Chapter 2

The “Nonreplication Curse” In Schizophrenia Molecular Genetic Research

“Scientists have not identified a single gene that would meet any reasonable standard as a ‘gene for’ schizophrenia, intelligence, depression, or extraversion.”

—Behavioral genetic researcher Eric Turkheimer, in his 2015 review of The Trouble with Twin Studies65

“Finding and Losing” Schizophrenia Genes

Although there have been many claims that various genes are “associated” (correlated) with schizophrenia, decades of molecular genetic studies have failed to produce a single gene that causes it. In 2002, sociologist Peter Conrad described the pattern of gene discovery claims in psychiatry, followed by retractions and failures to replicate, as the “finding and losing” of such genes.66 Schizophrenia gene finding attempts appear to date back to a 1958 French study.67 In a 1973 study, another research group claimed that their “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.”68 A widely reported yet non-replicated schizophrenia “gene discovery” was published in 1988 by the Sherrington/Gurling group, who believed that they had found “the first strong evidence for the involvement of a single gene in the causation of schizophrenia.”69 A November 10th, 1988 front page New York Timesarticle about this study proclaimed, “Schizophrenia Study Finds Strong Signs of Hereditary Cause.” The Times also reported (subsequently non-replicated) schizophrenia gene discoveries in 1995, 1997, 2002, 2006, 2008, 2013, and (most likely) 2016.

In the mid-1980s, leading genetic researchers in psychiatry and behavioral genetics were preparing for the discovery of the genes they believed caused psychiatric disorders such as schizophrenia and bipolar disorder, in an era characterized by what leading behavioral genetic researcher Robert Plomin and his colleagues called in 2013 the “euphoria of the 1980s.”70 Also looking back in 2013, psychiatric geneticist Stephen Faraone wrote, “In the 1970s and 1980s, hope ran high as new methods in molecular genetics promised quick discoveries and answers to basic questions of etiology [cause] and pathophysiology.”71

The 1980s and 1990s did witness an explosion of molecular genetic research attempting to pinpoint the genes believed to underlie human behavioral differences and psychiatric disorders. This was followed by the publication of the initial working draft of the human genome sequence in 2001, which many researchers believed would lead to rapid gene discoveries in psychiatry and psychology. Faraone and his psychiatric geneticist colleague Ming Tsuang wrote in 1999, “From the perspective of psychiatric genetics, the Human Genome Project (HGP) is an immense factory producing and refining the tools we will need to discover the genes that cause mental illness.”72 And according to genetic researchers Kathleen Merikangas and Neil Risch, writing in 2003, “Completion of the human genome project has provided an unprecedented opportunity to identify the effect of gene variants on complex phenotypes, such as psychiatric disorders.”73 But it didn’t happen.

In 2013 Faraone described the frustrating “nonreplication curse” that had plagued psychiatric molecular genetic research “for decades.”74 Five years earlier, he and his colleagues had written in an academic journal that “it is no secret that our field has published thousands of candidate gene association studies but few replicated findings.”75 But in a sense non-replication is a secret because the general public has been told a very different story.

Gene Discovery Claims by Authoritative Experts

Over the years there have been several examples of authoritative genetic researchers and their supporters claiming schizophrenia gene discovery. Edward Shorter, in his biologically oriented 1997 A History of Psychiatry, claimed that “by 1995, the gene or genes causing schizophrenia had been tentatively placed somewhere on chromosome 6.”76 In 1997, Tsuang and Faraone wrote, “In our view, schizophrenia researchers appear to have found genes that exert a small effect on the onset of schizophrenia.”77

Prominent psychiatric investigator C. Robert Cloninger published a 2002 article entitled “The Discovery of Susceptibility Genes for Mental Disorders” in the prestigious Proceedings of the National Academy of Sciences, where he announced that genes for schizophrenia had been “discovered” in the summer of that year by three separate research teams.78 In 2003 the editors of Science, among the world’s top scientific journals, declared that the “identification” of “mental illness” genes was the second most important “scientific breakthrough” of the year.79 “Schizophrenia, depression, and bipolar disorder often run in families,” the editors of Science wrote, “but only recently have researchers identified particular genes that reliably increase one’s risk of disease.”

