Schizophrenia Research Forum - A Catalyst for Creative Thinking

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.

References:
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 (Irv Gottesman) with one of the giants of psychiatric epidemiology (Preben Mortensen). The paper contributes more fuel to the bonfire underneath the Kraepelinian dichotomy between schizophrenia and bipolar disorder.

The new paper from Gottesman et al. presents the risk of various mental health outcomes (e.g., schizophrenia, bipolar disorder, any disorder) in the offspring of parents with one, two, or no affected parents with either schizophrenia or bipolar disorder. As expected, the more affected parents with a particular disorder, the greater the chance that their offspring will develop the same condition. In addition, the offspring of two parents with different conditions (schizophrenia or bipolar disorder) had an increased risk compared to the offspring of well parents. Apart from the expected increased risk of schizophrenia in the offspring of two parents with schizophrenia, the risk of bipolar disorder was also four times higher than the value for the general population (4.8 percent, 95 percent confidence interval = 0.2-9.4). Conversely, the risk of schizophrenia is also elevated in the offspring of two parents with bipolar disorder (10.8 percent, 95 percent confidence interval = 2.1-21.4; about 10 times higher than in the general population). Because these pedigrees are rare, the confidence intervals around the estimates are imprecise. While noting issues related to sample size, the authors draw attention to how their results support other recent findings that indicate a genetic overlap between schizophrenia and bipolar disorder.

The new study builds on two recent papers. Lichtenstein and colleagues published a paper last year that demonstrated an unexpectedly high co-segregation between schizophrenia and bipolar disorder based on a population-based analysis of Swedish families (Lichtenstein et al., 2009). Last year, Naomi Wray and colleagues from the International Schizophrenia Consortium found convincing evidence that the genetic architecture between the two disorders was shared (International Schizophrenia Consortium, 2009). Combined with the new paper from Gottesman and colleagues, these papers provide convergent evidence indicating that the traditional clinical taxonomy based on surface-level symptom profile does not reflect the upstream genetic architecture.

No doubt, the clinical distinction has some lingering utility from the perspective of treatment. However, the evidence demonstrates that, from a genetic perspective, the division between schizophrenia and bipolar disorder is now well past its ”use-by date” (Craddock and Owen, 2010). Can we continue to hide behind Kraepelin’s frock coat for much longer?

Letting go of cherished beliefs is frightening for any research community. The issue is that we do not have a reasonable alternative yet. This is not entirely the fault of psychiatry—it is an issue for all of neuroscience. Alas, we know very little about normal brain function, and even less about abnormal brain function. How can we hope to unravel the neurobiological correlates and upstream causal factors of mental illness when we are forced to rely on surface-level symptoms? As a field, we need to roll up our collective sleeves, engage actively with general neuroscience, and get the work done.

References:

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

International Schizophrenia Consortium, Purcell SM, Wray NR, Stone JL, Visscher PM, O'Donovan MC, Sullivan PF, Sklar P. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. 2009 Aug 6;460(7256):748-52. Abstract

Craddock N, Owen MJ. The Kraepelinian dichotomy - going, going... but still not gone. Br J Psychiatry. 2010 Feb;196(2):92-5. Abstract

View all comments by John McGrathComment by:  Peter Propping
Submitted 16 March 2010
Posted 16 March 2010

The study by Gottesman et al. is extremely important. Its value derives from the fact that the incidences come from a registry-based ascertainment of cases and from a country with national health insurance. Thus, the usual selective influences on ascertainment can largely be excluded. The empirical risk figures derived from this dual-mating study are much higher than in offspring where only one parent was affected by either schizophrenia or bipolar disorder. In the present study, however, the risk figures were somewhat lower than reported in some earlier studies (conducted in Germany, the United States, and the United Kingdom), where the cases had been ascertained through clinical admissions (Kahn, 1923; Kallman, 1938; Schulz, 1940; Elsässer, 1952; Lewis, 1957; Gershon et al., 1982). The major explanation is likely to be the ascertainment bias in the earlier studies.

Interestingly, this study found somewhat higher risks for both schizophrenia and bipolar disorder in the offspring of matings where one parent had schizophrenia and the other bipolar disorder. This points to a genetic overlap between the predispositions to the two diseases. An overlap is also suggested by recent molecular studies (e.g., Steinberg et al., 2010). If a genetic association has been found with one of the two disorders, it should also be tested in the other disorder.

