Kendler2013 - What psychiatric genetics has taught us about the nature of psychiatric illness and what is left to learn
- Year read:#read2022
- Subject: Genetics
- Bibtex: @kendler2013
- Bibliography: Kendler, K. S. (2013). What psychiatric genetics has taught us about the nature of psychiatric illness and what is left to learn. Molecular Psychiatry, 18(10), 1058–1066. https://doi.org/10.1038/mp.2013.50
There are multiple possible scenarios about the biological basis of psychiatric disorders that can emerge from GWAS studies: from a complete failure to integrate genetic findings into a coherent picture, to a high coherence where all or most genetic findings map to a single inter-connected biological pathway [@kendler2013].
- Will findings from GWAS studies in psychiatry display biological coherence? (the detected SNP and CNV tell a sensible biological story):
- (i) being in the same metabolic pathway
- (ii) acting at different stages in a biological system (such as a neurotransmission system)
- (iii) having coordinated expression in developmental time
- (iv) shown to physically interact with each other
- No coherence scenario: efforts to integrate genes into a coherent picture of the underlying biology of the disorder will fail (figure 2a).
- Minimal coherence: Small pockets of connectivity, no connections between the pockets. Etiologically distinct symptoms just happen to occur within the same individual.
- Moderate coherence: A number of pockets of biological coherence that would reflect relatively discrete and substantial pathways of risk, but they would not connect up into one grand pathway. This could happen if we have several independent pathways to major psychiatric syndromes.
- High coherence: Most or all identified SNP/CNV findings will map to a single coherent inter-connected biological pathway (figure 2d). Individual genes would reflect a system with high Equifinality.
Pessimistic scenario (no or low coherence):
Perhaps there are too many ways for the human brain to produce the symptoms and signs of psychiatric disorders (for example, sad mood, auditory hallucinations, grandiosity) for us to have any chance for biologically coherent pathways to emerge from the hundreds or thousands of risk variants that make small contributions to risk.
We cannot assume that anything that is heritable will be biologically coherent.
What should we expect to see? The most pessimistic prediction that we will observe only a mess is unlikely. But discovering a highly coherent single pathway to illness also seems improbable. We can hope that the heterogeneity is not too great and the real level of illness not too hidden in the upper reaches of the mindbrain system. If this is true, important insights into the nature of psychiatric illness are likely to await our efforts.