In a 2022 article I made the case that, contrary to the consensus view, there exists no valid evidence that genes play a role in causing schizophrenia (psychosis). I made the complete case in the 2023 Routledge English-language Edition of Schizophrenia and Genetics: The End of An Illusion (a greatly revised version of a previously self-published e-book). The current article is adapted from sections of Chapters 3 and 6 of Schizophrenia and Genetics, where I examined a 2020 popular work whose author promoted psychiatry’s problematic “heritability of schizophrenia” story. In this article I add expanded analyses, much new information, and updates.
The general theme of books and articles appearing since the 1980s popularizing behavioral genetic and psychiatric genetic research starts with supposedly misguided environmentalist and psychoanalytic ideas that “mental disorders” are sometimes caused by “refrigerator mothers” or “schizophrenogenic mothers.” After bashing these strawmen, the story continues that environmental theories of causation were eventually discredited by scientists performing family, twin, and adoption studies, some of whom went on to discover predisposing genetic variants (hereafter “genes”) at the molecular genetic level. That’s the story, but is it the true story?
The Galvin Family, Abuse, and “Schizophrenia”
Continuing these themes, in 2020 journalist Robert Kolker published Hidden Valley Road: Inside the Mind of an American Family (hereafter HVR; previously reviewed in a 2020 MIA article by Patrick Hahn). This was the tragic story of a real White middle-class family of 14. Don and Mimi Galvin had 12 children, born between 1945 and 1965. They lived at the end of an isolated unpaved road in Colorado Springs, Colorado, USA. This is how Stephen Rodrick of Rolling Stone described the Galvin family:
“On the surface, the Galvins were a postwar American dream. Don was a World War II veteran helping to jump-start the just-opened Air Force Academy in Colorado Springs alongside his witty and selfless wife. The first 10 Galvin kids, born beginning in 1945, were handsome boys who became high school football and hockey stars in their growing boomtown. Two beautiful daughters, Lindsay and Margaret, followed them. The Galvins lived on the outskirts of the city, on Hidden Valley Road, and were the envy of other families throughout Colorado Springs.”
Of the ten Galvin boys, six were eventually diagnosed with schizophrenia, including the fourth-born Brian who committed murder-suicide in 1973 at age 22. They also were diagnosed with other psychiatric conditions. Kolker recognized in an interview that “these brothers were all different and manifested their illnesses differently.” Although psychiatry lumped the brothers’ differing behavioral patterns under the “schizophrenia” umbrella, others could conclude that they experienced six different “illnesses.” In keeping with psychiatric orthodoxy, Kolker saw schizophrenia as a “complex disease” and a “brain condition.”
My specialty is analyzing genetic research in psychiatry and other behavioral science areas, and therefore the genetic research aspects of HVR are the focus of this article. The concept of “schizophrenia” is itself controversial, as are psychiatry’s criteria for determining who gets this label. The term “psychosis” to describe people’s experiences is preferable. These issues have been examined by many authors over the years.
Critics of Genetic Research Were Left Out of the Story
It is an enormously difficult task for a non-scientist journalist like Robert Kolker to jump into a field and to write a book about 100 years of research, and the at times heated controversies surrounding it. I am a clinical psychologist who has been writing on the genetics of schizophrenia topic for 25 years (including a doctoral dissertation and three books). To get the facts right (hopefully), I still need to get help from colleagues, review and edit countless drafts, reread articles and books, and stay up to date on the latest research and commentaries, which includes needing to understand molecular genetic research publications I was never trained to understand. So while I recognize and appreciate how challenging this task must have been for Kolker, I wish he had interviewed and discussed the works of genetic research critics to present all sides of the story.
Kolker did mention people who have promoted environmental theories of schizophrenia, but he did not address points raised by the critics of schizophrenia family, twin, adoption, and molecular genetic research. While I admire Kolker’s ability and willingness to jump into the contentious and complex “genetics of mental disorders” debate, I am duty bound to highlight the errors he made, and to show that the story he told about genetics is a mistaken one.
