Table 12.

Potential biomarkers from cellular data in various MH-related disorders

Author name or study ID	Disorder	Molecular features/biological functions affected	Study summary/key findings	Source
Sancesario et al. [185]	AD	A meta-analysis of 96 articles related to Alzheimer’s disease that included 12 meta-analyses, 21 re-analyses of existing data and 63 original studies. Studies of brain tissues identified the following affected pathways including dopamine metabolism, mitochondrial function, oxidative stress, protein degradation, neuroinflammation, vesicular transport and synaptic transmission. Studies of the blood identified the following affected pathways including pathways involved in immune function, inflammation, RNA processing, protein chaperones, mitochondrial function and programmed cell death.	Pathways identified in both blood and brain tissue were mitochondrial function, protein degradation and inflammation indicated that AD was a systemic disease and not localized to any one region [185]	Both blood and brain tissue
Reitz et al [186]	AD	These included amyloid pathway, immune and inflammation system, lipid transport and metabolism, synaptic cell functioning, Tau pathology, cell migration, hippocampal synaptic function, cytoskeletal function and axonal transport and microglial and myeloid cell function	Identification of major pathways associated with AD, including immune system involvement and synaptic function	Various
Mirza et al. [187]	AD	The study of the electrophysiological changes indicated the following pathways contributed to the pathophysiology of AD including Glutamate receptor signaling, CREB signaling, dopamine- DARPP32 feedback in cAMP signaling and fMLP signaling in neutrophils	Implicates various neurotransmitter systems	Various
Li et al. [188]	AD	Identified nitric oxide, reactive oxygen species in macrophages (NOROS), NFkB and mitochondrial dysfunction and the major pathways associated with late onset AD (LOAD) [188]	Major pathways associated with late-onset AD, highlighting oxidative stress and immune response	Various
Mengsi et al. [158]	AD	Used gene expression data from 76 AD patients and discovered that the GABAergic (related to neurotransmitter GABA) system, neurons and synaptic function were affected in AD	AD affects neurotransmitter systems and synaptic function	Brain
Di Resta et al. [12]	AD	Reviewed the AD disease from an omics perspective. The molecular analyses shed light on AD pathogenesis, the cellular level analysis provided a systems biology perspective that could enable more effective treatment options	Concluded that an integration of molecular and cellular level analyses could better help with understanding of this complex disease	Various
Pang et al. [163]	AD	Several functional genes expressed together were affected in AD patients, including ERBB2, ERBB4, OCT3, MIF, CDK13 and GPI. Several pathways were found to be significantly dysregulated in EC and HIP brain regions, including PI3K-AKT signaling pathway, MAPK signaling pathway, oxidative phosphorylation, synaptic vesicle cycle, cell–cell adhesion, cytokine-mediated signaling pathway, proteasome, arginine and proline metabolism and pentose phosphate pathway	Analysis of two important brain regions in AD patients the entorhinal cortex (EC) and hippocampus (HIP) compared to normal controls	EC and HIP
[189, 190]	AD	In AD patients, the protein Tau is no longer able to help with forming structures that transport nutrients within nerve cells, which eventually leads to cell death. Hyperphosphorylation, i.e. signaling mechanisms used by the cell to regulate mitosis of this tau protein is known to be associated with AD	Importance of tau protein dysfunction and hyperphosphorylation	Clones of human brain τ isoforms
[191, 192]	AD	Researchers found S100A9 increased in the brains of AD patients. S100A9 is a calcium binding protein that plays an important role in the regulation of inflammatory processes and immune response [191, 192]	Increased S100A9	Various; ultracentrifugation-electrostatic repulsion hydrophilic interaction chromatography (UC-ERLIC) coupled mass spectrometry-based proteomics profiling of soluble and aggregated amyloidal plaque
