Tuesday, February 19, 2013

Five DECADES of Gene Finding FAILURE In Psychiatry

Mad In America has;

Two generations of molecular genetic researchers have attempted, yet failed, to discover the genes that they believe underlie the major psychiatric disorders. The most recent failure is a molecular genetic study that was unable to find genes for symptoms of depression.1 Like most genetic researchers in psychiatry, the authors failed to consider the possibility that no such genes exist, and instead concluded that much larger samples of at least 50,000 subjects are needed to detect genes. Also like other genetic researchers in psychiatry, they based their search on the belief that previous kinship studies of families, twins, and adoptees have definitively established the genetic basis of the psychiatric disorder in question. This position is promoted by mainstream psychiatry and by supporters of psychiatric genetics, a subfield of psychiatry founded in Germany around 100 years ago and currently centered in the Unites States and Europe. The questionable validity of DSM psychiatric disorders and the “mental illness” concept are important topics, but here I will focus on genetic research using these concepts.
As far back as 1969, genetic researchers in psychiatry performed a molecular genetic study of manic-depression (bipolar disorder) and concluded that they had found proof that the condition was caused by genes: “Affective disorder in which mania occurs is probably linked on the X chromosome…  This finding clarifies some aspects of transmission. It also proves a genetic factor in manic-depressive disease.2 Like subsequent gene discovery claims in psychiatry, these results were not replicated by other research teams. As Stephen Faraone and his psychiatric genetic colleagues recognized in 2008, “It is no secret that our field has published thousands of candidate gene association studies but few replicated findings.”3 In a sense, however, these negative results are a “secret” because the media usually tells a much different story to the general public. The public has been misled by sensationalized reporting in the popular press, often in concert with leading researchers, to believe that genes for the major psychiatric disorders have been found.
Molecular genetic attempts to uncover “schizophrenia genes” go back to the beginning of the 1970s and earlier.4 In a highly publicized case a generation ago, Sherrington and colleagues believed they had identified a genetic marker for schizophrenia, but this result was not replicated.5 Despite the sequencing of the human genome and the publication of more than 1,700 schizophrenia molecular genetic studies, we have witnessed over 40 years of gene finding claims, and over 40 years of subsequently non-replicated findings. A 2012 study, co-authored by many of the world’s leading schizophrenia molecular genetic researchers, compared 732 previously identified “hypothesis-driven candidate genes” for schizophrenia with genome-wide association study (GWAS) results. The researchers found no association between these previously identified genes and schizophrenia, and concluded that their negative results “suggest, but do not prove, that many traditional ideas about the genetic basis of SCZ [schizophrenia] may be incorrect,” and that “it is possible that the next few years will lead to marked changes in major hypotheses about the genetic basis of SCZ.”6
Clearly, psychiatric molecular genetic research is massively plagued by false positive results, and systematic error appears to have been repeated year-after-year, and decade-after-decade. In this context, leading psychiatric genetic researchers have publicly asked funding sources not to “give up” on schizophrenia molecular genetic GWAS research.7 Researchers tend to downplay the implications of years of negative findings at the same time that they claim that some new technology or method will finally deliver the promised genes.
A parallel process has occurred in the behavioral genetics field,8 where many years of concerted gene finding attempts have failed to identify genes for traits such as IQ,9 personality,10 and traits studied in the social sciences.11 As critical behavioral geneticist Douglas Wahlsten wrote in a 2012 review, “In human behavior genetics…powerful new methods have failed to reveal even one bona fide, replicable gene effect pertinent to the normal range of variation in intelligence and personality.”12
Researchers in psychiatry long ago abandoned the search for a major causative single gene, and now view schizophrenia and other psychiatric conditions as “multifactorial complex disorders,” seeing them as being caused by a complex interaction of multiple genes and multiple environmental risk factors. It is important to note, however, that the failure to discover genes is currently a defining feature of “multifactorial complex disorders” in psychiatry. While continuing to search for genes, researchers frequently claim that the environmental factors contributing to the development of psychiatric disorders are unknown, or are not well understood.
