Schizophrenia Twin Research as Reported in The Gene: An Intimate History — Getting the Facts Straight

In his 2016 book The Gene: An Intimate History, cancer physician and researcher Siddhartha Mukherjee chronicled the initial idea of the gene, taking readers through the history of genetics up to the current “post-genome” period by interweaving science, social history, and his own personal narrative. In the process he documented some of the crimes of the eugenics movement and the monstrous atrocities committed by German National Socialism in the name of eugenics and biology, while noting the Nazi’s promotion of twin research. He also criticized aspects of intelligence testing and genetic theories of racial inferiority based on IQ tests. At the same time, Mukherjee supported and promoted many contemporary behavioral genetics positions. Based largely on twin studies and gene discovery claims, he concluded,

“Gender. Sexual preference. Temperament. Personality. Impulsivity. Anxiety. Choice. One by one, the most mystical realms of human experience have become progressively encircled by genes. Aspects of behavior relegated largely or even exclusively to cultures, choices, and environments, or to the unique constructions of self and identity, have turned out to be surprisingly influenced by genes.”¹

The critics have shown, however, that a close examination of the evidence does not support this conclusion.

In recent reports (see Part One and Part Two) I showed that Mukherjee got many of the basic facts wrong about the “Minnesota Study of Twins Reared Apart” (MISTRA), a “separated twin” study that has been put forward for decades, albeit incorrectly, as providing the ultimate proof that human behavioral similarities and differences are largely “in the genes.”² This occurred in his book, and in a 2016 article Mukherjee published in The New Yorker.

Mukherjee on Schizophrenia Twin Research

An additional area of inaccurate reporting in The Gene: An Intimate History was Mukherjee’s description of schizophrenia twin research, which has been conducted since the 1920s. Researchers in this area use “classical twin method” comparisons between reared-together MZ (monozygotic, identical) and reared-together same-sex DZ (dizygotic, fraternal) twin pairs. MZ pairs are said to share 100% of their segregating genes, whereas (like ordinary siblings) same-sex DZ pairs are said to share only 50% on average. When both members of a twin pair are diagnosed/labeled with schizophrenia, the pair is concordant for the condition; when one twin is diagnosed/labeled but the other is not, they are discordant for schizophrenia. If a study finds that MZ pairs are significantly more concordant than DZ pairs, twin researchers conclude that this points to an underlying genetic component, and then estimate the “heritability” of schizophrenia (0%-100%). Genetic interpretations of their results, however, depend on the validity of the twin method’s controversial MZ-DZ “equal environment assumption” (EEA), and the evidence shows that this assumption is false. This suggests that MZ-DZ schizophrenia concordance rate differences can be explained entirely by the more similar environments and emotional bond experienced by MZ pairs.³ (A brief critique of the EEA can be found here.)

Similar to mainstream psychiatry conceptions, in Mukherjee’s view schizophrenia is “a complex, polygenic illness, involving multiple variants, multiple genes, and potential environmental or chance triggers.”⁴ At the same time, critics of the schizophrenia concept and of genetic research in this area have put forward compelling alternative conceptions.⁵

Selective Critique of the Twin Method and Its “Conceptual Gridlock”

Mukherjee championed the MISTRA “reared-apart” (separated) twin approach precisely because studies using reared-together pairs were based on the twin method’s controversial EEA. He wrote that MZ pairs are “reared in the same home, by the same parents, [are] often schooled in the same classrooms by the same teachers, [and are] dressed, fed, and nurtured identically.”⁶ These reared-together MZ pairs, Mukherjee realized, “offered no self-evident way to separate the effects of genes versus the environment.” Comparing MZ pairs to DZ pairs, in his view, only “partially solved” this problem. He noted the critics’ argument that MZ-DZ comparisons are “intrinsically flawed” because MZ pairs may be “treated more similarly…by their parents” than are DZ pairs. This led to a “conceptual gridlock” in studies of reared-together MZ pairs, he wrote, because “geneticists knew” that studying such pairs involved the “impossibility of unbraiding the twisted strands of nature and nurture.”⁷ Mukherjee focused on the shakiness of the twin method’s MZ-DZ equal environment assumption—and the twin study “impasse” it had created—in order to dramatically highlight the need to study reared-apart twins.⁸