A team of psychiatric genetic researchers announced in 2004, “Schizophrenia genes have been found at last.”80 A year later, leading psychiatric geneticist and twin researcher Kenneth Kendler and a colleague wrote, “Despite years of pessimism, the first generation of linkage and association studies in schizophrenia has succeeded in identifying replicated susceptibility genes.”81 There are more examples. (In a survey covering the period 1997-2007, Kendler was the world’s 4th ranked psychiatric researcher in terms of the number of times his articles were cited. Stephen Faraone ranked ahead of him at #3. Michael Rutter was #5.)

Although follow-up studies failed to confirm these “breakthroughs” and “discoveries,” the public is largely unaware of the “nonreplication curse” and has been led to believe that “genes for schizophrenia” and other psychiatric disorders have already been discovered. One reason for this, in the words of a leading genetic researcher, is that “people working in the schizophrenia genetics field have greatly overinterpreted their results.”82 Researchers, laboratories, and universities are no doubt aware that public statements of discovery, optimism, and excitement attract more research funding and prestige than do public statements of failure, disappointment (video), and frustration. Typically, the news media follows right along.

The first molecular genetic methods were linkage and association studies. In a linkage study, researchers look for genetic markers linked with a disease gene among family members. Findings are represented as a logarithm of odds (LOD) score, which expresses the probability that the linkage occurred by chance. Linkage studies are designed to identify areas of the chromosome where relevant genes might be located, but are unable to identify actual genes. Association studies compare the frequency of genetic markers among unrelated affected individuals and a control group.

Since the completion of the Human Genome Project in the early 2000’s, psychiatry and other behavioral fields have placed hopes on the workhorse of “genome-wide association” (GWA) studies. These supposedly “hypothesis-free” studies use modern gene sequencing technology, which is constantly becoming cheaper, faster, and more-fine-grained, to rapidly scan markers across the genomes of ever-increasing numbers of affected and non-affected people to find common genetic variants associated with particular diseases or behaviors. GWA studies attempt to identify single-nucleotide polymorphisms (commonly known as “SNPs”) associated with the condition or characteristic under study. Another type of genetic variant is a CNV (copy-number variant), which falls into the rare variant category.

Molecular genetic studies are subject to methodological problems, a dependence on questionable assumptions, and potential environmental confounds.83 A confound is an unforeseen or uncontrolled-for factor that threatens the validity of conclusions researchers draw from their studies. Confounding occurs when the association between two variables is caused by a third variable that influences both (video).

The Schizophrenia “Gene Pond” Is Empty

Schizophrenia researcher Timothy Crow wrote in 2008 that molecular genetic researchers investigating disorders such as schizophrenia had previously thought that “success was inevitable—one would ‘drain the pond dry’ and there would be the genes!” But he concluded, “The pond is empty.”84 The schizophrenia “gene pond” remains empty of causative genes, or contains only “fool’s gold” false positive findings.85 “At best,” wrote the author of a 2017 Scientific American article, “the tangled genetic landscape of schizophrenia is…a series of faint hints of what causes the illness.”86 Indeed, to paraphrase psychologist Ken Richardson’s 2017 observation about failed attempts to discover genes for intelligence (IQ), the schizophrenia gene discovery bubble appears to be bursting.87

Nevertheless, new claims continue to pop up almost every year. In 2013 there appeared a highly publicized report from the “Cross Disorder Group” of the Psychiatric Genomics Consortium, whose authors claimed to have identified shared genes associated with five psychiatric disorders: autism spectrum disorder, attention/deficit-hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder, and schizophrenia.88 The Psychiatric Genomics Consortium (PGC) was formed in 2007 to study schizophrenia and other psychiatric disorders in light of previous failures. According to its website, “The purpose of the Psychiatric Genomics Consortium (PGC) is to unite investigators around the world to conduct meta- and mega-analyses of genome-wide genomic data for psychiatric disorders.” The PGC currently has over 800 collaborators in 38 countries, and has used samples from over 900,000 participants.89 It was formed on the basis of researchers’ and institutions’ willingness to share raw data and expertise in order to produce very large sample sizes. A 2014 study by the “Schizophrenia Working Group” of the PGC identified 108 regions of the genome it claimed were associated with schizophrenia.90

Another highly publicized gene discovery claim was the C4 variant “synaptic pruning” study published by Sekar and colleagues in 2016.91 This study was conducted by researchers at the Stanley Center for Psychiatric Research at the Broad Institute, located in Boston, Massachusetts (video). In 2014, the Institute received a $650 million funding commitment from a wealthy donor to help in the search for genes. Another group claimed in 2017 that thousands of genes are “associated with” schizophrenia. It is certain that more claims will appear in the future.92

Journalist Michael Balter wrote in a 2017 article that despite the news media’s tendency towards “overzealous enthusiasm,” given the historic “trail of disappointment” left by schizophrenia genetic research, media “hype” surrounding recent claims is “somewhat understandable.”93 On the contrary, because previous claims did not hold up, a healthy media response to new claims would not be enthusiasm or hype, but extreme skepticism and caution—similar to the “oh no, not again” skepticism and caution Peanuts comic strip character Charlie Brown responded with whenever Lucy van Pelt asked him to kick the football she was holding. We should assume by default that any new claim is a false positive finding, until proven otherwise.

