Human Genetic Predispositions – the hidden politics of genomic science

Introduction

Most modern medical research assumes that inherited genetic predispositions underlie the current epidemics of (non-infectious) diseases and disorders. A partial list includes type II diabetes, heart disease, cancer, autism, various mental illnesses, myopia, and stroke. Historically, this genetic determinist paradigm in medicine was driven by tobacco industry funding. The industry calculated it could deflect public blame for the lung cancer epidemic away from tobacco and onto personal ‘genetic weaknesses’, e.g., putative ‘lung cancer genes’ and ‘addiction genes’. The main evidence that supports the existence of such gene variants has been experiments known as twin studies. However, there are good reasons to believe that twin studies are a flawed methodology that vastly overestimates genetic contributions.

The resources on this page reveal the unscientific origins and consequent scientific failure of the gene-focused disease paradigm. Resources are organized by topic. The first is The Political Role of Human Genetic Research. This is followed by articles showing how Twin Studies Create Misleading Heritability Estimates. These estimates led to the creation and subsequent Failure of the Common Disease-Common Variant (CD-CV) Hypothesis. The CD-CV hypothesis was that a few common gene variants (i.e. mutations) would be responsible for each disease. Its proponents assumed that genetic screening for key variants would identify those at risk of disease and that variant identification would lead to new treatments. Researchers subsequently carried out thousands of genome-wide (GWA) and candidate gene (CGA) association studies to identify these variants. However, both theoretical and experimental Mistakes Were Made with GWA and CGA Studies. The results of such studies are almost entirely non-reproducible and their findings have not supported the CD-CV hypothesis, nor do they support a major role for genetics in common diseases.

Challenging the current gene-centered paradigm, many researchers have asked How Much Can Genomics and Genetic Testing Benefit Public Health? They and others suggest instead a focus on Preventing and Treating Complex Diseases by addressing known causes such as poor diet, lack of exercise, poverty, and pollution. It is time for the common understanding of The Biological Role of DNA to be updated to address the known complexities of organisms and their environmental interactions.

 

New and Classic Scientific Articles

The Political Role of Human Genetic Research:
Past and Present

 

Jonathan Latham and Allison Wilson. “The Great DNA Data Deficit: Are Genes for Disease a Mirage?Independent Science News. December 2010.
This introductory article reviews the almost complete failure of genome-wide association (GWA) studies to identify genes that strongly predispose their carriers to common diseases. It argues this finding should be seen as “the most important scientific breakthrough in understanding human health in twenty five years.” It reviews recent GWA results, twin studies, and other data, all of which suggest that genes are not the best predictors of disease nor the best targets for prevention or cure. The authors suggest it is time to rethink how we fund scientific research into common diseases — from heart disease, stroke, cancers, diabetes, to disorders such as autism, ADHD and dementia, and mental health issues such as schizophrenia and depression. The article includes a list of links to additional books and papers on the topic.


Gundle, Kenneth R., Molly J. Dingel, and Barbara A. Koenig. “‘To Prove This is the Industry’s Best Hope’: Big Tobacco’s Support of Research on the Genetics of Nicotine Addiction Addiction 105.6 (2010): 974-983.
Analysis of the Legacy Tobacco Documents illustrates how “the search for a genetic basis for smoking behavior is consistent with industry’s decades-long plan to deflect social responsibility away from the tobacco companies and onto individuals’ genetic constitutions.


Wallace, Helen M. “Big Tobacco and the Human Genome: Driving the Scientific Bandwagon?Genomics, Society & Policy 5.1 (2009).
“The tobacco industry first began to promote the idea that a minority of smokers are ‘genetically predisposed’ to lung cancer in the 1950s.” Wallace uses tobacco industry documents to investigate its role in funding the ‘scientific bandwagon’ “in which genetics has come to dominate the cancer research agenda.” Wallace concludes “the tobacco industry has played a significant role in shaping research agendas, in particular, by promoting the idea that individual genome screening would be of benefit to public health“.


Book:
Campbell, T. Colin and Howard Jacobson. Whole: Rethinking the Science of Nutrition. BenBella Books, Inc., 2013.
T. Colin Campbell draws from his 50 years of research experience to show how genetic and nutritional reductionism dovetail with powerful interests to undermine scientific understanding. The resulting misinformation greatly harms individual and public health. Campbell explains how adoption of a ‘wholistic’ paradigm will reinvigorate science and revolutionize health care.


