Myopia, or short-sightedness, is one of the most common causes of sight impairment worldwide. By 2050, five billion people- half the world’s population- will be short-sighted, compared to ~1.4 billion people today.
People with myopia have relatively long eyes, so that light is focused in front of the retina instead of directly onto it. Since the eye continues to grow throughout childhood, someone who develops myopia as a child will continue to get worse as they grow older, with greater risk of sight-threatening complications.
Previously, we showed that for each additional year we spend in education, the more myopic we become, on average, as a population. Evidence from other studies suggests that this may be because we spend less time outside, reducing our exposure to natural daylight. Other risk factors for myopia include the time we spend on near work, urbanization, socioeconomic position, diet, pregnancy-related factors and genetics. Children with myopia tend to engage in less physical activity, but physical activity alone is not protective against myopia.
Myopia is more prevalent in countries adopting a Western diet and lifestyle, and many of the genes that increase the risk of myopia are involved in insulin/glucose signalling and obesity/fat metabolism. Insulin signalling also appears to influence the normal growth of the eye. As the Western diet is linked to greater intake of food with higher energy loads, one hypothesis is that compensatory increases in blood glucose and insulin levels send increased growth signals to the eyes.
This project aims to determine how genetic and environmental factors interact with insulin signalling to affect myopia. Changes in insulin signalling happen naturally in children around puberty, and so we would like to use information in the Avon Longitudinal Study of Parents and Children on eye growth, glasses prescriptions, blood levels of glucose and insulin before, during and after puberty on thousands of children followed prospectively from birth, to find out how they interact to affect eye growth. Additionally, there are normal variants in our genes that influence fasting levels of insulin and glucose and we will find out how these genetic variants are linked to myopia. These analyses should provide novel insights into the relationship between insulin signalling and myopia, and have the potential to identify novel targets for treatment.

Previous research has shown that autism spectrum disorder is caused by a combination of both genetic and environmental factors. Although studies have identified genes that associated with having ASD, the specific pathways involved in the development and progression of ASD is not well understood. In addition, less is known about the genetic contributions to autistic traits in the more general population and also on the progression of these autistic traits. In this project we would like to address this important gap in our knowledge by investigating these genetic contributions in more detail and by attempting to identify the specific biological pathways that lead to the development of ASD, autistic traits and the progression of these traits over time. To do this we will use data from several cohorts, including Children of the Nineties. The results from this study may inform population health and may help develop more targeted interventions for individuals with ASD symptoms.

Epidemiological research has shown that adolescents worldwide are chronically sleep deprived due to increased use of technology at night, consumption of caffeinated beverages, as well as more academic and social demands (1-3). Sleep fragmentation and sleep loss have been associated with emotional dysregulation (4), increased psychosis (5), and higher risk-taking behaviours, including substance abuse (6). Adolescents are particularly exposed to the risk of developing substance use disorders (SUDs) and related psychiatric comorbidities (7,8), hence it is particularly important to measure to what extent and how adolescent chronic sleep restriction contributes to the development of such mental disorders. So far, longitudinal analysis using ALSPAC data have found that less total sleep time at age 15 years predicts symptoms and diagnosis of anxiety and depression later in life (9). However, the prospective association between adolescent sleep and development of SUDs has not been explored.
One of the mechanisms through which sleep loss can affect brain function is by inducing epigenetic changes, dynamic modifications that can powerfully regulate gene expression, without changing the heritable genetic sequences. Epigenetic changes in the form of DNA methylation have been associated with both altered sleeping patterns (10,11) and SUDs in adults (12-15). Our goal is to determine whether adolescent sleep patterns predict the risk of developing SUDs later in life and to what extent epigenetic changes are associated with both adolescent chronic sleep restriction and drug consumption. Since, despite recent declines, alcohol remains the substance most widely used by today’s teenagers, this research proposal will focus on alcohol drinking and alcohol use disorders. The results of this analysis will guide future causal experiments to identify the biological mechanisms mediating the consequences of sleep loss and to develop new strategies to reduce alcohol abuse and improve mental health.

