Understanding Genetic and Environmental Causes of Human Disease
A recent article in the Archives of General Psychiatry by Hallmayer et al. discussed the role of genetic and environmental factors in autism and autism spectrum disorders (ASD). The study was a heritability analysis of 192 pairs of twins, which attributed 37 percent of the variation in risk of autism to genetic factors and 55 percent to shared environmental factors. The authors contrasted their findings with those of previous studies, which had given genetics a much higher share (up to 90%).
Rather than contradicting previous research, the new results provide more evidence that autism, like many other common diseases, results from both genetic and environmental factors. The way that these elements – often called “nature and nurture” – influence health outcomes has been discussed for decades but is often misunderstood, even among scientists.
Disease Causation is Not as Easy as… Pie
Heritability analysis focuses on sources of variation in specific populations. A common misinterpretation of these types of analyses is that the causes of a particular disease are cleanly, though errantly, summed up as slices of a pie – or in pie chart fashion. For example, it is not uncommon to have the explanation of disease presented as “25 percent genetic and 75 percent environmental,” adding up to 100 percent of cases. Furthermore, from the perspective of “either/or,” a person with gene variant “X” is thought to be destined to develop colon cancer no matter what his diet, whereas a person with gene variant “Y” can smoke all she wants yet will never develop lung cancer, and so on. However, what we have learned from gene-disease association studies is that, in reality, human disease is rarely a product of such simple and clearly defined relationships. Causation of human disease is not about nature OR nurture but more about nature AND nurture.
Disease Outcomes “Stew”
Most common diseases–such as coronary heart disease, cancer, and diabetes, which affect millions of Americans–are caused by modifiable environmental risk factors such as cigarette smoking, diet, and sedentary lifestyle. Because gene-environment interactions underlie almost all human diseases, a large role for the environment does not preclude an equally large role for genetic factors. Interaction among genetic and environmental factors allows the total contribution of individual risk factors to exceed 100%.
Rather than slices of pie, perhaps we should consider another metaphor from the culinary world: vegetable stew – in which genes are represented by the many different ingredients and the environment by the time length and temperature of the cooking and whether the pot or pan used is constructed of cast iron, earthenware, or steel. Every skilled chef knows that any change in the preparation of stew, soup or similar entree can result in a completely different taste. Each cut of vegetable: carrot, tomato, onion, potato, mushroom, celery, etc and every spice could be of a different variety. Once assembled, the ingredients blend and cook together to produce a combined yet completely unique flavor. Biologic processes function in a similar way, as genes respond to a continually varying environment over time to produce various health outcomes.
Even though we may know many ways to prevent common disease through the manipulation of environmental factors, one important reason to study and understand genetic factors is that our current public health approaches to prevention have not been entirely successful. Most people do not get enough physical activity or eat a healthy diet. Many are obese or overweight, and many do not adhere to public health screening recommendations. Genetic research may help us better understand disease risks and target our environmental interventions to people who need them the most in order to best achieve public health goals with scarce resources.
Keep in mind that, in spite of having mapped the sequence of the human genome, scientists do not yet have the tools to quantify or even guess at the vast array of gene-environment interactions important to human health. In general, genetic tests that are developed and marketed to the public for predicting risk of common diseases do not account for environmental risk factors, much less for gene-environment interactions. Not surprisingly, these tests tend to have little predictive value {CDC Podcast on Personal Genomic Tests}. Genes do not define one’s destiny and public health messages which pertain to daily life decisions are as relevant today as ever before: eat a healthy diet, exercise, and don’t smoke.
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August 15, 2011 at 9:00 am ET - Patricia Newcomb
Stew is an appealing metaphor for the complex adaptive systems responsible for health. A dash of cayenne in the kitchen can result in a taste tsunami at the table or an extra potato can have virtually no effect. Unless they come from a can, no two vegetable stews taste the same and it is clear by now that no two humans, including monozygotic twins, have exactly the same biochemical identities and environmental contexts. Given this interesting situation, how much more precisely can we really target people for public health interventions? If 1 percent of the population have a genetic variant that is associated with development of heart disease, how reasonable is it to test everyone for the variant in order to deliver more of the same information to these individuals? This behavior presupposes a very high regard for the predictive power of genetic testing on the part of the public similar to the belief that a few extra grains of cayenne will alter the taste of my stew. It seems that genetic testing might be more useful for guiding treatment of individuals who already have disease or other known strong risk factors.
