Genetic Testing for Mental Health

Serotonin Transporter (SLC6A4): This gene is responsible for coding the protein that clears serotonin metabolites (5-HT) from the synaptic spaces in the central nervous system (CNS). This protein is the principal target for many of the serotonin reuptake inhibitors (SSRIs). By inhibiting the activity of the SLC6A4 protein, the concentration of 5-HT in the synaptic spaces is increased. A common polymorphism in this gene consists of insertion or deletion of 44 base pairs in the serotonin-transporter-linked polymorphic region (5-HTTLPR), leading to the terminology of the long (L) and short (S) variants of this gene. These polymorphisms have been studied in relation to a variety of psychiatric and nonpsychiatric conditions, including anxiety, obsessive compulsive disorder, and response to SSRIs.

Serotonin Receptor (5HT2C): This gene codes for 1 of at least 6 subtypes of the serotonin receptor that is involved in the release of dopamine and norepinephrine. These receptors play a role in controlling mood, motor function, appetite, and endocrine secretion. Alterations in functional status have been associated with affective disorders such as anxiety and depression. Certain antidepressants, e.g., mirtazapine and nefazodone, are direct antagonists of this receptor. There is also interest in developing agonists of the 5HT2C receptor as treatment for obesity and schizophrenia, but no such medications are commercially available at present.

Serotonin Receptor (5HT2A): The 5HT2A gene codes for another subtype of the serotonin receptor. Variations in the 5HT2A gene have been associated with susceptibility to schizophrenia and obsessive-compulsive disorder and response to certain antidepressants.

Sulfotransferase Family 4A, Member 1 (SULT4A1): SULT4A1 encodes a protein that is involved in the metabolism of monoamines, particularly dopamine and norepinephrine.

Dopamine Receptors (DRD1, DRD2, DRD4): The DRD2 gene codes for a subtype of the dopamine receptor, called the D2 subtype. The activity of this receptor is modulated by G-proteins, which inhibit adenyl cyclase. These receptors are involved in a variety of physiologic functions related to motor and endocrine processes. The D2 receptor is the target of certain antipsychotic drugs. Mutations in this gene have been associated with schizophrenia and myoclonic dystonia. Polymorphisms of the DRD2 gene have been associated with addictive behaviors, such as smoking and alcoholism.

The DRD1 gene encodes another G-protein coupled receptor that interacts with dopamine to mediate some behavioral responses and modulate D2 receptor-mediated events. Polymorphisms of the DRD1 gene have been associated with nicotine dependence and schizophrenia.

The DRD4 gene encodes a dopamine receptor with a similar structure; DRD4 polymorphisms have been associated with risk-taking behavior and attention deficit hyperactivity disorder.

Dopamine Transporter (DAT1 or SLC6A3): Similar to the SCL6A4 gene, this gene product encodes a transporter that mediates the active reuptake of dopamine from the synaptic spaces in the CNS. Polymorphisms in this gene are associated with Parkinson disease, Tourette syndrome, and addictive behaviors.

Dopamine Beta-Hydroxylase (DBH): The dopamine beta-hydroxylase protein encoded by this gene catalyzes the hydroxylase of dopamine to norepinephrine. It is primarily located in the adrenal medulla and in postganglionic sympathetic neurons. Variation in the DBH gene has been investigated as a modulator of psychotic symptoms in psychiatric disorders and in tobacco addiction.

Gated Calcium Channel (CACNA1C): This gene is responsible for coding of a protein that controls activation of voltage-sensitive calcium channels. Receptors for this protein are found widely throughout the body, including skeletal muscle, cardiac muscle, and in neurons in the CNS. In the brain, different modes of calcium entry into neurons determine which signaling pathways are activated, thus modulating excitatory cellular mechanisms. Associations of polymorphisms of this gene have been most frequently studied in relation to cardiac disorders. Specific polymorphisms have been associated with Brugada syndrome and a subtype of long QT syndrome (Timothy syndrome).

Ankyrin 3 (ANK3): Ankyrins are proteins that are components of the cell membrane and interconnect with the spectrin-based cell membrane skeleton. The ANK3 gene codes for the protein Ankyrin G, which has a role in regulating sodium channels in neurons. Alterations of this gene have been associated with cardiac arrhythmias such as Brugada syndrome. Polymorphisms of this gene have also been associated with bipolar disorder, cyclothymic depression, and schizophrenia.

Catechol-O-Methyltransferase (COMT): This gene codes for the COMT enzyme that is responsible for the metabolism of the catecholamine neurotransmitters, dopamine, epinephrine and norepinephrine. COMT inhibitors, such as entacapone are currently used in the treatment of Parkinson disease. A polymorphism of the COMT gene, the Val158Met polymorphism, has been associated with alterations in emotional processing and executive function and has also been implicated in increasing susceptibility to schizophrenia.

Methylenetetrahydrofolate reductase (MTHFR): This is a widely studied gene that codes for the protein that converts folic acid to methylfolate. Methylfolate is a precursor for the synthesis of norepinephrine, dopamine, and serotonin. It is a key step in the metabolism of homocysteine to methionine, and deficiency of MTHFR can cause hyperhomocysteinemia and homocysteinuria. The MTHFR protein also plays a major role in epigenetics, through methylation of somatic genes. A number of polymorphisms have been identified that result in altered activity of the MTHFR enzyme. These polymorphisms have been associated with a wide variety of clinical disorders, including vascular disease, neural tube defects, dementia, colon cancer, and leukemia.

Gamma-Aminobutyric acid (GABA): A receptor: This gene encodes a ligand-gated chloride channel composed of 5 subunits that responds to GABA, a major inhibitory neurotransmitter. Mutations in the GABA receptor have been associated with several epilepsy syndromes.

Mu and k Opioid Receptors (OPRM1 and OPRK1): OPRM1 encodes the mu opioid receptor, which is a G-protein coupled receptor that is the primary site of action for commonly used opioids, including morphine, heroin, fentanyl, and methadone. Polymorphisms in the OPRM1 gene have been associated with differences in dose requirements for opioids. OPRK1 encodes the kappa opioid receptor, which binds the natural ligand dynorphin and a number of synthetic ligands.

Cytochrome P450 genes (CYP2D6, CYP2C19, CYP3A4, CYP1A2, CYP2C9, and CYP2B6): These 6 genes code for hepatic enzymes that are members of the cytochrome p450 family, and are responsible for the metabolism of a wide variety of medications, including many psychotropic agents. For each of these genes, polymorphisms exist that impact the rate of activity, and therefore the rapidity of elimination of drugs and their metabolites. Based on the presence or absence of polymorphisms, patients can be classified as rapid metabolizers (RM), intermediate metabolizers (IM), and poor metabolizers (PM).

P-Glycoprotein Gene (ABCB1): This gene, also known as the MDR1 gene, encodes P-glycoprotein which is involved in the transport of most antidepressants across the blood-brain barrier. ABCB1 polymorphisms have been associated with differential response to antidepressants that are substrates of P-glycoprotein, but not to antidepressants that are not P-glycoprotein substrates.

UDP-Glucuronosyltransferase Gene (UGT1A4): This gene encodes an enzyme of the glucuronidation pathway that transforms small lipophilic molecules into water-soluble molecules. Polymorphisms in UGT1A4 have been associated with variation in drug metabolism, including some drugs used for mental health disorders.