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How Do Genetic Risk Factors Contribute to Psychiatric Disorders?

In a recent article published in Science, researchers investigated whether certain psychiatric disorders share genetic risk factors. These genetic risk factors act indirectly along molecular signaling pathways and environmental influences to affect synaptic function and cause disease.

People with psychiatric disorders face many challenges in their life. Despite seeking assistance or medical intervention, these individuals are often left suffering. Psychiatric disorders are prevalent and often extremely debilitating.

Genetic risk factors are known to predispose individuals to develop certain psychiatric disorders, but it is unknown how possessing risk factors actually contribute to disease development. Environmental factors also contribute to disease occurrence and symptom severity, further complicating our understanding of how and why these diseases occur. Treatment options are limited; effectiveness of treatment varies among individuals and therapeutics tend to reduce symptoms while producing additional unwarranted effects. Therapeutic strategies are often the same or very similar regardless of the specific psychiatric disorder or the individual’s unique characteristics. By understanding the role of risk factors in producing psychiatric disorders, scientists can develop therapeutics that target the disease pathology, not just the symptoms.

In a study published in Science, researchers from the USA and Denmark aimed to elucidate the role of risk factors in producing disease across five psychiatric disorders: autism spectrum disorder (ASD), schizophrenia, bipolar disorder, depression, and alcoholism. Researchers assessed the expression of genes known to predispose people to psychiatric disorders and found that these psychiatric disorders share distinct perturbations in gene expression. This suggests that the same molecular pathways are involved in disease development across psychiatric disorders.

It is important to note that there was a lack of overlap with alcoholism and the other psychiatric disorders, suggesting similarities in gene expression are likely not due to comorbid substance abuse or poor overall general health. Researchers also found that administration of antipsychotic medication partially normalized the changes in gene expression.

Which Genetic Pathways Overlap in Psychiatric Disorders?

The researchers were interested in determining which molecular pathways and cellular functions were involved in pathogenesis. In ASD, schizophrenia, and bipolar disorder, astrocyte-related pathways are broadly upregulated and involved in regulating synaptic function. In depression, pathways regulating inflammation were upregulating, affecting hormone levels. However, it is uncertain whether the changes in gene expression involved in these molecular pathways are the cause or consequence of the disease.

When researchers correlated the genetic risk factors to the changes of gene expression, they found that gene expression patterns reflect the biological processes underlying the genetic variation. A more in-depth analysis revealed that genetic variation in patients with genetic disorders acts indirectly to downregulate synaptic function in ASD, schizophrenia, and bipolar disorder.

Genetic Variation Acts Indirectly Through Molecular Signaling Pathways

Altogether, researchers determine that shared genetic factors underlie a significant proportion of gene expression perturbations in psychiatric disorders. Further, genetic risk factors don’t act directly to cause disease, rather genetic variation acts indirectly through molecular signaling pathways that are also affected by environmental factors.

This novel research may help researchers better understand the pathogenesis of psychiatric disorders and why some people possessing genetic risk factors develop psychiatric disorders while others do not. This may further help in developing more effective treatments for psychiatric disorders.

Written by Mallory Wiggans

Reference: Gandal et al. (2018). Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap. Science 359, 693-697.


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