In-Depth Notes on Schizophrenia and GWAS Studies

Schizophrenia is classified as a psychiatric, neurobiological, neurologic, neurodevelopmental, or brain disorder often referred to as a "mental illness."

After the lecture, you should be able to:
- Explain the Genome-Wide Association Study (GWAS) focused on schizophrenia.
- Interpret key results from the GWAS studies conducted by the Schizophrenia Working Group (SWG) of the Psychiatric Genomics Consortium (PGC) in 2014 and 2022.
- Identify functions of genes highlighted in the 2014 study.

ZNF804A gene: A pivotal success in GWAS for schizophrenia. A follow-up study confirmed its association as a risk gene through analysis of 6,666 patients against 9,897 controls.
- Insights into clinical associations, biological mechanisms, and neuronal functions were presented in a 2017 study.
Transcription factor gene TCF4: Known to play a role in the development of the nervous system (Purcell et al., 2009).
Neurogranin (NRGN): Specializes in brain expression, especially in dendritic spines, functioning as a protein kinase substrate and binding calmodulin; critical for neuronal calcium signaling (Shi et al., 2009).
Major Histocompatibility Complex (MHC) region on chromosome 6: Involved in immune response (Stefansson et al., 2009).

Formed in 2007 to unify global investigators for meta- and mega-analyses of genome-wide data pertaining to psychiatric disorders.
The primary goal was to aggregate existing schizophrenia samples and GWAS genotypes into a comprehensive analysis.

Landmark study termed the largest molecular genetic research in schizophrenia with 36,989 cases and 113,075 controls analyzed.
Results found 128 independent associations of SNPs across 108 loci, with 83 new associations; odds ratio ≤ 1.2.
Findings highlighted brain-expressed genes and supported existing hypotheses, emphasizing possible therapeutic pathways.
Significant associations were found at genes related to glutamatergic neurotransmission, further linking immune system involvement to schizophrenia.

Gene Functions: Genes associated with synaptic function and plasticity, glutamatergic and possibly dopaminergic neurotransmission, neuronal calcium signaling, neurodevelopment, and immune processes were identified.
Neurotransmitter Types:
- Amino Acids: e.g., glutamate (excitatory), GABA (inhibitory).
- Biogenic Amines: e.g., dopamine, serotonin.
- Neuropeptides and Others: e.g., opiate peptides, acetylcholine.

Mediated by:
- Metabotropic Glutamate Receptors (mGluRs): Activate biochemical pathways, not ion channels.
- Ionotropic Glutamate Receptors (iGluRs): Ligand-gated ion channels, allowing cation flow; includes AMPA and NMDA receptors.
NMDA receptors enhance synaptic excitability when acting together with non-NMDA receptors.

Common associations in the recent large GWAS pointed to several candidate genes involved in the pathophysiology of schizophrenia:
- DRD2: Major target for antipsychotic drugs.
- Genes impacting synaptic transmission, such as GRM3 and GRIN2A, suggest links to neurotransmission mechanisms that are critical for pathogenesis.
Copy Number Variations (CNVs): Specific deletions (e.g., 22q11.2) linked with elevated schizophrenia risk. Important roles observed in gene clustering around NMDAR and ARC complexes.

Next Generation Sequencing (NGS): A broad term encompassing various efficient techniques for sequencing the whole genome at a low cost.
De Novo mutations: Rare genetic mutations with significant implications associated with schizophrenia risk.

Genetic variations play a substantial role in the manifestation of schizophrenia symptoms, although they often have small individual effect sizes. They offer potential avenues for therapy understanding and development.

Analyzed genetic data from 76,755 schizophrenia cases and 243,649 controls. Identified associations at 287 genomic loci with a focus on neuronal genes, indicating a strong relevance of synaptic biology in schizophrenia.
Highlighted common and rare variants, including significant receptors and ion channels crucial for synaptic functionality and related to neurodevelopmental disorders.
Implications suggest the convergence of genetic liability in both male and female participants, although the low Polygenic Risk Score suggests limited diagnostic potential.

Epigenetic modifications such as methylation can influence gene expression without altering the DNA sequence. Some changes pertain to genes related to GABA and BDNF, suggesting broader environmental interactions with genetic predispositions to schizophrenia.

Patients often display decreased brain volumes compared to healthy individuals, indicating potential chronic effects of the illness. The dopamine hypothesis and glutamate hypothesis provide insights into underlying neurochemical changes, with increased inflammation indicated as a component of the disease process.