“Running in the Family” ≠ Genetic
Contrary to the commonly held view, “running in the family” does not equal “it’s genetic,” because families share a common environment as well as common genes. In the 2020 second edition of How Genes Influence Behavior, Jonathan Flint and Kenneth Kendler, two of the world’s leading psychiatric genetic researchers, recognized that a condition running in the family can be caused by the common environment families share:
“In human families, relatives can be similar because they share environments or because they share genes, or both. Relatives share all kinds of environments. They live in the same neighborhoods, often attend religious services together, eat a similar diet, are exposed to the same level of harmony or conflict in their home, and might all live close to an industrial plant that pumps out pollution into the air or water. All of these reasons and more could explain the resemblance among members of the same family.”
On this single point, that a condition running in the family cannot be interpreted genetically, psychiatric geneticists and the field’s critics are in agreement. This means that, as Flint and Kendler acknowledged, theoretically the prevalence of psychosis in the Galvin family could have been caused by environmental influences, by hereditary influences, or by a combination of both.
Kolker mentioned the “paradox” that “schizophrenia does not appear to be passed directly from parent to child.” Indeed, in a 2006 Swedish study based on a population-based cohort of over 7 million individuals, researchers found that in families where one member was diagnosed with the supposedly “highly heritable” schizophrenia condition, in more than 96% of these families there were no other similarly diagnosed members. The Galvin family psychosis cluster was an unfortunate aberration.
“Torrents” of Sexual Abuse
Kolker described how sexual abuse was rampant in the Galvin family. There was no escaping it. For the youngest child Lindsay, “it seemed as if” the second-born Galvin son Jim, who was 18 years her senior, “had taken [sexual] liberties with every young child around him.” She told her mother Mimi “that she had been sexually abused by her brother Jim countless times over several years.” Other siblings may have had similar stories.
Adding another layer of abuse and trauma, Mimi believed that a trusted Catholic priest, who was also a family confidant, had been sexually “pursuing her boys like boxes of cereal at the supermarket until he found the one he liked the best. ‘He had culled my family,’ she said. ‘He knew it was a big family of boys.’” The oldest son Donald, who had been a church altar boy and made two suicide attempts at age 12, was sexually abused by this trusted priest. His later “schizophrenia symptoms” included a preoccupation with religious matters and the reciting of prayers for days on end.
Mimi Galvin herself had been a victim of childhood sexual abuse, and was understandably overwhelmed by the task of parenting and protecting 12 children in relative isolation with a frequently absent husband.
So now we have identified sexual abuse as a major non-genetic source of psychological distress and “psychopathology” in the Galvin family. Although he acknowledged a role for environmental factors, for Kolker it’s mainly genes that tell the story of psychosis in this family, stating flatly, “Sexual abuse does not cause schizophrenia. That much is certain. Even a torrent of sexual abuse like what Mimi had envisioned still could not answer the bigger question of why there had been so much mental illness in their family.” A torrent of sexual abuse. Kolker went further and declared, “to be sure, no studies have ever suggested that abuse does cause schizophrenia.” Who was telling him such things?
As reviewed by psychologist John Read in several chapters in the 2013 second edition of Models of Madness and in a later publication, since the turn of the 21st century studies have linked schizophrenia and other psychotic conditions to childhood adversities such as having experienced bullying, emotional abuse, incest, neglect, parental loss, physical abuse, and sexual abuse—adversities and trauma that clinicians who work with people diagnosed with psychotic disorders are well aware of. Since then, other studies have supported a link between schizophrenia/psychosis and childhood adversity and trauma.
The Galvin sons also were abused by the psychiatric establishment. At one point Peter Galvin was taking six different prescribed neuroleptic (“anti-psychotic”) drugs at the same time: Geodon, Risperdal, Risperdal Consta (a long-acting injectable form of Risperdal), Zyprexa, Prolixin (another long-acting injectable), and Thorazine. Jim and Joe Galvin both died at the age of 53 from a condition known as “neuroleptic malignant syndrome,” which refers to poisoning caused by years of taking prescribed neuroleptic drugs. According to Kolker, Mimi “had no compunction about saying that Jim and Joe both died of the medicine that was supposed to help them.”
