Effects of season of birth and a common MTHFR gene variant on the risk of schizophrenia

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Abstract

Season of birth – in particular winter birth – has been persistently related to increased schizophrenia risk. Variation in folate intake is among the explanations for this seasonal effect. Methylenetetrahydrofolate reductase (MTHFR) is an essential enzyme in the folate mediated methylation transfer reactions. Interestingly, the MTHFR gene has been related to schizophrenia risk in various studies. We investigated a possible interaction between MTHFR 677 C>T polymorphism and winter birth in the development of schizophrenia in a group of 742 schizophrenia patients and 884 control subjects. All subjects were of Dutch ancestry. Winter birth (December up to and including February) was associated with a 20% increase in schizophrenia risk (odds ratio (OR) of 1.20 and 95% confidence interval (CI), 0.96–1.5; P = 0.113). The MTHFR 677TT genotype was associated with an overall schizophrenia risk of 1.13 (95% CI, 0.82–1.57; P = 0.454) compared with the MTHFR 677CC genotype. In the winter period the MTHFR 677TT genotype associated schizophrenia risk was 0.90 (95% CI, 0.47–1.70; P = 0.744). In conclusion, neither winter birth nor MTHFR genotype were significantly associated with increased schizophrenia risk. There was no evidence for interaction between MTHFR 677TT genotype and winter birth in the development of schizophrenia.

Introduction

Schizophrenia is thought to be a complex and chronic brain disorder caused by multiple interacting genes influenced by environmental factors (Tandon et al., 2008) possibly starting in utero (Weinberger, 1987). An environmental factor that has persistently been related to schizophrenia risk is the season of birth. Since the first report in 1929 (Tramer, 1929), numerous studies have been published providing evidence for a correlation between schizophrenia and season of birth (Davies et al., 2003, Torrey et al., 1997). For individuals born in the Northern Hemisphere in particular birth during late winter or early spring has been associated with a 5–10% greater likelihood of developing schizophrenia (Bembenek and Kociuba, 2005, Davies et al., 2003, Mino and Oshima, 2006, Selten et al., 2000, Torrey et al., 1997). A winter birth effect has been associated also with several other diseases of the central nervous system, such as Multiple Sclerosis, Alzheimer's disease, Parkinson's disease (Mattson and Shea, 2003), and neural tube defects (NTD) (Blom et al., 2006). Remarkably, schizophrenia and NTD show similarities in a number of other epidemiological findings such as post famine peaks and urban place of birth (Zammit et al., 2007). These overlapping patterns of risk for schizophrenia and NTD may indicate one or more shared etiological risk factors.

In neural tube defects the findings that periconceptual folate administration was followed by a reduction in occurrence (Czeizel and Dudás, 1992) and recurrence (MRC Vitamin Study Research Group, 1991) of NTD initiated research in the role genes involved in the folate-related pathways. The first and nowadays most consistently replicated folate-sensitive genetic factor of NTD is the MTHFR 677 C>T polymorphism (Blom et al., 2006, Van der Put et al., 1995). The 677 C>T polymorphism results in a thermolabile enzyme with decreased activity. MTHFR specific activity in homozygous 677TT genotype individuals is 30–50% of that of 677CC wild-type genotype individuals (Chango et al., 2000, Frosst et al., 1995). The MTHFR specific activity in 677CT heterozygotes shows a intermediate value. The 677TT genotype may cause elevated plasma homocysteine concentrations and aberrant methylation especially when folate concentrations are in the low-to-normal range (Jacques et al., 1996, Tanaka et al., 2009). MTHFR is a key enzyme in homocysteine metabolism which provides methyl groups for the formation of DNA, RNA, lipids, or neurotransmitters and plays a role in the composition of purines and pyrimidines (Mason, 2003). These methylation processes are vital for normal cell functioning, especially during periods of rapid growth. In vitro and animal studies support the view of direct adverse effects of homocysteine on neuronal cells showing that the nervous system is sensitive to folate deprivation and raised homocysteine levels (Mattson and Shea, 2003). Meta-analyses also support the association of the MTHFR 677 C>T polymorphism and risk of schizophrenia (Allen et al., 2008, Muntjewerff et al., 2006, Yoshimi et al., 2010).

We propose that folate as seasonally varying environmental factor acting in utero might influence the risk of schizophrenia in concert with the MTHFR gene. Folate requirements during gestation are 5 to 10 fold those in nonpregnant women (Bailey, 2000, Chitambar and Antony, 2005) a demand that must be met by adequate maternal dietary intake. Seasonal variation of maternal nutrient intake in pregnancy has been determined, showing that folate intake was lowest in winter months (Watson and McDonald, 2007), which may affect fetal development.

We hypothesized an interaction between MTHFR 677 C>T polymorphism and winter birth in the development of schizophrenia. In this context low folate especially during the last gestational trimester may act as a potential environmental risk factor interacting with the MTHFR gene. We investigated the frequency and its variation of this polymorphism according to seasonality of birth in a group of schizophrenia patients and control subjects.

Section snippets

Subjects

We included 742 unrelated schizophrenia patients (75% male), mean age of 39 years (SD = 14). The patients were recruited from different psychiatric hospitals and institutions throughout the Netherlands, coordinated via academic hospitals in Amsterdam, Groningen, Maastricht and Utrecht. Detailed medical and psychiatric histories were collected, including the Comprehensive Assessment of Symptoms and History (CASH), an instrument for assessing diagnosis and psychopathology. All patients met the

Month of birth and schizophrenia risk

The calculated ORs for schizophrenia risk in relation to month of birth relative to January are plotted in Fig. 1. We estimated that the natural logarithm of the month-specific odds ratios was best described by a cosine function log(OR) = −0.12 + 0.09 * cos((6.28/12) * month + 0.90). The amplitude of the periodic function was an odds ratio of 1.09 (95% CI: 0.92–1.29) with a trough in August and a peak in February. The calculated ORs as estimates of relative risk for schizophrenia in those who are born in

Discussion

Consistent observations have indicated a positive association between schizophrenia and winter birth and between schizophrenia and the MTHFR 677TT polymorphism. In our study, we tested the hypothesis that the risk of schizophrenia is associated with month of birth when the MTHFR genotype is taken into account. Our findings suggest no interaction between MTHFR 677 C>T polymorphism and winter birth in the development of schizophrenia.

Three previous studies have investigated the interaction between

Role of the funding source

The GROUP project was supported by the Netherlands Organization for Health Research and Development (Zon-Mw) (grant number: 10.000.1001), and genome-wide SNP genotyping of the schizophrenia sample was funded by the National Institute of Mental Health (grant number: RO1 MG078075 to R.A.O.). These funding sources had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Contributors

Jan-Willem Muntjewerff and Martin den Heijer were responsible for design of the study, analysis of data, interpretation of data and writing of the manuscript. Roel Ophoff, Jacobine Buizer-Voskamp and Eric Strengman contributed to collection of data and analyses of the samples. All authors contributed to and approved the final manuscript.

Conflict of interest

All authors declare that they have no conflicts of interest.

Acknowledgement

The authors wish to thank the GROUP Consortium members for their support (see Appendix A).

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