paraventricular thalamus

The mediodorsal thalamus (MD) and adjacent midline nuclei are important for cognition and mental illness, but their cellular composition is not well defined. Using single-nucleus and spatial transcriptomics, we identified a conserved excitatory neuron gradient, with distinct spatial mapping of individual clusters. One end of the gradient was expanded in human MD compared to mice, which may be related to the expansion of granular prefrontal cortex in hominids. Moreover, neurons preferentially mapping onto the parvocellular division MD were associated with genetic risk for schizophrenia and bipolar disorder. Midbrain-derived inhibitory interneurons were enriched in human MD and implicated in genetic risk for major depressive disorder.

neuroscience↗

bioRxiv2024

Brain transcriptomic signatures for mood disorders and suicide phenotypes: an anterior insula and subgenual ACC network postmortem study

Mood disorders affect over ten percent of humans, but studies dissecting the brain anatomical and molecular neurobiological mechanisms underlying mood (dys)functions have not consistently identified the patterns of pathological changes in relevant brain regions. Recent studies have identified pathological changes in the anterior insula (Ant-Ins) and subgenual anterior cingulate (sgACC) brain network in mood disorders, in line with this networks role in regulating mood/affective feeling states. Here, we applied whole-tissue RNA-sequencing measures of differentially expressed genes (DEGs) in mood disorders versus (vs.) psychiatrically unaffected controls (controls) to identify postmortem molecular pathological markers for mood disorder phenotypes. Using data-driven factor analysis of the postmortem phenotypic variables to determine relevant sources of population variances, we identified DEGs associated with mood disorder-related diagnostic phenotypes by combining gene co-expression, differential gene expression, and pathway-enrichment analyses. We found downregulation/under expression of inflammatory, and protein synthesis-related genes associated with psychiatric morbidity (i.e., all co-occurring mental disorders and suicide outcomes/death by suicide) in Ant-Ins, in contrasts to upregulation of synaptic membrane and ion channel-related genes with increased psychiatric morbidity in sgACC. Our results identified a preponderance of downregulated metabolic, protein synthesis, inflammatory, and synaptic membrane DEGs associated with suicide outcomes in relation to a factor representing longevity in the Ant-Ins and sgACC (AIAC) network. Our study revealed a critical brain network molecular repertoire for mood disorder phenotypes, including suicide outcomes and longevity, and provides a framework for defining dosage-sensitive (i.e., downregulated vs. upregulated) molecular signatures for mood disorder phenotypic complexity and pathological outcomes.

neuroscience↗

bioRxiv2019

Deep transcriptome sequencing of subgenual anterior cingulate cortex reveals disorder-specific expression changes in major psychiatric disorders

How do differences in onset, symptoms, and treatment response arise between various mental illnesses despite substantial overlap of genetic risk factors? To address this question, we carried out deep RNA sequencing of human postmortem subgenual anterior cingulate cortex, a key component of limbic circuits linked to mental illness. Samples were obtained from 200 individuals diagnosed with bipolar disorder, schizophrenia, or major depression, and controls. Differential expression analysis in cases versus controls detected modest differences that were similar across disorders, although transcript-level differences were more pronounced. Case-case comparisons revealed greater expression differences between disorders, including many genes and transcripts that were expressed in opposite directions in each diagnostic group, compared to controls. Relative transcript abundances were associated with common genetic variants that accounted for disproportionate fractions of diagnosis-specific heritability. Inherited genetic risk factors shape the brain transcriptome and contribute to diagnostic differences between broad classes of mental illness.

genomics↗

bioRxiv2017

Sodium valproate rescues expression of TRANK1 in iPSC-derived neural cells that carry a genetic variant associated with serious mental illness

Biological characterization of genetic variants identified in genome-wide association studies (GWAS) remains a substantial challenge. Here we used human induced pluripotent stem cells (hiPSC) and their neural derivatives to characterize common variants on chromosome 3p22 that have been associated by GWAS with major mental illnesses. HiPSC-derived neural progenitor cells carrying the risk allele of the single nucleotide polymorphism (SNP), rs9834970, displayed lower baseline TRANK1 expression that was rescued by chronic treatment with therapeutic dosages of valproic acid (VPA). Although rs9834970 has no known function, we demonstrated that a nearby SNP, rs90832, strongly affects binding by the transcription factor, CTCF, and that the high-affinity allele usually occurs on haplotypes carrying the rs9834970 risk allele. Decreased expression of TRANK1 perturbed expression of many genes involved in neural development and differentiation. These findings have important implications for the pathophysiology of major mental illnesses and the development of novel therapeutics.\n\nHighlightsO_LIhiPSC-derived neural cells carrying a mental illness risk allele showed lower expression of TRANK1\nC_LIO_LIValproic acid rescued TRANK1expression in cells carrying the risk allele\nC_LIO_LIRisk haplotypes usually carry an allele that increased CTCF binding\nC_LIO_LIReduced expression of TRANK1 perturbed genes involved in neural development and differentiation\nC_LI\n\nIn BriefUsing neural derivatives of human induced pluripotent stem cells, Jiang et al. demonstrate that genetic variants associated with mental illness alter transcription factor binding and decrease expression of a nearby gene, an effect which is rescued by valproic acid.

genetics↗