When Mukherjee turned specifically to schizophrenia twin research based on reared-together pairs, however, he did an about-face.⁹ His argument that MZ behavioral resemblance could be caused by the more similar environments they experienced was forgotten. He did not suggest that reared-together MZ pairs “offered no self-evident way to separate the effects of genes versus the environment.” Nor did Mukherjee question genetic researchers’ practice of interpreting higher MZ versus DZ schizophrenia concordance in favor of genetics. Even though “geneticists knew” that interpreting reared-together MZ behavioral resemblance is problematic due to the “conceptual gridlock” created by the “impossibility of unbraiding the twisted strands of nature and nurture,” Mukherjee did not apply this observation to schizophrenia twin studies, which he claimed supply definitive evidence in favor of genetics (see below).

The “First Clues” of Genetic Causation

“The first clues about the etiology of schizophrenia,” Mukherjee wrote, “came from twin studies. In the 1970s, studies demonstrated a striking degree of concordance among twins.”¹⁰ He cited a 1977 autism twin study as the single source of this claim, whose authors mentioned schizophrenia twin research only in passing.¹¹ The only new schizophrenia twin study published in the 1970s was a 1973 Danish study by Margit Fischer, who found an MZ concordance rate of 36% (9/36), versus a DZ rate of 18% (8/45).¹²

Schizophrenia twin research goes back to 1928, when Hans Luxenburger published his German study.¹³ The first American study was published by Aaron Rosanoff and colleagues in 1934.¹⁴ Mukherjee discussed the “enormous National Academy of Sciences (NAS) study [that] published [twin] data definitively linking schizophrenia to genetic causes.” He claimed that this investigation found that “identical twins possessed a striking 30 to 40 percent concordance rate for schizophrenia.”¹⁵ But there was nothing “striking” about this finding, since earlier researchers had reported similar or higher concordance rates since the 1920s. They key question, as always, is how we should interpret these findings.

The original NAS schizophrenia twin study, which was based on U.S. military veterans identified by a twin registry, was published by American psychiatrist William Pollin and his colleagues in 1969. Recognizing that “nine major twin studies of schizophrenia” beginning with Luxenburger had come before them, Pollin and colleagues reported an MZ concordance rate of only 13.8%. Although they concluded that genetic factors play a role, they also concluded that, because “85 per cent of the affected monozygotic pairs in the sample were discordant for schizophrenia,” the “role of the suggested genetic factor appears to be a limited one.”¹⁶ Pollin and colleagues recognized that the twin method’s assumption that MZ and DZ environments are similar (the EEA) is “incorrect,”¹⁷ and concluded that “the variance between the two groups may be explained by environmental as well as by genetic hypotheses.”¹⁸

Mukherjee’s NAS figures were based on Kenneth Kendler and Dennis Robinette’s 1983 “16-Year Update” of Pollin and colleagues’ original 1969 NAS study. This update increased the original MZ sample of 80 pairs to 164 pairs, but only 30 pairs were concordant for schizophrenia, resulting in a modest combined total 18.3% pairwise concordance rate. In this “definitive” study, therefore, over 80% of the genetically identical MZ pairs were discordant for schizophrenia—a diagnosis viewed by Mukherjee and others as being “powerfully influenced” by genetics.¹⁹ Kendler and Robinette’s “striking 30 to 40 percent concordance rate” (to be precise, 30.9%) was based on these researchers artificially inflating the percentage by using the “probandwise” concordance method, which double counts the number of concordant pairs. They did not assess the validity of the EEA, and concluded that their results “support the etiologic importance of genetic factors in schizophrenia.”²⁰

