Spinal curvature (scoliosis) affects 3-6% of the population. Scoliosis generally appears in children while they are growing. The curves can get worse both while growing and more slowly with aging. New scoliosis also occurs in adults (called degenerative scoliosis). Large curves are associated with significant problems and may require surgery. Little is known about the causes of curve onset, progression and prognosis. What is needed is a clinical prediction tool to decide which people with scoliosis are most likely to progress and need ongoing monitoring, and who can be reassured and discharged. However, development of a prediction tool needs large scale population-based research to identify predictors. This has been limited so far, because the traditional method of identifying scoliosis is to carry out spinal X-rays which impart a high dose of radiation, and are not ethical for screening the whole population.

To address this, we have developed and validated a method of measuring scoliosis from standard total body dual energy X-ray absorptiometry (DXA) scans, a low-radiation technique using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a population-based birth cohort. We have then applied our DXA Scoliosis Method (DSM) to 7000 DXA scans from the ALSPAC aged 9 research clinic and 5000 DXA scans from the aged 15 research clinic, and have identified novel associations between early life physical activity and body composition with onset of scoliosis by aged 15. However, the prevalence of scoliosis at aged 15 is relatively low (7.9% in ALSPAC) and to carry out appropriately powered epidemiological studies we need to combine data from multiple research cohorts. We have identified additional research cohorts that have total body DXA scans already performed (approximately 84,500 individuals). We plan to use these cohorts to generate a prediction tool for scoliosis onset and progression. However, our manual method for identifying and measuring scoliosis from DXA scans is labour intensive, and further research is not feasible until we automate this method.

We therefore are proposing development and validation of a fully automatic system to identify and measure spinal curvature from total body DXA scans based on our manual method. The engineering department at the University of Oxford has already developed a similar automated system for three-dimension images of the spine based on magnetic resonance imaging (MRI) scans. We plan to modify this system to allow automatic collection of data on spinal scoliosis from total body DXA scans for future research purposes. This modification process will have two stages: (1) development of a new software algorithm to extract the required features and classify spinal images based on a subset of anonymised DXA images from ALSPAC; and (2) validation of the software on a further dataset of anonymised images from ALSPAC.

Iodine as a component of thyroid hormones is essential for the foetal brain development and iodine is considered by the WHO to be the most important preventable cause of brain damage in the world. It has been shown that even mild iodine deficiency of the mother during pregnancy can lead to lower IQ of the developing child in the UK (Bath et al. 2013). We seek support to explore the database from the AVON Longitudinal Study of Parents and Children (ALSPAC) on the availability of maternal iodine status during pregnancy in healthy young adult participants, who received a brain imaging (magnetic resonance imaging, MRI). We will associate brain anatomical markers such as grey and white matter volume, with the maternal iodine status to test our hypothesis that maternal iodine deficiency during pregnancy has long-term adverse effects on brain development. This study will be pilot study to explore the influence of maternal diet during pregnancy on the offspring’s long-term brain development, cognitive functioning and health.

The aim of this study is to examine how much physical activity children with asthma, eczema and obesity and combinations of these three conditions take part in and how that may be different to children who do not have these conditions. To do this we will use the accelerometer data that were collected in ALSPAC which provide very accurate measures of physical activity at ages 11, 13 and 15 and compare levels of physical activity across the groups. The data will tell us if the physical activity levels of children with these conditions are lower and if so how big that difference is for each group.

Communication disorders and learning disabilities are a major burden on the educational system and have long-term impact on children as they grow up and enter adulthood. It is important to understand how environmental and genetic factors increase susceptibility for these disorders in hopes of preventing them and/or developing targeted treatments. Our group has conducted a genome-wide study of DNA markers associated with speech production in a cohort of children from Cleveland, OH, USA, and have identified novel genes that are associated with articulation. First, we wish to replicate these findings in the ALSPAC cohort. Second, studies have shown that chemical markers on our DNA, called methylation marks, may influence various learning and behavioral measures. In our cohort of children from Cleveland, we have observed an association between DNA methylation patterns and the ability of children to repeat nonsense and multisyllabic words, and we wish to repeat this analysis in the ALSPAC cohort for independent verification of these findings. Third, we aim to examine how maternal chemical exposures might affect a child’s later development of communication disorders through effects on their DNA. Fourth, as we know that many children are affected with both communication disorders and other learning disabilities, it is important to understand why some children are affected by some disorders and not multiple disorders. There is evidence to suggest that the same genes influence both communication and learning disorders. We seek to better understand those relationships.