Enter Robert Freedman and Lynn DeLisi
Having knocked down the beleaguered “schizophrenogenic mother” strawman yet again, and after eliminating trauma and even “torrents” of sexual abuse as possible causes of schizophrenia and psychosis, Kolker promoted gene-centered explanations while largely overlooking the fact that reared-together siblings influence each other’s behavior and are not diagnosed with schizophrenia independently of each other. He believed that diagnosing schizophrenia is “more of an art than a science.” Because there are no biological tests for schizophrenia, one aspect of this “art” has always been that doctors’ and psychiatrists’ diagnoses are influenced by the idea that “if your siblings (or your identical co-twin) have schizophrenia, the behavior that brought you to my office makes me think you probably have it too.”
Kolker featured the work of two psychiatric researchers who, with the help of Galvin family blood samples, supposedly had helped uncover schizophrenia’s biological/genetic roots. The two were Robert Freedman of the University of Colorado Medical Center in Denver, who pinned hopes on the CHRNA7 gene, and Harvard professor of psychiatry Lynn DeLisi, who focused on the SHANK2 gene in collaboration with neurobiologist Stefan McDonough and others. Freedman “was on the hunt for a physiological understanding of” schizophrenia, whereas DeLisi, “wanted to track down the genetic components of schizophrenia.” What DeLisi and Freedman would learn from the Galvin family, wrote Kolker, “helped unlock our understanding of the disease.” (Kolker also mentioned another group’s 2016 finding of a supposedly landmark association between the C4 gene and schizophrenia. A 2022 study, however, found no evidence for a C4-schizophrenia link.)
Kolker didn’t say it’s a proven fact that SHANK2 and CHRNA7 play a role in causing schizophrenia, but for him the likelihood that they do was strong enough to portray Freedman and DeLisi as gene discoverers (he referred to their work as gene “discoveries” on pages 246, 247, and 272). Undoubtedly, Freedman and DeLisi were motivated by a desire to prevent and better treat human suffering and dysfunction, but the winners of the “genes for schizophrenia” hunt also stand to receive prizes and professional honors, and possibly to reap financial rewards.
In theory, scientific research is the unbiased process of identifying the underlying causes of observed phenomena in nature. In the world we currently live in, this process is often distorted and even corrupted by the needs of corporations and governments to increase profits and to justify maintaining the social and political status quo, which includes financially rewarding people and institutions that help them achieve these goals. There’s a gold rush aspect of psychiatric molecular genetic research.
While recognizing that environmental factors or triggers are necessary to produce schizophrenia, Kolker portrayed Freedman and DeLisi as having helped seal the case against the misguided supporters of purely environmental (non-genetic) theories. He emphasized that Hidden Valley Road “is a work of non-fiction,” but as I will show, there are fictional aspects to the story he told about CHRNA7 and SHANK2.
The Historic Candidate Gene Era “Flop”
Both Freedman and DeLisi studied the Galvins and other families in search of “candidate genes” that play a role in causing schizophrenia. A psychiatric candidate gene association study attempts to identify genetic influences on a condition by generating hypotheses about it, and then identifying genes that might play a role in causing it. Genes become schizophrenia “candidates” based on their role in influencing brain functions believed to be related to the condition. A candidate gene has been defined as “a gene believed a priori to be involved in the pathophysiology of the disorder.”
What Kolker didn’t tell us, presumably because he didn’t know, is that the psychiatric candidate gene effort that began in the early 1990s ended as an expensive bust. The major depression candidate gene literature, for example, turned out to be, as psychiatric drug researcher Derek Lowe wrote in a 2019 Science article, “all noise, all false positives, all junk.” In his 2018 book Blueprint: How DNA Makes Us Who We Are (which I reviewed in the Winter, 2022 edition of the American Journal of Psychology), one of the world’s leading behavioral geneticists, Robert Plomin, described over two decades of behavioral candidate gene research as an “approach [that] failed everywhere,” a “fiasco,” and a “flop.” By Plomin’s 2018 count, for schizophrenia alone “over 1,000 papers reported candidate gene results for more than 700 genes.” Plomin then asked, “how can so many published papers have got it so wrong?”
In the 2020 edition of How Genes Influence Behavior, Flint and Kendler (and Ralph Greenspan) conceded that in the end, “literally thousands” of physiological candidate gene papers “have taught us nothing useful about the genetic basis of psychiatric disease.” As psychologist Stuart Ritchie commented in 2020, “reading through the candidate gene literature is, in hindsight, a surreal experience: they were building a massive edifice of detailed studies on foundations that we now know to be completely false.”
