Monday, October 21, 2013

Twin Studies And The "Nonreplication Curse" In Psychiatric Genetic Research

Twin Studies And The "Nonreplication Curse" In Psychiatric Genetic Research

Jay Joseph

October 21, 2013

In the spring of 2013, the American Psychiatric Association (APA) officially admitted that it has no genes for its disorders. In an official APA press release dated May 3rd, 2013, DSM-5 Task Force head David Kupfer stated, “In the future, we hope to be able to identify disorders using biological and genetic markers that provide precise diagnoses that can be delivered with complete reliability and validity. Yet this promise, which we have anticipated since the 1970s, remains disappointingly distant. We’ve been telling patients for several decades that we are waiting for biomarkers. We’re still waiting.”[1] In this statement, despite decades of gene discovery claims in professional publications and in the media, and despite the reality that psychiatry has “been telling patients for several decades” that they have faulty genes and chemical imbalances in their brains, American psychiatry came clean about its failure to support its claims with actual scientific findings.
In this context, psychiatry and other fields studying behavior and medical conditions have developed the  “missing heritability” position, which in psychiatry is an attempt to explain the failure to identify genes for psychiatric disorders by claiming that genes exist and await discovery once better methods are found.2
In 2010, researchers developed a new molecular genetic research method, sometimes referred to as “Genome-wide Complex Trait Analysis,” or GCTA. As described by behavioral geneticist Robert Plomin and his colleagues, the GCTA method “compares chance genetic similarity across hundreds of thousands of SNPs for each pair of individuals in a matrix of thousands of unrelated individuals . . . the large sample size makes it possible to estimate heritability directly from DNA markers measured on the microarray.” However, “it does not identify which SNPs are responsible for the heritability of a trait.”3 The method does not identify associated genetic variants such as SNPs (single-nucleotide polymorphism, a common type of genetic variation among people), but rather estimates total genetic variance on the basis of comparing the genetic profiles of a large group of unrelated people. In other words, it can produce a “finding” of genes even when no specific genes are identified.
The original GCTA study, published in 2010 by Yang and colleagues, assessed the genetic basis of human height variation.4 Previous researchers had estimated the heritability of height at 80%, yet genome-wide association (GWA) studies had identified only 5% of the genetic variants responsible. Using the new GCTA method, Yang and colleagues estimated that the proportion of height variance “explained by the SNPs” is 45%.
Although the GCTA method was developed as a means of solving the “missing heritability” problem, like GWA studies and other methods it is based on assuming the validity of heritability estimates for human behavioral traits, as well as assuming that twin and adoption studies have established the genetic basis of psychiatric disorders. The validity of each of these assumptions, however, is very questionable.5 And yet, leading behavioral geneticists such as Robert Plomin and Eric Turkheimer have embraced GCTA, seeing it as a way out of the missing heritability conundrum.6 Turkheimer even saw it as the ultimate refutation of the arguments of twin research critics, writing that “the new paradigm” has put criticism of the assumptions of family and twin studies “to rest.” Turkheimer believed that the GCTA method “should drive a stake through the heart of a classical line of argument against classical behavioral genetics and its attendant statistical assumptions.”7
However, cracks in the GCTA method have already begun to appear. In 2013, Trzaskowski, Plomin and colleagues conducted a study on anxiety-related behaviors in childhood, finding GCTA variance estimates of 1% to 19% (none reaching statistical significance), whereas twin method reared-together MZ-DZ (identical twin pair-fraternal twin pair) comparisons had produced heritability estimates of 50% to 61%.8 In another 2013 publication, Viding, Plomin and their colleagues performed a GCTA study of “callous-unemotional (CU) behavior in children.” Although the authors of previous CU twin studies had estimated heritability ranging from 45% to 67%, the GCTA results showed that “estimates of heritability were near zero.” Viding and colleagues even coined a new term for this discrepancy, calling it the “missing GCTA heritability.”9
Finally, in an October, 2013 study published in the Journal of the American Academy of Child and Adolescent Psychiatry, Trzaskowski, Dale, and Plomin compared GCTA results with twin method results in a study of “childhood behavior problems” which included autistic, depressive, hyperactive, anxiety, and conduct symptoms. The title of their article was clear: “No Genetic Influence for Childhood Behavior Problems from DNA Analysis.”10 The researchers used a large sample of over 2,000 twin pairs, and over 2,000 individuals for the GCTA analysis, and were confronted with a large difference between the twin method results and the GCTA results. The twin study findings reflected the usual behavioral genetic conclusions based on MZ-DZ comparisons, with the researchers calculating heritabilities in the 40%-60% range. The GCTA estimates, however, “are nonsignificant and mostly zero for self-report and parental measures of behavioral problems.” They again referred to this discrepancy as the “missing GCTA heritability.” The researchers spent much of the rest of their publication trying to explain their contradictory findings, describing unexpected results in ways that did not challenge the genetic theories upon which gene searches are based. In doing so, they rejected the possibility that both the GCTA method and the twin method are based on false assumptions and concepts. The most controversial aspect of the twin method has been twin researchers’ theoretical assumption that reared-together MZ and same-sex DZ twin pairs grow up experiencing similar (“equal”) environments. The evidence indicates that this assumption is false.