Some dubious examples of behavioral molecular genetic “findings” include a 2005 association between two genes and “creative dance performance,” a 2006 claim of a gene association for “loneliness,” a 2014 claim that “some important genes…potentially impact the neural basis of crying in response to emotional stimulus,” a 2008 gene that predicted voter turnout in a U.S. presidential election, a 2010 claim that a particular gene “conferred an increased risk of joining a gang and using a weapon in a fight for males but not for females,” and a 2014 report of a gene “associated with credit card borrowing behavior.”94 Researchers claiming schizophrenia gene discoveries use similar methods to arrive at their conclusions.

Due to the epidemic of “genes for behavior” replication failures, in 2012 Behavior Genetics editor John Hewitt proposed raising the standards for accepting molecular genetic studies for publication. “The literature on candidate gene associations is full of reports that have not stood up to rigorous replication,” he wrote. “As a result, the psychiatric and behavior genetics literature has become confusing and it now seems likely that many of the published findings of the last decade are wrong or misleading and have not contributed to real advances in knowledge.”95 Nevertheless, leading scientific journals continue to publish large quantities of gene discovery claims for various psychiatric disorders and behavioral characteristics that history has shown are very unlikely to hold up. The journal Molecular Psychiatry seems to specialize in such publications.

The APA Contradicts Itself

The APA’s position on whether schizophrenia susceptibility genes have been discovered appeared in two versions in the spring of 2013. In an official May 3rd, 2013 APA press release, DSM-5 Task Force chair David Kupfer admitted that psychiatry has been “waiting” for the identification of “biological and genetic markers” for its disorders “since the 1970s”:

“The promise of the science of mental disorders is great. 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.”96

In the concurrently published schizophrenia section of the DSM-5, on the other hand, the APA wrote that “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.”97 This was an interesting claim because a major feature of the DSM-5, as its creators had conceptualized it almost a dozen years earlier, was the incorporation of expected “post-genomic era” psychiatric gene discoveries into its “multiaxial” diagnostic system—discoveries that never came.98 The main difference between the May 3rd 2013 press release and the 2013 DSM-5 is that hardly anyone knows about (or has read) the press release, whereas entire fields have been misinformed in at least 18 languages by the DSM-5’s claim that a “spectrum” of schizophrenia “risk alleles” has been identified.

New Molecular Genetic Methods Will Not Uncover Genes If They Do Not Exist

In his 2014 book Misbehaving Science: Controversy and the Development of Behavior Genetics, sociologist Aaron Panofsky described the processes and results of molecular genetic research in behavioral genetics, which are mirrored by genetic research in psychiatry.99 “Molecular genetics,” Panofsky wrote, “has been a major disappointment, if not an outright failure, in behavior genetics….This scientific failure has been a well-kept open secret.” Panofsky identified methods developed by researchers to cope with these failures, which include lowering their expectations, and “technological optimism.” The last method refers to researchers arguing (and hoping) that “the next level of technology will overcome past disappointments.” Yet as we have seen during the past four decades in psychiatry, it never does. Two more recently developed “next levels of technology” are “Genomewide complex trait analysis (GCTA),100 and “polygenic scoring.”101 As Crow put it in 2011, with “successive trawls with nets of decreasing mesh size, the genes fail to appear.”102 The obvious point is that if genes predisposing for schizophrenia and psychosis do not exist, molecular genetic research methods will not be able to “find” them.