Howard et al. [146]	MDD	Performed gene set enrichment analysis (GSEA) on the 269 genes that they found to be associated with MDD and found the following pathways as significantly enriched including post synapse, synapse, neuron spine, excitatory synapse, behavior, cognition, neuron projection, modulation of synaptic transmission and regulation of synapse structure or activity [146, 193, 194]	Pathways associated with MDD, revealing potential therapeutic targets	Various
Pantazatos et al. [143]	MDD	Used RNA-seq and found the following pathways affected in MDD including lower expression of immune-related pathways like chemokine receptor activity, chemotaxis and cytokine biosynthesis and angiogenesis and vascular development	Insights into immune system involvement in MDD.	Brain
Forero et al. [60].	MDD	Performed one of the largest meta-analysis of gene expression studies in MDD that covered 24 datasets that included a total of 753 samples. A functional analysis of the DEGs in MDD identified the following biological processes and KEGG pathways enriched with DEGs including synaptic transmission, neuron projection, Alzheimer’s disease pathway and proteasome pathways	Identification of biological processes and pathways in MDD	Various
[139]	MDD	Studies have also identified a change in the abundance of pro-inflammatory and oxidative stress response proteins in MDD. Other pathways implicated include LXR/RXR activation, acute phase response signaling, FXR/RXR activation, agranulocyte adhesion diapedesis and granulocyte adhesion diapedesis	Changes in the abundance of pro-inflammatory and oxidative stress response proteins in MDD	Blood
Multiple studies [7, 32, 137, 140, 193, 195]	MDD	Dysfunctional metabolic pathways for ATP production have been observed in MDD [193, 195]. This includes mitochondrial dysfunction and issues with glucose transporter proteins [32, 140]. Changes in energy metabolism-related proteins have also been identified [7, 32]. Studies have explored dysregulation in the glutamate system in MDD, particularly in the context of ketamine studies [137]	Dysregulation in metabolic and glutamate systems	Various; various; various, various, brain; various
Silva-Costa et al. [196]		The study of proteomic-based biomarker studies associated with MDD found gene biomarkers as part of several biological processes including inflammatory system, immune and inflammatory systems, lipid metabolism, carboxypeptidase activity, retinoid metabolic process, artery morphogenesis, coagulatory systems, cell communication, protein metabolism, regulation of the nervous system, energy metabolism, oxidative stress, and cell communication and oligodendrogenesis [196].	Identifies potential gene biomarkers associated with MDD.	various
Multiple studies [197]. [198].	MDD	Mehta et al. reviewed gene expression and RNA-seq studies from postmortem brain and peripheral blood for potential links to MDD and found biological processes that include inflammatory response, cell survival, apoptosis and oxidative stress [197]. Lin and Tsai [198] also reviewed gene expression-based studies in MDD to identify biomarkers related to peripheral immune response and growth factors, endocrine factors and metabolic markers	Several systems implicated including immune and inflammatory, oxidative stress and more	Postmortem brain and peripheral blood; peripheral blood cells
[139]. [199].	SCZ	Multiple proteins associated with SCZ belonged to the following pathways including LXR/RXR activation, FXR/RXR activation, hepatic fibrosis and hepatic stellate cell activation and atherosclerosis signaling [139]. A total of 99 peptides were found associated with BD and 202 peptides [139]. The pathways altered in SCZ included oxidative phosphorylation, mitochondrial dysfunction, EIF2 signaling, protein ubiquitination Pathway, mTOR signaling, CDK5 signaling, among others [199]	Pathways associated with SCZ, suggesting targets for further research and potential therapeutic interventions.	Blood; prefrontal pyramidal cells
Multiple studies [49, 159–161, 176, 200–202]	SCZ	Genetic variants of the genes GFAP [159], GLUL [160] and S100B [161] [49] were implicated including astrocyte function, including signal transduction, tyrosine kinase signaling, G protein–coupled receptor signaling, small GTPase-mediated signaling, cell adhesion and gene transcription [49, 200]. Other cell processes found altered in SCZ include reduced migration in neural precursor cells [201], Cytoskeletal effects [176], aberrations in mitochondrial function [202]	Cell processes found altered in SCZ	Various; brain; brain; various; various; brain; brain; fibroblasts