Book: Lewontin, Richard C. Biology as Ideology: The Doctrine of DNA. House of Anansi, 1991.
Short and elegant. GeneticistRichard Lewontin argues that traits (e.g. height) are the product of genes, chance, and environment and these are irreducibly intertwined. He discusses logical fallacies underpinning socio-biology and the perils of scientific reductionism for society. See book review on Independent Science News: Biology as Ideology: The Doctrine of DNA. Discover why researchers, politicians and so many others are attracted to genetic determinist arguments.

Twin Studies Create Misleading Heritability Estimates


Beckwith J. and Morris-Singer C.A. (2012) “Missing Heritability: Hidden Environment in Genetic Studies of Human Behavior” Book Chapter in: NOMOS LII: Evolution and Morality. Eds: Fleming J, Levinson S; New York: NYU Press; p. 122-136.
The search for genetic predispositions has been driven by heritability estimates derived from twin studies. Twin studies estimate trait ‘heritability’ by comparing concordance of disease and behavior phenotypes between sets of identical and non-identical twins. The consistent failure of GWA studies to find sufficient variation to support twin study heritability estimates has been called the “missing heritability”. Beckwith and Morris-Singer show how erroneously attributing environmental influences to genetics can account for the so-called “missing heritability”. The authors challenge numerous assumptions underlying the genetics of behavior.


Joseph, Jay. “The Genetics of Political Attitudes and Behavior: Claims and Refutations.” Ethical Human Psychology and Psychiatry 12.3 (2010): 200-217.
Explains why “the main theoretical assumption of the twin method, which holds that monozygotic and dizygotic twin pairs experience equal environments (the EEA), is untenable.” Proposes that twin study estimates of genetic effects can be completely explained by non-genetic factors.


Richardson, Ken, and Sarah H. Norgate. “A Critical Analysis of IQ Studies of Adopted Children.” Human Development 49.6 (2007): 319-335.
Recent IQ adoption studies claim that additive genetic variance underlies variation in IQ. Richardson and Norgate identify non-genetic effects (e.g. age at testing; restriction of range; family treatment effects) that undermine the conclusions of adoption studies.


Rose, Steven PR. “Commentary: Heritability Estimates—Long Past Their Sell-By Date.” International Journal of Epidemiology 35.3 (2006): 525-527.
Biological systems are complex, non-linear, and non-additive. Heritability estimates are attempts to impose a simplistic and reified dichotomy (nature/nurture) on non-dichotomous processes.” Recommends that researchers “attempt to analyse causes, not variances.” Summarizes problems with heritability estimates.


Joseph, Jay. “Not in Their Genes: A Critical View of the Genetics of Attention-Deficit Hyperactivity Disorder .” Developmental Review 20.4 (2000): 539-567.
Joseph examines both twin studies and adoption studies for ADHD and identifies numerous factors that invalidate the equal environment assumption (EEA). Validity of the EEA is critical to the validity of heritability estimates derived from twin studies.


Stoltenberg, Scott F. “Coming to Terms with Heritability (1997).” Genetica 99.2-3 (1997): 89-96.
To quote Stoltenberg, “In a genetic sense, only the constituents of the gametes are inherited, traits are developed anew in each individual. However, when scientists make statements suggesting that a behavior is heritable they perpetuate the misunderstanding that behaviors are passed down from parents to offspring much like a baton that is passed from one relay runner to the next.” With his careful discussion of “technical” vs “folk” heritability and what is actually inherited, Stoltenberg clears up various misconceptions and suggests a new word “selectability” as a possible solution to the ongoing confusion of both scientists and the public over discussions about heritability.

The Failure of
the Common Disease/Common Variant (CD-CV) Hypothesis

 

Buchanan, Anne V., Kenneth M. Weiss, and Stephanie M. Fullerton. “Dissecting Complex Disease: The Quest For the Philosopher’s Stone?.” International Journal of Epidemiology 35.3 (2006): 562-571.
The authors ask, “why have not the traditional methods of epidemiology and genetics been sufficient to determine the causes of complex diseases, and why is individual risk essentially impossible to predict?” They discuss the difficulties with determining specific genetic or environmental causes for complex diseases but note that “fortunately, many of the most common complex diseases are among the very ones that can generally be prevented or modified with behavioural changes like diet and exercise” — allowing prevention or therapy without exact determination of cause. “….perhaps it is time for scientists to rethink the quest.”