Patrick Sullivan co-founded the Psychiatric Genomics Consortium (PGC) in 2007, and is one of the world’s leading psychiatric genetic researchers. In a 2017 article, he described psychiatric candidate gene studies, which cost hundreds of millions of dollars, as being based on “guesswork,” and that his “field was pretty bad at guessing.” Sullivan concluded that “historical candidate gene studies didn’t work, and can’t work,” and “I strongly suggest that we abandon candidate gene guesswork (as historically applied) as they have only provided false directions and wasted effort.”
The initial excitement and numerous subsequent discovery claims accompanying psychiatry’s candidate gene goldrush eventually gave way to the crushing realization that all that had been found was genetic fool’s gold, and that the method should be “ditched.”
The CHRNA7 Gene
Linkage study failure. Kolker wrote in HVR that a 1997 Freedman et al. molecular genetic linkage study “identified CHRNA7 as the first gene ever to be definitively associated with schizophrenia. He and his colleagues had made history.” However, schizophrenia linkage research (described here), which began with high hopes in the 1980s, also turned out to be a flop. In a 2000 article, Lynn DeLisi concluded that “on close inspection,” Freedman’s 1997 study found no linkage to the schizophrenia “illness,” based on “8 families afflicted with schizophrenia.” And in a subsequent analysis by DeLisi and colleagues, appearing five years after Freedman’s supposedly “historic” schizophrenia linkage discovery, the authors concluded, “No linkage appears to be consistently replicable across large studies. Thus, it has to be questioned whether the genetic contribution to this disorder is detectable by these strategies…”
Kolker’s source for his claim that “Freedman discovered the first gene ever to be definitively associated with schizophrenia” was Denver Post staff writer Carol Kreck, the author of a 1999 article for the newspaper. It is unclear whether Kreck came up with this “first discovery” claim on her own, or whether someone fed it to her.
Candidate gene study failure. Returning to candidate gene research, Kolker apparently was unaware of the 2015 schizophrenia candidate gene analysis published by M. S. Farrell and leading researchers who concluded, specifically in relation to CHRNA7 and other schizophrenia candidate genes, “We can state with high confidence that the large common variant genetic effects originally reported in many initial candidate gene studies are highly unlikely to be true.” In a 2017 assessment of CHRNA7 and 24 other widely studied schizophrenia candidate genes, Emma Johnson and colleagues found that “variants in the most-studied candidate genes were no more associated with schizophrenia than were variants in control sets of noncandidate genes.” Final nails in the CHRNA7 coffin, it would seem.
Although schizophrenia candidate gene research had already achieved “flop” status by the time Kolker was researching and writing his book, he described how one of the Galvin daughters “remembered champagne being popped as she walked into Freedman’s lab,” where the supposed “CHRNA7 discovery” was being celebrated as she sought advice on whether she and her husband should have children.
Presumably no champagne flowed in the aftermath of a 2008 candidate gene study Freedman himself co-authored, with the title “No Significant Association of 14 Candidate Genes With Schizophrenia in a Large European Ancestry Sample: Implications for Psychiatric Genetics.” This study found no significant association between CHRNA7 and schizophrenia. The results, according to Freedman’s own study, “were consistent with chance expectation.” This 2008 study was not mentioned or referenced in HVR. Similarly, Freedman failed to mention or reference it in his 2010 book The Madness Within Us: Schizophrenia as a Neuronal Process, where he called CHRNA7 a “gene associated with schizophrenia.” In a 2006 chapter Freedman co-wrote with Patrick Sullivan and others in The American Psychiatric Publishing Textbook of Schizophrenia, CHRNA7 was not listed among the nine “best current candidate genes for schizophrenia.”