“Fleets” of Twin Studies that Never Existed

Discussing a “study published by the geneticist Irving Gottesman in 1982,” Mukherjee wrote,

“For identical twins with the severest form of schizophrenia, Gottesman had found the concordance rate was 70 to 90 percent; nearly every identical twin with one of the severest variants of schizophrenia had been found to have a twin with the same illness. This high degree of concordance between identical twins suggested a powerful genetic influence on schizophrenia” (italics in original).²¹

Mukherjee cited a 1984 study by Peter McGuffin and colleagues in support of this claim. McGuffin and colleagues, however, did not mention 70%-90% concordance for pairs with the most severe form of schizophrenia, but they did reference Gottesman and Shields’1972 book Schizophrenia and Genetics: A Twin Study Vantage Point, which included a section on “severity and concordance.”²² Although Gottesman and Shields found that the MZ co-twins of twins with more severe symptoms had a higher incidence of schizophrenia, they did not suggest that schizophrenia MZ concordance approaches 100% in these cases.²³ Mainstream psychiatry texts usually state that the pooled schizophrenia MZ concordance rate across studies is about 50%, while others have calculated rates in the 22%-25% range based on the more methodologically sound studies.²⁴ It is worth noting that in the McGuffin et al. 1984 study that Mukherjee cited, schizophrenia concordance rates using the most restrictive “Schneider” criteria produced an MZ rate of only 22%, versus a higher DZ rate of 50%. McGuffin et al. calculated schizophrenia heritability in this small sample as zero.²⁵

According to Mukherjee, “Throughout the 1980s, fleets of twin studies strengthened the case for a genetic cause of schizophrenia.” In “study upon study,” he wrote, “the concordance among identical twins exceeded that of fraternal twins so strikingly that it was impossible to deny a genetic cause.” These fleets of 1980s twin studies, in Mukherjee’s view, helped “bring sanity to the study of madness” because they helped overturn unsupported “seductive” psychoanalytic explanations of psychosis.²⁶

Contrary to Mukherjee’s account, however, no “fleets” of schizophrenia twin studies appeared in the 1980s. Here I cite four authoritative mainstream publications in support of this contention.

1. A chapter in the 2000 edition of Kaplan & Sadock’s Comprehensive Textbook of Psychiatry by Kendler, one of the world’s leading authorities on schizophrenia genetic research, produced a table of what he counted as all 13 schizophrenia twin studies published between 1928 and 1998. The only 1980s-era investigation he listed was the previously discussed 1983 Kendler and Robinette update, which only added some pairs to the original 1969 NAS twin study.²⁷
2. In his award-winning 1991 book Schizophrenia Genesis, Gottesman, another leading authority on schizophrenia genetic research, produced a table listing the “newer” schizophrenia twin studies appearing since 1961.²⁸ Apart from the 1983 Kendler and Robinette NAS study update, and Anne Farmer and colleagues’ 1987 reanalysis of Gottesman’s own 1966 study based on DSM-III diagnostic criteria, no study published in the 1980s appeared in this table.
3. In an influential 2003 schizophrenia twin study meta-analysis (analysis of combined studies) by Patrick Sullivan, Kendler, and Michael Neale (cited by over 1,270 sources according to Google Scholar), the only 1980s study listed was the 1983 Kendler and Robinette update.²⁹
4. Psychiatric geneticist Ming Tsuang, a “world-renowned leader in the genetics of schizophrenia,” published an article in 2000 entitled “Schizophrenia: Genes and Environment” (cited by over 500 sources according to Google Scholar). In a table, Tsuang listed all schizophrenia twin studies published since 1963. Once again, the Kendler and Robinette NAS study update and the Farmer et al. reanalysis were the only 1980s-era studies listed.³⁰

These accounts stand in striking contrast to Mukherjee’s unreferenced and non-existent “fleets of twin studies” published “throughout the 1980s.”

