Gene Quest
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These days, we know better than to search for a depression gene or a bipolar gene.
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Genes and mental illness. The use of DNA markers has shown that manic-depressive illness can be caused by a single gene, proclaimed a 1987 news piece in Nature, the same journal that published Watson and Crick's groundbreaking discovery of the double helix structure of DNA 34 years earlier. According to the study article in the same journal, an analysis of gene variants in a population of Old Order Amish "has made it possible to localize a dominant gene conferring a strong predisposition to manic depressive disease to the tip of the short arm of chromosome 11."
Two years later, the same researchers acknowledged that they had badly miscalculated. It turned out this dominant gene was something of a 98-pound weakling. What went wrong?
"Bipolar disorder is a complex illness probably caused by multiple genes," Raymond DePaulo MD, chair of John Hopkins Department of Psychiatry and Behavioral Sciences, told me back in 2002. Single-gene conditions such as cystic fibrosis are the exception rather than the rule. More common are "multifactorial" disorders such as bipolar, the result of the interactions of multiple genes and environmental situations.
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At the time, Dr DePaulo had been involved in three studies that indicated: 1) A genetic overlap between schizophrenia and bipolar; 2) A possible genetic distinction between bipolar I and bipolar II; 3) A possible link between bipolar and panic disorder.
Merely finding a gene is not enough, Dr Dr Paulo added. "We have to show biologically what the gene does, what the mutation does, to cause the disease," he explained.
Basically, genes act as "on-off" switches. But they don't switch on "depression" or "bipolar" or anything else that can be defined as a mental illness. Instead, they activate proteins that regulate how cells function and organize themselves into interacting with other cells. This in turn may influence whether a certain individual is predisposed to depression or bipolar, but you're highly unlikely to find that out by looking for a direct link. This is particularly true when an illness such as bipolar leaves no obvious biological marker, equivalent to high blood sugar in diabetes.
In Psychiatry's Big Bang, I describe first how one NIMH brain scan study identified heightened limbic activity in test subjects with a "short" variation to the serotonin transporter gene, then a second study that found double the number of individuals with depression who had this same gene variation AND who had been exposed to recent stress.
Previous researchers had come up empty simply trying to link this particular gene variation ("genotype") to a mood disorder ("phenotype"). These days, this particular gene variation is one of the most researched, with promising leads turning up in all manner of stress-related behaviors.
Thinking Outside the Box
Accordingly, researchers are increasingly looking to the underlying biology of "endophenotype," such as sleep and circadian rhythms and appetite regulation. The schizophrenia researchers have led the field. For instance:
At the 2003 American Psychiatric Association annual meeting, Robert Freedman MD of the University of Colorado stressed that "the DSM-IV was not designed with human gene function in mind and genes do not encode for psychopathology." Instead, he went on to say, "genes encode simple molecules in cells that alter cell function and brain information processing."
In an article in the Jan 2007 Schizophrenia Bulletin, Dr Freedman and his fellow endophenotype pioneer David Braff MD of USCD give the example of a certain form of colon cancer, where multiple polyp formation, rather than cancer itself, is the genetically heritable trait.
Dr Freedman has been exploring a link between "sensory gating disturbance" and why people with schizophrenia crave nicotine. A normal person, for instance can tune out the second of two repetitive sounds. Many people with schizophrenia, however, cannot, and so have great trouble concentrating.
Dr Freedman's team found that auditory gating is modulated by the alpha7 nicotinic receptor, with linkage to chromosome 15q14. Alpha7 is reduced in the hippocampi of patients with schizophrenia. In one study, patients on nicotine lost their response to the second sound. Nicotine, Dr Freedman said, can serve as a model for future treatment, but instead of making a toxin we can make an agonist.
Another area of endophenotype research in schizophrenia includes several forms of eye movement dysfunction, which is apparent in many individuals with schizophrenia. Likewise, researchers are tracking down genetic causes and effects in working memory, attentional deficits, and other cognitive effects associated with this illness.
