Correspondence
Risk Factors for Schizophrenia
N Engl J Med 1999; 341:370-372July 29, 1999
- Article
To the Editor:
Mortensen et al. (Feb. 25 issue)1 acknowledge that a family history of schizophrenia is the best-established risk factor for the disorder but suggest that environmental factors, including the place and season of birth, are major determinants. This argument is based on estimates of the population attributable risk regarding factors found to be associated with schizophrenia in their population-based cohort. Unfortunately, their assertions about the relative importance of various risk factors overlook the fact that the calculation of population attributable risk is dependent on the frequency of the risk factor in a population. The calculation of relative risk, however, is not dependent on the population base rate. Thus, for a given relative risk (RR), the population attributable risk can be calculated with use of the following equation: population attributable risk=P(RR–1)÷P[(RR–1)+1], where P is the prevalence of the risk factor in the population.2
Figure 1Figure 1
Relation between the Population Attributable Risk and the Prevalence of a Risk Factor When the Relative Risk (RR) Is Fixed. shows the curvilinear relation between the population attributable risk and the prevalence of a risk factor for three fixed relative risks and demonstrates that a modest relative risk can correspond to a very high attributable risk if the risk factor is common.Thus, although Mortensen and colleagues have provided us with an elegant set of epidemiologic data on schizophrenia, their interpretation of these data is questionable. Their ability to replicate the associations between the season of birth, the place of birth, and schizophrenia is intriguing, but far from demonstrating that these are proxy variables for major environmental factors, the findings probably reveal that in Denmark, more people live in urban areas or are born in February or March than have a first-degree relative with schizophrenia. The relative risk of schizophrenia among the identical twins of patients with schizophrenia is about 503,4 and is little changed in the small sample of identical twins reared apart. The relative risk among adopted children in Denmark with a biologic parent with schizophrenia is about 10,4 which is well within the range reported1 for children reared in the same household as an affected parent. Such findings seem to point to genetic or early neurodevelopmental factors (or both) as major determinants.
4 ReferencesPeter McGuffin, M.B., Ph.D.
Institute of Psychiatry, London SE5 8AF, United KingdomIrving I. Gottesman, Ph.D.
University of Virginia, Charlottesville, VA 229031
Mortensen PB ,Pedersen CB ,Westergaard T , et al. Effects of family history and place and season of birth on the risk of schizophrenia. N Engl J Med 1999;340:603-608
Full Text | Web of Science | Medline2
Kramer MS. Clinical epidemiology and biostatistics: a primer for clinical investigators and decision-makers. Berlin, Germany: Springer-Verlag, 1988.
3
Cardno AG ,Marshall EJ ,Coid B , et al. Heritability estimates for psychotic disorders: the Maudsley twin psychosis series. Arch Gen Psychiatry 1999;56:162-168
CrossRef | Web of Science | Medline4
McGuffin P, Owen MJ, O'Donovan MC, Thapar A, Gottesman II. Seminars in psychiatric genetics. London: Gaskell, 1994.
To the Editor:
In the study by Mortensen et al. of risk factors for schizophrenia, the ratio of males to females was 2.3:1.0 in the 2669 patients with schizophrenia. Clinical information on both parents was available for 91 percent of the patients, and 120 affected parents were identified (37 fathers and 83 mothers). Unless there is a sex-specific genetic risk factor, the male:female ratio in the group of affected parents should resemble that in the probands; instead, the ratio was reversed (1.0:2.2). With this correction for male predominance, chi-square analysis comparing the observed and expected ratios in the 120 affected parents reveals a statistically significant difference (P< 0.001). Even if one conservatively predicts that an equal number of fathers and mothers will be affected, the observed and expected ratios are significantly different (P<0.001).