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August 17, 2011 at 7:35 am ET - Keith Grimaldi
Yes it is a very good metaphor. Regarding Patricia’s question I would say the opposite, the very complexity requires us to pursue genetics to unravel prevention.
Heart disease is not a single entity, it’s a stew! There are many ways to arrive at heart disease and genetics influences the pathway – inflammation, lipid uptake, metabolism and transport, hypertension, obesity, etc, etc, etc.
The stew metaphor is good but we need to be careful not to take it too far, a few grains of cayenne pepper may not change the taste…noticeably. Like a few extra grams of unhealthy living will not have any noticeable effect, at least not for 20 years or so. Simplifying the cooking metaphor a bit helps – two different varieties of potato will require a different type of preparation to create a crispy and light roast potato. One type might need pre-boiling while the other can go straight into the pot.
What we need for genetics is to understand this as much as possible to deliver personalized prevention. I agree that a cardiac disease risk panel that simple tells you whether or not you have an apparently increased risk of heart disease is not much use for prevention. Everyone will have raised risks of some common disease so that the advice would be unchanged from current public health advice.
What would be useful would be to understand from genetics who is more at risk of dyslipidemia when consuming a high saturated fat diet, who might be more at risk of salt-sensitive hypertension (rather than some other kind). This sort of information is available in small amounts, we need to know much more, and it promises the double benefit of both targeted prevention as well as treatment.
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August 18, 2011 at 2:42 pm ET - Abe Ibrahim
This is a wonderful way of presenting the real machine of underlying biology and is novel as far as I know. Provides an excellent educational approach. The approach is clear – and the graphics are nice. I particularly like the hourglass graphic which I have not seen before – but that is definitely a picture worth a thousand words.
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August 24, 2011 at 9:44 am ET - Culinary Metaphor Used To Understand Gene-Environment Interactions « health care commentaries from around the world
[...] *This blog post was originally published at Genomics and Health Impact Blog* [...]
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September 25, 2011 at 4:26 pm ET - Rosy Favero
I adore your website content and really liked analyzing the posts and just had to comment in them. I think that its top notch. I discovered your site from the search on aol, keep up with the great efforts, I’m going to make sure to check back often.
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January 18, 2012 at 11:29 am ET - Gavin Thompson
Pretty good stuff!
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January 20, 2012 at 8:50 am ET - Albert Rogers
Superb writing Mr. Bowen! Very informational! I have never read such wonderful writing and never have I seen such beautiful, well drawn pictures! These are indeed worth a thousand words! Keep it up; I will be very interested in your next blog, hopefully with more pictures! Genetics is a very interesting subject, you should continue with your wonderful writing skills! Reading this blog makes me want to watch my diet now! Thank you!
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March 12, 2012 at 2:20 am ET - OMICS Blog - Scientific Journals | Conferences » Omics Group
[...] of DNA in each of our cells, with 5-10 million inherited variants that are different among us. This genetic variation along with environmental influences provides a blueprint for health throughou…. There is definite interest among the public and scientists about the personal utility of this [...]
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March 29, 2012 at 8:06 am ET - Leveraging Existing Biospecimen Resources to Advance Cancer Epidemiology Research » Cancer Epidemiology Matters Blog
[...] and environmental risk factors contribute to the occurrence of most common cancers (1). Moreover, these relationships with cancer risk are complicated by the fact that the spectrum of [...]
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May 24, 2012 at 3:45 pm ET - june peters
Hi All-
This stew metaphor is even more complex than the stew cooking on the stove tonight; it’s also the stew that my grandmother cooked while pregnant that affects my current health.
For example, I’ve recently become familiar with Michael Skinner’s work in “environmental epigenetics” in showing trans-generational effects of environmental exposures like fungicides altering health and behavior several generations hence. e.g.,trans-generational inheritance of epigenetic marks leading to ovarian disease states due to transient exposure of an F0 gestating female rats on F1 and F3 generation progeny; or in a different study affecting the weight and different responses to stress of male progeny for 4 generations.
This is really getting interesting!
june
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