Schizophrenia is a disorder that is characterized by delusions, hallucinations, disorganized speech or behavior, and socio-occupational impairment. The duration of observation and variability in symptoms can make the accurate diagnosis difficult. Identification of biomarkers for schizophrenia (SCZ) can help in early diagnosis, ascertaining the diagnosis, and development of effective treatment strategies. Here we review peripheral blood-based gene expression studies for identification of gene expression biomarkers for SCZ. A literature search was carried out in PubMed and Web of Science databases for blood-based gene expression studies in SCZ. A list of differentially expressed genes (DEGs) was compiled and analyzed for overlap with genetic markers, differences based on drug status of the participants, functional enrichment, and for effect of antipsychotics. This literature survey identified 61 gene expression studies. Seventeen out of these studies were based on expression microarrays. A comparative analysis of the DEGs (n = 227) from microarray studies revealed differences between drug-naive and drug-treated SCZ participants. We found that of the 227 DEGs, 11 genes (ACOT7, AGO2, DISC1, LDB1, RUNX3, SIGIRR, SLC18A1, NRG1, CHRNB2, PRKAB2, and ZNF74) also showed genetic and epigenetic changes associated with SCZ. Functional enrichment analysis of the DEGs revealed dysregulation of proline and 4-hydroxyproline metabolism. Also, arginine and proline metabolism was the most functionally enriched pathway for SCZ in our analysis. Follow-up studies identified effect of antipsychotic treatment on peripheral blood gene expression. Of the 27 genes compiled from the follow-up studies AKT1, DISC1, HP, and EIF2D had no effect on their expression status as a result of antipsychotic treatment. Despite the differences in the nature of the study, ethnicity of the population, and the gene expression analysis method used, we identified several coherent observations. An overlap, though limited, of genetic, epigenetic and gene expression changes supports interplay of genetic and environmental factors in SCZ. The studies validate the use of blood as a surrogate tissue for biomarker analysis. We conclude that well-designed cohort studies across diverse populations, use of high-throughput sequencing technology, and use of artificial intelligence (AI) based computational analysis will significantly improve our understanding and diagnostic capabilities for this complex disorder.
In The Pune Maternal Nutrition Study, vitamin B12 deficiency was seen in 65% of pregnant women, folate deficiency was rare. Maternal total homocysteine concentrations were inversely associated with offspring birthweight, and low vitamin B12 and high folate concentrations predicted higher offspring adiposity and insulin resistance. These findings guided a nested pre-conceptional randomised controlled trial ‘Pune Rural Intervention in Young Adolescents’. The interventions included: (1) vitamin B12+multi-micronutrients as per the United Nations International Multiple Micronutrient Antenatal Preparation, and proteins (B12+MMN), (2) vitamin B12 (B12 alone), and (3) placebo. Intervention improved maternal pre-conceptional and in-pregnancy micronutrient nutrition. Gene expression analysis in cord blood mononuclear cells in 88 pregnancies revealed 75 differentially expressed genes between the B12+MMN and placebo groups. The enriched biological processes included G2/M phase transition, chromosome segregation, and nuclear division. Enriched pathways included, mitotic spindle checkpoint and DNA damage response while enriched human phenotypes were sloping forehead and decreased head circumference. Fructose-bisphosphatase 2 (FBP2) and Cell Division Cycle Associated 2 (CDCA2) genes were under-expressed in the B12 alone group. The latter, involved in chromosome segregation was under-expressed in both intervention groups. Based on the role of B-complex vitamins in the synthesis of nucleotides and S-adenosyl methionine, and the roles of vitamins A and D on gene expression, we propose that the multi-micronutrient intervention epigenetically affected cell cycle dynamics. Neonates in the B12+MMN group had the highest ponderal index. Follow-up studies will reveal if the intervention and the altered biological processes influence offspring diabesity.
The need for molecular biomarkers for schizophrenia has been well recognized. Recently, peripheral blood gene expression profiling and machine learning (ML) tools have become popular for biomarker discovery. The stigmatization associated with schizophrenia advocates the need for diagnostic models with higher precision. In this study, we propose a strategy to develop higher-precision ML models using ensemble learning. We performed a meta-analysis using peripheral blood expression microarray data. The ML models: Support Vector Machines (SVM), and Prediction Analysis for Microarrays (PAM) were developed using differentially expressed genes as features. The ensemble of SVM-radial and PAM predicted test samples with a precision of 81.33% (SD: 0.078). The precision of the ensemble model was significantly higher than SVM-radial (63.83%, SD: 0.081) and PAM (66.89%, SD: 0.097). The feature genes identified were enriched for biological processes such as response to stress, response to stimulus, regulation of the immune system, and metabolism of organic nitrogen compounds. The network analysis of feature genes identified PRF1, GZMB, IL2RB, ITGAL, and IL2RG as hub genes. Additionally, the ensemble model developed using microarray data classified the RNA-Sequencing samples with moderately high precision. The pipeline developed in this study allows the prediction of a single microarray and RNA-Sequencing sample. In summary, this study developed robust models for clinical application and suggested ensemble learning for higher diagnostic precision in psychiatric disorders.
In the Pune Maternal Nutrition Study, low maternal vitamin B12 and high folate concentrations during pregnancy predicted adiposity and insulin resistance (diabesity) in the children. Based on these findings, we designed an RCT (PRIYA) to provide these nutrients pre-conceptionally to reduce diabesity in the offspring. The interventions included: 1) vitamin B12+multi-micronutrients and protein supplement (B12+MMN), 2) vitamin B12 alone, and 3) placebo. A total of 149 women became pregnant and delivered in the trial. We report results of RNA sequencing in the cord-blood mononuclear cells in 88 deliveries. Gene expression analysis revealed 20 differentially expressed genes (FDR <0.1, a discovery threshold) between the B12+MMN and placebo groups. The enriched biological processes included: chromosome segregation, nuclear division and organelle fission. A cell cycle checkpoint gene Claspin (CLSPN) was expressed less in the B12+MMN group but proliferation markers did not differ. No difference was observed between the B12 alone and placebo groups. The B-complex vitamins are essential for nucleotide synthesis and generation of S-Adenosyl Methionine, a universal cellular methyl donor and thereby may contribute to the regulation of gene expression. Vitamins A and D, and zinc in MMN may also influence gene expression. We propose that the multi-micronutrient intervention influenced rate of progression of specific phases of cell cycle without affecting proliferation. Vitamin B12 alone was not sufficient. We highlight a novel molecular mechanism for the effect of multi-micronutrients during fetal development, and a plausible mechanism for intergenerational nutritional programming. Follow up studies will help understand their implications on the future phenotype.
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