Patenting CHRNA7. Freedman told Kolker he was an “unpaid advisor” to the drug companies. However, although unmentioned in HVR, Freedman and a colleague applied for a CHRNA7 patent in 2003 (backed by a 104-page application-support document), and they were granted this patent in 2009. A disclosure statement published that year in the American Journal of Psychiatry, which Freedman edited at the time, stated, “Dr. Freedman holds a patent through the VA [U.S. Department of Veterans Affairs] for discovery of a genetic variant in schizophrenia.” A 2015 Freedman publication stated that this patent was for CHRNA7: “Dr. Freedman has a patent on the genomic structure of CHRNA7 and SNPs in the promoter through the Department of Veterans Affairs. He derives no income from this patent.” The statement did not say whether he stood to earn future income from the patent, but it is likely that the VA and others would profit from the production of future drugs and tests based on CHRNA7, were it shown to be a true biological marker for schizophrenia. It seems that Freedman patented the gene in part to profit in the future from tests in the same way as Myriad Genetics had patented the BRCA1 and BRCA2 breast cancer genes for that purpose in the 1990s. What Freedman told Kolker about CHRNA7 in their “extensive interviews” may have been influenced by the former’s financial and professional stake in the gene.
The ability to patent genes is controversial (the U.S. Supreme Court ruled against some aspects of gene patenting in 2013), and the ethics of researchers and institutions patenting existing parts of the human body, and potentially harming patients and discouraging future research by doing so, is questionable (see this video). The website disclosing information about Freedman’s CHRNA7 patent called it a “method of identifying individuals predisposed [to] schizophrenia.” The website shows that the patent expired in September, 2017 due to a “failure to pay maintenance fees,” but was renewed at a later date and is currently paid through February, 2024.
The previously mentioned articles and analyses by leading psychiatric genetic researchers and others documenting the failure of CHRNA7 and the entire behavioral candidate gene era were available as Kolker was researching and writing his book. Had he been aware of these publications and understood their implications, he might have described the Freedman laboratory’s champagne party as one of countless examples of “surreal” celebrations of failed psychiatric candidate gene “guesswork.”
The SHANK2 Gene
Turning to DeLisi’s SHANK2 gene, schizophrenia genetic review articles rarely mention it. In a biologically oriented 2022 review article on schizophrenia appearing in The Lancet, for example, there was no mention of SHANK2 (or CHRNA7). A January, 2023 PubMed.gov search for the combined terms “SHANK2” and “schizophrenia” returned only 21 articles since the publication of a 2016 article DeLisi co-authored on the topic, where she and her colleagues wrote that SHANK2 “represents a compelling candidate for a high penetrance variant.” Four years later, in the wake of the candidate gene collapse, DeLisi received the International Society of Psychiatric Genetics “Ming Tsuang Lifetime Achievement Award,” in addition to a similar award in 2022 from the Schizophrenia International Research Society. In the statements describing her achievements, there is no mention of SHANK2.
In the 2017 (most recent) edition of DeLisi’s popular book 100 Questions & Answers About Schizophrenia: Painful Minds, despite devoting many pages to genetics, the terms “SHANK” or “SHANK2” do not appear even once. Scientists usually mention their discoveries in the books they write.
DeLisi published an academic journal article on schizophrenia genetics in 2022, where she wrote of gene discovery in multiplex families like the Galvins as a goal for future research, but not as a something that had been achieved. (In “multiplex” families, multiple individuals are affected by a specific disease or condition.) Towards the end of her long career in psychiatric genetic research, DeLisi could not claim any gene discoveries in multiplex families:
“Unfortunately, so many gaps exist in our understanding of normal brain development and variation, that it is difficult to put together this puzzle in its complete form so far by finding unique mutations in multiplex families.”
DeLisi mentioned Kolker and Hidden Valley Road in this 2022 article, writing that Kolker “suggests with some ‘literary license’ that science has made lots of progress.” DeLisi said that Kolker “describes how several years of persistent research on this family paid off with the finding that a mutation in the SHANK-2 gene appeared to be present in all the affected individuals,” but she distanced herself from Kolker’s description. SHANK2 also was found in the “unaffected mother” (Mimi Galvin), wrote DeLisi, and later was “found to be present in one of the unaffected female siblings and her female offspring…All three of the females had a previous lifetime history of major depression, but none had a psychosis.” The source DeLisi gave for these findings was “DeLisi, unpublished data,” and the question then becomes why these findings were not published.
The SHANK2 candidate gene theory that DeLisi at best saw as inconclusive, and which was not mentioned in her book on schizophrenia or in lifetime achievement award statements, was presented to the world by Kolker as the likely gene “mutation responsible for the [Galvin] family illness,” and as a major component of “the genetic flaw that caused schizophrenia in the Galvin boys.”