Obesity is a major public health issue, especially in low- and middle-income countries. These countries also suffer from a heavier burden of cardiovascular disease (CVD). Obesity is associated with higher risk of CVD, possible pathways have been investigated, including chronic low grade inflammation and oxidative stress. A recent study gives evidence that adiposity may cause DNA methylation, a mechanism of altering DNA expression without changing DNA sequence. However, whether DNA methylation mediated the association of adiposity with CVD risk is not clear. This study aims to assess this potential mediated effect, and may therefore use DNA methylation to identify high risk group of CVD. And since DNA methylation has a potential to be reversed, this may also provide insight into CVD prevention among overweight and obese population.
Therefore, this study investigates whether maternal and child body mass index (BMI) is associated with cardio-metabolic risk score in adolescence, and whether this association is mediated by DNA methylation in cord blood and childhood. The cardio-metabolic risk score is derived as the mean of five physical or biological measurements related to cardiovascular disease, i.e. systolic blood pressure, waist circumference, insulin resistant, triglycerides and HDL-cholesterol.

One approach in psychiatric research is to find out what differences between people put them at risk for mental health problems. Understanding these vulnerabilities helps in identifying key areas for intervention. Since psychiatric diagnostic categories do not align well with specific genetic, brain function, and behavioural measures, focus has recently shifted to the study of common mechanisms of ill health, which cut across diagnostic categories.

Some researchers have proposed that emotional lability may be one of these common mechanisms or risk factors. Emotional lability (EL) - emotional changeability, irritability and temper problems - is common in the general population. It is seen alongside a broad range of psychiatric illnesses, and in young people is associated with the development of mental health problems. However, not much is known about how emotional lability develops, how it relates to environmental risks, and what biological factors (genetic, cognitive and brain function) underpin it.

This exciting project will examine these poorly understood areas, to help us to understand the risks and impacts of emotional lability, and reveal potential avenues for intervention. Emotional lability will be examined in the ALSPAC study, a unique study of over 14,000 children born in the Bristol area, with around 6,000 followed up from birth into adulthood. This exceptional dataset includes mental health, genetic, environmental risk, and structural brain imaging information, and questionnaire and interview measures of emotional lability. Here, the project will examine environmental risks, longitudinal development, and brain imaging markers associated with emotional lability.

This is a revised version of our application B2311 (2015).

Insulin-like peptide 3 (INSL3) is a relatively new hormone which is made by the steroid-producing Leydig cells of the testes in men. Unlike the male sex steroid testosterone, it is secreted into the bloodstream in a constant way which is independent of daily rhythms and the irregular feedback mechanisms from the brain and pituitary gland. It is therefore an ideal biomarker for the so-called ‘functional capacity’ of the Leydig cells, which is equivalent to their total number and maturity status, and which indicates their total capacity to make steroid hormones (1,2). In adult men we have shown that INSL3 (and hence Leydig cell functional capacity) declines with age, such that in older men it is a good indicator of poor androgen production and associated organ dysfunction (3,4). New data by us now show that within any one individual INSL3 remains consistently low or high over periods of years, reflecting the fact that the Leydig cells are relatively fixed in number throughout adult life, neither growing nor dying (4). Importantly, we have shown that there is a 10-fold variation in INSL3 blood levels in both older and younger men, and that if a young man has a low INSL3 concentration in his blood, we can predict that he will have poor androgen production and hence related debility (bone and muscle weakness, cognitive decline, sexual dysfunction, cardiovascular disease) in old age (4,5). But we have no idea as to what causes this 10-fold spread of INSL3 values in young men.

In this retrospective study, we wish to measure INSL3 in the later blood samples from the ALSPAC cohort of boys collected at 17-18 years of age and most recently at 21-22 years of age (ca. 1500 boys). By applying already collected basic data (birthweight, gestational age at birth, maternal smoking, height and weight through puberty; Tanner staging) for these boys at previous ages, we can calculate pubertal transition, and thus gain insight into possible factors (birthweight; childhood BMI; timing of puberty; height at 8 years; etc) which might be associated with Leydig cell functional capacity in young adulthood, and thus the early factors which might contribute and predict androgen-related debility in old age.

