Monday, January 5, 2015

Quotations From The Genetics "Graveyard": Nearly Half A Century of False Positive Claims In Psychiatry


January 5, 2015
In a 1992 essay, British psychiatric genetic researcher Michael Owen wondered whether schizophrenia molecular genetic research would become the “graveyard of molecular geneticists.”1 Owen predicted that if major schizophrenia genes existed, they would be found within five years of that date. He was optimistic, believing that “talk of graveyards is premature.”2 Owen now believes that genes for schizophrenia and other disorders have been found, and was subsequently knighted for his work. Despite massively improved technology, however, decades of molecular genetic gene finding attempts have failed to provide consistently replicated evidence of specific genes that play a role in causing the major psychiatric disorders. In 2013, the American Psychiatric Association admitted as much.
A defining feature of psychiatry over the past half-century has been the publication of gene finding claims based on elevated statistical associations between people diagnosed with a disorder and particular genetic variants or chromosomal regions, followed by retractions or failures to replicate. Currently, researchers in psychiatry and its subfield of psychiatric genetics continue to search for the genes that they believe underlie psychiatric disorders, and have adopted the “missing heritability” position to explain the failure to discover genes. At the same time, some critics have argued that genetic interpretations of psychiatric family, twin, and adoption studies are wrong, and have misled researchers into believing that genes must exist.3
I present below a small sample of gene discovery claims from the past 45 years in order to further encourage healthy skepticism towards recent and future claims that genes for several major psychiatric disorders have at long last been discovered. Based on this history, all gene discovery claims in psychiatry should be assumed to be false-positive associations between genes and disorders until proven otherwise. It is also important to understand that even if a gene (genetic variant) is associated with a psychiatric disorder, it does not necessarily mean that it plays a role in causing it.
In all likelihood the newer claims will join the earlier ones seen below, and will inhabit the “graveyard” that a generation ago Owen and others feared would be the final resting place of psychiatric molecular genetic research. Psychiatric genetics appears to be moving towards an eventual status as a “null field” of science. As the epidemiologist John Ioannidis defined it in a 2005 article entitled “Why Most Published Research Findings Are False,” a “null field” is an area of research “with absolutely no yield of true scientific information,” which produces a large number of false positive findings.4 Future historians of science may well view the current “missing heritability” stage of psychiatric genetic research as a station on the road to its eventual place alongside other abandoned null fields in the history of science, and subsequently non-replicated claims will be woven into the story of how psychiatric genetics attained this unenviable designation.
The following examples of gene discovery or genetic linkage claims in psychiatry go back to 1969. These quotations are taken from the publications of leading genetic researchers writing in original studies and reviews. Sensational “gene discovery” claims found in popular media articles and popular books, which are often based on these publications, are not included here.