In this data set, there is either an overrepresentation of affected mothers or an underrepresentation of affected fathers. The latter case is possible, since the clinical histories of 251 fathers were unknown; if we assume that the male:female ratio in the group of affected parents reflects the ratio in the probands, 154 of these unknown fathers should have schizophrenia, a rather high proportion. Alternatively, a maternally inherited genetic factor, either X-linked or mitochondrial, could account for an overrepresentation of affected mothers.
This finding of a reversal of the male:female ratio from one generation of patients with schizophrenia to the next is not unique.1 Although the explanation for this change is unclear, it is important to note that in mitochondrial genetics there can be sporadic expression of maternally inherited phenotypes and that the expression of mitochondrial genes appears to be altered in patients with schizophrenia.2
2 ReferencesRussell H. Swerdlow, M.D.
Daniel Binder, B.S.
W. Davis Parker, M.D.
University of Virginia Health Sciences Center, Charlottesville, VA 229081
Shimizu A ,Kurachi M ,Yamaguchi N ,Torii H ,Isaki K . Morbidity risk of schizophrenia to parents and siblings of schizophrenic patients. Jpn J Psychiatry Neurol 1987;41:65-70
Medline2
Whatley SA ,Curti D ,Marchbanks RM . Mitochondrial involvement in schizophrenia and other functional psychoses. Neurochem Res 1996;21:995-1004
CrossRef | Web of Science | Medline
To the Editor:
Mortensen et al. correlated the incidence of schizophrenia according to the month of birth and found the highest incidence among those born in February and March and the lowest incidence among those born in August and September. In the entire population studied, were more children born in February and March than in August and September? Among those in whom schizophrenia did not develop, how many were born in February and March and how many in August and September?
Ralph Weilerstein, M.D.
1080 Miller Ave., Berkeley, CA 94708Author/Editor Response
The authors reply:
To the Editor: Swerdlow et al. suggest that X-linked or mitochondrial inheritance could account for the difference in the male:female ratio between the affected parents of patients with schizophrenia and their offspring. However, we believe that the explanation is more simple: a relatively smaller proportion of men with schizophrenia than of women with schizophrenia have any children. The possibility is confirmed by comparing the relative number of person-years at risk for men and women in Table 1 of our paper.
Regarding Weilerstein's comment: the relative numbers of births in February and March and in August and September were taken into account in the analyses that included the exact number of person-years of exposure to risk for subjects born in each of these months.
McGuffin and Gottesman disagree with our suggestion that environmental factors can be major determinants of schizophrenia. Instead, they suggest that the high relative risk of schizophrenia among the identical twins of affected patients and adopted children who had a parent with schizophrenia means that genetic or early neurodevelopmental factors are the major determinants. They ascribe the high population attributable risk we reported to the high frequency of the factors we studied — in other words, many people are born in cities or during February and March. Although we agree with many of their comments, we do not agree that on this basis, our conclusion is erroneous.
As McGuffin and Gottesman point out, the population attributable risk has two determinants, the relative risk and the frequency of the exposure in a population. The unknown risk factors underlying the association between schizophrenia and the season or place of birth may be common and therefore of substantial importance on a population level, even if the risk associated with them is small, or even trivial, for any individual subject. We do not challenge the role of genes in causing schizophrenia, nor do we find it fruitful to view genetic and environmental risk factors as competing or mutually exclusive.
Phenylketonuria is an example of a disease that could be eliminated either by removing the susceptible genotype or by removing phenylalanine from the diet (i.e., the attributable risk for each factor is 100 percent). At present, primary prevention of schizophrenia is not possible. However, just as for phenylketonuria, in the future there may be more than one way of preventing schizophrenia. Whether preventive measures targeting genetic or environmental factors are feasible, however, remains in question.
Preben Bo Mortensen, D.M.Sc.
Psychiatric Hospital of Aarhus, DK-8240 Risskov, DenmarkCarsten Bøcker Pedersen, M.Sc.
Statens Serum Institut, DK-2300 Copenhagen, DenmarkHenrik Ewald, D.M.Sc.
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