A Lost Twin Study that Did Appear in the 1980s

Interestingly, a virtually unknown schizophrenia twin study by Markku Koskenvuo and colleagues was published in the 1980s in a relatively obscure academic journal (cited by only 26 sources according to Google Scholar).³¹ Based on a large sample consisting of 73 MZ and 225 same-sex DZ pairs obtained from Finnish hospital records, the researchers found a modest 11% MZ concordance rate, versus a 1.8% rate in the DZ group. This 11% MZ rate is the lowest ever recorded, and is much lower than the 50% pooled figure endorsed by Mukherjee and mainstream psychiatry.³² Koskenvuo and colleagues concluded that their results “are in accordance with a hypothesis that postulates great environmental influence (high proportion of discordant pairs) with apparent genetic liability (high difference in MZ and DZ concordance rates),” while recognizing that the “greater environmental similarity between MZ than DZ twin partners can…bias conclusions” in favor of genetics.

This 1984 Finnish study does not appear in review articles, textbook chapters, and other publications by Gottesman, Kendler, Sullivan, Tsuang and most other authoritative schizophrenia genetics experts.³³ It stands among other misreported, misinterpreted, dismissed, downplayed, and “lost” studies in the genetics of behavior arena, whose results run counter to dominant and heavily promoted genetic theories.³⁴

Schizophrenia Adoption Research

The findings more often cited by mainstream psychiatry as “definitively linking schizophrenia to genetic causes” were produced by the schizophrenia adoption studies published in the 1960s-2000s. As a pair of behavioral genetic commentators put it, “When a single [environmental] theory is monolithic in a field, contrary findings can break paradigms. . . . It is just this role, we believe, that the first adoption studies of schizophrenia played in the 1960s.”³⁵ And in 1976, Gottesman wrote that the schizophrenia adoption studies carried out in Denmark and the United States (Oregon) provided the genetic “straw” that “broke the environmentalist’s back.”³⁶

Mukherjee’s only mention of this “paradigm-breaking” body of adoption research was his unreferenced claim that “when a child of a schizophrenic parent is adopted at birth by a nonschizophrenic family, the child still has a 15 to 20 percent risk of developing the illness…demonstrating that the genetic influences can be powerful and autonomous despite enormous variations in environments” (italics in original).³⁷ However, the “risk” is actually lower and was not statistically significant in some studies, most children (adoptees) were not adopted at or near birth, and there is no evidence that these children grew up experiencing “enormous variations in environments.” In addition, although researchers must assume that the placement of children was random (adoption studies’ “no selective placement assumption”), it is unlikely that the children of “schizophrenic” parents were randomly placed into the full range of available adoptive homes in the societies where these studies were performed.³⁸

As I showed in a previous article and elsewhere, the massive methodological problems and biases in schizophrenia adoption research indicate that no study published to date has come close to providing scientifically acceptable evidence that disordered genes play a role in causing schizophrenia and psychosis.³⁹ Nearly a half-century of failed attempts to produce confirmed discoveries of genes  believed to cause schizophrenia provide additional support to this position, and these failures are only one component of the larger story of decades of gene discovery false alarms in psychiatry.

Conclusion

In his 2016 book The Gene: An Intimate History, Siddhartha Mukherjee made definitive claims in favor of genetics on the basis of schizophrenia twin research, even though he was only marginally familiar with this body of research. Mukherjee understood that genetic and environmental influences are difficult to disentangle in studies of reared-together MZ pairs, which led to the “conceptual gridlock” that compelled researchers to study reared-apart twins. However, he failed to see that schizophrenia twin research is also caught in this gridlock. Although much of what he wrote about schizophrenia twin research is wrong—just as much of what he wrote about the MISTRA and reared-apart twin studies is also wrong—his status as a Pulitzer Prize winning medical authority contributes to the misinformation and mythology surrounding genetic research in psychiatry, psychology, and the social and behavioral sciences in general.

* * * * *