Terwilliger, Joseph D., and Harald HH Göring. “Gene Mapping in the 20th and 21st Centuries: Statistical Methods, Data Analysis, and Experimental Design.” Human Biology 81.5 (2000): 663-728.
In 2000 the authors asked whether untested and unrealistic assumptions hinder geneticists’ understanding of complex traits and diseases. The authors cited the common disease-common variant (CD-CV) hypothesis (“which assumed that common alleles with high attributable fractions, such as APOE4 and Alzheimer disease, would dominate trait etiology) as a prime example of such assumptions. Terwilliger and Göring suggested instead “that a larger number of less common alleles is likely to be involved in the etiology of complex disease”.


Terwilliger, Joseph D., and Harald HH Göring. “Update to Terwilliger and Göring’s “Gene Mapping in the 20th and 21st Centuries” (2000): Gene Mapping When Rare Variants are Common and Common Variants are Rare.” Human biology 81.5/6 (2009): 729-733.

In 2000 Terwilliger and Göring argued against the the common variant/common disease (CD-CV) hypothesis which was, at the time, widely believed to be a plausible model for the genetics of complex diseases (i.e. cancer, diabetes, Alzheimer’s etc.). “Ten years and billions of taxpayer dollars later, our once “extreme” position has replaced the mainstream opinion of a decade ago, as the recent flood of empirical data from genome-wide association studies consistently yields results that are inconsistent with the CD-CV hypothesis and rosy scenarios about personalized medicine.” Terwilliger and Göring argue (again) it is time to rethink research into common disease causation.


Jonathan Latham and Allison Wilson. “The Great DNA Data Deficit: Are Genes for Disease a Mirage?Independent Science News. December 2010
(See the first resource under heading: The Political Role of Human Genetic Research: Past and Present) this introductory article also has an explanation of the CD-CV hypothesis and how it has been disproved by GWA studies.


Pearce, Neil. “Epidemiology in a Changing World: Variation, Causation and Ubiquitous Risk Factors.” International Journal of Epidemiology 40.2 (2011): 503-512.
Many disease risk factors are now ubiquitous or nearly ubiquitous in certain populations: inactivity; high levels of consumption of animal products and processed foods; cancer causing chemicals; and radiation exposure, to name a few. Where risk factors are ubiquitous, causes of population variation in disease may be attributed solely to genes, while often the best methods of prevention or cure would be lifestyle changes or improving environmental health. To illustrate, “we live on a planet where almost everyone has a high-phenylalanine diet…. PKU is regarded as a classically genetic disease, but the intervention is environmental. This is because PKU is ‘caused by the joint effect’ of the gene and the high-phenylalanine diet. In fact, 100% of cases of PKU are caused by the gene (and essentially its heritability is 100%), since 100% of cases could in theory be prevented by eliminating the gene from the population. However, 100% of cases can also be prevented by reducing phenylalanine in the diet.” Therefore, to develop an accurate understanding of causes, and effective methods for their prevention or treatment, researchers must take into account ubiquitous and thus often hidden risk factors.

 

Mistakes Were Made with GWA and CGA Studies


Ioannidis, John PA, et al. “Replication Validity of Genetic Association Studies.” Nature Genetics 29.3 (2001): 306-309.
Evaluating by meta-analysis “370 studies addressing 36 genetic associations for various outcomes of disease” the authors find that “the first study tended to give more impressive estimates of disease protection or predisposition than subsequent research.” They discuss why.


Lambert, Christophe G., and Laura J. Black. “Learning from our GWAS Mistakes: from Experimental Design to Scientific Method.” Biostatistics 13.2 (2012): 195-203.
Lambert and Black discuss basic experimental design errors and the “errors of omission” that continue to plague GWA studies. These range from the use of different DNA sources and lack of block randomization of cases and controls to the chasing of correlations rather than attempting to falsify hypotheses. “Often a deeper investigation into what appears as an isolated occurrence leads to appreciation of a broader problem.” They note the value of mistakes – if we learn from them. A valuable reminder of what makes science ‘scientific’.


