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With Two Affected Parents, Schizophrenia Risk in Offspring Skyrockets

9 March 2010. Having two parents with schizophrenia multiplies the risk of offspring following in their footsteps to a psychiatric facility, over and above the risk conferred by having one affected parent, says a new study in the March Archives of General Psychiatry. Irving Gottesman, of the University of Minnesota Medical School in Minneapolis, and colleagues find that when both parents had received treatment for schizophrenia, 27.3 percent of their offspring had also received this diagnosis, a much higher percentage than if only one or neither parent had. The researchers suggest that these findings could inform molecular genetics studies and the personal decision-making of “super-high-risk” individuals.

Gottesman and his collaborators in Denmark tapped an enviable database; it contained national registry data on the over 2.6 million people who lived in Denmark in 1968 or later and their biological parents. (The study is also impressive in its duration: Gottesman began the study in the early 1970s with the late Margit Fisher as a collaborator.) The researchers linked these data to records of admissions to inpatient and, from 1995 on, outpatient, psychiatric facilities. They believe that these records identified most people in need of treatment for schizophrenia or bipolar disorder, since Denmark provides universal health insurance and has no private psychiatric facilities.

Using these records, the researchers searched for parent pairs, regardless of marital status, who had been admitted to a psychiatric facility between 1 April 1970 and 1 January 2007. They singled out those who had received discharge diagnoses of schizophrenia, bipolar affective disorder, or unipolar depressive disorder. They then checked to see if their offspring had been admitted for these or related diagnoses. Comparison groups consisted of subjects with one admitted and one never-admitted parent, and those with two never-admitted parents.

By 2007, the offspring in the study ranged from 10 to 52 years old. For the outcome measure, Gottesman and colleagues calculated the cumulative incidence of psychiatric admission by the time the offspring reached age 52. This shows the percentage of subjects who had received a diagnosis by the end of the follow-up period relative to those at risk.

Two parents, two strikes
The 196 parent pairs in which both members had schizophrenia had produced 270 children. Of these, 27.3 percent (95 percent confidence interval 18.3-36.2) had been discharged with a schizophrenia diagnosis by age 52. As for the 8,006 couples in which only one parent had been treated for schizophrenia, 7.0 percent (95 percent confidence interval = 6.4-7.7) of their 13,878 offspring had also received this diagnosis. In contrast, the incidence dropped to 0.86 percent (95 percent confidence interval = 0.83-0.88) in the children of couples in which neither member had received a schizophrenia diagnosis during the study.

Subsequently, the researchers widened their net to encompass offspring with other psychiatric disorders in addition to schizophrenia. They started by including schizophrenia-related disorders, such as schizoid personality disorder, paranoid disorders, schizoaffective disorder, and various psychoses other than manic-depressive psychosis. When both parents had a schizophrenia diagnosis, the percentage of offspring with related disorders rose to 39.2 percent (95 percent confidence interval = 28.8-48.6). Looking even more broadly at mental illness in general, the study found that 67.5 percent (95 percent confidence interval = 59.0-75.9) of offspring from two parents with schizophrenia had received a psychiatric diagnosis.

Similar findings emerged for bipolar disorder. In 83 couples, both parents had received treatment for bipolar disorder. By age 52, 24.9 percent (95 percent confidence interval = 14.0-35.8) of their 146 offspring had, too. When one parent had bipolar disorder and the other no psychiatric history, the percentage of treated children fell to 4.4 percent (95 percent confidence interval = 4.0-4.9). In comparison, only 0.48 percent (95 percent confidence interval = 0.46-0.51) of children born of two parents never treated for bipolar disorder received treatment for it themselves.

Gottesman and colleagues note that their estimates of increased risk from parental illness mirror those from smaller studies done long ago (see Gottesman and Bertelsen, 1989; Rosenthal, 1966). However, their study did not track how the extreme vulnerability to mental illness passed from one generation to the next. “Evidence must converge from twin, family, and adoption studies to convince the scientist that the largest part of the familiality we observed in this study for schizophrenia and bipolar disorder was indeed attributable to genetic factors, and such data exist in abundance,” they write.