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“Affective disorder in which mania occurs is probably linked to the X chromosome. . . . This finding clarifies some aspects of transmission. It also proves a genetic factor in manic-depressive disease.”5
“Detailed analysis suggests that the genetic loci for manic-depressive illness and the two kinds of colorblindness may be located on the same chromosome. A dominant X-linked gene may thus be involved in the pathogenesis of manic-depressive illness.”6
“These results suggest that there may be genes linked to the Gc locus that cause psychosis in general and that there may be genes linked to the Gm and/or Rhesus systems that cause schizophrenia.”7
“Evidence is accumulating that bipolar affective illness…may be linked to both red-green color blindness and the Xg blood group, each the manifestation of genes on the X chromosome.”8
“Erythrocyte catechol-O-methyl transferase (COMT) activity was studied in 53 patients with primary affective disorders and 38 controls and in selected relatives. Patients with affective disorders tended to have higher activity levels than normals, after correcting for sex differences. The COMT activity was positively correlated between relatives and is heritable. Within families, elevation of COMT activity distinguished healthy relatives from probands and ill relatives. This suggests that COMT activity elevation and affective illness do not show independent assortment and implies that COMT activity identifies genetic vulnerability to affective disorder.”9
“Our studies also indicate that some schizoaffective syndrome [sic] may be transmitted through the X-chromosome, as has been demonstrated for some families with bipolar manic-depressive illness. It is thus conceivable that some schizoaffective phenotype may express an allelic form of bipolar illness.”10
“Despite inconsistencies in the studies to date, there does seem to be a reasonable prospect that associations exist between the HLA system and subtypes of schizophrenia. In the author’s view, the most promising association at present looks to be that between HLAA9, HLACW4 and the paranoid subtype.”11
“These results provide confirmation that a major psychiatric disorder [bipolar affective disorder] can be caused by a single genetic defect.”12
“Here we demonstrate genetic linkage of two DNA polymorphisms on the long arm of human chromosome 5 to schizophrenia in seven British and Icelandic families.”13
“In summary, the results of our two-stage genome-wide search for susceptibility genes…suggest that the oligogenic or polygenic model of schizophrenia is most likely to be correct and that genes on at least five different chromosomes—6p, 8p, 9, 20, and 22—seem to be involved.”14
“In our view, schizophrenia researchers appear to have found genes that exert a small effect on the onset of schizophrenia.”16
“In summary, these linkage studies indicate that BP [bipolar disorders] susceptibility loci may exist near 18p11.11, 18q21, 21q21, 4p24 and Xq26….Within the next 5 years, susceptibility genes for these serious disorders will be identified.”
“Our results replicate and extend previous findings of the association between the DAT1 gene and childhood ADHD. This represents one of the first replicated relations of a candidate gene and a psychiatric disorder in children.”17
“Although still in their infancy, molecular genetic studies have already implicated several genes as mediating the susceptibility to ADHD.”18
“Research on the genetic basis of mental disorders crossed a major watershed this summer. For the first time, specific genes have been discovered that influence susceptibility to schizophrenia. … The discovery of some of the pathogenic molecular mechanisms associated with schizophrenia is truly a landmark event in the history of psychiatry.”19
“These findings suggest that variations in a gene on 16p13 may contribute to common deficits found in both ADHD and autism.”20
“Prior evidence has supported the existence of multiple susceptibility genes for schizophrenia. Multipoint linkage analysis of the 270 Irish high-density pedigrees that we have studied, as well as results from several other samples, suggest that at least one such gene is located in region 6p24-21.”21
“Maximum LOD score (MLS) analysis identified suggestive linkage for 17p11…and four nominal regions with MLS values 11.0, including 5p13, 6q14, 11q25, and 20q13. These data, taken together with the fine mapping on 16p13, suggest two regions as highly likely to harbor risk genes for ADHD: 16p13 and 17p11.”22
“Schizophrenia genes have been found at last. A potentially exciting phase of research is imminent. It is likely that more susceptibility genes and the functional significance of variations within them will be identified.”23
“These findings meet conservative criteria for ‘suggestive’ linkage. The gene encoding the norepinephrine transporter protein (SLC6A2) maps to this broad region, making SLC6A2 both a positional and physiological candidate for influencing social phobia risk.”24
“Despite years of pessimism, the first generation of linkage and association studies in schizophrenia has succeeded in identifying replicated susceptibility genes.”25
“Genetic linkage and association analysis for loneliness in Dutch twin and sibling pairs points to a region on chromosome 12q23–24.”26
“The results of these models indicated that the DRD2 gene and the DRD4 gene interacted with family risk to predict variation in the age of first criminal arrest.”27
“Common polygenic variation contributes to risk of schizophrenia and bipolar disorder.”28
“There are strongly supported associations with common alleles for both disorders [schizophrenia and bipolar disorder] and, in the case of schizophrenia, clear evidence for involvement of CNVs. The robustly associated loci are still few in number and cumulatively account for a small amount of the population variance in risk. Nevertheless, they represent a step change in that they clearly indicate the tractability of these disorders to genomic approaches.”29
“Male carriers of low MAOA activity alleles are at risk for becoming a gang member and, once a gang member, are at risk for using weapons in a fight.” (Link)
“Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4.”30
“Schizophrenia is conceptualized as a complex disorder. Genomewide association studies (GWAS)…show that many genes are involved in complex disorders, with each gene conferring only a small effect on the phenotype.”31
Schizophrenia “liability is conferred by a spectrum of risk alleles, common and rare, with each allele contributing only a small fraction to the total population variance. The risk alleles identified to date are also associated with other mental disorders.”32 [This is taken from the DSM-5, published in the spring of 2013. At the time of publication, the APA issued a press release admitting that no genes for psychiatric disorders had been discovered.]