References:

Steinberg S, Mors O, Børglum AD, Gustafsson O, Werge T, Mortensen PB, Andreassen OA, Sigurdsson E, Thorgeirsson TE, Böttcher Y, Olason P, Ophoff RA, Cichon S, Gudjonsdottir IH, Pietiläinen OPH, Nyegaard M, Tuulio-Henriksson A, Ingason A, Hansen T, Athanasiu L, Suvisaari J, Lonnqvist J, Paunio T, Hartmann A, Jürgens G, Nordentoft M, Hougaard D, Norgaard-Pedersen B, Breuer R, Möller H-J, Giegling I, Glenthøj B, Rasmussen HB, Mattheisen M, Bitter I, Réthelyi JM, Sigmundsson T, Fossdal R, Thorsteinsdottir U, Ruggeri M, Tosato S, Strengman E, GROUP, Kiemeney LA, Melle I, Djurovic S, Abramova L, Kaleda V, Walshe M, Bramon E, Vassos E, Li T, Fraser G, Walker N, Toulopoulou T, Yoon J, Freimer NB, Cantor RM, Murray R, Kong A, Golimbet V, Jönsson EG, Terenius L, Agartz I, Petursson H, Nöthen MN, Rietschel M, Peltonen L, Rujescu D, Collier DA, Stefansson H, St Clair D, Stefansson K. Expanding the range of ZNF804A variants conferring risk of psychosis. Mol Psychiatry. 2010 Jan 5. Abstract

Kahn E (1923). Studien über Vererbung und Entstehung geistiger Störungen. IV. Schizoid und Schizophrenie im Erbgang. Springer: Berlin.

Kallmann FJ (1938). The genetics of schizophrenia. Augustin: New York.

Schulz B (1940). Kinder schizophrener Elternpaare. Z Ges Neurol Psychiat 168:332-81.

Elsässer G (1952). Die Nachkommen geisteskranker Elternpaare. Thieme: Stuttgart.

Lewis AJ (1957). The offspring of parents both mentally ill. Acta Genet 7:349-65. Abstract

Gershon ES, Hamovit J, Guroff JJ, Dibble E, Leckman JF, Sceery W, Targum SD, Nurnberger JI Jr, Goldin LR, Bunney WE Jr. (1982). A family study of schizoaffective, bipolar I, bipolar II, unipolar and normal control probands. Arch Gen Psychiat 39:1157-67. Abstract

View all comments by Peter ProppingComment by:  Jehannine Austin
Submitted 19 March 2010
Posted 19 March 2010

The study recently published by Irving Gottesman and colleagues in the Archives has—as the authors point out—potentially important clinical implications. Using Denmark’s national registry data (>2.6 million individuals), the researchers calculated the cumulative incidences (to age 52) of psychiatric diagnoses in offspring of couples where one or both had previously been diagnosed with schizophrenia or bipolar disorder. The results clearly show that the probability of developing psychiatric illness is higher among offspring of individuals who have one parent with schizophrenia or bipolar disorder than among those who have no affected parents, and that the probability of developing psychiatric illness is highest among those who have both parents affected.

Probabilities that children will develop psychiatric disorders are of considerable interest amongst individuals with severe mental illnesses like schizophrenia and bipolar disorder. Further, American Psychiatric Association practice guidelines (American Psychiatric Association, 2002) for the treatment of individuals with bipolar disorder who are considering having children suggest that genetic counseling (which incorporates provision and discussion of risks for children to be affected) may be useful. Accordingly, Gottesman’s group points out that the probabilities documented in their paper may be useful for individuals with psychiatric disorders with regard to personal decision-making about issues such as childbearing. Indeed, we have previously shown that perceived risk for offspring to develop psychiatric illness may influence childbearing decisions (Austin et al., 2006).

It becomes relevant to question how the risks for offspring of individuals with psychiatric illness to develop severe mental illnesses are perceived by affected individuals. In an online survey, we asked 250 individuals with a history of psychotic illness or bipolar disorder what they thought was the chance for an individual with one affected parent to develop psychosis. We found that 43 percent of this group indicated that they thought the chance was 50 percent or greater (unpublished data).

Other commentary on this article highlighted that the probability of severe mental illness “skyrockets” when both parents are affected. But, for a sizable proportion of affected individuals who dramatically overestimate the chance for offspring to be affected, the figures derived by Gottesman’s group will actually be reassuring or lower than anticipated.

The figures reported by Gottesman’s group are a welcome resource for those of us who seek to provide individuals with severe mental illness with the most accurate probability estimates possible for these outcomes in the context of genetic counseling. As the authors point out, however, the probability figures they generated are “applicable to groups of people, not to the individuals themselves.” These figures are a useful foundation for the derivation of individualized probability estimates, in a manner that has been described elsewhere (Austin et al., 2008; Austin and Peay, 2006). No matter how reliable the study from which such probabilities are generated, however, they remain probabilities and, as John Adams writes, “Estimates of the probability of particular harms are quantified expressions of ignorance” (Adams, 2003). Essentially, we can’t say for sure whether a particular individual will develop severe mental illness or not.

