Science
Gene Quest
These days, we know better than to search for a depression gene or a bipolar gene.
A series of fairly recent Johns Hopkins studies challenges our assumptions about bipolar disorder, namely: 1) psychotic bipolar disorder may be a genetic subtype of bipolar disorder, possibly sharing some of the same chromosomes as schizophrenia, a thought that would have been apostasy until recently; 2) bipolar II may be genetically distinct from bipolar I, with individuals in bipolar II families showing an affinity to chromosome 18q21; 3) a possible link between bipolar and panic disorder, which a JAMA editorial called "striking."
What do these findings tell us? Bipolar disorder is a complex illness probably caused by multiple genes, says Raymond DePaulo MD, co-author of the three Johns Hopkins studies and chair of that university’s Department of Psychiatry and Behavioral Sciences. It may take any three of ten genes, for instance, to cause bipolar disorder. Say one in five people carried any one of these three genes, then rough mathematics (1/5 x 1/5 x 1/5) would yield 1/125, representing approximately the one percent of the population that has bipolar disorder.
Right now, research is at the statistical association stage, with expert consensus centering on anywhere from six to ten chromosomal regions. But that hardly constitutes evidence. "We have to show biologically what the gene does, what the mutation does, to cause the disease," Dr DePaulo told this writer.
Or, in the words of David Weinberger MD, Chief of the Clinical Brain Disorders Branch at the NIMH, speaking at the 2003 American Psychiatric Association’s annual meeting, "how we get there from here," from identifying the gene to its cellular function to its role in the systems in the brain to its affect on behavior. He pointed to his own (Hariri lead author) 2002 ground-breaking study of what needs to be done. In that study, brain scans revealed a greater amygdala response (associated with fear) in individuals with the short allele (variant) of the serotonin transporter gene SLC6A4 (responsible for reuptake of serotonin) when asked to look at images of faces, which could well be the first study linking genes to emotions in humans.
In 2003, a team of researchers at the University of Wisconsin and King's College (London) investigating the same gene reported that in a large population, those with the short allele who had been subjected to at least four recent life stresses (such as employment, finances, housing, health, and relationships) were twice as likely to become depressed.
The authors of that study argued that genetic research trying to link genes to illness has not proven fruitful for complex psychiatric disorders. Instead, they have pursued a different line of enquiry based on the interactions between genes and environment, which assumes some genetic variants are more resistant to environmental stressors than others and which can be uncovered in part by measuring the effects of these stressors.
One Researcher’s Quest
In 2000, John Kelsoe MD of the University of California at San Diego informed this writer:
"We have identified a gene on chromosome 22 which we believe plays a role in the susceptibility to both bipolar disorder and schizophrenia."
Before you let your hallelujah ring through the rafters, it pays to recall the false alarm that was raised in 1987 after a study of Amish families supposedly yielded the culprit near the tip of the short arm of chromosome 11. The researchers were forced to concede defeat two years later.
What's so different this time? For one, Dr Kelsoe and his team have the complete human genome at their disposal. Over the last several years, they have scanned the entire genome in a set of families with bipolar, attempting to identify a chromosomal region consistently associated with the illness.
The approach is called linkage analysis, and it led to "very strong evidence" for the presence of a gene on chromosome 22, identified by two peaks. This region has already been implicated in many studies of schizophrenia.
With the publishing of the entire genome, the team discovered that one of the peaks - at 22q12.1 - corresponded to the location of GRK3, whose normal role is to regulate the response and level of sensitivity to several neurotransmitters, including dopamine. It has long been argued that a supersensitivity to dopamine may play a role in bipolar and schizophrenia.
In four human subjects, reduced GRK3 expression corresponded with bipolar I, while the other two subjects not showing a GRK3 decrease had bipolar II.
In parallel with these studies, Dr Kelsoe and collaborator Alexander Niculescu MD, PhD were experimenting with amphetamine administration to rats as an animal model of mania. In Dr Kelsoe's words:
"We examined the role of 8,000 genes in the response to amphetamine and found that the gene with the biggest response to amphetamine mapped in man to that exact region on chromosome 22 that we identified in our clinical family studies. Since then we have examined this gene in detail and found what we believe are several abnormalities that prevent it from working properly in a portion of people with bipolar disorder."