“In the past 6 years, with the advent of large-scale genomewide association analyses, the [psychiatric genetics] field has gone from having essentially no confirmed risk loci to approximately 200.”33
“Recent studies applying new genomic technology to large samples have yielded substantial advances in identifying specific, associated DNA variants as well as clarifying the underlying genetic architecture of the disorder.”34
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1. Owen, M. J., (1992), Will Schizophrenia Become a Graveyard for Molecular Geneticists?Psychological Medicine, 22, 289-293, p. 290.
2. Owen, 1992, p. 292.
4. Ioannidis, J., (2005), Why Most Published Research Findings are FalsePLoS Medicine, 2, 696-701, p. 700.
5. Reich, et al., (1969), Family History Studies: V. The Genetics of Mania, American Journal of Psychiatry, 125, 1358-1369, p. 1367.   

6. Mendlewicz et al., (1972), Evidence for X-Linkage in the Transmission of Manic-Depressive Illness, JAMA, 222, 1624-1627, p. 1624.

7. Elston et al., (1973), Possible Linkage Relationships between Certain Blood Groups and Schizophrenia or Other Psychoses, Behavior Genetics, 3, 101-106, p. 105.
8. Guze, S., (1973), Hereditary Transmission of Psychiatric Illness, American Journal of Psychiatry, 130, 1377-1378, pp. 1377-1378.
9. Gershon, E. S., & Jonas, W. Z., (1975), Erythrocyte Soluble Catechol-O-Methyl Transferase Activity in Primary Affective Disorder: A Clinical and Genetic Study, Archives of General Psychiatry, 32, 1351-1356, p. 1351.
10. Mendlewicz, J., (1977), “Genetic Studies of Schizoaffective Illness,” in E. Gershon et al., (Eds.),The Impact of Biology on Modern Psychiatry (pp. 229-240), New York: Plenum Press, p. 238.
11. McGuffin, P., (1979), Is Schizophrenia an HLA Associated Disease? Psychological Medicine, 9,721-728, p. 726.
12. Baron et al., (1987), Genetic Linkage between X-Chromosome Markers and Bipolar Affective Illness, Nature, 326, 289-292, p. 289.
13. Sherrington et al., (1988), Localization of a Susceptibility Locus for Schizophrenia on Chromosome 5, Nature, 336, 164-167, p. 164.
14. Moises et al., (1995), An International Two-Stage Genome-Wide Search for Schizophrenia Susceptibility Genes. Nature Genetics, 11, 321-324, p. 324.
15. Tsuang, M. T., & Faraone, S. V., (1997), Schizophrenia: The Facts (second ed.), Oxford: Oxford University Press, pp. 52-53.
16. Berrettini, W., (1997), “Molecular Linkage Studies of Manic-Depressive Illness,” in K. Blum & E. Noble (Eds.), Handbook of Psychiatric Genetics (pp. 261-272), Boca Raton, FL: CRC Press, p. 267.
17. Waldman et al., (1998), Association and Linkage of the Dopamine Transporter Gene and Attention-Deficit Hyperactivity Disorder in Children: Heterogeneity Owing to Diagnostic Type and Severity, American Journal of Human Genetics, 63, 1767-1776, p. 1767.
