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Family Roots for Autism, Schizophrenia, Bipolar Disorder

27 July 2012. The clinical demarcations among autism, schizophrenia, and bipolar disorder are not set in stone, and a new study suggests they have shared roots. Published online July 2 in Archives of General Psychiatry, the study finds that having a first-degree relative with schizophrenia or bipolar disorder increased risk for autism in three separate samples, with odds ratios ranging from 1.5 to 12.

Led by Patrick Sullivan of the University of North Carolina in Chapel Hill, the study echoes and extends an earlier Danish study that found having a parent with schizophrenia was a significant risk factor for autism (Larsson et al., 2005). The findings hint at common causes behind the disorders—an idea consistent with recent genomic findings in which certain rare copy number variants (CNVs) boost risk for both autism and schizophrenia (e.g., 3q29, 15q13.3, 16p11.2) (see SRF related news story and SRF news story; Malhotra and Sebat, 2012). Given emerging evidence for common etiology between schizophrenia and bipolar disorder (ISC, 2009), the new study also considers a family history of bipolar disorder. Whether such shared risk factors—genetic or environmental—can produce distinct clinical outcomes, or whether they call attention to phenotypic commonalities between these disorders (e.g., autism was once considered childhood schizophrenia) remains unclear.

Swedish and Israeli samples
First author Sullivan and colleagues in Sweden and Israel evaluated the family histories of people with autism identified in three samples: 25,432 cases from the National Patient Register in Sweden, 4,982 cases culled from ASD treatment center records in Stockholm County in Sweden, and 386 cases from conscript records in Israel, which contain medical and psychiatric assessments to determine a person’s eligibility for mandatory military service. For comparison, for each autism case the researchers identified 10 controls matched for sex, age, birth year, and sex of relatives in the Swedish samples; in the Israeli sample, the researchers looked at groups of two or more siblings who did not have an autism diagnosis.

The researchers found an association between autism and a family history of schizophrenia or bipolar disorder. For example, in the Swedish national sample, having a parent or sibling with schizophrenia increased the odds of autism, giving an odds ratio (OR) of 2.9 in the case of a parent, and 2.6 in the case of a sibling. Similarly, having a parent or sibling with bipolar disorder resulted in ORs of 1.9 and 2.5, respectively. The Stockholm County sample results were similar, though they tracked only parent history: having a parent with schizophrenia or bipolar disorder yielded ORs of 2.9 and 1.6, respectively.

Within the Israeli sample, the researchers focused on whether having a sibling with schizophrenia was a risk factor for autism, and found a whopping increase in risk, with an OR of 12. This was accompanied by large confidence intervals, though, which the researchers surmise reflect the smaller sample size of this group. They also mention that, because these conscript assessments are conducted at 17 years of age, those with a schizophrenia diagnosis likely have an earlier-onset form, which may confer greater risk.

Without mental retardation
Family history seemed associated with the type of autism not accompanied by mental retardation, according to information available in the Stockholm County sample. For autism cases without mental retardation, ORs for a parent with schizophrenia or bipolar disorder were 2.6 and 1.5, respectively—higher than ORs obtained for autism cases with mental retardation, which were 1.6 and 1.1 for parental schizophrenia and bipolar disorder, respectively.

Combined with the previous Danish study, this makes four samples with evidence for family history of schizophrenia or bipolar disorder as a risk factor for autism. This consistency firms up the association, which may encourage researchers to cast a wider net across multiple psychiatric diseases in searching for the explanations of one of these disorders. Such etiological overlap also suggests looking harder at the current clinical definitions of these disorders, which may have more in common than typically appreciated.—Michele Solis.

Sullivan PF, Magnusson C, Reichenberg A, Boman M, Dalman C, Davidson M, Fruchter E, Hultman CM, Lundberg M, Långström N, Weiser M, Svensson AC, Lichtenstein P. Family History of Schizophrenia and Bipolar Disorder as Risk Factors for AutismFamily History of Psychosis as Risk Factor for ASD. Arch Gen Psychiatry. 2012 Jul 2:1-5. Abstract

Comments on News and Primary Papers
Comment by:  Bernard Crespi
Submitted 30 July 2012 Posted 30 July 2012

In a new paper in Archives of General Psychiatry that has received considerable media attention, Sullivan et al. (Sullivan et al., 2012) use register data from Sweden and Israel to show higher rates of ASDs among individuals with family histories of schizophrenia and bipolar disorder. The authors interpret these results as indicating that ASD, schizophrenia, and bipolar disorder share etiology. This is a very interesting hypothesis that, if supported, would have important implications for our understanding of the genetic underpinnings of schizophrenia in relation to other conditions. However, two alternative hypotheses not involving shared causation may, at least in part, help to explain their results.

First, a recent set of studies demonstrates that drug treatments for schizophrenia and bipolar disorder increase the incidence of ASDs, or their biologically based phenotypic correlates, in offspring. Croen et al. (Croen et al., 2011) reported that prenatal exposure to...  Read more

View all comments by Bernard Crespi

Comment by:  William Carpenter, SRF Advisor (Disclosure)
Submitted 30 July 2012 Posted 30 July 2012

Shared risk for ASDs in bipolar and schizophrenia families is important, and the apparent gradient in risk with schizophrenia being greater than bipolar may be informative. From the view that schizophrenia and bipolar disorder are heterogeneous syndromes, the following is surmised:

  • The association with ASDs probably is related to specific aspects of shared features, perhaps impaired social affiliation or neurodevelopmental pathology.
  • These features are more common in schizophrenia than in bipolar disorder, so the gradient may be determined by the difference in proportion of relevant probands with the key features.
  • If the same data could be reduced to family definition based on probands who have impaired social affiliation and/or neurodevelopmental psychopathology, then the odds ratios might be substantially higher and the ORs for schizophrenia and bipolar disorder might be more similar.

View all comments by William Carpenter

Comment by:  John McGrath, SRF Advisor
Submitted 30 July 2012 Posted 30 July 2012
  I recommend the Primary Papers

This impressive study adds to the growing body of evidence demonstrating that heritable factors are shared among autism, schizophrenia, and bipolar disorder. The authors suggest that genetic factors could underlie the findings, but also remind the reader that environmental factors could play a role. They note that twin-based studies of heritability in schizophrenia and autism have demonstrated appreciable contributions for environmental factors that were shared between the affected individuals—usually referred to as common environmental effects. It should be noted that in this context, the word “common” does not equate with “prevalent.” With respect to shared genetic factors, the growing body of evidence regarding structural variation such as copy number variants is impressive. With respect to non-genetic factors, more work is needed—prenatal infection (which could trigger maternal immune activation) and nutrition (e.g., low vitamin D) might be candidate domains. If there are shared environmental risk factors contributing to schizophrenia, bipolar disorder, and...  Read more

View all comments by John McGrath
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