Psychiatric Genetic Revolution – is calcium the key?

DNA Rendering. Photo: ynse. used under CretaiveCommons

DNA Rendering. Photo: ynse. used under CreativeCommons

Dr. Berrettini and I published Principles of Psychiatric Genetics in late 2012. Since then, there have been several interesting developments in Psychiatric Genetics worth calling your attention to. The first is a set of articles from the Cross-Disorder Group of the Psychiatric Genomics Consortium (PGC). The PGC has revolutionized the field of psychiatric genetics in the last decade by bringing together investigators from around the world to pool their carefully collected clinical samples in order to provide the numbers for powerful analyses of common gene variants in major psychiatric disorders such as schizophrenia and bipolar disorder. Whereas the original genome-wide association studies in psychiatry included ~1000 cases and 1000 controls, we are now able to amass collections of 25,000 cases with schizophrenia and 37,000 controls because investigators have come together under the PGC umbrella. This has provided the power to detect more than 100 common single gene variants associated with schizophrenia.

The particular article I wanted to feature was one from the Cross-Disorder Group in that consortium (Cross-Disorder Group of the PGC, Lancet, 2013). Samples were combined from persons with schizophrenia, bipolar disorder, depression, attention-deficit hyperactivity disorder, and autism. There were four single gene variants that were identified from the group of disorders considered together. The fascinating aspect of this was that two of the four were genes controlling calcium channels in the brain. The investigators were also able to test an entire group of calcium-channel related genes (72 genes in all) and demonstrate that variations in this set of gene markers was associated with vulnerability to these conditions, especially to schizophrenia and bipolar disorder. This is a new finding in psychiatry, and it is potentially very relevant to clinical management of these conditions. Calcium channel abnormalities have been described in these disorders, but this hypothesis was not central to a consideration of the neurobiology of these disorders. Over the past three decades, much more energy has been spent on theories involving neurotransmitters such as serotonin, dopamine, and norepinephrine. However, it may be that calcium channel signaling problems are causal to neurotransmitter variation. Calcium flow into the cell is necessary for cell excitation and signaling. Many of the critical second messenger systems in the cell (which carry a signal within the cell after a neurotransmitter hits its target receptor) are dependent on calcium.

Calcium channel inhibitors are available, and have been used to treat cardiovascular conditions for several decades (e.g., verapamil, nifedipine, nimodipine) . They have also been used to treat psychiatric conditions, with some success, but not consistent success. It may be that these agents must be targeted to specific individuals who demonstrate calcium channel gene abnormalities. Or it may be that newly designed drugs with more subtle effects on calcium activity are needed. In any case, this seems like an important clue with ramifications for our understanding of the biology of these disorders, as well as possible treatment strategies.

Another paper from the same group was published later in 2013 (Lee et al, Nature Genetics). This used a method for analyzing the heritability of medical conditions based on genome-wide data. Even if the power is not adequate to identify all of the gene variants individually, you can use the available information on gene arrays (small plastic chips that contain short sequences from every gene in the genome) to test whether or not you have captured some of the variation or not. It could be that testing every gene in the genome in this way would still not give you much information about diagnosis. This was thought to be the case for several years after these techniques were introduced. Many investigators felt that psychiatric disorders were simply too complex in their inheritance to be analyzed by the gene chips. There was too much “missing heritability” (evidence of inheritance from family studies that was not able to be tracked to variations at the gene level). This recent paper demonstrated convincingly that this idea is not true. The psychiatric disorders are analyzable at the level of individual gene variants and functions. We now can be confident that 25-40% of the reason that one person becomes ill with schizophrenia or major depression or autism while another person does not is related to common genetic variation that can be measured in the laboratory. We don’t yet know what all the pertinent genes do but we can anticipate that the answers will be available to us in the coming years. Part of the answer probably relates to calcium channel genes, as noted above.

There is another set of data from this paper that is tremendously important for our ideas of psychiatric diagnosis. For the past hundred years, we have clearly separated schizophrenia (a chronic disorder) and bipolar disorder (an episodic condition). There are different treatments for these conditions and different expectations for how well people will do in overcoming the symptoms. One of the lessons from the latest round of genetic analyses is that there is substantial overlap in the genetic vulnerability factors for the two disorders. The “covariance” between schizophrenia and bipolar disorder is 25-30%. Therefore we should expect that some of the disruption in neurobiological systems will be the same for the two disorders and some will be different. This is consistent with evidence from genetic linkage studies summarized by my colleague Dr. Berrettini some years ago and it is consistent with recent family studies as well. The new information, though, is more specific regarding the amount of overlap. It suggests that we should consider these two diseases similar in type and origin.

John I. Nurnberger, Jr. is co-editor of Principles of Psychiatric Genetics (out now).

Principles of Psychiatric Genetics

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One Response to Psychiatric Genetic Revolution – is calcium the key?

  1. Rosemary Jones says:

    It is so sad that clinicians are still using labelling with no causal validity, labelling that is contravening the Mental Capacity Act of 2005 because most patients and clients do not like these words – psychotic, schizophrenia and bi-polar. Who wants to be called words like that ?

    Nor does such labelling automatically direct patients to suitable treatment programs, though now we know schizophrenia responds to antibiotics, so, in some crazy way, maybe keeping the name and the link would at least help patients in the cerebral infective category of excess dopamine and similar contingencies conditions.

    It seems to be clear that in certain cases genes transform to reflect these conditions, so which comes first is not as straightforward as some geneticists propose – each to their own.But it is straightforward that impact accidents, infections, oxygen deficits and overloading are stress making, and stress makes our brains respond in ways which we classify as psychotic.

    It is tautological that all conditions responding to anti psychotic medications (dopamine antagonist medications) have that responding in common, and therefore could be termed under an umbrella label which indicated the excess dopamine production, which in turn plays havoc with our more recently evolved cognitive processes, and which results in hallucinations, mixed up language, and assessment and memory problems.

    Such a label could be HYPERDOMANISM, which, like hyperthyroidism, having no horrible connotations, would not cause patients to be depressed, shamed and even kill themselves.

    Blanket or umbrella terms may be partly explanatory, but for labelling to be entirely useful, these terms must be accompanied by additional ones with even greater causal depth.

    Cerebral oxygen deficiency due to blockage of cervical and/or cranial arteries.
    Cerebral infective syndrome due to virus or bacteria.
    Cognitive overload due to too much anger or grief, hard work or street drug hyperactivity without sufficient back up compounds.
    Cerebral damage due to blows to the head.
    Cerebral toxicity.

    Once patients know what is causing their problems, they are far more likely to refuse to be maintained in a state of ill health for the rest of their lives, and demand to be made as well as possible. Most of the other stuff is a red herring, and to only be countenanced when the most obvious causes of mental ill health have been eliminated.

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