Genetic Insider Accounts and Genome-wide Association Studies (GWAS)
Although a major theme of Hidden Valley Road was that CHRNA7 and SHANK2 were real or probable schizophrenia gene discoveries—even as the evidence suggested they were in fact non-discoveries—Kolker did provide some interesting insights into how schizophrenia molecular genetic researchers privately viewed their results, based on the many conversations and interviews he had with them. DeLisi favored the approach of looking for schizophrenia genes in multiplex families like the Galvins, whereas the GWAS (“genome-wide association study”) approach beginning in the period 2005-2007 compares genes among large groups of diagnosed and non-diagnosed people. A GWAS might indicate an association (correlation) between genetic variants and a given condition, but it does not provide evidence that genes play a role in causing the condition. Correlations are not causes, and may in fact be spurious correlations and/or the result of systematic error, as schizophrenia linkage and candidate gene researchers learned the hard way (see this excellent analysis by Evan Charney).
DeLisi shared her thoughts about schizophrenia GWAS research with Kolker. “I don’t believe that these hundred genes or markers are going to lead to anything,” she told him (in reference to a 2014 GWAS). Indeed, “hypothesis-free” GWAS publications have reported all kinds of improbable “findings” in the past few years, including the discovery of statistically significant gene associations (“hits”) for characteristics such as getting concussions, self-reported childhood maltreatment, crying habits, female sexual dysfunction, food liking, household income, ice cream flavor preferences, leadership traits, loneliness, being a morning person, musical beat synchronization, risk taking behavior, regular attendance at a sports club, pub, or religious group, sexual behavior, and white wine liking. These supposed findings are enormous red flags for potentially spurious results in schizophrenia GWAS investigations, just as similar candidate gene “findings” were enormous red flags during the candidate-gene era. The behavioral GWAS era will likely experience the same fate as the failed linkage and candidate gene eras.
Kolker described earlier GWAS investigations as a “blistering disappointment,” which led researchers to “double down” and resolve “to build a bigger and better GWAS.” The disconnect between researchers’ private “blistering disappointment” and public discovery claims and dauntless optimism is stunning, as the issue now seems more related to institutions maintaining government and corporate grants, individual researchers protecting salaries and corporate “consultation fees,” the possibility of striking it rich with drug patents and direct-to-consumer and other types of tests, reputations, and being published in prestigious journals.
Speaking about the candidate gene era, Plomin hinted in Blueprint at corrupted aspects of the behavioral science research publication process when he attributed failure in part to “chased” probability values and “cheating,” practices otherwise known in the current scientific replication crisis as “p-hacking.” P-hacking describes the practice of researchers consciously or unconsciously manipulating definitions and data, behind the scenes, to transform non-findings into publishable career-enhancing “findings” that fall below the conventional .05 level of statistical significance.
DeLisi, Freedman, and Kolker on the Danish-American Schizophrenia Adoption Studies
Psychiatry justifies molecular genetic research by the belief that previous family, twin, and adoption studies established schizophrenia as a genetically based disease, beyond any doubt. As I argued in Schizophrenia and Genetics, this belief constitutes the fundamental error of schizophrenia gene-finding strategies. DeLisi, Freedman, and Kolker all saw Seymour Kety, David Rosenthal and colleagues’ 1968 Danish-American adoption studies, which used three main research designs, as signaling a historic turning point in support of psychiatric genetic theories of schizophrenia, yet none appeared to understand the basic design of these studies.
In the 2017 edition of 100 Questions & Answers, DeLisi wrote that in the Kety-led 1968 study, the “investigators showed that an excess of schizophrenia was present in the biological relatives of individuals with schizophrenia, but not the adoptive relatives.” In fact, Kety and colleagues did not make that comparison, and Kety himself called such a comparison “fallacious” and “improper.”