In 2008, leading genetic researchers developed the “missing heritability” position to explain the fewer-than-expected gene findings for some common medical conditions, and the lack of findings for the major psychiatric disorders.13 Regarding schizophrenia, bipolar disorder, ADHD, depression, and other psychiatric conditions, proponents of this position argue that genes are “missing” because researchers must find better ways to uncover them. From the “missing heritability” standpoint, genetic variants that underlie psychiatric disorders and psychological trait variation will be found once researchers develop better methods and collect larger samples. However, psychiatric gene searches are based on the mistaken assumption that genes must exist, due to researchers’ failure to examine the numerous potentially invalidating flaws of previous psychiatric family, twin, and adoption studies. The best explanation for why psychiatry has witnessed five decades of gene finding failures, despite well-funded concerted worldwide efforts using cutting edge technology, is not that “heritability is missing,” but rather that previous and current claims that these family, twin, and adoption studies prove something about genetics are mistaken. I hope to discuss the invalidating flaws, biases, and false assumptions underlying these studies in future postings.14
Interestingly, when the environmental causes of non-psychiatric medical conditions are widely understood and recognized, in most cases society pays little attention to uncovering a possible genetic component. For example, in light of increasing head injuries and concussions, the U.S. National Football League (NFL) is currently in the process of changing professional football rules to reduce the violent head collisions that cause concussions. Although some medical researchers have looked at possible genetic factors relating to concussions, I am unaware of anyone connected with the NFL calling for twin studies of concussion, or for molecular genetic studies attempting to pinpoint concussion susceptibility genes. Few argue that we must assess NFL players for a genetic vulnerability in order to understand concussions, and no one to my knowledge is attempting to calculate concussion “heritability” estimates. The reason is clear: when the environmental causes of a condition are understood and recognized (such as blows to the head), the possibility that some people are more genetically vulnerable (predisposed) than others for developing the condition becomes largely irrelevant.
In psychiatry, despite clinical and research evidence that many people eventually diagnosed with schizophrenia and other psychotic disorders are impacted by trauma, abuse, and other adverse experiences,15 the field’s attention is largely focused on what it believes to be the genetic and biological bases of psychosis. Based on how they typically approach psychiatric disorders, if psychiatric genetic researchers were put in charge of preventing concussions in professional football, it is likely that they would (1) emphasize that concussed players have a genetically-based brain disease, (2) prioritize the use of twin studies and molecular genetic studies in an attempt to unravel the “genetic architecture” of concussions, (3) argue that the environmental causes of concussions are not well understood, (4) pay little attention to the role of head trauma, and (5) conduct genetic counseling sessions with newly drafted players. This is clearly the wrong approach, even if some players are more genetically predisposed than others to suffer concussions.
Nevertheless, politically and economically powerful groups with an interest in diverting attention away from the harmful environmental conditions they often create are very interested in supporting, financing, and promoting genetic approaches. For example, the tobacco industry has promoted the study of genetic predispositions for developing lung cancer.16 Studying possible genetic predispositions is much more than a research approach—it is one of the methods used to promote the idea that environmentally-caused medical conditions and psychiatric disorders are mainly the result of heredity.17
Although some researchers currently claim that several genes for the major psychiatric disorders have already been discovered, these claims are likely to suffer the same fate as similar non-replicated claims we have heard for decades (easily found in Google searches such as “schizophrenia gene discovery,” “ADHD gene discovery,” “bipolar gene discovery,” and in the online archives of scientific journals that have published the “thousands” of subsequently non-replicated gene finding claims). Science writer John Horgan wrote about these non-replicated claims in 2004, and the point is even more relevant today with an additional nine years of gene finding failures behind us:
“Over the past 15 years or so, researchers have announced the discovery of ‘genes for’ attention-deficit disorder, obsessive-compulsive disorder, manic depression, schizophrenia, autism, dyslexia, alcoholism, heroin addiction, high IQ, male homosexuality, sadness, extroversion, introversion, novelty seeking, impulsivity, violent aggression, anxiety, anorexia, seasonal affective disorder, and pathological gambling. So far, not one of those claims has been confirmed.”18
Statements of this type are rarely found in the popular media.
The time has come to suspend psychiatric molecular genetic research and to undertake a thorough public reassessment of the original family, twin, and adoption studies that inspired the fruitless search for genes in the first place. At the same time, the familial, social, and political causes of psychiatric conditions must become the focus of attention.19
In a mocking jab at critics such as R. D. Laing and Thomas Szasz, psychiatric investigator Seymour Kety, the lead researcher of the influential yet severely flawed Danish schizophrenia adoption studies, famously wrote in 1974: “If schizophrenia is a myth, it is a myth with a strong genetic component!”20 Schizophrenia molecular genetic research was relatively new in those days, but now the results of decades of molecular genetic research are in: There appear to be no genes for schizophrenia. We could therefore revise Kety’s position to bring it in line with current scientific results: “If schizophrenia is a genetic disorder, it is a genetic disorder without any genes.”