Together this set of data implicated the gene both through function and chromosomal position.
Collaborator Thomas Barrett MD, PhD then sequenced much of the gene to find six sequential variants - single-nucleotide polymorphisms (SNPs or "snips") - in the promoter of the gene, that region of the gene that switches the gene on or off. Dr Barrett then tested 153 families for association to these mutations and found that one of these, P-5, occurs three times more frequently in affected individuals. These findings were replicated at the University of Toronto with a separate set of 237 families, and in 2003 the researchers published their findings in Molecular Psychiatry.
Thus a picture begins to emerge, albeit still a hypothetical one: A P-5 mutation causing GRK3 to fail, resulting in the brains’ receptors’ inability to desensitize to dopamine, ending in a situation akin to, in Dr Kelsoe’s words, "being born on cocaine."
Now to the wider scheme of things: The study found that the GRK3 variant occurred in only three percent of bipolar families. Since single-gene disorders are a rarity, it probably isn’t the only gene responsible for illness in this population. For the other 97 percent of those with bipolar, multiple genes are believed to be the rule, as well, leaving researchers with the daunting task of teasing out candidates from some 16,500 genes believed to be expressed in the brain
Meanwhile, Cast Your Minds Back To ...
"We wish to suggest a structure for the salt of deoxyribose nucleic acid (DNA)," began a one-page paper published in Nature more than 50 years ago. With what can only be called hyperbolic understatement, the article went on to say: "This structure has novel features which are of considerable biological interest." The authors were James Watson and Francis Crick, the structure was the double helix, and biological science would never be the same.
April 2003's American Journal of Psychiatry commemorated the fiftieth anniversary of the publication of Watson and Crick's groundbreaking paper with several articles devoted to "the genomic era," which, according to an editorial, "is about much more than 'finding genes.' It is about understanding how they get turned on, or turned off. It is about examining the complex interactions between genes and the huge array of nongenetic factors that influence their effects. It is about our capacity as scientists and clinicians to improve diagnosis, treatment, and, ultimately, prevention."
So far, the literature concerning genes and the brain has focused on less than one percent of the genome, representing a mere 300 or so genes. Yet our research on mice tells us 55 percent of our genes (roughly 16,500 genes) are expressed in the brain. According to Thomas Insel MD and Francis Collins MD, PhD, directors of the NIMH and Human Genome Project, respectively: "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."
Thinking Outside the Box to Endophenotype
The hunt for depression and bipolar genes can be likened to searching for pieces of hay in a haystack. There is no one gene that is likely to stand out. Instead, we're searching for what are probably common and fairly humdrum mutations to what may be more than ten genes, each with a modest effect. The search is further confounded by the fact that unlike say diabetes, a mood disorder leaves no discernible biological footprint equivalent to blood glucose. Not surprisingly, our efforts to link social wallflower genes to phantom footprint symptoms - or "phenotype" - by studying twins and families and isolated populations have been disappointing, yielding at best some possible suspects.
Accordingly, researchers are thinking outside the DSM box to the underlying biology of "endophenotype," such as sleep and circadian rhythms and appetite regulation. Intriguingly, some of the suspect genes we have identified may be responsible for more than one illness, raising such possibilities as schizophrenia and bipolar patients sharing some of the same psychosis genes.
The following example from schizophrenia gene research illustrates endophenotype at work:
At the 2003 APA 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."
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.
Eventually, we may be able redefine mental illness according to "genotype" that would render the DSM obsolete. As Insel and Collins conclude:
"Students of the history of psychiatry looking back from the Watson and Crick centennial in 2053 may wonder how we could have been so interested in serotonin and dopamine in 2003 when many hundreds of more important factors remained to be found."
Updated Feb 11, 2008
Articles on Genes
It's as easy as ATCG.
These days, we know better than to search for a depression gene or a bipolar gene.
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A new science peels away another layer of the genetic onion.
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