DeLisi, Freedman, and Kolker said that the Danish-American researchers counted diagnoses of “schizophrenia,” when in fact they counted what Kety and Rosenthal called “schizophrenia spectrum disorders” ranging all the way down to “uncertain borderline schizophrenia,” “uncertain acute schizophrenia,” “inadequate personality,” “vague schizoid tendencies,” and “perversion.” Anyone who reads the original research publications will see that Kety, Rosenthal et al. counted these vaguely defined mostly non-psychotic conditions/judgements as “schizophrenia.” In the previously mentioned DeLisi 2022 publication, she continued to misrepresent and misunderstand how the Danish-American studies were performed.
As Rosenthal once admitted, he and his colleagues “broadened the definition of schizophrenia as widely as it may have ever been reasonably conceived before.” Even this was an understatement, in part because Rosenthal counted “manic-depressive psychosis” as a schizophrenia spectrum disorder at the same time as he viewed schizophrenia and manic-depression as “genetically distinct and different disorders.”
The molecular genetic studies that DeLisi, Freedman and many others performed were based on schizophrenia diagnostic criteria found in the 1994 fourth edition of American psychiatry’s Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), meaning that they defined schizophrenia very differently from the way the adoption researchers who inspired their work defined it. Schizophrenia molecular genetic researchers continue to study a very different “disorder” from the one Kety and Rosenthal studied.
In The Madness Within Us, Freedman wrote, in reference to earlier twin studies, that the “environmental factors” experienced by MZ (identical) and DZ (fraternal) twin pairs “should about equalize in the two different types of twins.” Whether or not these environments should equalize, they don’t by a longshot, as almost everyone else in the world—including most twin researchers—understands.
Freedman believed that the Danish-American adoption studies provided the “most dramatic proof that schizophrenia is a heritable illness.” As he wrote in The Madness Within Us:
“The demonstration that the risk for schizophrenia in children of mothers who have schizophrenia remains, even if the child is adopted by another mother close to the time of birth, was historically the most dramatic proof that schizophrenia is a heritable illness and hence a biologically based outcome, rather than a psychologically based outcome.”
This is a rough description of the design used in the Rosenthal-led “Adoptees” study, which started with schizophrenia spectrum disorder biological parents as the first-identified relatives or “probands.” However, Freedman cited a Kety et al. 1971 article that described the Kety-led “Adoptees’ Family” study, where the design used adoptees, not parents, as the probands.
A major reason why Kolker believed that the case for genetic explanations was airtight, and that family dynamics explanations were weak or discredited, was that the Danish-American adoption studies had confirmed the earlier alleged “gold standard” findings from twin research. Kolker said that the famed psychiatrist Emil Kraepelin published the first schizophrenia twin study in 1918. In fact, Kraepelin never performed or published such a study. In Schizophrenia and Genetics, I explained in two chapters why twin studies fail to provide any evidence in favor of genetic influences.
Kolker believed that the Danish-American adoption studies showed that family environments play little if any role in causing schizophrenia or psychosis. In Chapter 14 of HVR, he briefly described these studies as they were first presented at a famous 1967 conference on schizophrenia research, held at Dorado Beach, Puerto Rico and published in book form the following year. His descriptions were at times inaccurate, and he did not seem to have a firm grasp on how these studies were performed. For example, Kolker said that the Kety-led study’s control group consisted of “schizophrenia patients who grew up in their own families,” which is not true. The actual control group consisted of the first- and second-degree biological relatives of adoptee probands not diagnosed with a schizophrenia spectrum disorder.
Kolker is far from being the only writer to get the Kety-led study’s control group wrong. In Schizophrenia and Genetics and earlier publications I showed that the authors of textbooks and important works, including leading psychiatric and psychiatric genetic researchers, routinely misrepresent adoption studies’ methods and results.
Kolker wrote that at Dorado Beach, Rosenthal “discredited the idea that bad parenting created the [schizophrenia] disease.” I am not aware of Rosenthal making such a statement, and in his Dorado Beach conference summary chapter, Rosenthal concluded only that “intrafamilial” and other environmental factors had not been “proved.” He didn’t say these factors were discredited.