But even in the unlikely case that some causative genes are eventually found, society and science could still choose to focus on environmental causes and interventions. This can help prevent symptoms from occurring in the same way that an anti-bullying campaign can help reduce the suffering of potential victims, regardless of whether or not they are genetically susceptible to psychological suffering caused by bullying. Joanna Moncrieff wrote that because “we know that poverty, unemployment, insecure attachments, familial disruption, low self-esteem, abuse etc. play a role [in causing schizophrenia]…we would be better concentrating on how to eliminate these from our society if we really want to reduce the impact of mental disorder, rather than pouring more money into the bottomless pit of genetic research.”103

When environmental causes are recognized and understood, the possible role of genetics becomes largely irrelevant. One of countless examples is that, because we know that concussions are caused by a blow to the head, we focus on attempts to protect people from experiencing blows to the head, rather than on determining the “heritability” of concussions and then searching for concussion vulnerability genes.104 The genetic predisposition concept in psychiatry speaks more to what researchers don’t know (or deny or de-emphasize) about the environment than it does to what they believe they do know about genetics.

The “Heritability” of Schizophrenia Is “Missing”

The current “missing heritability” era began around 2008. In psychiatry, the claim that “heritability is missing” is an attempt to explain the failure to identify genes that cause or predispose for psychiatric disorders by claiming that genes exist and await discovery once better methods are found, and larger samples are obtained.105 Two years prior to the appearance of “missing heritability,” I published a book entitled The Missing Gene: Psychiatry, Heredity, and the Fruitless Search for Genes.106 My use of the word “missing” in 2006, however, differed from the way that genetic researchers have used it since 2008. I argued, and continue to argue, that there is little if any scientifically acceptable evidence pointing to the existence of predisposing genes for the major psychiatric disorders. For people convinced that family, twin, and adoption studies have provided indisputable evidence in support of genetics—and I will argue in Chapters 3-5 that these studies have supplied no such evidence—genes are “missing” because researchers have not yet been able to find them, or because claimed gene associations or discoveries “explain only a small portion of the variance,” or possibly because heritability estimates are “inflated.”107

Problems with the “missing heritability” concept in psychiatry include the following points:

1. It is based on the mistaken belief that genes must be identified in order to understand human behavior, or to be able to treat and prevent psychiatric disorders (as opposed to simply reducing or removing symptoms)

2. It is based on researchers’ and psychiatry’s belief that previous family, twin, and adoption studies have established the genetic basis of schizophrenia and other psychiatric disorders beyond question (see Chapters 3-5 for an alternative view)

3. It assumes the validity of the controversial heritability concept itself (see below)

4. Based on point #2, psychiatric researchers reject in advance the possibility that genes for behavioral differences and psychiatric disorders do not exist. In doing so, they eliminate the possibility that they will interpret negative findings as evidence that the genetic hypothesis is incorrect, which renders it impossible to falsify. For example, in a 2003 essay, former head of the NIMH Thomas Insel and Human Genome Project leader Francis Collins wrote, “With the evidence of heritability in all of these [psychiatric] disorders, there is no question that susceptibility genes for all of these disorders will ultimately be found”108

Heritability: “One of the Most Misleading Terms in the History of Science”

The heritability concept was developed in the mid-20th century to help predict the results of selective breeding programs of farm animals, but was extended by behavioral geneticists and others into a measure of the degree of genetic influence on psychiatric disorders, and behavioral characteristics such as IQ and personality.109 A “heritability estimate” is a percentage ranging from 0% to 100% (or a number ranging from 0.0 to 1.0). Heritability estimates are derived from correlations among relatives, most often from the results of twin studies. They are also produced by more complex, yet controversial, “biometrical model fitting” procedures, which attempt to test the “fit” between a model of genetic and environmental relatedness against the observed data.110 As Plomin and other leaders of the behavioral genetics field defined it, heritability is “the proportion of phenotypic differences among individuals that can be attributed to genetic differences in a particular population.”111 For Plomin, a heritability estimate indicates “how much genetics contributes to a trait.”112

It is claimed that heritability estimates measure the relative magnitude of environmental and genetic influences on psychiatric disorders. In 1967, Gottesman and his frequent collaborator James Shields wrote that heritability estimates quantify the “degree of genetic determination” of schizophrenia. And according to Faraone and Tsuang, “Heritability measures the degree to which the vulnerability to develop a disorder is influenced by genes.”113 Heritability estimates are widely used in psychiatry as an indicator of the supposed strength of genetic influences on a given disorder, and are used to guide molecular genetic research. The “heritability of schizophrenia” estimate, based mainly on twin research, is widely reported by mainstream sources as around 80%.114

