Prenatal Factors and Risk of Schizophrenia in a Finnish National Birth Cohort

描述(由申请人提供)：我们建议进行迄今为止最大规模的精神分裂症产前暴露的血清流行病学研究，并首次利用国家出生队列。芬兰产妇队列(FMC)包括从1983年到现在芬兰几乎所有的孕妇；总样本量为150万。产前血清样本取自每个孕妇，芬兰精神病学登记处包含几乎所有住院和非住院病例的精神分裂症诊断。在拟议的芬兰精神分裂症产前研究(FIPS-S)中，我们建议：1)检查几种血清学记录的产前感染、免疫激活生物标记物、甲状腺激素和吸烟与精神分裂症的关系；2)评估精神分裂症的产前和围产期危险因素之间的相互作用和中介关系；3)评估出生后因素之间的关系，包括儿童和成年早期的因素，以及 产前暴露在预测精神分裂症风险中的作用；4)为未来该队列中精神分裂症的基因-环境交互作用研究奠定了基础。为此，我们将采用嵌套病例对照设计。病例(N=1,500)被定义为患有精神分裂症和分裂情感障碍的FMC队列成员，对照组(N=1,500)代表FMC中与病例首次诊断时的出生日期、种族、出生地和在芬兰居住的病例匹配的未受影响的子女。病例和匹配的对照将通过FMC队列和芬兰国家精神病学登记之间的联系来确定。将对病例母亲和对照母亲的产前血清样本进行血清学记录的暴露检测。将利用与芬兰其他几个国家登记处的记录联系来获得关于产科并发症、儿童发育和早期成人发病前智力功能的标准化数据。这项研究的优势包括：1)大样本量和随之而来的高统计能力；2)评估与其他风险因素的相互作用和中介影响；3)几乎完全覆盖芬兰所有因精神分裂症出生和住院的人，这最大限度地减少了选择偏见；以及4)人口的同质性，最大限度地减少了由于人口分层造成的混乱。鉴于我们研究中包括的许多暴露在人群中是常见的，这项研究有可能确定精神分裂症的产前和其他早期发展病因，这可能有助于通过预防性公共卫生措施根除相当一部分精神分裂症病例。这项工作也有望刺激旨在识别精神分裂症新致病机制的翻译研究。最后，这项拟议的研究有可能导致未来研究精神分裂症病因学中早期发育先兆和易感基因之间的相互作用。公共卫生相关性：这项工作具有很高的公共卫生意义。确定精神分裂症的产前病因及其与其他发育因素的相互作用，有可能通过公共卫生措施根除相当一部分精神分裂症病例，如接种流感疫苗、预防性传播疾病、补充甲状腺激素和 针对孕妇的禁烟运动。此外，这项建议中描述的研究未来有可能识别与产前暴露和精神分裂症病因学中的其他发育先兆相互作用的易感基因。

DESCRIPTION (provided by applicant): We propose to conduct the largest seroepidemiologic study of prenatal exposures in schizophrenia to date, and the first to utilize a national birth cohort. The Finnish Maternity Cohort (FMC) consists of virtually all pregnancies in Finland from 1983 to the present; the total sample size is 1.5 million. Prenatal serum samples were obtained from each gravida, and the Finnish psychiatric registries contain diagnoses of schizophrenia on virtually all hospitalized and non-hospitalized cases. In the proposed Finnish Prenatal Study of Schizophrenia (FIPS-S), we propose to: 1) examine the relation between schizophrenia and several types of serologically documented prenatal infections, biomarkers of immune activation, thyroid hormone, and smoking; 2) assess interactive and mediating relationships between prenatal and perinatal risk factors for schizophrenia; 3) evaluate relationships between postnatal factors, including those during childhood and early adulthood, and prenatal exposures in the prediction of schizophrenia risk; 4) lay the groundwork for future gene-environment interaction studies of schizophrenia in this cohort. For this purpose, we shall use a nested case-control design. Cases (N=1,500) are defined as FMC cohort members who developed schizophrenia and schizoaffective disorder and the controls (N=1,500) represent unaffected offspring in the FMC matched to the cases on date of birth, ethnicity, birth place and residency in Finland at the time of first diagnosis of the case. Cases and matched controls will be identified by linkage between the FMC cohort and national Finnish psychiatric registries. Prenatal serum specimens will be assayed for serologically documented exposures in mothers of cases and controls. Record linkages with several additional national Finnish registries will be used to obtain standardized data on obstetric complications, childhood growth, and early adult premorbid intellectual function. Advantages of the study include: 1) the large sample size, and consequent high statistical power; 2) assessment of interactive and mediating effects with other risk factors; 3) virtually complete coverage of all births and hospitalizations for schizophrenia in Finland, which minimizes selection bias; and 4) homogeneity of the population, which minimizes confounding due to population stratification. Given that many of the exposures included in our studies are common in the population, this study has the potential to identify prenatal and other early developmental etiologies of schizophrenia, which may facilitate the eradication of a considerable portion of schizophrenia cases through preventive public health measures. This work also holds the promise of stimulating translational research aimed at identifying new pathogenic mechanisms for schizophrenia. Finally, the proposed investigation has the potential to lead to future studies on interactions between early developmental antecedents and susceptibility genes in the etiology of schizophrenia. PUBLIC HEALTH RELEVANCE: This work has high public health significance. The identification of prenatal etiologies of schizophrenia, and their interaction with other developmental antecedents, has the potential to lead to the eradication of a considerable portion of schizophrenia cases through public health measures, such as the administration of influenza vaccination, the prevention of sexually transmitted diseases, thyroid hormone supplementation, and anti-smoking campaigns targeted to pregnant women. Moreover, the research described in this proposal has future potential for the identification of susceptibility genes that interact with the prenatal exposures and other developmental antecedents in the etiology of schizophrenia.