18. Faraone, S. V., & Biederman, J., (2000), Nature, Nurture, and Attention Deficit Hyperactivity Disorder, Developmental Review, 20, 568-581, p. 572.
19. Cloninger, C. R., (2002), The Discovery of Susceptibility Genes for Mental Disorders,Proceedings of the National Academy of Sciences, 99, 13365-13367, pp. 13365, 13367.
20. Smalley et al., (2002), Genetic Linkage of Attention-Deficit/Hyperactivity Disorder on Chromosome 16p13, in a Region Implicated in Autism, American Journal of Human Genetics, 71,959-963, p. 959.
21. Straub et al., (2002), Genetic Variation in the 6p22.3 Gene DTNBP1, the Human Ortholog of the Mouse Dysbindin Gene, is Associated with Schizophrenia, American Journal of Human Genetics, 71, 337-348, p. 337.
22. Ogdie et al., (2003), A Genomewide Scan for Attention-Deficit/Hyperactivity Disorder in an Extended Sample: Suggestive Linkage on 17p11, American Journal of Human Genetics, 72, 1268-1279, p. 1268.
23. Elkin et al., (2004), Have Schizophrenia Genes Been Found? Current Opinion in Psychiatry, 17,107-113, p. 107.
24. Gelernter et al., (2004), Genome-Wide Linkage Scan for Loci Predisposing to Social Phobia: Evidence for a Chromosome 16 Risk Locus, American Journal of Psychiatry, 161, 59-66, p. 59.
25. Fanous, A. H., & Kendler, K. S., (2005), Genetic Heterogeneity, Modifier Genes, and Quantitative Phenotypes for Psychiatric Illness: Searching for a Framework, Molecular Psychiatry, 10, 6-13, pp. 10-11.
26. Boomsma et al., (2006), Genetic Linkage and Association Analysis for Loneliness in Dutch Twin and Sibling Pairs Points to a Region on Chromosome 12q23-24, Behavior Genetics, 36, 137-146, p. 137.
27. DeLisi e al., (2008), The Etiology of Criminal Onset: The Enduring Salience of Nature andNurture, Journal of Criminal Justice, 36, 217-223, p. 220.
28. International Schizophrenia Consortium, (2009), Common Polygenic Variation Contributes to Risk of Schizophrenia and Bipolar Disorder, Nature, 460, 748-752, p. 748.
29. Owen et al., (2010), Suggestion of Roles for Both Common and Rare Risk Variants in Genome-Wide Studies of Schizophrenia, Archives of General Psychiatry, 67, 667-673, p. 670.
30. Psychiatric GWAS Consortium Bipolar Disorder Working Group, (2011), Large-Scale Genome-Wide Association Analysis of Bipolar Disorder Identifies a New Susceptibility Locus near ODZ4,Nature Genetics, 43, 977-983, p. 977.
31. Sanders et al., (2012), “Schizophrenia Genetics,” in A. Brown & P. Patterson (Eds.), The Origins of Schizophrenia (pp. 175-209), New York: Columbia University Press, p. 177.
32.  American Psychiatric Association, (2013), Diagnostic and Statistical Manual of Mental Disorders (5th ed.), Arlington, VA: Author, p. 103. [DSM-5]
33. Smoller, J. W., (2014), Psychiatric Genetics and the Future of Personalized Treatment,Depression and Anxiety, 31, 893-898, p. 897.
34. Rees et al., 2015, Genetics of Schizophrenia, Current Opinion in Behavioral Sciences, 2, 8-14, p. 8.
Jay Joseph
The Gene Illusion: I bring a critical perspective to claims in the media and the scientific literature that genetic factors underlie psychiatric disorders. My new book, “The Trouble with Twin Studies: A Reassessment of Twin Research in the Social and Behavioral Sciences,” is available from Routledge.

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