EXCLUSIVE
by Adam James

April 14, 2008

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The genes most widely believed to cause schizophrenia are, in fact, unlikely to play a role in the condition, according to the most comprehensive genetic study of its kind.

The results published in a paper in this month’s American Journal of Psychiatry will re-ignite the so-called "nature/nurture" debate in schizophrenia, which one in 100 people are diagnosed with.

America-based clinical psychologist Dr Jay Joseph and author of The Missing Gene: Psychiatry, Heredity, and the Fruitless Search for Genes said: “The reason that this latest study did not find evidence for a gene is that there are no such genes. For 25 years psychiatry has been looking for a schizophrenia gene. They keep failing."

A total of 23 researchers from America, Australia and France examined a total of 14 “candidate genes” that, until now, scientists have claimed to be most linked to schizophrenia.

The study is significant because it is based on the genetic material of 1,870 unrelated patients diagnosed with schizophrenia or schizoaffective disorder, and 2002 control patients. This made it the largest ever sample in a study examining the genetics of schizophrenia.

The study tested the hypothesis that a type of DNA difference called single nucleotide polymorphisms (SNPs) in the 14 genes has a role in causing schizophrenia.

In total, 433 SNPs in these genes were examined in a bid to “tag” the DNA variation linked to schizophrenia among people of European descent.

"We did not detect a significant association of schizophrenia with SNPs in 14 candidate genes that have been of great interest to the field,” wrote the authors.

"Our results suggest that, taken together, common DNA variants in these 14 genes are unlikely to explain a large proportion of the genetic risk for schizophrenia in populations of European ancestry.”

It is the “most comprehensive” study yet into a genetic link to schizophrenia, wrote Dr Steven Hamilton of the Department of Psychiatry and Institute for Human Genetics at the University of California in an editorial in the journal.

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”.

"The genetics of schizophrenia has remained illusive at a molecular level for more than 20 years,” he said.

Psychiatry has argued for a genetic basis for schizophrenia since the 1970s when studies on same-egg twins who were separated at birth and were both diagnosed with schizophrenia.

But some scientists argue the twin studies could equally support the hypothesis that a person's upbringing causes schizophrenia, as the twins shared the same background.

They also highlight that modern molecular research has consistently failed to locate genetic markers for schizophrenia.

Mary Boyle, emeritus professor of clinical psychology at the University of East London, said: “Research has never shown any link between genes and schizophrenia. There has been a vast amount of time and money spent. Yet nothing has come from it. If this was any other area [of research] serious questions would have been asked.

"If people want to continue this research good luck to them. But my worry is that they are being given public funding.”

Dr Joseph said: "Many people have dedicated their life to the genetics of schizophrenia. And they are not going to now turn around and they have been wrong. It is up to a young generation of researchers to introduce a new scientific paradigm.”

Nick Craddock, professor of psychiatry at Cardiff University and a leading UK geneticist said, however, that it can not be concluded from this study that genes are not involved in the aetiology of schizophrenia.

"This study does not mean none of these genes might be involved,” he said.

"There maybe different variants [of these genes]. And it certainly does not mean that genes are not involved in schizophrenia. It does mean that these particular 14 genes do not seem to have a major role in the sample used in this study."

Professor Craddock agreed with the journal study’s authors who suggested more “robust” findings on a genetic cause for schizophrenia could come from examining variants on a multitude of genes, called genome-wide association methods.

"There is now a move towards studies looking at half a million different [gene] variants. This is the way to go,” said Professor Craddock.

The 14 genes investigated in the American Journal of Psychiatry paper, entitled No Significant Association of 14 Candidate Genes With Schizophrenia in a Large European Ancestry Sample: Implications for Psychiatric Genetics were RGS4, DISC1, DTNBP1, STX7, TAAR6, PPP3CC, NRG1, DRD2, HTR2A, DAOA, AKT1, CHRNA7, COMT, and ARVCF.

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