Rosenthal’s own study found no evidence in support of genetics. It is fascinating to note that the famous and widely cited Adoptees study Rosenthal and colleagues presented at Dorado Beach, and published in 1968, produced no statistically significant results in the genetic direction, and Rosenthal did not claim to have obtained such results. Based even on Rosenthal’s 1968 extraordinarily broad definition of what counted as a schizophrenia spectrum disorder, the results were Index group adoptees 13/39 (33%) versus Control group adoptees 7/47 (15%). The one-tailed probability value for this Index-Control group comparison is .07, not statistically significant at the .05 level used in the Danish-American studies and most areas of science. The actual result of Rosenthal’s 1968 study, therefore, was a failure to discover genetic influences on schizophrenia (a result confirmed ten years later in this Rosenthal publication).
Kolker said that at Dorado Beach, Rosenthal “declared that biology…appeared to explain nearly every single documented instance of the illness,” and that it “seemed to” Rosenthal that his findings provided “proof that nature, not nurture, won the argument.” Whatever Rosenthal may have declared or allegedly proved about schizophrenia, the negative results of his own 1968 Adoptees study led to the opposite conclusion.
In contrast to Rosenthal’s 1968 Adoptees study, Kety’s 1968 Adoptees’ Family study did report statistically significant results. However, Kety and colleagues achieved these results only by engaging in “questionable research practices” such as greatly expanding the definition of schizophrenia after unexpectedly failing to find enough traditionally defined cases to perform the study, by dismissing or downplaying the impact of potential environmental confounds (such as the selective placement of adoptees), by including “homosexuality” as a schizophrenia diagnostic indicator, and by changing group comparisons at the last minute to avoid statistically non-significant results (see Chapter 6 of Schizophrenia and Genetics).
Instead of endorsing psychiatry’s and other behavioral science fields’ ongoing support of the massively flawed and openly p-hacked Danish-American adoption studies, and twin studies based on obviously false assumptions, had Kolker approached his project with a more critical eye he might have concluded that Rosenthal’s 1968 negative-result (failure to reject the null hypothesis) study discredited the idea that genetics “created the disease.”
The “schizophrenia as a strongly heritable disease” story doesn’t become true because it is repeated ad nauseum in online postings and articles, in the social media, in textbooks, in popular books, in scholarly review articles, in the opening paragraphs of most molecular genetic research publications, and in books by famous scientist authors. Instead, it is necessary to closely examine the original studies and their assumptions to determine whether they support this story. The biopsychiatrists Kolker relied on say they do. The critically minded authors Kolker mostly ignored say they don’t. Replication crisis scrutiny certainly extends to the review of books such as HVR that help popularize scientific research, where unsupported gene discovery claims reach and influence a general audience, and are endorsed by famous celebrities and even former U.S. Presidents.
In Blueprint, Plomin recalled that “hundreds of candidate gene stories…that…were not true…led to hundreds of media reports about ‘genes for intelligence’ or ‘the gene for schizophrenia.’” Apparently, Kolker didn’t “get the memo” about the historic schizophrenia candidate gene collapse. Because he (albeit mistakenly) believed that CHRNA7 and SHANK2 were real or probable causative gene discoveries, his account of the genetic aspects of the Galvin family’s story produced a Hollywood-like hopeful and triumphant message in the face of otherwise tragic events—a Lorenzo’s Oil-type discovery theme, only this time based on non-discoveries. Kolker would have done better to have arrived at a more realistic conclusion, similar to the one arrived at by Sam Dolnick, the New York Times reviewer of his book:
“If there were justice in the world, the Galvins’ genes would have provided the key to understanding and preventing schizophrenia, perhaps redeeming some measure of their pain. Unfortunately, science doesn’t indulge in narrative satisfaction….The Galvins’ genes seem to hold no silver bullet, no Rosetta Stone.”
Overall, despite some glimpses into the tragic world of a family riddled with abuse and dysfunction, in addition to glimpses into the behind-the-scenes world of molecular genetics insiders, Hidden Valley Road reproduced psychiatry’s long-running yet unsupported “genetics of schizophrenia” narrative. The author presented a story of persevering medical scientists using the genes of multiplex families to make historic discoveries. Others might see the “genes for schizophrenia” story as a half-century-long train wreck.
The author thanks Mike Jones for helpful feedback on an earlier draft of this article. All opinions expressed in this article are the author’s own.
Mad in America hosts blogs by a diverse group of writers. These posts are designed to serve as a public forum for a discussion—broadly speaking—of psychiatry and its treatments. The opinions expressed are the writers’ own.
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