Further Reading
Joseph, J. (2011). The Crumbling Pillars of Behavioral GeneticsGeneWatch, 24 (6), 4-7.
Joseph, J. (2012). The “Missing Heritability” of Psychiatric Disorders: Elusive Genes or Non-Existent Genes? Applied Developmental Science, 16, 65-83.
Krimsky, S. & Gruber, J. (Eds.). (2013). Genetic Explanations: Sense and Nonsense. Cambridge, MA: Harvard University Press.
Latham, J., & Wilson, A. (2010). The Great DNA Data Deficit: Are Genes for Disease a Mirage? The Bioscience Research Project.
Lewontin, R. C. (2009, May). Where are the Genes? Genewatch.

1 Hek et al. (2013). A Genome-Wide Association Study of Depressive SymptomsBiological Psychiatry. Advance online publication. DOI: 10.1016/j.biopsych.2012.09.033; see also “Depression Gene Search Disappoints
2 Reich et al. (1969). Family History Studies: V. The Genetics of Mania. American Journal of Psychiatry, 125, 1358-1369.
3 Faraone et al. (2008). The New Neuropsychiatric Genetics. American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 147B, 1–2
4 Elston et al. (1973). Possible Linkage Relationships Between Certain Blood Groups and Schizophrenia or Other Psychoses. Behavior Genetics, 3, 101-106.
5 Sherrington et al. (1988). Localization of a Susceptibility Locus for Schizophrenia on Chromosome 5. Nature, 336, 164-167.
6 Collins et al. (2012). Hypothesis-Driven Candidate Genes for Schizophrenia Compared to Genome-Wide Association Results. Psychological Medicine, 42, 607-616.  For an opposing viewpoint within psychiatric genetics, in 2012 Michael Owen claimed that “possibly thousands” of schizophrenia genes have been discovered: “We now have molecular genetic evidence that a very large number of genes, possibly thousands, contain risk alleles for schizophrenia in the population.” See Owen, M. J. (2012). Implications of Genetic Findings for Understanding Schizophrenia. Schizophrenia Bulletin, 38, 904-907.
7 Sullivan et al. (2012). Don’t Give Up On GWAS. Molecular Psychiatry, 17, 2-3
8 Joseph, J. (2011). The Crumbling Pillars of Behavioral GeneticsGeneWatch, 24 (6), 4-7.
9 Chabris et al. (2012). Most Reported Genetic Associations with General Intelligence are Probably False Positives. Psychological Science, 23, 1314-1323.
10 Plomin, R. (2013). Child Development and Molecular Genetics: 14 Years Later. Child Development, 84, 104-120; Wahlsten, D. (2012). The Hunt for Gene Effects Pertinent to Behavioral Traits and Psychiatric Disorders: From Mouse to Human. Developmental Psychobiology, 54, 475-492.
11 Benjamin et al. (2012). The Genetic Architecture of Economic and Political Preferences. PNAS, 109, 8026-8031; Charney, E., & English, W. (2012). Candidate Genes and Political Behavior.American Political Science Review, 106, 1-34.
12 Wahlsten, 2012.
13 Maher, B. (2008). The Case of the Missing Heritability. Nature, 456, 18-21; Manolio et al. (2009). Finding the Missing Heritability of Complex Diseases. Nature, 461, 747-753.
14 For problems with family, twin, and adoption studies, see Joseph, J. (2004). The Gene Illusion: Genetic Research in Psychiatry and Psychology Under the Microscope. New York: Algora. (2003 United Kingdom Edition by PCCS Books); Joseph, J. (2006). The Missing Gene: Psychiatry, Heredity, and the Fruitless Search for Genes. New York: Algora; Joseph, J. (2010). Genetic Research in Psychiatry and Psychology: A Critical Overview. In K. Hood, C. Tucker Halpern, G. Greenberg, & R. Lerner (Eds.), Handbook of Developmental Science, Behavior, and Genetics (pp. 557-625). Malden, MA: Wiley-Blackwell.
15 Kessler et al. (2010). Childhood Adversities and Adult Psychopathology in the WHO World Mental Health SurveysBritish Journal of Psychiatry, 197, 378-385; Read, J. (forthcoming). Childhood Adversity and Psychosis: From Heresy to Certainty. In J. Read & J. Dillon (eds.). Models of Madness (2nd ed.). London: Routledge; Read et al. (2009). Time to Abandon the Bio–Bio–Bio Model of Psychosis: Exploring the Epigenetic and Psychological Mechanisms by Which Adverse Life Events Lead to Psychotic Symptoms. Epidemiologia e Psichiatria Sociale, 18, 299–310.
16 Proctor, R. N. (1995). Cancer Wars: How Politics Shapes what we Know and Don’t Know About Cancer. New York: Basic Books; Wallace, H. (2009). Big Tobacco and the Human Genome: Driving the Scientific Bandwagon? Genomics, Society and Policy, 5, 1-54.
17 See Chaufan, C. (2007). 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 and Medicine, 65, 1730–1741.
18 Horgan, J. (2004, November 6th). Do Our Genes Influence Behavior? Chronicle of Higher Education.
19 Belle, D., & Bullock, H. (2013). Poverty, Unemployment, Economic Inequality, and Mental Health. In M. Shally-Jensen (ed.), Mental Health Care Issues in America: An Encyclopedia (Vol. 2; pp. 541-546). Santa Barbara, CA: ABC-CLIO.
20 Kety, S. S. (1974). From Rationalization to Reason. American Journal of Psychiatry, 131, 957-963.

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