Tuesday, October 28, 2008

Genetics of mental illnesses: More is Less

Genetic research into psychiatic disorders appears to be undergoing a systemic deflation not unlike that in the financial markets. As I posted a couple of weeks ago, a survey article in the then-current Scientific American showed that genetic studies of human intelligence had labored mountainously and brought forth a 0.4 per cent mouse. Today comes a special issue of Nature Neuroscience dedicated to the neuropsychiatric diseases, and it's the same story. The initial radiant hope that today's mega-billion dollar genetic research apparatus would nail the culprit genes responsible for schizophrenia, autism, bipolar disorder, or depression, has dimmed to a faint glimmer. The more we can see, the less we find.

In the roundup article, Steven Hyman (Department of Neurobiology, Harvard) works hard at sounding upbeat, but has little to work with. Family studies, rich in anecdotal material, suggest that autism, schizophrenia, bipolar illness, and major depression must have major genetic components. Therefore it should be a simple matter to find the genes, and then to develop medications that target those genes.

Over the past two decades, however, efforts to identify risk-conferring alleles for the common forms of neuropsychiatric disorder have largely been unrewarding. Despite the significant role for genes highlighted by aggregate measures of their influence (Table 1), the underlying genetics of common neuropsychiatric disorders has proved highly complex, as attested by unpredictable patterns of segregation in families, lack of Mendelian ratios in twin studies and serious difficulties in replicating genetic linkage studies.

Anecdotes notwithstanding, the given illness frequently appears in people without the suspected genetic traits, fails to appear in people with the traits, and appears in people with other traits believed to be associated with an entirely disparate disorder. Current technology can easily identify "highly penetrant" genetic variations that cause a narrow subset of disorders, such as some types of Alzheimer's disease and macular degeneration, but the candidate genes involved with the most common psychiatric disorders make only a very slight dent in the etiology. It doesn't help that the clinical definitions of the psychiatric disorders tend to lack objective physiological markers, so that diagnosis rests ultimately on clinicians' opinions, which may vary widely.

Neither Hyman's article nor the remaining items in the special issue of Nature Neuroscience focus on addictive substance abuse, but you could substitute "alcoholism" into the paragraphs just quoted and come out with the same result. I've summarized the research on that topic in my forthcoming book. By April, when the book comes out, it should be amply clear that the deflation of the genetic myth in alcoholism is only part of a larger panorama of reassessment. The better our genetic research tools become, the more clearly we can see, the more obvious it becomes that we cannot blame our genes for our disorders, nor can we hope for a magic pill to set us right. It's just not going to be that easy.

Thursday, October 16, 2008

Genetics: The more we see, the less there is

In the concluding chapter of my forthcoming book (link), I look at the evidence for an alcoholism gene.  My research showed that the more powerful our tools become, the less we find in the way of genetic causality.  Modern genetic research has wiped away any basis for the idea that alcoholism is a genetically transmitted disease.  The most that can be said is that some people appear to inherit a lower responsiveness to alcohol, so that if they drink, they must drink more to get the same high.  For details, see my book, due out in April.  

Now comes an article in Scientific American, by science journalist Carl Zimmer,  reporting on modern research into the genetics of intelligence.  Here too, the conventional wisdom has been that genes play a major role.  But when the most powerful computer-assisted research tools are turned on the human genome, the supposed genetic factor all but evaporates.  Intelligence turns out to depend very weakly on a diversity of genes. The most influential of these genes contributes just 0.4 per cent (less than one half of one per cent), and this gene is believed to influence also a variety of other cell functions -- so that it is not specific to intelligence as such.  

Much of the myth of genetic causality rests on twin studies.  This is true both in alcoholism and in intelligence research, as well as in other fields (for example, autism).   Zimmer cites research showing that twin studies involving affluent families show a strong apparent genetic influence, while similar studies involving twins from poorer families show virtually no genetic factor at work.  The modern molecular genetic studies suggest that the apparent genetic influence reported in some twin studies may be a chimera due to false methodological assumptions.   Twin studies have been severely criticized, and some scientists consider them junk.  The SciAm article is in the October 2008 issue at p. 68; a link is (temporarily) here.

Spirituality strikes out

Two controlled trials of the effect of spirituality on addiction recovery showed no improvement for the patients given spiritual guidance as part of the usual treatment regimen, either in their addiction recovery or in their spiritual practices.  In fact, in one trial, the patients provided with spiritual guidance made less progress in overcoming depression and anxiety than the patients not given spiritual treatment.

Details are in the Journal of Substance Abuse Treatment, July 25 2008.  The abstract is here.  Thanks to David Kaiser Ph.D. for flagging the item.