1. Crowley SJ, Wolfson AR, Tarokh L, Carskadon MA. An update on adolescent sleep: New evidence informing the perfect storm model. J Adolesc. 2018;67:55-65. doi:10.1016/j.adolescence.2018.06.001
2. Short MA, Weber N, Reynolds C, Coussens S, Carskadon MA. Estimating adolescent sleep need using dose-response modeling. Sleep. 2018;41(4). doi:10.1093/sleep/zsy011
3. Owens J, Adolescent Sleep Working Group, Committee on Adolescence. Insufficient sleep in adolescents and young adults: an update on causes and consequences. Pediatrics. 2014;134(3):e921-932. doi:10.1542/peds.2014-1696
4. Ben Simon E, Vallat R, Barnes CM, Walker MP. Sleep Loss and the Socio-Emotional Brain. Trends Cogn Sci. 2020;24(6):435-450. doi:10.1016/j.tics.2020.02.003
5. Ritter PS, Höfler M, Wittchen H-U, et al. Disturbed sleep as risk factor for the subsequent onset of bipolar disorder--Data from a 10-year prospective-longitudinal study among adolescents and young adults. J Psychiatr Res. 2015;68:76-82. doi:10.1016/j.jpsychires.2015.06.005
6. Short MA, Weber N. Sleep duration and risk-taking in adolescents: A systematic review and meta-analysis. Sleep Med Rev. Published online March 27, 2018. doi:10.1016/j.smrv.2018.03.006
7. Spear LP. Alcohol Consumption in Adolescence: a Translational Perspective. Curr Addict Rep. 2016;3(1):50-61. doi:10.1007/s40429-016-0088-9
8. Saalfield J, Spear L. The ontogeny of ethanol aversion. Physiol Behav. 2016;156:164-170. doi:10.1016/j.physbeh.2016.01.011
9. Orchard F, Gregory AM, Gradisar M, Reynolds S. Self-reported sleep patterns and quality amongst adolescents: cross-sectional and prospective associations with anxiety and depression. J Child Psychol Psychiatry. Published online June 17, 2020. doi:10.1111/jcpp.13288
10. Massart R, Freyburger M, Suderman M, et al. The genome-wide landscape of DNA methylation and hydroxymethylation in response to sleep deprivation impacts on synaptic plasticity genes. Transl Psychiatry. 2014;4(1):e347-e347. doi:10.1038/tp.2013.120
11. Lahtinen A, Puttonen S, Vanttola P, et al. A distinctive DNA methylation pattern in insufficient sleep. Sci Rep. 2019;9(1):1193. doi:10.1038/s41598-018-38009-0
12. Liu C, Marioni RE, Hedman ÅK, et al. A DNA methylation biomarker of alcohol consumption. Mol Psychiatry. 2018;23(2):422-433. doi:10.1038/mp.2016.192
13. Lohoff FW, Roy A, Jung J, et al. Epigenome-wide association study and multi-tissue replication of individuals with alcohol use disorder: evidence for abnormal glucocorticoid signaling pathway gene regulation. Mol Psychiatry. Published online May 12, 2020. doi:10.1038/s41380-020-0734-4
14. Montalvo-Ortiz JL, Cheng Z, Kranzler HR, Zhang H, Gelernter J. Genomewide Study of Epigenetic Biomarkers of Opioid Dependence in European- American Women. Sci Rep. 2019;9(1):4660. doi:10.1038/s41598-019-41110-7
15. Camilo C, Maschietto M, Vieira HC, et al. Genome-wide DNA methylation profile in the peripheral blood of cocaine and crack dependents. Rev Bras Psiquiatr Sao Paulo Braz 1999. 2019;41(6):485-493. doi:10.1590/1516-4446-2018-0092

DNA methylation (DNAm) plays a central role in gene regulation. It helps to define how cells respond to environmental signals and, ultimately, contributes to health or susceptibility to disease. However, the amount and the effects of differences in DNAm from one person to another is poorly understood. Understanding DNAm variability is a complex area of research as DNAm varies from one type of cell to another and can change over time. In addition, DNAm is influenced by genetic, molecular and environmental and other factors. So far, most epidemiological studies of DNAm have been performed in blood comprising diverse cell types. Furthermore, it is unknown whether DNAm changes lead to other molecular changes (for example gene expression) or whether the reverse is true, with molecular changes leading to changes in DNAm. Together, this makes the interpretation of DNAm variability difficult.

A powerful avenue into researching the functional consequences of changes in DNAm levels is to correlate DNA sequence variants such as single nucleotide polymorphism (SNPs) to DNAm levels to find both local and distal (for example on other chromosomes) effects. Having completed the largest genetic study of DNAm worldwide to date (through the Genetics of DNA Methylation Consortium) by scanning 10 million SNPs genomewide, we have identified 270k SNP-DNAm associations. This was achieved by analysing about 400,000 DNAm sites in blood, which is only 2% of 28 million DNAm sites across the genome. There is a huge potential for improved understanding of DNAm variation between individuals and its influence on health and disease by studying other regulatory regions of the genome, disease-relevant cell type or context and by developing novel epidemiological approaches where effects of multiple cell types and regulatory features are combined in a population-based setting.

We propose to integrate a suite of state-of-the-art technologies to characterise the functional role of DNAm. We will use novel sequencing technologies based on long reads with the ability to measure all 28 million sites and to determine both the DNAm level and the genotype at single molecule level. We will exploit these properties to provide insights on highly complex genomic regions, differential DNAm between alleles and detection of different modifications. We will systematically map genetic influences on DNAm across a wide range of tissues, cell types and ancestries. We will use this resource to understand the regulatory role of non-coding variants associated with disease traits by studying shared genetic variation and by using genotype as a causal anchor. We will further develop epidemiological approaches to explore the functional role of DNAm variation between individuals in large population-based epidemiology studies. We will validate causal relationships between DNAm sites and traits with epigenetic editing experiments where we manipulate DNAm sites to study the effects of gene regulation to disease. We will establish an openly accessible data resource that will enhance our understanding of environmental and genetic influences on genome function in humans.