In bipolar, the obvious endophenotype has to do with severely disrupted circadian rhythms that are regulated by the suprachiasmatic nucleus (SCN), the brain's master clock located in the pineal gland, governed by the CLOCK (circadian locomoter output cycles kaput) gene. As researcher Colleen McClung of the University of Texas SW explained in a 2007 journal article, that although the mechanism by which the circadian clock might influence mood is still unclear, "we are starting to understand this strong association between circadian rhythms and bipolar disorder."
Whole Genome
Another new approach to genetic research is "whole genome association," made possible by advances in gene chip technology. A 2007 multicenter whole genome study involving 4,387 individuals with bipolar and 6,209 controls across three independent datasets found an association involving a variation in the ANK3 gene. ANK3 is a protein that regulates the assembly of voltage-gated sodium channels in the neuron, a process altered in mice who are administered lithium.
Epigenetics
The conventional wisdom on genes goes something like this: DNA is transcribed onto RNA, which form proteins, which are responsible for just about every process in the body, from eye color to ability to fight off illness. But even as the finishing touches were being applied to the sequencing of the human genome (completed in April 2003), unaccountable anomalies kept creeping in, strangely reminiscent of the quarks and dark matter and sundry weird forces that keep muddying the waters of theoretical physics.
Enter the science of epigenetics, which attempts to explain the mysterious inner layers of the genetic onion that may account for why identical twins aren't exactly identical and other conundrums, including why some people are predisposed to mental illness while others are not. Scientific American devoted a two-part article to the topic in its November and December 2003 issues. To summarize:
Only two percent of our DNA - via RNA - codes for proteins. Until very recently, the rest was considered "junk," the byproduct of millions of years of evolution. Now scientists are discovering that some of this junk DNA switches on RNA that may do the work of proteins and interact with other genetic material. "Malfunctions in RNA-only genes," explains Scientific American, "can inflict serious damage."
Epigenetics delves deeper into the onion, involving "information stored in the proteins and chemicals that surround and stick to DNA." Methylation is a chemical process that, among other things, aids in the transcription of DNA to RNA and is believed to defend the genome against parasitic genetic elements called transpons. An 2003 MIT study created mice with an inborn deficiency of a methylating enzyme. Eighty percent of these mice died of cancer within nine months.
A late 2003 PubMed search of epigenetics and bipolar disorder revealed but two articles. A Jan 16, 2011 search turned up 83. Arturas Petronis MD, PhD, of the University of Toronto authored both of the 2003 articles. In one of them, he filled in some of the blanks:
We know that there is a high concordance of identical twins with bipolar disorder, but epigenetics, he explains, may account for the 30 to 70 percent of cases where only one twin has the illness.
Identical twins share the same DNA, but their epigenetic material may be different. Moreover, whereas DNA variations are permanent, epigenetic changes are in a process of flux and generally accumulate over time. This may explain, Dr Petronis theorizes, why bipolar disorder tends to manifest at ages 20–30 and 45-50, which coincides with major hormonal changes, which may "substantially affect regulation of genes ... via their epigenetic modifications."
The dynamics of epigenetic changes may also account for the fluctuating course of bipolar, Dr Petronis speculates, perhaps more so than static DNA variations.
Finally, as Scientific American points out, the fact that epigenetic anomalies can be reversed makes them inviting targets for a new generation of meds.
In a 2003 pilot study, Dr Petronis and his colleagues investigated the epigenetic gene modification in a section of the dopamine 2 receptor genes in two pairs of identical twins, one pair with both partners having schizophrenia and the other having only one partner with the illness. What they discovered was that the partner with schizophrenia from the mixed pair had more in common, epigenetically, with the other set of twins than his own unaffected twin.
Parting Thought
We have a treasure trove of new genes to explore, including many that may prove more important than the few neurotransmitters and intracellular signaling molecules that have been studied so intensively these past 50 years.
Thomas Insel MD and Francis Collins MD, PhD, directors of the NIMH and Human Genome Project, respectively, writing in a special issue of the American Journal of Psychiatry (April, 2003) that commemorated the fiftieth anniversary of the discovery of the double helix structure.
This article replaces four previous articles, Jan 16, 2011
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