In an accompanying article, psychiatric geneticist Stephen Faraone, a strong supporter of genetic theories and research in psychiatry, recognized that the 2013 Trzaskowski, Dale, and Plomin study contradicted the findings of the “Cross Disorder Group of the Psychiatric Genomics Consortium” study published in February, 2013.11 Readers may recall that the results of this study were reported with great fanfare in the media as constituting important new gene discoveries in psychiatry (see myMarch 4th, 2013 MIA blog). As Faraone candidly posed the question, “Nonreplication had been the curse of molecular psychiatric genetics for decades. Has it returned in a new guise?”12
The answer to Faraone’s question probably is yes, because due to major problems and false assumptions underlying previous family, twin, and adoption studies, in addition to the questionable validity and reliability of psychiatric disorders in general,13 the “curse” Faraone referred to is merely the scientific likelihood that genes for the major psychiatric disorders do not exist. This is a cause for celebration, not despair, as society can now part ways with genetic diversions and focus on environmental causes, interventions, and prevention.
Although in 2011 Turkheimer believed that the GCTA method would “drive a stake through the heart of” criticism of behavioral genetic theories and methods, and would finally put criticism of twin studies “to rest,” the opposite scenario appears to be playing out before us, as leading behavioral genetic researchers struggle to prevent negative GCTA findings, and the obvious false assumptions underlying twin research, from driving a stake through the heart of twin studies themselves.
In other GCTA studies showing positive results, it is likely that the method produces false positive findings based on systematic errors and a reliance on questionable assumptions and concepts, similar to those found in GWA studies and other types of molecular genetic research methods that have largely failed to uncover genes for behavioral traits. Evan Charney of the Duke Institute for Brain Science listed several potential biases in GCTA studies, including the failure to adequately account for genetic differences based on variation found among differing populations (population stratification), which introduces a potential environmental confound into GCTA studies. Charney concluded that the GCTA search for thousands of genetic variants of tiny effect “is the last gasp of a failed paradigm.”14 Commenting on a 2011 GCTA study of IQ, critical geneticist Mae-Wan Ho wrote, “This exercise sounds more like a counsel of despair than a solution to the problem.”15
Most likely, these will become the final appraisals of the GCTA method once it runs its course in psychiatry and behavioral genetics, which recent history tells us will be followed by yet another molecular genetic technique promising to deliver the long-lost “missing heritability,” “missing GCTA heritability,”16 “phantom heritability,” or some other future “missing [fill-in-the-blank] heritability.” Therefore, although the GCTA approach does appear to be a “gasp of a failed paradigm,” it is probably not the last gasp. What actually is “missing” is an independent commission charged with the task of thoroughly examining psychiatric family, twin, and adoption studies (including related theories, assumptions, and original publications) in order to determine whether or not these studies prove anything about genetics.
1 American Psychiatric Association (2013, May 3rd). Chair of DSM-5 task force discusses future of mental health research; Statement by David Kupfer, M.D. American Psychiatric Association [Press release].
2 Joseph, J. (2012). The “missing heritability” of psychiatric disorders: Elusive genes or non-existent genesApplied Developmental Science, 16, 65-83.
3 Plomin et al. (2013). Behavioral Genetics (6th ed.). New York: Worth Publishers.
4 Yang et al. (2010). Common SNPs explain a large proportion of the heritability for human height.Nature Genetics, 42, 565–569.
5 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. (2013). The use of the classical twin method in the behavioral sciences: The fallacy continues. Journal of Mind and Behavior, 34, 1-39.
6 Plomin et al. (2013); Turkheimer, E. (2011). Still missing. Research in Human Development, 8,227-241.
7 Turkheimer (2011).
8 Trzaskowski, Eley, et al. (2013). First genome-wide association study on anxiety-related behaviours in childhoodPLoS ONE, 8(4), 1-7.
9 Viding et al. (2103). Genetics of callous-unemotional behavior in childrenPLoS ONE, 8 (7), 1-9.
10 Trzaskowski, Dale, & Plomin (2013). No genetic influence for childhood behavior problems from DNA analysis. Journal of the American Academy of Child and Adolescent Psychiatry, 52, 1048-1056.
11 Cross-Disorder Group of the Psychiatric Genomics Consortium. (2013). Identification of risk loci with shared effects on five major psychiatric disorders: A genome-wide analysis. Lancet, 381, 1371-1379.
12 Faraone, S. (2013). Real progress in molecular psychiatric genetics. Journal of the American Academy of Child and Adolescent Psychiatry, 52,1006-1008.
13 Kirk, Gomory, & Cohen. (2013). Mad Science: Psychiatric Coercion, Diagnosis, and Drugs. New Brunswick, NJ: Transaction.
15 Ho, M. (2013). No genes for intelligence in the fluid genome. In R. Lerner & J. Benson (Eds.), Advances in Child Development and Behavior, 45, 67-92. San Diego: Elsevier.

Jay Joseph
The Gene Illusion: Genetic theories and research in psychiatry, psychology, and other behavioral sciences from a critical perspective. I will provide a counterweight to the claims in the media and scientific literature that important genetic factors underlie psychiatric disorders and behavioral traits.

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