(No outline received).

Objective: Toexamine genetic and environmental risk factors for developing sub-clinical, psychosis-like symptoms (PLIKS) during adolescence. Specifically:

1. To investigate whether genetic variation within NRG1, DTNBP1, DAAO, G72, RGS4 and CHRNA7 are associated with PLIKS.

2. To investigate whether cannabis or tobacco alter risk of PLIKS.

3. To examine the interplay between genetic variation and cannabis or tobacco exposure on risk of PLIKS, as well as the interplay with other risk factors for schizophrenia, including markers of neurodevelopmental abnormalities.

Background:Approximately 15% of the population report psychotic-like experiences not meeting criteria for clinical disorders. These occur more commonly than schizophrenia, and are likely to be closer to underlying aetiological pathways. Studies of PLIKS may increase understanding of schizophrenia aetiology, and help focus prevention and intervention strategies. All the genes above, as well as cannabis and tobacco, are thought to effect glutamatergic transmission. Examination of gene-environment interplay may provide further insights into aetiological mechanisms.

Design: Cohort study (nested case-control for genetic associations).

Method: The ALSPAC birth cohort of 14,000 children, currently age 11-12 will be used. Large quantities of data, including DNA, are already available. PLIKS and substance use data were collected at age 11-12 and will be re-collected at 13-14 & 15-16. Outcome to be investigated is risk of PLIKS (quantitative and dichotomous measures). Genetic analyses will include examinationunder different genetic models, haplotype analysis, and family-based association. Regressionmodels will also be used to examine association with cannabis/tobacco usewhilst adjusting for confounders, and for exploratory analysis of gene-environment interplay.

The aetiology of adverse pregnancy outcomes such as pre-eclampsia and fetal growth retardation is likely to be multifactorial and influenced by a complex interplay between maternal, fetal and placental factors. Given that a successful pregnancy outcome is highly dependent on the establishment and maintenance of an adequate placental circulation, it is possible that abnormalities of placental vasculature, leading to inadequate fetomaternal circulation, may be responsible for at least some poor pregnancy outcomes. This has led to an interest in the thrombophilias as risk factors for adverse pregnancy outcome. The factor V Leiden mutation is the most common form of inherited thrombophilia.1 A point mutation in the factor V gene at nucleotide position 1691, resulting in an arginine to glutamine substitution, reduces the sensitivity of the factor V protein to inactivation by activated protein C (activated protein C resistance) resulting in a pro-coagulant state and an increased risk of thrombosis.2 The trait is inherited in an autosomal dominant manner with the risk of thrombosis increased seven times in heterozygotes and 80 times in homozygotes. 3 Studies have shown that the distribution of the factor V Leiden mutation varies in different populations, being present in about 5% of Caucasian individuals (Europeans, Jews, Arabs and Indians) and virtually absent in Africans and Asians.

Rey et al 2003 published a meta-analysis confirming the association between recurrent fetal loss and the factor V Leiden mutation.4 Rai et al 2002 aimed to tease out the isolated contribution of factor V Leiden by comparing FVL+ women with recurrent fetal loss to FVL- women with the same history of fetal loss. The live birth rate was significantly lower among the women who carried the mutation confirming that factor V Leiden independently increases the risk of fetal loss.5 Data from our recently published meta-analysis concludes that factor V Leiden is also associated with a 2.9 fold (95%CI 2.0-4.3) increased risk of severe pre-eclampsia and a 4.8 fold (95% CI 2.4-9.4) increased risk of fetal growth retardation6.

A function enhancing mutation in the Prothrombin gene (Prothrombin G20210A) results in higher circulating levels of prothrombin, the precursor of thrombin. This mutation is present in 2.3 % of the general population is associated with a 3-4 fold increased risk of thromboembolism. The Leiden thrombophilia study reported a relative risk of 2.8 with the 20210A Prothrombin gene variant in 2.3% of healthy carriers and 6.2% of consecutive controls.