Depino et al. [203]	SCZ	A review of animal models of SCZ found changes in dopaminergic function and reduction in neurogenesis (the process that produces the cells of the nervous system)	Altered dopaminergic function and neurogenesis in SCZ	Animal models
Multiple studies: Wang et al. [204].	SCZ	A review of RNA-seq-based studies in SCZ found GABA function, glutamate function, myelin and oligodendrocyte related processes affected. Other biological processes related to immune and inflammatory pathways (including genes IL6 and SERPINA3) and response to virus or bacteria were also affected [204]	Biological processes affected in SCZ	Various
[7, 44]	SCZ	Patients with SCZ were found to have abnormal smooth-pursuit eye movement and reduced anterior cingulate volumes; enlarged lateral and third ventricular volumes and white matters abnormalities [7, 44]	Potential biomarkers and structural anomalies associated with SCZ	Various; various
[7, 205, 206]	SCZ	Changes in oligodendrocytes, energy metabolism (NADPH) [7, 206], glutamatergic neurotransmission and cannabinoid metabolism [7, 205]	Dysregulations in SCZ	Various; cerebrospinal fluid (CSF); postmortem mediodorsal thalamus (MDT)
Arion et al. [199]	SCZ	Transcriptome alterations in pyramidal cells of prefrontal cortex (SCZ patients)	Transcriptome changes specific to SCZ, less prominent in BD and MDD	Prefrontal pyramidal cells
[61]	SCZ and MDD	Oxidative phosphorylation was the most affected pathway in MDD whereas glycolysis pathway was the most affected in SCZ brains. Pathways found commonly affected between SCZ and MDD include WNT pathway, MAPK, PTEN signaling pathways, glutamate signaling that includes SLC38A2, GRM7, GRIA2; neurodevelopment-related genes including RUNX3, ITGB1, FMR1, STAT3 and SCZ susceptibility genes PDGFRA and PPARG [61]	Shared and distinct pathways in SCZ and MDD; potential targets for understanding and treating these disorders	Blood, serum and plasma
[207]	BD	Mitochondrial dysfunction may be associated with decreased in mitochondrial respiration, downregulation of proteins involved in mitochondrial respiration. It could also cause changes in mitochondrial morphology, increased mitochondrial DNA polymorphisms [207]	Mitochondrial dysfunction’s potential contribution to BD progression	Various
[7, 208, 209]	ASD	Fragile X syndrome is the most commonly studied genetic cause for Autism [7, 208]. Hormozdiari et al. studied WES data from 1116 patients with Autism to identify two sets of gene networks. One set was found associated with Wnt, Notch, SWI/SNF and NCOR complexes. The second set was associated with synaptic function, including long-term potentiation and calcium signaling [209]	Gene network analysis reveals two sets of genes associated with ASD, shedding light on molecular pathways involved in synaptic function and complex biological processes	Various; various; various
[7, 141, 210, 211]	ASD	Research has linked ASD with several biological processes including oxidative stress and mitochondrial dysfunction [210], increased polarity of glyoxalase 1 (GLO1) [141] and protein phosphorylation [7, 211]	Biological processes associated with ASD	Various; brain; various; saliva
Multiple studies [7, 162, 212–214]	ADHD	Biological processes affected in ADHD include prefrontal dopamine deficiency, central dopaminergic dysfunction, changes in oxidative metabolism and immunity [7, 212, 213]. In recent years, dopaminergic and noradrenergic systems have risen as potential genetic and biochemical markers in ADHD diagnosis [214]. McCaffrey et al. [162] studied RNA markers in case-controlled subjects and a study of twins which revealed the genes in the galactose metabolism pathway as affected	Biological processes associated with ADHD that could be studied further towards design of targets for diagnostics and therapeutics	Various; blood; various; blood; various
[58, 65]	PTSD	RNA-seq analysis in individuals with PTSD revealed glucocorticoid receptor signaling and immunity-related pathways. The authors found the key biological processes associated with PTSD to be immune dysregulation and HPA axis [58]. Gupta et al. studied PTSD data from military veterans, and the micoRNAs associated with immune response inflammation were found to play a pivotal role in PTSD in veterans [65]	The key biological processes associated with PTSD are immune dysregulation and HPA axis	Blood; various