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Large Family Study Links Genetics of Schizophrenia, Bipolar Disorder

27 January 2009. Schizophrenia and bipolar disorder are diagnosed as distinct diseases, but do they share an underlying cause? That debate has gone on since Emil Kraepelin defined the two types of psychoses more than 100 years ago. Modern molecular genetics studies suggest shared origins (see SRF related news story; and see SRF related news story), but epidemiological work has yielded less consistent results.

New results from the largest family study to date could put that debate to rest. In a study of more than nine million Swedish people over 30 years, Paul Lichtenstein and colleagues at the Karolinska Institute in Stockholm, Sweden, find that first-degree relatives of people with schizophrenia are at higher risk for bipolar disorder, and vice versa. The work, published in the January 17 issue of the Lancet, shows a shared genetic risk for the two diseases, and adds to calls from some clinicians and researchers to rethink and revise the diagnostic distinction between the disorders (see SRF Live Discussion led by N. Craddock and M. Owen).

Lichtenstein, Christina Hultman, and collaborators had previously developed a linked database combining a multigeneration register of two million Swedish families and the public hospital records for all psychiatric inpatient admissions between 1973 and 2004 (Lichtenstein et al., 2006). They used this information to assess the risk of disease in first-degree relatives of 35,985 people treated for schizophrenia and 40,487 with bipolar disorder.

In agreement with the group’s previous results, first-degree relatives of people with schizophrenia had a nine times higher risk of getting the disease than unrelated control subjects. They also showed an increased risk among half-siblings, though it was not as large as full siblings (3.6 times for maternal and 2.7 times for paternal half-siblings, respectively). The data also included adopted families, where there was an increased risk of disease for adopted children whose biological parent had schizophrenia, or for siblings adopted into different families where one had the disease.

For bipolar disorder, a similar pattern emerged. The risk for first-degree relatives was elevated nearly eight times. Half-siblings and adopted children showed a lower, but still elevated risk, similar to that seen in the schizophrenia cohort.

The elevated risk cut across disorders. Siblings of subjects with schizophrenia had nearly a four times higher risk of bipolar disorder, and vice versa. The risk carried over in adopted children where a biological parent was affected, and in siblings separated by adoption. Half-siblings showed a variable low elevation in risk that was mostly not statistically significant.

From these results, the investigators calculated the genetic contribution to schizophrenia (heritability) at 64 percent and 59 percent for bipolar disorders. The correlation of genetic risk for the two disorders was 0.60, a number that indicates a large part, but not all, of the genetic risk for the disorders is shared. “Thus, some genes are probably associated with the risk for both disorders, and some with the risk for only one disorder,” the authors write. “This possibility should be considered in future research and clinical studies.”

“These results challenge the current nosological dichotomy between schizophrenia and bipolar disorder, and are consistent with a reappraisal of these disorders as distinct diagnostic entities,” the authors conclude.

That view is echoed in an accompanying editorial from Michael Owen and Nick Craddock of Cardiff University, United Kingdom. “We now must ask whether clinical practice and research can continue to be best served by persistence in basing our diagnoses on the binary concept,” they write. The answer to that question raises another: If the Kraepelinian dichotomy is abandoned, they ask, with what should it be replaced? Owen and Craddock advocate new diagnostic criteria that detail and carefully measure key domains of psychopathology. The question is timely, they say, because the next editions of both major diagnostic manuals, the DSM-V (Diagnostic and Statistical Manual of Mental Disorders) and ICD11 (International Classification of Diseases and Related Health Problems) are in development now.—Pat McCaffrey.

Lichtenstein P, Yip BH, Björk C, Pawitan Y, Cannon TD, Sullivan PF, Hultman CM. Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet. 2009 Jan 17;373(9659):234-9. Abstract

Owen MJ, Craddock N. Diagnosis of functional psychoses: time to face the future. Lancet. 2009 Jan 17;373(9659):190-1. Abstract

Comments on News and Primary Papers
Primary Papers: Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study.

Comment by:  William Carpenter, SRF Advisor (Disclosure)
Submitted 28 January 2009 Posted 29 January 2009
  I recommend this paper

This is a very interesting analysis and the largest and...  Read more

View all comments by William Carpenter

Comment by:  Alastair Cardno
Submitted 7 April 2009 Posted 7 April 2009
  I recommend the Primary Papers

The results of the family/adoption study by Lichtenstein...  Read more

View all comments by Alastair Cardno
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