A meta-analysis with pooled data from nine studies (n=2087) indicated a significant association between the prothrombin G20210A mutation with late non-recurrent fetal loss (2.30,1.09-4.87) 4 A number of small case-control studies have conflicting results with respect to a possible association between prothrombin and the risk of pre-eclampsia and intrauterine growth restriction; and larger prospective studies are needed to clarify a possible relationship. There have been no studies evaluating a possible risk of adverse pregnancy outcome associated with the fetal Prothrombin G20210A mutation.

Most of the research in this area has been in the form of case-control studies which are notoriously subject to bias. We are therefore proposing a nested case-control study, which is methodologically more vigorous.

Placental thrombi resulting in placental infarction may occur on either side of the maternal-fetal interface, and theoretically the fetal as well as the maternal factor V Leiden genotype may influence the risk of adverse pregnancy outcome. Therefore, we aim to address the effect, not only of maternal factor V Leiden and prothrombin G20210A mutation, but also of fetal factor V Leiden and prothrombin G20210A mutation on pre-eclampsia, intrauterine growth retardation and late fetal death.

1 Rosendaal F. Thrombosis Series: Venous thrombosis: a multi causal disease. Lancet 1993;353:1167-73.

2 Bertina R, Koelenan B, Koster T, Rosendall FR, Dirven RJ, de Ronde H, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994;369:65-67.

3 Spina V, Aleandri V, Morini F. The impact of Factor V Leiden on pregnacy. Hum Reprod Update 2000;6: 301-306.

4 Rey E, Kahn S, David M, Shier I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003; 361:901-908.

5 Rai R, Backos M, Elgaddal S, Shlebak A, Regan L. Factor V leiden and recurrent miscarriage-prospective outcome of untreated pregnancies. Human Reproduction 2002;17:442-445.

6 Dudding TE, Attia J. The association between adverse pregnancy outcomes and maternal factor V ledien genotype: a meta-analysis. Thromb Haemost 2004;91:700-11.

(No outline received).

(No outline received).

(No outline received).

The idea that nutrition in early life (foetal and infant) influences or 'programmes' long term health outcomes

has major implications for human biology, public health practice, inequalities in health and policy

development as well as for product development and wealth creation.

The scientific objectives of EARNEST with an indication of which THEMES will contribute to their

achievement are listed below.

* Quantification of the effects of early programming on later cardiovascular diseases, obesity, diabetes,

cognitive and mental disorders, bone health and some cancers (Themes 1-3)

* Definition of the relative importance of critical periods in foetal and early life on later disease (1-3)

Exploration of the impact of genetic determinants on early programming effects and on subsequent

outcome (3)

* Understanding the role of specific nutrients and their interactions in the maternal and infant diet on

programming effects on disease and their risk factors (1-3)

* Understanding mechanisms for early programming on later disease and their risk factors (3)

* Development of appropriate strategies for treating and especially for preventing the amplification of

adverse programming effects of early nutrition (1)

* Exploration of the public health impact of how knowledge about early programming affects consumer

behaviour (4)

* Quantification of the impact of early nutrition on the economic burden of adult ill-health (5)

* Improvement of training and enhancement of training opportunities for all including accession countries

(8)

Objectives are given in a broad sense for the themes, more specifically for the included workpackages and

for the individual activitiesm wherever possible and meaningful.

(No outline received).

As part of our analyses of prenatal nutrition we plan to analyse the effects of prenatal alcohol exposure on childhood atopic outcomes. We propose, in addition to analysing the maternal questionnaire data on alcohol intake, to utilise a Mendelian randomisation approach in order to remove potential bias and confounding and add rigour. We would like to analyse the maternal ADH1B variant (data requested) which has been shown to predict alcohol intake in pregnancy in ALSPAC. A DTA covering analysis of genetic data is already in place with QMUL. We have all other variables (maternal exposure, confounders and childhood atopic outcomes) needed to carry out these analyses.