References:

American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 2002;159(4 Suppl):1-50. Abstract

Adams J. Risk and morality: three framing devices. In RV Ericson and A Doyle (Eds.), Risk and Morality. Toronto: University of Toronto Press, 2003:87-103.

Austin J, Smith GN, Honer WG. The genomic era and perceptions of psychotic disorders: Genetic risk estimation, associations with reproductive decisions and views about predictive testing. Am J Med Genet B Neuropsychiatr Genet. 2006;141B(8):926-8. Abstract

Austin JC, Peay HL. Applications and limitations of empiric data in provision of recurrence risks for schizophrenia: A practical review for healthcare professionals providing clinical psychiatric genetics consultations. Clin Genet. 2006;70(3):177-87. Abstract

Austin JC, Palmer CG, Rosen-Sheidley B, Veach PM, Gettig E, Peay HL. Psychiatric disorders in clinical genetics II: Individualizing recurrence risks. J Genet Couns. 2008;17(1):18-29. Epub 2007 Dec 11. Abstract

View all comments by Jehannine Austin

Comments on Related News


Related News: New Genetic Variations Link Schizophrenia and Bipolar Disorder

Comment by:  Mary Reid
Submitted 28 September 2006
Posted 29 September 2006

It's of interest that Vazza and colleagues suggest that 15q26 is a new susceptibility locus for schizophrenia and bipolar disorder. I have suggested that reduced function of the anti-inflammatory SEPS1 (selenoprotein S) at 15q26.3 may reproduce the neuropathology seen in schizophrenia.

View all comments by Mary Reid

Related News: New Genetic Variations Link Schizophrenia and Bipolar Disorder

Comment by:  Patricia Estani
Submitted 5 October 2006
Posted 6 October 2006
  I recommend the Primary Papers

Related News: Large Family Study Links Genetics of Schizophrenia, Bipolar Disorder

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 et al. (2009) and our twin study (Cardno et al., 2002) are remarkably similar. Using a non-hierarchical diagnostic approach, the genetic correlation between schizophrenia and bipolar/mania was 0.60 in the family/twin study and 0.68 in the twin study. The heritability estimates were somewhat lower in the family/adoption (~60 percent) than twin study (~80 percent), but can still be said to be substantial and similar for both disorders.

When we adopted a hierarchical approach, with schizophrenia above mania, we found no monozygotic twin pairs where one twin had schizophrenia and the other had bipolar/mania, but with their considerably larger sample, Lichtenstein et al. (2009) were able to confirm a significantly elevated risk for bipolar disorder in siblings of probands with schizophrenia (RR = 2.7), even when individuals with co-occurrence of both disorders were excluded.

I think there is a potentially interesting link between the family/adoption and twin studies focusing mainly on non-hierarchical diagnoses: Owen and Craddock’s (2009) commentary on the family/adoption study, where they advocate a dimensional approach, and Will Carpenter’s SRF comment regarding the value of domains of psychopathology. The non-hierarchical approach (where individuals can have a diagnosis of both schizophrenia and bipolar disorder during their lifetime) could be viewed as a form of dimensional/domains of psychopathology approach, with schizophrenia and bipolar disorder each having a dimension of liability, and there is now evidence from family, twin, and adoption analyses that these dimensions are correlated, i.e., that there is some overlap in etiological influences.

If schizophrenia and bipolar disorder share some causal factors in common, what might be the implications for the unresolved status of schizoaffective disorder? Our twin study suggested that the genetic (but not environmental) liability to schizoaffective disorder is entirely shared with schizophrenia and mania, defined non-hierarchically (Cardno et al., 2002). If so, and if schizophrenia and bipolar disorder share some genetic susceptibility loci in common, while other loci are not shared, then risk of schizoaffective disorder (or perhaps the bipolar subtype) could be elevated either by the coincidental co-occurrence of non-shared susceptibility loci, or by the occurrence of loci that are common to both disorders.

In this case, any loci that influence risk of schizoaffective disorder (bipolar subtype?) should also increase risk of schizophrenia and/or bipolar disorder, and this model would be refuted if any relatively specific susceptibility loci for schizoaffective disorder were confidently identified.

Some further outstanding issues:



References:

Cardno AG, Rijsdijk FV, Sham PC, Murray RM, McGuffin P. A twin study of genetic relationships between psychotic symptoms. American Journal of Psychiatry 2002;159:539-545. Abstract

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;373:234-9. Abstract

Owen MJ, Craddock N. Diagnosis of functional psychoses: time to face the future. Lancet 2009;373:190-191. Abstract

View all comments by Alastair Cardno