This is part of an EU proposal which will be led by Olle Bygren at the Karolinska Institute in Stockholm. The over-arching aim of the study is to determine transgenerational effects of smoking, stress and famine on subsequent generations. We propose to undertake the following two work-packages using ALSPAC:

1. Transgenerational smoking studies:

Detailed information was collected from the parents during pregnancy concerning their own backgrounds, including their childhood. The details included the age at which the parents started to smoke, the maximum amount they had smoked in their lifetime, the duration in years that they had smoked,and the amounts they were smoking at three stages of the study pregnancy. There was also information on the preceding generation [including whether the parents' own parents were smokers, and whether the grandmother smoked when expecting the study parent]. Information on the study 'child' is now available concerning the age at which he/she started smoking, and the amount smoked in adolescence and will be available for the early 20s.

The data currently available allow detailed time-related data on active and passive smoke exposure of the grandparents, the parents and the child. Although we have carried out research projects on: (a) the association between paternal onset of regular smoking in the pre-puberty [slow growth] period, and (b) exploration of the effects of parental prenatal smoke exposure on the anthropometry of the study children, there is much still to be done.

The long-term effects across the generations of active and passive smoke exposure will be assessed for the first time in a human population. This work-package will determine whether there are other outcomes [we have already shown associations with height, fat and lean mass in the next generation to age 17; these observations will be extended in this work-package to age 24]. Candidate outcomes will include factors that have been linked with smoking in a single generation or with prenatal exposure, but not across generations. Possibilities include: markers of the metabolic syndrome such as insulin resistance, reproductive outcomes such as miscarriage and subfertility; myopia; hyperactivity; conduct disorder and criminal behaviour; neurocognitive and motor development.

2. Transgenerational stress studies:

Detailed information was collected from the parents during pregnancy concerning their own backgrounds, including their childhood. Information included traumatic events, such as separation, divorce or death of a parent, physical or emotional abuse and neglect, with a childhood traumatic life event scale of over 40 items. The parents also completed life event scales to cover the first half of pregnancy, and subsequent approximately annual periods for the first 10 years after delivery. In parallel a series of similar questions elicited traumatic events experienced by the study child at approximately annual periods.

The data currently available allow detailed time-related data on traumatic events to the parents and to the child. Ideally, the study would benefit from knowledge of traumas to the generation before. This work package will be used to make detailed enquiries of the parents in regard to the childhood of their own parents. This would particularly enquire about their experience of World War II - where were they, were they evacuated, were they bombed, did they lose family members as a consequence, etc.

Outcome variables that will be considered include neurocognitive development and motor abilities [we have already shown a strong association between maternal stress in mid-childhood and developmental coordination disorder in the child], as well as growth. We will look in particular at differences between the study offspring according to whether the maternal or paternal parents experienced the trauma, the ages at which it occurred, and the sex of the offspring.

Questions to include:

Have you ever been diagnosed with any of the following?

YES BY A DOCTOR YES BY SELF NO NOT SURE

Asthma

Eczema

Psoriasis

Hypertension (high blood pressure)

Heart Attack/Myocardial Infarction

Stroke

Polycystic Ovary Syndrome

Endometriosis

Crohn's Disease

Ulcerative Colitis

Ankylosing Spondylitis

Psoriatic arthritis

Spondyloarthropathy

Rheumatoid Arthritis

Sjogren's Syndrome

Lupus

Grave's Disease

Multiple Sclerosis

Hashimoto's Thyroiditis

Type 1 Diabetes (Juvenile onset diabetes)

Type 2 Diabetes (Adult onset diabetes)

Schizophrenia

Bipolar Disorder

Depression

Chronic Fatigue Syndrome / ME

Any other diseases/medical conditions (please give details):

Aims of proposal: The aims of this proposal fall within 3 work themes:

Work theme 1: Epidemiology and environmental risk. We aim to investigate the development of psychotic experiences, at-risk mental states and transition to psychotic disorder from childhood through early adulthood, and examine how social adversity and cannabis use affect these outcomes.

The main questions that we will address in Work theme 1 of this proposal are:

i) What is the prevalence and incidence rate of psychotic experiences, high-risk mental states, and psychotic disorder at age 24 years?

ii) What proportion of those with psychotic experiences or high-risk mental states at age 18 persist, remit, or transition to psychotic disorder at age 24?

iii) How do trajectories of psychosis using data from ages 12, 18 and 24, relate to changes in social and occupational functioning over this time period, independently of time-varying confounders?

iv) What is the effect of a) social adversity, indexed by measures of childhood maltreatment, harsh parenting, peer- or sibling-victimization or disturbed peer relationships, and b) cannabis use, and changes in these exposures over time, on incident psychotic experiences?

Work theme 2: Cognitive vulnerability. We aim to examine whether (i) cognitive models of psychosis based on deficits found in patients with schizophrenia in relation to source monitoring, reasoning bias and predictive coding are associated with psychotic experiences in the general population, and (ii) whether social adversity and cannabis use are associated with these deficits.

The main questions that we will address in Work theme 2 of this proposal are:

i) Are deficits in cognitive processes relating to source-monitoring, reasoning bias, and predictive coding in young adults associated with psychotic experiences at this age, and are these symptom-specific (as hypothesised for source-monitoring (hallucinations) and reasoning bias (delusions))?

ii) To what extent are associations between these cognitive processes and psychotic experiences independent of intellectual ability, adolescent depression, and other potential confounders?

iii) Are experiences of social adversity and cannabis use during adolescence associated with deficits in these cognitive processes, and to what extent might these deficits explain associations between these environmental exposures and psychotic experiences in young adults?