References:

1. Ivell R, Anand-Ivell R (2009) The biology of Insulin-like Factor 3 (INSL3) in human reproduction. Human Reproduction Update 15: 463-476.
2. Ivell R, Wade JD, Anand-Ivell R. (2013) Insulin-like factor 3 (INSL3) as a biomarker of Leydig cell functional capacity. Biol Reprod 88: 147
3. Anand-Ivell RJK, Wohlgemuth J, Haren MT, Hope PJ, Hatzinikolas G, Wittert G, Ivell R. (2006) Peripheral INSL3 concentrations decline with age in a large population of Australian men. Int J Androl 29: 618-626.
4. Ivell R, Heng K, Anand-Ivell R, Wu F, and the EMAS Consortium. (2017) The Leydig cell biomarker Insulin-like peptide 3 (INSL3) in the European Male Aging Study (EMAS). Abstract 87. International Congress of Andrology, Copenhagen, May 2017.
5. Atlantis E, Martin SA, Haren MT, O’Loughlin PD, Taylor AW, Anand-Ivell R, Ivell R, Wittert GA (2009) Demographic, physical and lifestyle factors associated with androgen status, the Florey Adelaide Male Aging Study (FAMAS). Clinical Endocrinology 71: 261-272.
6. Anand-Ivell R, Heng K, Hafen B, Setchell B, Ivell R (2009) Dynamics of INSL3 peptide expression in the rodent testis. Biol Reprod 81: 480-487.
7. Johansen ML, Anand-Ivell R*, Mouritsen A, Hagen CP, Mieritz MG, Søeborg T, Johannsen TH, Main KM, Andersson AM, Ivell R, Juul A. (2014) Serum levels of Insulin-like factor 3, Anti-Müllerian Hormone, Inhibin B and Testosterone during pubertal transition in healthy boys: a longitudinal pilot study. Reproduction 147: 529-535.
8. Monteilh C, Kieszak S, Flanders WD, Maisonet M, Rubin C, Holmes AK, Heron I, Golding J, McGeehin MA, Marcus M. (2011) Timing of maturation and predictors of Tanner stage transitions in boys enrolled in a contemporary British cohort. Paed Perinat Epidem 25: 75-87.
9. Khairullah A, May MT, Tilling K, Howe LD, Leonard G, Perron M, Richer L, Veillette S, Pausova Z, Paus T (2013) Height-based indices of pubertal timing in male adolescents. Int J Dev Sci 7: 105-116.
10. Khairullah A, Klein L, Ingle SM, May MT, Whetzel CA, Susman EJ, Paus T (2014) Testosterone trajectories and reference ranges in a large longitudinal sample of male adolescents. PLOS One 9: e108838.

The aim of this project is to investigate the genetic contribution to the timing, speed and duration of puberty growth in girls and boys of the Avon Longitudinal Study of Parents and Children. This project is an update on previous work conducted by the Early Growth Genetics (EGG) Consortium (Cousminer et al., 2013) with denser genetic data and a greater ethnic diversity in samples.

It is estimated that a quarter of adults in the United Kingdom are obese. In addition to obesity being strongly heritable, the increased availability and affordability of energy dense foods has contributed to this global public health problem. However obesity can sometimes be caused by disorders of single genes. The Melanocortin 4 receptor (MC4R) is a gene that works in the brain to influence both appetite and how fast energy is burned off in the body. People who have mutations that disrupt the function of even just one of the two copies of the MC4R are often obese from early childhood. MC4R is the most common single gene disorder responsible for obesity and although estimates of its frequency in the population have been made, we don’t know exactly how common it is. We also don’t know exactly what the chances of a person carrying one bad copy of the MC4R gene has of becoming obese or when during their life this would start to be noticeable. To address this we will identify carriers of significant MC4R mutations by carrying out sequencing of the gene on DNA samples collected from the ALSPAC G1 cohort and by using our knowledge and lab testing to determine which mutations actually do impair the function of MC4R and which are just variations of normal

This work will tell us a) what the frequency of significant MC4R mutations are in a relatively unselected UK population b) how often such mutations lead to obesity

There are now trials ongoing of specific treatments for obesity associated with MC4R mutations. If those trials prove positive then it will be very important to know how many patients in the UK might benefit and to set up systems to identify MC4R deficient children