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.