Work theme 3: Genetic risk. We aim to examine whether genetic risk for schizophrenia, based on risk score profiling, is associated with deficits in the cognitive processes described above, and explore how genetic risk for schizophrenia is manifest in relation to neurocognitive, psychopathological, and social phenotypes from childhood through to young adulthood.

The main questions that we will address in Work theme 3 of this proposal are:

i) Does schizophrenia liability as indexed by risk score predict:

* source-monitoring, reasoning bias or predictive coding performance?

* neurocognition (processing speed, working memory, and verbal and performance IQ)?

* psychopathology (psychotic experiences, negative symptoms, depression, anxiety, and autism spectrum disorder traits)?

* social-environmental stressors (social adversity and cannabis use)?

* reduced social and occupational functioning?

ii) Do patterns of association between risk score and neurocognition and psychopathology differ by developmental stage (childhood (0-12), adolescence (13-18), and early adulthood (19-24))?

iii) How does risk of psychotic experiences at age 24 vary in relation to risk score and co-exposure to social adversity or cannabis use?

Aim: To develop and validate a clinical algorithm integrating genetic and non-genetic (clinical characteristics and cardiovascular imaging) factors for the perinatal prediction of coronary artery disease in adulthood.

Aims/hypotheses

* We will determine whether habitual exposure to high impacts influences peak bone mass (PBM), by investigating whether these impacts explain the relationship between habitual physical activity and PBM as measured by DXA

* We will examine whether effects of high impacts on PBM translate into greater bone strength, by studying relationships between high impacts and cortical bone strength as assessed by pQCT

* We will determine if a critical time exists in bone development when high impacts exert the greatest long term effects on PBM

* We will investigate whether relationships between exposure to high impacts and PBM represent a causal effect, as opposed to common dependence on intrinsic muscle strength (assessed by jumping mechanography), given physical activity affects muscle strength and muscle strength independently affects bone mass

* We aim to identify whether factors which influence PBM act via altered responsiveness to high impact activity

o We will determine whether individuals with low fat mass show weaker relationships between high impact activity and PBM. Whether such a relationship is explained by altered calorie intake will be investigated, along with the contribution of altered eating behaviour

o We will study whether interactions exist between high impact activity, PBM and constitutive factors affecting cortical bone development eg insulin, adiponectin, bone resorption

* What are the other benefits of high impact exercise for musculoskeletal health? We will investigate whether high impact exercise is associated with musculoskeletal pain, or aspects of hip shape implicated in the pathogenesis of osteoarthritis.

Aims

This study has five specific aims

1. To describe the prevalence of psychotic and affective symptoms at age 18 years according to neighbourhood-level characteristics at 18-years old, 12-years old, 7 years old and birth using advanced spatial epidemiology

2. To conduct Hierarchical Bayesian Modelling (HBM) to investigate the extent to which psychotic and affective symptoms share a common risk component at the neighbourhood level at each period of the life course

3. To conduct multilevel logistic regression to examine whether duration of exposure to neighbourhood level social disadvantage is associated with the risk of psychotic symptoms at age 18.

4. To examine whether maternal and child-reported perceptions of neighbourhood safety and cohesion are associated with elevated levels of psychotic symptoms, depressive and anxiety symptoms and internalising and externalising disorders in chilhdood

5. To explore the pathways through which exposure to neighbourhood social disadvantage over the life course is associated with psychosis risk, with particularly interest in the mediating role of urban living on the association between individual-level early life adversity, childhood cognitive ability and psychotic symptoms at ages 12 and 18.

Objectives

Genome-wide association studies (GWAS) have identified genetic variants associated with body mass index (BMI) and blood pressure (BP) in both adults and children (Speliotes 2012, and the International Consortium for Blood Pressure GWAS 2011).

We, at Vascular Physiology Unit, have shown that although greater childhood obesity is associated with adverse metabolic risk factors, there was no evidence of vascular damage by obesity at age 9-11 years in the ALSPAC subjects. Systolic BP was strongly associated with greater adiposity and also increased vascular dysfunction at that age (Charakida 2012). The causal direction and nature of the association between BMI and BP is unclear at this age.

I will investigate the effect of BMI, BP and other metabolic traits on vascular dysfunction ain the young by using a combination of Mendelian randomization and conventional analyses to unravel the complex association between BMI, SBP, metabolic traits and their causal role in vascular dysfunction.

I will be working in collaboration with Kaitlin Wade (PhD student at Bristol) on this project.

Aims

1. Characterise the hearing of the cohort from the ages 7 to 14

2. Explore the associations of a range of exposures (physiological, environmental, genetic and epigenetic) with hearing at age 7 to 14

3. Directly assess the hearing of the ALSPAC cohort at age 24

4. Characterise the changes in hearing from age 7 to 24

5. Explore the association of a range of exposures (physiological, environmental, genetic and epigenetic) with the changes in hearing

6. Examine the impact of hearing loss at age 24 on educational outcomes & employment

7. Examine the association of hearing at age 24 with co-morbidities such as visual impairment, mental health, cognitive abilities and precusors to CVD.

Aims: The proposed project aims at investigating the potential mediating role of DNA methylation in the relationship between breastfeeding and children's cognition.