Charney, Evan, and William English. “Candidate Genes and Political Behavior.” American Political Science Review 106.01 (2012): 1-34.
Charney and English dissect a 2008 paper that clams to have demonstrated that “two genes predict voter turnout” (Fowler and Dawes, 2008). The authors illustrate how myriad methodological problems undermine the validity of Candidate Gene Association (CGA) studies. These problems include faulty genotype classifications and population stratification. They reanalyze Fowler and Dawes’ own data to show that in fact “two genes do not predict voter turnout.”

 

How Much
Can Genomics and Genetic Testing Benefit Public Health?

 

Hall, Wayne D., Rebecca Mathews, and Katherine I. Morley. “Being More Realistic about the Public Health Impacts of Genomic Medicine.” PLoS medicine 7.10 (2010).
Questions the health benefits of predicting disease risk from genetic risk information, now or in the future. It also highlights the costs of genetic risk estimates, which include false positives. Other costs include undermining belief in the value of lifestyle change and misuse by industries avoiding responsibility (e.g.the tobacco industry).


Wallace, Helen M. “Genetic Screening for Susceptibility to Disease.” eLS (2009).
Extremely valuable article to understand the overarching purpose behind the push for genetic testing. “No genetic susceptibility tests exist that meet medical screening criteria, and there is growing scepticism in the scientific literature that they will ever do so. Yet, there is a significant political and commercial commitment to genetic screening for disease susceptibility” and to linking DNA data to medical records so that these can be “mined” forthe ‘prediction and prevention’ of disease.” Wallace dissects the scientific and political impetus behind genetic testing and it proposed uses.


Wallace Helen M. “A Model of Gene-Gene and Gene-Environment Interactions and Its Implications for Targeting Environmental Interventions by Genotype.” Theor Biol Med Model. Vol. 3:35 (2006).
The practical value of “targeting environmental interventions by genotype depend(s) on the environmental and genetic contributions to the variance of common diseases, and the magnitude of any gene-environment interaction.” Wallace develops a new model to examine these interactions and concludes the public health benefits of such targeted interventions may be limited.


Chaufan, Claudia, and Jay Joseph. “The ‘Missing Heritability’ of Common Disorders: Should Health Researchers Care?International Journal of Health Services 43.2 (2013): 281-303.
Is our society basically healthy and do those who fall ill or do poorly have a “genetic predisposition”? Can public health benefit from human genetic information? The authors argue  that “focusing on genetics is a monumental diversion” from truly health-promoting research and policy.

 

Preventing and Treating Complex Diseases

 

Joseph, Jay. “A Human Genetics Parable.” Journal of Mind & Behavior 32.3 (2011).
Nature vs Nurture or Heredity vs Environment. Cleverly illustrates the divergence in opinion and strategy between those who believe that meaningful causes of and solutions to psychiatric disorders and common medical conditions will be found in an individual’s genes and those who believe that assessment and modification of environment (including social class, upbringing, diet, environmental exposure, and lifestyle) hold more promise. Would make an excellent discussion piece for students.


Chaufan, Claudia. “How Much Can a Large Population Study on Genes, Environments, Their Interactions and Common Diseases Contribute to the Health of the American People?.” Social Science & Medicine 65.8 (2007): 1730-1741.
Using type 2 diabetes as an example, Chaufan answers her own question and describes what a meaningful American public health policy would look like.


Booth, Frank W., et al. “Waging War on Modern Chronic Diseases: Primary Prevention Through Exercise Biology.” Journal of Applied Physiology 88.2 (2000): 774-787.
Suggests why modern medicine’s current “war on chronic disease” – which focuses on genetic causation and development of “secondary and tertiary disease treatments” is failing to stem the epidemic of chronic disease. Proposes disease prevention strategies, with a focus on diet and exercise, as more fruitful “weapons”. Illustrates how technology decreases human activity and with inactivity comes increased ill-health.


