A Danish National Birth Cohort study of maternal HSV-2 antibodies as a risk factor for schizophrenia in their offspring
Introduction
Schizophrenia is a severe, chronic, and devastating disorder, affecting approximately 1% of the adult population worldwide (Thorup et al., 2007, McGrath et al., 2004). Among the several candidates of environmental risk factors for schizophrenia, intrauterine exposure to infectious agents has attracted considerable interest during recent years (Yolken and Torrey, 2008a). Although conflicting studies exist, several infectious agents have been implicated, including influenza (Mednick et al., 1988, Brown et al., 2004a), Toxoplasma gondii (Brown et al., 2005, Mortensen et al., 2007, Niebuhr et al., 2008a, Torrey and Yolken, 2007), and Cytomegalovirus (Leweke et al., 2004, Kim et al., 2007, Torrey et al., 2006).
Infections of the genital tract in women have been associated with increased schizophrenia risk in their adult offspring (Babulas et al., 2006). A number of studies have focussed on a possible association between schizophrenia and maternal infection with herpes simplex virus 2 (HSV-2). Two studies by Buka et al. based upon the Collaborative Perinatal Project cohorts from Boston, Providence and Philadelphia (Buka et al., 2001, Buka et al., 2008) found an association between maternal antibodies against HSV-2 and later schizophrenia risk in the offspring. Conversely, a study based on the Kaiser Permanente Medical Care Plan in California (Brown et al., 2006) did not document an association, and also a previous smaller study by our group (Mortensen et al., 2007) did not find an association with levels of IgG antibodies against HSV-2. However, previous studies have to some extent been limited by sample size and the scope of the available data. More specifically, the statistical power to detect an association has been relatively modest in 3 of the 4 previous studies (Brown et al., 2006, Buka et al., 2001, Mortensen et al., 2007) Also, data on potentially important confounders have been difficult to obtain in most previous studies. For example, in Brown et al.'s study (2006) information about parental mental illness was not available, and in the Collaborative Perinatal Project (Buka et al., 2001, Buka et al., 2008), it was only available as self-reported maternal history; and in our previous study (Mortensen et al., 2007), the sample size was too small to have sufficient power to assess this potentially important confounder.
We therefore utilized the National Danish Neonatal PKU Biobank including more than 1.5 million individuals born in Denmark since May 1, 1981. We followed these individuals up through the use of the unique identifiers and population-based registers available in Denmark, linking the information on the children in both the cohort and their parents and siblings to a number of registers including the Danish Psychiatric Central Register. This study was based upon a new sample independent of our previous study population (Mortensen et al., 2007).
Obstetric variables as preterm birth have been associated with schizophrenia risk (Byrne et al., 2007). We therefore included gestational age as a possible confounder and also as an interacting factor in our analyses of the possible association between maternal HSV-2 exposure and schizophrenia risk in their adult offspring.
Section snippets
Data sources
The study was based upon a linkage between The Danish Psychiatric Central Register (Munk-Jørgensen and Mortensen, 1997) and the Civil Registration System (Pedersen et al., 2006), as well as the dried blood spot samples (DBSS) from The Newborn Screening Biobank (Norgaard-Pedersen and Hougaard, 2007). These samples have been systematically stored and are possible to retrieve for individuals born in Denmark since May 1, 1981.
Selection of cases and controls
We extracted all individuals who as of September 2005 had been diagnosed
Main results
Fig. 2 shows the distribution of maternal anti-HSV-2 IgG levels for cases and controls separately; cases tend to have higher IgG levels than controls.
In the neonatal blood samples from 16.1% of 602 cases and 11.1% of 602 matched controls, anti-HSV-2 IgG levels were above 0.2, i.e., above the pre-defined cut point for seropositivity (Table 1), yielding a significant association between IgG levels against HSV-2 over 0.2 and schizophrenia risk (IRR 1.51; 95% CI 1.08–2.10; p = 0.02).
Using the
Discussion
We replicated the findings from two previous studies by Buka et al., 2001, Buka et al., 2008 insofar that we found a relative risk for schizophrenia of 1.56 among offspring of HSV-2 seropositive mothers, adjusted for age, gender, date of birth and time of diagnosis.
We furthermore assessed the possible confounding effect of other possible risk factors as age of father or mother and urbanicity of place of birth, as well as mental illness in the mother or siblings. This did not affect the
Conclusion
We replicated an association between maternally derived IgG antibodies against HSV-2 and schizophrenia risk in the offspring. This association is unlikely to be caused by confounding by psychiatric family history, place of birth or parental age.
Role of funding source
The funding agency had no further role in the design, conduct or reporting of the study, or the decision to submit the report for publication.
Contributors
Preben B. Mortensen, Carsten B. Pedersen, David M. Hougaard, Bent Nørgaard-Petersen, Ole Mors, Anders D. Børglum, and Robert H. Yolken.
Conflict of interest
None.
Acknowledgement
The study was supported by a grant from the Stanley Medical Research Institute.
References (60)
- et al.
Maternal exposure to herpes simplex virus and risk of psychosis among adult offspring
Biol. Psychiatry
(2008) - et al.
Obstetric conditions and risk of first admission with schizophrenia: a Danish national register based study
Schizophr. Res.
(2007) - et al.
Failure to alleviate symptoms of schizophrenia with the novel use of an antiviral agent, acyclovir (Zovirax)
Biol. Psychiatry
(1987) - et al.
Antibodies to measles in individuals with recent onset psychosis
Schizophr. Res.
(2010) - et al.
Paternal and maternal age as risk factors for psychosis: findings from Denmark, Sweden and Australia
Schizophr. Res.
(2004) - et al.
Are exposure to cytomegalovirus and genetic variation on chromosome 6p joint risk factors for schizophrenia?
Ann. Med.
(2007) - et al.
Toxoplasma gondii as a risk factor for early-onset schizophrenia: analysis of filter paper blood samples obtained at birth
Biol. Psychiatry
(2007) - et al.
Neonatal immunology
Semin. Perinatol.
(1998) - et al.
The role of pro-inflammatory factors in mediating the effects on the fetus of prenatal undernutrition: implications for schizophrenia
Schizophr. Res.
(2008) - et al.
Serological evaluation of herpes simplex virus type 1 and type 2 infections in pregnancy
Sex. Transm. Infect.
(1999)