All in the family?
According to some studies, schizophrenia and bipolar disorder share genetic roots (see SRF related news story; SRF news story; SRF news story; also see SRF live discussion). If true, then having one parent with schizophrenia and another with bipolar disorder could heighten the risk of developing each disorder beyond that associated with having just one ill parent. In the new study, pairings of these differently diagnosed couples resulted in offspring with a cumulative incidence of 15.6 percent (95 percent confidence interval = 7.1-24.0) for schizophrenia and 11.7 percent (95 percent confidence interval = 2.1-21.4) for bipolar disorder. Statistically, their risk did not differ from that of subjects who owed their start in life to one diagnosed parent and an apparently healthy one, but the researchers ascribe that to small group sizes.

While we await future studies to clarify whether tendencies to develop schizophrenia and bipolar disorder go hand-in-hand, a study in the March American Journal of Psychiatry hints that children with other disorders may appear in the family photos. A research team led by Boris Birmaher of the Western Psychiatric Institute and Clinic in Pittsburgh, Pennsylvania, reports that having one or more parents with bipolar disorder hikes the likelihood of attention deficit hyperactivity disorder eightfold (odds ratio = 8.17; 95 percent confidence interval = 1.3-52.6), and that of multiple psychiatric disorders sixfold (odds ratio = 6.4; 95 percent confidence interval = 1.1-40).

Opportunity and risk
Gottesman and colleagues contend that their own findings could help to inform the life choices of super-high-risk individuals in such areas as marriage and childbearing. Even so, they caution against misusing such sensitive health information. They write, “It is important to keep in mind that the yields from genetic epidemiology and the strategies implemented are applicable to groups of people, not to the individuals themselves.” In particular, they express concerns about using such data to set health insurance premiums or to condone eugenics-based policies.

As for the research repercussions of their work, the investigators write, “By joining advances in molecular genetics that are adapted for use in epidemiological genetic screening, our kinds of data with the risk groups described might lead to a large and rapid step forward in the understanding of the etiologies of major mental disorders.” They suggest that, with strict privacy guards in place, genomewide association studies could test DNA from the offspring of two affected parents. They could obtain this DNA from the Guthrie cards that contain drops of blood from newborn babies, gathered routinely to test for disease and often stored for many years.—Victoria L. Wilcox.

Gottesman II, Laursen TM, Bertelsen A, Mortensen PB. Severe mental disorders in offspring with 2 psychiatrically ill parents. Arch Gen Psychiatry. 2010 Mar;67(3):252-7. Abstract

Birmaher B, Axelson D, Goldstein B, Monk K, Kalas C, Obreja M, Hickey MB, Iyengar S, Brent D, Shamseddeen W, Diler R, Kupfer D. Psychiatric disorders in preschool offspring of parents With bipolar disorder: The Pittsburgh Bipolar Offspring Study (BIOS). Am J Psychiatry. 2010 Mar;167(3):321-30. Epub 2010 Jan 15. Abstract

Comments on News and Primary Papers
Primary Papers: Severe mental disorders in offspring with 2 psychiatrically ill parents.

Comment by:  John McGrath, SRF Advisor
Submitted 4 March 2010 Posted 4 March 2010

This paper links one of the giants of psychiatric genetics...  Read more

View all comments by John McGrath

Comment by:  Peter Propping
Submitted 16 March 2010 Posted 16 March 2010

The study by Gottesman et al. is extremely important. Its...  Read more

View all comments by Peter Propping

Comment by:  Jehannine Austin
Submitted 19 March 2010 Posted 19 March 2010

The study recently published by Irving Gottesman and...  Read more

View all comments by Jehannine Austin
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