Genetics: DNA Causation Unravels

In several earlier posts here, I quoted from scientific journals reporting on the findings of modern genetic research -- or rather, the surprising absence of such findings.  For the first time ever, science has the tools to find out exactly where the genes are that we have long believed underly major diseases.  What the tools are telling us is that the supposed genetic causality isn't there, or it's much weaker than previously thought.  We can now say with confidence that the "alcoholism gene" does not exist; that the genetic contribution to alcoholism, such as it is, is spread over an as yet unknown number of genes, each of which has only a minute influence, and that this influence is profoundly mixed up with and moderated by environmental factors.
Now the current issue of Scientific American (Oct. 2010) reports similar findings for genetic research into a broad range of other diseases.  In its article, "Revolution Postponed: the Human Genome Project has failed so far to produce the medical miracles that scientists promised,"  the journal describes a growing realization in the scientific community that the old model of genetic science, where variations in specific genes cause specific illnesses, has very limited validity.    The journal quotes David Goldstein, director of the Center for Human Genome Variation at Duke University, one of the major research centers:

It's an astounding thing that we have cracked open the human genome and can look at the entire complement of common genetic variants, and what do we find? Almost nothing.  That is absolutely beyond belief.

Another researcher, David Botstein of Princeton, describes the effort to map disease-causing genetic variations as an experiment that had to be done in order to know that it did not work.  It was, he said, "a magnificent failure."

Walter Bodmer, a pioneer of the modern genomics research effort, says that the effort to find genetic variants that cause major diseases is a biological dead end.  "The vast majority of [common] variants have shed no light on the biology of diseases."

These findings are profoundly upsetting long-held beliefs about genetic causality and forcing scientists to rethink the whole model of what genes do.  The old model which saw DNA as a kind of computer program that determines the fate of the organism is out the window.  The processes are much more complex and involve a great deal more interaction with the environment than had been previously thought.

The takeaway for people who have serious issues with alcohol and/or other addictive substances is:  don't blame your genes.  Your genes are OK.  Your DNA will be just as happy, and very likely much happier, when you stop hammering your brain cells with addictive substances.

Goodbye Genetics, Hello Epigenetics

For the first time in history, science now has tools that can definitively answer long-standing questions about the role of genetics as the cause of diseases.  So far, the results have been devastating for believers in genetic causality.  The better we can see, the less genetic causality we find.

I've previously summarized the minimalist findings of modern genetics research for a number of psychiatric disorders, including addiction, here and here in this blog, and in my book, Empowering Your Sober Self.

Now comes another blockbuster study, this time of schizophrenia, a disease commonly believed to have a strong genetic component.  According to the November issue of Scientific American, summarizing a recent report in Nature, "three crack teams of investigators pooled genomic data from 8,000 schizophrenics of European ancestry but could lay claim to only a handful of weak genetic risk markers."

By contrast, says the same article, epidemiologists have been able to find significant correlations between schizophrenia and environmental and cultural conditions.  Growing up as an immigrant or as a racial minority in a big city, particularly in densely populated and troubled neighborhoods, is a significant risk factor for the disease.

These studies have given a boost to the field of epigenetics -- the study of how environmental conditions evoke or overwrite genetic predispositions.  The primitive notion that our DNA is our destiny is giving way to the understanding that our genes do nothing until they are activated.  Environmental conditions (including not only the chemicals that enter our body but also the decisions we make, the people we hang with, and the stress we undergo) determine whether a gene gets turned on or off.  Our genetic array is like a keyboard, and our interaction with the world governs what melody gets played on it.

By coincidence, a recent issue of Counselor, the magazine for addiction professionals, features an article, "Epigenetics Has Come to the Addiction Field," by Mike Taleff, Ph.D.  Taleff's main point is that it's not genetics that makes a person an alcoholic or other addict.  It is the repeated consumption of alcohol and other drugs that programs a person's genetic material to crave the drug and prioritize its consumption.

This epigenetic understanding, says Taleff, can help a recovering person shed some common myths, such as the belief that "they are somehow morally, bad, defective, or otherwise flawed.  Often, this kind of thinking gets in the way of recovery."  Epigenetics teaches, by contrast, that becoming addicted "has little to do with your moral character."  Addiction is a result of the programming that addictive substances perform on your brain.

Many questions remain to be settled before science can claim that we have a comprehensive understanding of the causes of addiction.  But progress is being made.  For decades, addictionology was stuck in the belief that the alcoholic/addict's disorder was genetically programmed. Thanks to the enormous strides made by genetic science in the past decades, with the deciphering of the human genome and the subsequent advances, we can now say with considerable certainty that genetics supplies only a weak explanation at best. Now we need to turn our eyes toward the epigenetic factors:  environment, culture, and above all the neurochemical properties of the addictive substances themselves.

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.

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.