How Do Gene Variants Shape Protein Function in Psychiatric Pharmacogenomics?

John Miller, MD, outlined the foundational principles of psychiatric pharmacogenomics in the third episode of his series “A Journey Into Psychiatric Pharmacogenomics.”

Each gene is inherited as 2 copies, 1 from each parent, and codes for 1 of 4 major protein types: metabolic enzymes, receptors, energy-regulating enzymes, and neurotransmitter transport pumps. Cytochrome P450 (CYP450) enzymes were highlighted as the primary example of a metabolic enzyme family used throughout the series to illustrate how allelic variation drives differences in gene product activity.¹ Receptors are divided into 2 broad categories, Miller said: ionotropic receptors, such as the nicotinic channel, which respond rapidly to ligand binding by opening an ion channel, and metabotropic, or G protein-coupled, receptors, which cross the cell membrane 7 times, have been evolutionarily conserved across sponges, plants, and mammals, and can generate thousands of distinct intracellular responses depending on downstream coupling. The dopamine 2 receptor was cited as a representative G protein-coupled receptor. ATPase was presented as an example of an enzyme that maintains cellular energy supply, and neurotransmitter transport pumps, the target of selective serotonin reuptake inhibitors, were described as proteins that recycle neurotransmitter back into the presynaptic neuron rather than binding a postsynaptic receptor. Miller explained, "these are medications that don't block or bind to a receptor, but bind to a protein pump, whose job is to work like a vacuum cleaner presynaptically and pump a neurotransmitter back into the presynaptic cell so it can be recycled."

Gene variants were framed relative to a wild-type, or normal-functioning, reference gene; mutations can increase, decrease, or eliminate the resulting protein's activity. Because each protein-coding gene is inherited in 2 copies, an individual carrying 1 wild-type allele and 1 poorly functioning allele will produce a mixture of gene products reflecting intermediate activity, or phenotype. Miller noted, "if you have 1 wild type in 1 poorly functioning gene, the proteins that result as gene products will be of intermediate activity and that's what we call the phenotype."² Diagrams comparing normal-functioning, increased-activity, decreased-activity, and nonfunctioning gene variants illustrated how allelic combinations translate into a range of downstream protein or enzyme activity. The next installment of the series will examine how combinations of these 4 functional gene types produce the range of clinical phenotypes seen in practice.

Dr Miller is the medical director of Brain Health in Exeter, New Hampshire; editor in chief of Psychiatric Times; a voluntary consulting psychiatrist at Seacoast Mental Health Center in Exeter/Portsmouth, New Hampshire; and a consulting psychiatrist at Insight Meditation Society in Barre, Massachusetts.

References

1. Alchakee A, Ahmed M, Eldohaji L, et al. Pharmacogenomics in psychiatry practice: the value and the challenges. Int J Mol Sci. 2022;23(21):13485.

2. Ao A, Bourgeois JA, Miller JJ. Psychiatric pharmacogenomics: an overview. Psychiatric Times. June 23, 2026. https://www.psychiatrictimes.com/view/psychiatric-pharmacogenomics-an-overview