Epstein, Samuel S., et al. “The Crisis in US and International Cancer Policy.” International Journal of Health Services 32.4 (2002): 669-707.
The U.S. cancer establishment has been fighting and losing “the war on cancer” for over 40 years. The National Cancer Institute (NCI) and the American Cancer Society (ACS) together spend billions of taxpayer and donor dollars a year on failed approaches, while the cancer epidemic increases inexorably. Epstein argues most cancers can be prevented by eliminating workplace and environmental carcinogens and those in consumer products. However, conflicts of interest within the cancer establishment and academia ensure the public, legislators, and regulators remain uninformed of the causes of preventable cancer. Consequences of these failures include the needless suffering and early death of cancer victims and those who undergo unnecessary treatment due to false positives during cancer screening.


Epstein, Samuel S. “Losing the War Against Cancer: Who’s to Blame and What to Do About It.” International Journal of Health Services 20.1 (1990): 53-71.
Epstein details key sources of carcinogen exposure. Such data is vital to creating effective cancer prevention policy. He then describes the various obstacles to carcinogen regulation and other necessary prevention strategies. He illustrates how the NCI and ACS are “standing in the way of prevention” and outlines the play-book used by Industry to block appropriate regulation. He also critiques “lifestyle academics” like Sir Richard Doll and Bruce Ames, who he claims distract attention from important sources of involuntary exposure to carcinogens such as the workplace and consumer products. “Cancer must be thought of as an essentially preventable disease” and Epstein details how to go about preventing it.

 

The Biological Role of DNA

 

Charney, Evan.Behavior Genetics and Postgenomics.” Behavioral and Brain Sciences 35.5 (2012): 331.
Will it ever be possible to predict phenotype from genotype? Recent advances in the science of genetics (from retrotransposon activity to epigenetics) suggest an organism’s phenotype depends on many random and stochastic events that have not been incorporated into theories of perinatal development, brain function and behavior. Neither have they been incorporated into analyses of the validity of twin or gene association (GWA) studies.


Book: Krimsky, Sheldon, and Jeremy Gruber. Genetic Explanations: Sense and Nonsense (2013). Harvard University Press, 2013.
In the words of co-editor Sheldon Krimsky, “The chapters in this volume provide a counterargument to exaggerated, erroneous, or overly simplified claims about the role that DNA plays in cells, organisms, evolution, human behavior, and culture.” For an excellent review of this book and an updated view of the role of DNA that is based on modern scientific findings read: Review Essay on Genetic Explanations by Evan Charney.


Annila, Arto, and Keith Baverstock. “Genes Without Prominence: a Reappraisal of the Foundations of Biology (2014).” Journal of The Royal Society Interface 11.94 (2014): 20131017.
The sequencing of the human genome raises two intriguing questions: why has the prediction of the inheritance of common diseases from the presence of abnormal alleles proved so unrewarding in most cases and how can some 25,000 genes generate such a rich complexity evident in the human phenotype?” What if “the gene, as it is generally regarded, is a merely mechanistic, not a profound, concept?” Annila and Baverstock propose “biology can be better understood in terms of the physics of complex dissipative (energy consuming) systems and the 2nd law of thermodynamics, where the ability to extract energy (nutrient) from the environment provides the basis for natural selection.” Leaving DNA behind, they consider the role of proteins, metabolic pathways, cells, the environment and thermodynamics in creating phenotype.

 

Other Websites with Scientific Resources

 

Council for Responsible Genetics
The Council for Responsible Genetics represents the public interest and fosters public debate about the social, ethical and environmental implications of genetic technologies.” Topics include: patents, cloning, genetic testing, genetic determinism, privacy, bio-warfare and more.

GeneWatch UK
GeneWatch UK is a not-for-profit that aims to ensure genetic technologies are developed and used in the public interest — so that they promote human health, protect the environment, and respect human rights and the interests of animals. Genewatch covers human genetics, genetically modified organisms (GMOs), and biological weapons. They also monitor research agendas (including DNA databases and biobanks) and patenting. GeneWatch UK plays an essential role in keeping scientists and the public informed on key genetic issues.

HealthNewsReview.Org
How accurately does news reporting on health issues reflect actual scientific findings and their implications? Provides independent critical analysis of health stories in the news.

The Mermaid’s Tale
Subtitled A Conversation about the Nature of Genetic Causation in Evolution, Development and Ecology, the mermaid’s tale blog has amusing and erudite discussions of topics that range from disease causation to probabilities. Contributors include: Ken Weiss, Anne Buchanan and Holly Dunsworth.