The usefulness and validity of the heritability concept and accompanying heritability estimates, however, has “been the subject of unrelenting criticism from philosophers, biologists, and psychologists” for decades.115 Critics have argued convincingly that heritability estimates do not and cannot indicate the “degree of genetic influence” on psychiatric disorders and behavioral characteristics. Heritability estimates are based on the assumption that genetic and environmental influences are separate (additive) and do not interact, and that genetic and environmental variances can be partitioned in a way that indicates the relative strengths of each potential influence. It is clear, however, that genes and environments do interact, meaning that the additivity assumption is wrong.116 As Lewontin wrote, “If these causes ‘interact’ in any generally accepted meaning of the word, it becomes conceptually impossible to assign quantitative values to the causes of that individual event. Only if the causes are utterly independent could we do so.” According to developmental researcher Michael Meaney, “research in biology reveals that the genome cannot possibly operate independent of its environmental context.”117

According to psychologist David Moore and his co-author David Shenk, “The term ‘heritability’…is one of the most misleading in the history of science,” because “contrary to popular belief, the measurable heritability of a trait does not tell us how ‘genetically inheritable’ that trait is. Further, it does not inform us about what causes a trait, the relative influence of genes in the development of a trait, or the relative influence of the environment in the development of a trait” (italics in original).118 Some have argued that a heritability estimate serves no valid purpose apart from its original use as a predictor of the results of a selective breeding program.119

Although mainstream researchers will continue to cite family, twin, and adoption studies in support of their contention that behavioral characteristics and psychiatric disorders are influenced by genetic factors, Moore and Shenk wrote that when researchers assign a heritability estimate to such claims, it “does enormous damage to the public understanding of how human beings develop their individual traits and identities.”120 For this reason, although here I evaluate the evidence cited in support of the claim that schizophrenia has an important genetic basis, I will not address the dubious question of whether schizophrenia heritability estimates are “too high” or “too low.”121 It is not the task of critics to establish the “true heritability” of schizophrenia, or to demonstrate that it is zero, but rather to cast doubt upon the claim that the “heritability of schizophrenia” qualifies as a valid concept.

“Variation Explained by” Is Not the Same as “Strength”

As an example of how heritability estimates do not measure the “strength” or “magnitude” of genetic influences, we can look at favism (glucose-6-phosphate dehydrogenase deficiency), a disease marked by the development of hemolytic anemia. Favism is caused by a deficiency of glucose-6-phosphate caused by a genetic variant located on the X chromosome, combined with the consumption of fava (broad) beans or the inhalation of fava bean pollen. In other words, both “beans and genes” are necessary for favism to appear. (Because it is a sex-linked condition, favism is most often diagnosed in males. For the purposes of the example below, I will treat it as though males and females are equally susceptible.)

Imagine “Country A,” where all citizens (100%) carry the gene predisposing them to favism, but only 3% of them consume fava beans. Because all citizens carry the gene (zero genetic variation), but only some eat fava beans, all favism variation in Country A would be caused by environmental factors (fava bean consumption), and the heritability of favism would be 0%. Yet it would be quite mistaken for Country A scientists to conclude that genes play little or no role in causing the disease in their country. In fact, a genetic predisposition is a requirement for developing favism.122

Then imagine “Country B,” where all citizens (100%) eat a diet that includes fava beans, but only 3% of them carry the favism gene. Because all citizens eat fava beans (zero environmental variation), but only some carry the gene, all favism variation in Country B would be caused by genetic factors (carrying the gene), and the heritability of favism would be 100%. Yet it would be quite mistaken for Country B scientists to conclude that consuming fava beans plays little or no role in causing the disease in their country. In fact, consuming fava beans is a requirement for developing favism

As we see, heritability is about variation, not cause, and does not indicate the “strength” or “weakness” of the genetic influence—or by implication the strength or weakness of the environmental influence. In the above examples, the “heritability of favism” is 0% in Country A, and 100% in Country B, even though the causes of favism are the same in both countries. As Moore concluded, “Because heritability statistics are about accounting for variation and not about causation, they do not actually reflect the strength of influence of genes on the development of a trait, even if it seems like they do.”123 And yet, as Panofsky observed, with ongoing gene discovery attempts “failing to deliver,” molecular genetic researchers “grasp onto” heritability estimates “as a lifeline to justify their work.”124


In the following three chapters I will focus on the major problem areas in earlier schizophrenia family, twin, and adoption research, with a special emphasis on the widely cited Danish-American schizophrenia adoption studies of the 1960s-1990s. The most likely reason that genes that cause schizophrenia have not been found, after decades of attempts to discover them, will become more apparent by the end of this review.

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