ALSPAC has received funding to complete a data collection sweep for original ALSPAC participants that was due to commence in September 2020 and to continue data collection with the ALSPAC-G2 (children of the children cohort). The original objective of bringing QuinteT into ALSPAC was to learn from their trials activity and to deploy techniques for engagement, measurement, update/change of approach to improve study performance. ALSPAC also aims to improve recruitment in key groups; Males, low SES, disengaged and ethnic minorities. A proposal was funded by the CRN for QuinteT to review ALSPAC engagement activities with a subset of male participants involved in the FIT substudy.
Due to the Covid-19 pandemic, ALSPAC has had to cease all face to face data collection activities. ALSPAC is now looking to develop a “virtual visit” and would like to use the CRN funding for QuinteT evaluate the effectiveness of our messaging around these virtual visits and to help evaluate the success of these visits from the participant perspective.

There are multiple evidences in the literature that there is a clustering of energy balance related behaviors in children, however, the link with obesity related outcomes is not always consistent across the studies. Our goal is mobilize several European cohorts, all part of the lifecycle consortium, to achieve greater statistical power, and compare results across European countries.

Stuttering is a complex communication disorder, characterized by dysfluent speech, that can have a profound effect on an individual’s social and mental wellbeing. Up to 11% of children commence stuttering by 4 years of age. Whilst stuttering resolves for many, a third will develop a persistent stutter. Stuttering interventions are effective for some in the preschool years; yet, there are no effective treatments for older children, adolescents or adults, and it is not possible to predict who will develop persistent stuttering. The exact causes of stuttering are still unknown, but genetic factors play an important role.

We hypothesize that common genetic variation makes a substantial contribution to the risk of stuttering and propose that this is most effectively investigated by undertaking a genome-wide association study (GWAS), using a large population-based sample of people who stutter (PWS), recruited via an online questionnaire. Crucially, so far there is no published GWAS for stuttering, a clear gap in our genetic understanding of this disorder.

We are building a global collection of PWS, recruiting adults and children through a concerted media recruitment campaign. Alongside our efforts to recruit PWS directly, we are building a global network of cohorts with information on stuttering via the GenLang Consortium. We intend to combine data from both approaches, in a large-scale GWAS meta-analysis.

Understanding the genetics of stuttering will provide insights into the underlying biology, potentially leading to stratification of stuttering into clinically relevant subtypes, targeted treatment and drug targets. This will lead to better health and socioeconomic outcomes for PWS.

In a current project, we are trying to identify genetic factors associated with pubertal traits in Chilean Children. We are also interested on how genetic ancestry affects these traits. In order to know whether our results on Chileans are unique, we need to replicate the same analyses using a European cohort like ALSPAC.

Asthma is a major non-communicable disease affecting over 12% of children and estimated to affect 339 million people worldwide (1,22). It is a multifaceted and heterogeneous disease with different patterns of incidence and prevalence between children and adults and between males and females (3). Its etiology is thought to be a complex interplay between environmental exposures (such as air pollution, mold, pollen, and the weather), genetic susceptibility, and host factors (such as infections and nutrition); the underlying mechanisms, while not fully understood, may include airway inflammation and control of reactivity and airway tone (4).

Exposure to outdoor air pollutants such as particulate matter (PM) and nitrogen dioxide (NO2) have been associated with both childhood asthma and allergies (5–12). However, whether allergies such as atopic dermatitis (eczema) and allergic rhinitis (hay fever) mediate the relationship has not been well-characterized.

The atopic march, the linear progression starting with eczema with subsequent allergic rhinitis and asthma in later childhood is a well-known concept but it may not capture the trajectories of most children (13–15). Asthma often co-occurs with allergies like eczema and allergic rhinitis but the causal nature of this progression is unknown. Studies suggest that a dysfunctional skin barrier may be a site for allergic sensitization and contributes to the onset of eczema and progression to allergic rhinitis and childhood asthma (16). Eczema has often been found to precede development of asthma, but this is not always the case, with only an estimated 1-in-3 children with eczema developing childhood asthma later on (17,18). Similarly, asthma often co-occurs with allergic rhinitis due to shared common physiology such as heightened reactivity and bronchial hyperresponsiveness (19,20). It is considered a risk factor for asthma, with a 23-year follow-up finding allergic rhinitis three times more likely to develop asthma than those without allergic rhinitis (14,15). However, the evolution of the two appear to be bidirectional; a study in Italy following 99 patients with only allergic rhinitis or allergic asthma over 10 years found that 31.8% of participants with allergic rhinitis developed asthma, while 50% of those with asthma went on to develop allergic rhinitis (21).

In this proposal, we hypothesize that relationships between early-life stressors such as exposure to air pollutants and childhood asthma are at least partly mediated by common allergies and allergic diseases.

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