Pathway Analysis

Question 1

Why is pathway analysis important?

Answer 1

Knowing that a gene is implicated in disorder is not meaningful on its own, genes work in an intricate network of interactions, and so we need to interpret the data in the context of biological processes, pathways, and networks.

Question 2

What is the assumption of pathway analysis?

Answer 2

o Pathway analysis is based on the assumption that risk variants for a disease will converge on sets of genes with functions that are more closely related to each other than to random sets of genes.

Question 3

What is bioinformatics, what does it do?

Answer 3

Bioinformatics (in silico approach, exploitation of publicly available repositories such as gene ontology [GO] datasets- knowledge base-driven PA). Bioinformatics methods do something very simple; they sieve the genetic data and look to see if particular risk variants are present in specific biological processes or ‘pathways’, beyond what might be expected by chance.

Question 4

How does bioinformatics identify pathways?

Answer 4

 They do this by comparing the data from the psychiatric genetics work with existing datasets that catalogue the functions of genes (gene ontology or GO datasets) and then subject the initial relationships to a battery of vigorous statistical tests to ensure they are statistically sound, i.e. have not arisen by chance. Pathway analysis allows finding distinct cellular processes, diseases, or signalling pathways that are statistically associated with selection of deferentially expressed genes between two samples.

Question 5

Advantage of pathway analysis compared to simply identifying genes.

Answer 5

Reduces the complexity from thousands of genes, proteins and/or other biological mechanisms to just several hundred pathways,
Identifying pathways that differ between two conditions van have more explanatory power than a simple list of different genes/proteins.

Question 6

How has a synaptic pathway been implicated in schizophrenia?

Answer 6

 Perhaps unsurprising (though encouraging at the same time) that pathway analysis is highlighting the synapse as a target for at least part of the genetic risk for schizophrenia (and increasingly bi-polar disorder and autism).
The synapse mediates activity dependent plasticity in the brain, a fundamental neuronal process required for normal functioning across all areas of psychology; perception, attention, learning, memory, emotion, cognitive control – all of which can go awry in psychopathology.

Question 7

How has immune function been implicated in schizophrenia (prenatal effects, stress precipitation effects, neuroinflammation Bloomfield et al., 2015; PET imaging of activated microglia)

Answer 7

• Infections during pregnancy increases risk for psychiatric disorder in later life of the offspring.
• Stress activates the immune system and can precipitate mental illness.
• Schizophrenia/schizophrenia risk and neuro-inflammation.
• Schizophrenia as an autoimmune disease.
• Incidental findings of treating peripheral immune disorders (e.g., rheumatoid arthritis) with anti-inflammatory drugs.
• Bloomfield et al. (2015): PET imaging of activated microglia in brains of schizophrenics and people at very high risk for schizophrenia. Since people at high risk for schizophrenia, but not actually suffering from schizophrenia showed a similar pattern of activation, cannot be due to antipsychotic medication.

Question 8

How has control of gene expression been implicated in psychopathology?

Answer 8

Epigenetics???