Schizophrenia gene, where art thou?

September 5, 2008

It's now 80 years since scientisits first claimed schizophrenia was genetic. Yet, no such gene has been identified. Some private genetic research firms are now abandoning their search for a schizophrenia blood test, and a senior psychologist says the quest for the schizophrenia gene has been biggest failure in medical history. Is it? Adam James reports

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Is schizophrenia rooted in our DNA? Pick up a medical textbook or ask a psychiatrist. Both will tell you it is. Almost without exception.

Within psychiatric research it is accepted wisdom that schizophrenia is approximately 50% genetic, with DNA abnormalities "predisposing" a person to schizophrenia. Robin Murray, professor of psychiatry at London's Institute
of Psychiatry, states no "sensible person" questions schizophrenia's strong genetic underpinnings.

Environmental factors - including trauma, abuse, neglect, stress, cannabis use and maternal viruses during pregnancy - contribute the other 50% of causes, it is widely cited.

Yet, dissenting researchers argue psychiatry has consistently "hyped" the genetic basis for schizophrenia. Some argue there is no solid evidence at all for a genetic cause. "The scientific literature and the press repeatedly convey the misleading impression that schizophrenia is proven to be a genetic disorder," says psychiatrist Joanna Moncrieff, a senior lecturer in social and community psychiatry at University College of London.

Claims for the role of genes in the aetiology of schizophrenia has their roots in German eugenics of the late 1920s. But ironically, 80 years on, the one undisputed fact is that no schizophrenia gene has been identified.

This was confirmed in April when an American Journal of Psychiatry April study reported that the genes most widely assumed to play a causal role in schizophrenia are, in fact, unlikely to play a role.

Researchers examined 14 schizophrenia "candidate genes" identified from 25 years of molecular genetics. It was an unprecedented study as it analysed the genetic material of 1,870 patients diagnosed with schizophrenia or schizoaffective disorder, and 2002 control patients. It was the "most comprehensive" study of its kind, according to an editorial in the journal.

To critics, this non-finding was no surprise. "The reason that this study did not find evidence for a gene is that there are no such genes," asserted American clinical psychologist Dr Jay Joseph and author of The Missing Gene: Psychiatry, Heredity, and the Fruitless Search for Genes. "For 25 years
psychiatry has been looking for a schizophrenia gene. They keep failing."

Even the study's lead researcher Professor Pablo Gejman, director of the Centre For Psychiatric Genetics at Northwestern University in Illinois, admitted the results were not "as expected". He admitted: "The genetics of
schizophrenia has remained illusive at a molecular level."

Evidential claims for a genetic basis to schizophrenia first really gathered force in the sixties. The records of same-gene identical twins - from Finland to America - were examined to find the ratio of one "schizophrenic" twin having a "schizophrenic" co-twin.

American researchers Irving Gottesman and James Shield summarised these twin studies in their 1972 book, The Genetics of Schizophrenia. They claimed that if one twin had schizophrenia, his/her co-twin had an almost 50 per cent
(48%) chance of also being schizophrenic. Contemporary researchers regularly cite the work of Gottesman and Shields. Their 50 per cent genetic statistic has stuck for more than three decades.

Yet there have been rigorous critiques of Gottesman and Shields' work. In her book, Schizophrenia, a Scientific Delusion, Mary Boyle, emeritus professor of clinical psychology at the University of East London, listed
numerous methodological flaws in their study, including that they were unblind and the results were "massaged". Moreover, Gottesman and Shields had not, in fact, measured schizophrenia, but "schizophrenic spectrum". They had
judged identical twins to be "concordant" with schizophrenia, even if neither were diagnosed with schizophrenia. For example, one twin had "affective disorder", the other "schizoactive psychosis".

"The schizophrenic spectrum disorder was invented to render the results positive," claims Moncrieff.

But the fundamental flaw of almost all twin studies - including many of those now being conducted as part of the Institute of Psychiatry's Maudsley Schizophrenia Twin Study programme - is that a shared environment could as feasibly account for identical twins both being diagnosed schizophrenic.

In a bid to exclude the influence of "nurture", geneticists studied adoptees. In the mid-seventies US Harvard professor Seymour Kety and colleagues devised a methodology which, they hoped, would eliminate environment as a variable.

Their book, the Transmission of Schizophrenia, suggested 9% of blood-relations of adoptee schizophrenics had a schizophrenic diagnosis, compared with two per cent of the relatives of non-schizophrenic adoptees.

