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 Propping

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