This original and subsequent Kety adoption studies are, arguably, the most cited research in support of a genetic theory of schizophrenia. Again, critics, such as Boyle, Joseph and Open University biologist Steven Rose, have highlighted what they argue are gross methodological flaws. Not only was the schizophrenia spectrum again used, Kety invented another diagnosis called "latent schizophrenia". This was for "potential schizophrenics".

Moreover, American psychiatrist Peter Breggin has described his reaction when he read Kety's original study. He was "shocked" to find there was actually no increase in schizophrenia among close biological relatives, such as mothers, fathers, full brothers and sisters. "Thus the studies actually tended to disprove the genetic origin of the presumed illness," he wrote.

Nevertheless, geneticists are adamant there is sufficient twin, family and adoption study evidence to support a strong genetic schizophrenia link. Nick Craddock, professor of psychiatry at Cardiff University insists there is "lots of data" to support the 50% statistic. "We are sure that genetics is
involved," he asserts. Some geneticists argue schizophrenia has an 80 per cent genetic basis.

The genetic argument has been bolstered by reports that blood tests for schizophrenia are in the pipeline. For example, one company, Suregene, based in Louisville in America, issued a press release in2006 announcing that by this year it expected to have "perfected" a blood test to detect schizophrenia.

But Suregene's chief executive Mike Brennan has confirmed to psychminded.co.uk that the firm has dropped such plans. Instead, it is turning its attention to finding a genetic root to "paranoia", not schizophrenia. Mr Brennan said: "We've gone away from referring to the genetic test as a schizophrenia test, and started referring to it as a test for psychosis," he
said. Moreover, the test is for "research purposes" only.

Equally, another genetics firm, the UK-based and drug firm-backed Curidium, announced in a press release in July last year that it was producing a "blood diagnostic test", called PsychINDx, for schizophrenia/bipolar patients. But Curidium has confirmed that PsychINDx is not a schizophrenia
test, but one to assess which drug would be suitable for a particular patient's physiology.

Researchers hoping to crack a genetic schizophrenia code are now examining variants of millions of genes, a strategy known as genome-wide association. Yet, even the geneticists accept the clock is ticking. It's crunch time. "If
we don't get a [genetic] answer in two to three years and nothing striking comes up then any genetic effect is so tiny it's not worth finding," declares Professor Murray.

About time too, say some.Richard Bentall, professor of clinical psychology at the University of Bangor argues that with schizophrenia being an invalid, fuzzy medical diagnosis, the project was always doomed. "Geneticists have been
continuously confident they would find a gene for schizophrenia. There's probably been no big a failure in the history of medicine."

Importantly, the genetic consensus has determined how clinicians treat the one in 100 people diagnosed with schizophrenia. Anti-psychotic drugs are the first-line treatment for those with this diagnosis. These drugs are
presumed, in some way, to effect the underlying gene-determined physiology of schizophrenia. This assumption is often why any non-drug form of treatment is ridiculed, even demonised. One NHS psychologist, Rufus May from
Bradford, was earlier this year dubbed "dangerous" for advocating a non-drug approach. Some doctors advocated he be disciplined.

Practitioners such as Bentall argue there is sound evidence demonstrating that schizophrenia "symptoms", such as voice-hearing, delusions and thought disorders, are related to trauma, such as abuse. But they point out that an estimated 99 per cent of all psychiatric research into the causes of
schizophrenia is slanted towards genetics or bio-physiology.

"Millions upon millions of pounds have been spent on psychiatric genetics," says Prof Bentall. "Yet, it's been a complete damp squid."

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'Life not biology'

Ron Coleman was sexually abused when a child. In adulthood he heard abusive voices, was diagnosed with schizophrenia and was in and out of mental health services for 13 years. He now helps run Working To Recovery, a training organisation for services working with people diagnosed with psychosis. It is based in the Isle of Lewis, Scotland. Coleman is currently advising a World Health Organisation mental health project in Jerusalem. He says:

"It is becoming increasing obvious that the main reason [for schizophrenia] is not biology, but things that happened in a person's life.

For instance, people's voices are clearly asssociated with life
experiences - such as here in Palestine with the war between the Palestinian and Israelis. Research clearly shows there is a link to trauma.

And people can talk through these causes. What happened in someone's life is central to that person's recovery. This would not happen if schizophrenia was a biological condition.

If stress is genetic then some people may have a vulnerability. But this is not a vulnerability to schizophrenia.

I've looked at my family's past. I can see no genetic link. Apart from my grand-father getting dementia there's nothing. So where did the gene come from?

It's time to understand mental health problems as not being about a person's genes, but about society. It is something society has to deal with"

* An edited version of this article first appeared in Mental Health Today magazine

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