Selection bias is pervasive in human studies and even more so for epigenome-wide association studies (EWAS) due to the relatively high costs of measuring DNA methylation. Although this bias is often acknowledged, its impact on findings has not been evaluated. We aim to perform such an evaluation for EWAS performed in ALSPAC. We will characterise selection by comparing the characteristics of ALSPAC participants measured at baseline with and without DNA methylation profiles and then estimate the resulting bias using simulations informed by the data.

This study will investigate the relationship between anxiety and eating patterns during COVID-19. At this stage in the research, eating patterns are defined by three variables: number of snacks consumed per day, number of meals consumed per day, and dietary intake. We also wish to find out whether individuals with different eating behaviour traits show variable effects. It will entail a secondary data analysis of the Avon Longitudinal Study of Parents and Children (ALSPAC), a large ongoing study that recruited approximately 14,000 pregnant women from one geographical area in the UK in 1991. Specifically, we will look at their now young adult children (aged approximately 28 years) and their responses on three questionnaires over the course of the COVID-19 pandemic from April 2020 to March 2021.

The COVID-19 pandemic and related mitigation measures have had a profound impact of society and wellbeing. Much research (including that of ALSPAC) has focused on the impact of the mitigation measures, rather than the impact of the disease. ALSPAC forms part of larger consortia examining the impact of contracting COVID-19 and Long COVID on later consequences, one of which is mental health.

This project will specifically focus on the impact of COVID-19 status and Long COVID throughout the pandemic, on later mental health by examining depression and anxiety in both generations of ALSPAC.

COVID-19 has resulted in significant increases in psychological distress, concerns, and depressive symptoms. This increased vulnerability may have resulted from environmental and social changes caused by the pandemic crisis. Social contact modalities changed drastically due to lockdown restrictions throughout the COVID-19 pandemic. Stay at home and social distancing orders resulted in a decrease in in-person social contact, and a resulting increase in distant social contact via video calls, phone calls, and texts. Our study will explore whether these different forms of social contact influenced the levels of depression, and the possible factors driving this. Additionally, gender difference in the usage of social contact methods can have an association with the elevation of loneliness. Females are more susceptible to loneliness while keeping social distance due to COVID lockdown. Since females are more dependent on in-person social engagement, females could feel lonelier by the changes in social contact forms than males, which can further trigger depression. Hence, we will also consider whether the gender contributes to increasing depressive symptoms in relation to changes in social contact modalities caused by social distancing. Understanding how symptoms of depression may be predicted by different modes of social contact will prove key to ensuring those most at risk are supported to help prevent further increases in depression.

Paediatric cerebral visual impairments (CVIs) are vision problems caused by damage to the brain rather than the eyes. Injuries to the newborn brain are by far the most common causes, including injuries associated with prematurity, hypoxia-ischemia and/or infections in the perinatal period. Many of these children have multiple neurodevelopmental impairments affecting movement, cognition and/or behaviour, and require extra educational support. There is concern that in some of these children CVIs go unnoticed or mistaken for other problems. Recent work by our group has shown that CVIs might be more prevalent than previously appreciated in the population, highlighting the need for a panel of biomarkers/predictors which can promote earlier and more accurate identification of high-risk children.
Genetic variants may affect how the newborn brain responds to perinatal stresses capable of causing brain injury. Compared to other neurodevelopmental disorders, research into the genetic contributions to CVIs is lacking, although a few genetic associations have been reported (1, 2).
This study aims at evaluating whether candidate genetic variants in the main candidate pathways involved in perinatal brain injuries (glutamate signalling and inflammation) are associated with CVIs. This hypothesis has derived partly from work carried out by two of the applicants (CW and KL) in the DRIFT study(3), in which children were assessed 10-years after a new intervention to treat brain bleeds. A high proportion of these children had CVIs and the number of CVIs correlated with the degree of structural damage to the brain that the children sustained in infancy. The genetic variants we will investigate have been identified both from the wider literature and from our own previous work (4). This includes preliminary findings within the Bristol Neonatal Gene Study, implicating candidate genetic variants in the glutamate signalling and inflammation pathways in childhood motor and cognitive outcomes. For some of these variants, us and others have explicitly shown functional effects on glutamatergic and inflammatory regulation in in vivo models relevant to brain injuries.
Associations between candidate genetic variants and vision outcomes in children from the general population will be explored within ALSPAC. By combining research from the Bristol Neonatal Gene Study with the rich database of visual function data within ALSPAC, we will be able to consider of a range of potentially important perinatal factors (e.g. prematurity, birth complications, evidence of brain injuries during the neonatal stay in the hospital) that may modify the effect of genotype on visual outcomes. We will also examine the associations between the same SNPs with (a) cognitive and (b) motor findings. From the existing literature we expect there is to be associations and we will compare the effect sizes (ES) in analyses of associations between the vision data and the SNPs of interest, with those obtained when using the motor and cognitive data. These results will be used to onform designs for future powered studies.
Additionally, we will collect new prospective data for children at risk for CVIs, enrolled by the PI at the Bristol Eye Hospital. This new clinical data will include additional more in-depth vision assessments compared to those routinely offered in the standard clinic, which will be evaluated as novel biomarkers for CVIs. Genetic profiles of these children with clinical diagnoses of CVIs will be compared to those from ALSPAC representing the general population.
This work is a collaboration between research groups in Bristol and is complementary to a proposal already approved, submitted in 2019 by SR. Some of the work proposed here is already approved as part of that proposal - however use of the vision data is unique to this proposal

References

1. Bosch DG, Boonstra FN, de Leeuw N, Pfundt R, Nillesen WM, de Ligt J, et al. Novel genetic causes for cerebral visual impairment. European journal of human genetics : EJHG. 2016;24(5):660-5.
2. Bosch DG, Boonstra FN, Reijnders MR, Pfundt R, Cremers FP, de Vries BB. Chromosomal aberrations in cerebral visual impairment. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society. 2014;18(6):677-84.
3. Luyt K, Jary SL, Lea CL, Young GJ, Odd DE, Miller HE, et al. Drainage, irrigation and fibrinolytic therapy (DRIFT) for posthaemorrhagic ventricular dilatation: 10-year follow-up of a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed. 2020;105(5):466-73.
4. Pregnolato S, Chakkarapani E, Isles AR, Luyt K. Glutamate Transport and Preterm Brain Injury. Front Physiol. 2019;10:417.
5. Williams C, Northstone K, Sabates R, Feinstein L, Emond A, Dutton GN. Visual perceptual difficulties and under-achievement at school in a large community-based sample of children. PLoS One. 2011;6(3):e14772.

Cleft lip and/or palate (CLP) or orofacial cleft is a group of congenital birth defects affecting 1 in 700 newborns annually [1]. Commonly associated with structural problems relating to feeding, hearing, speech, and tooth development, recent research shows that affected individuals may also be at an elevated risk for psychological, social, and behavioral challenges [1],[2]. While many studies have sought to investigate the psychosocial effects of CLP, a 2005 systematic review was inconclusive, citing a dearth of longitudinal research and a lack of consistency and uniformity between studies [3]. In 2017, a Cleft Care UK study of five-year old children with unilateral CLP (UCLP) found that children born with UCLP had higher levels of behavioral problems than the general population, but that these findings required replication [1]. Researchers also suggest that children born with CLP may experience heightened psychosocial challenges around the school transition, and that this is worthy of investigation [1]. All of the contributing research cites a sufficient lack of large, longitudinal studies, focused on the psychological development of children born with CLP, and that this research is critical to the development of appropriate interventions for this population [1],[3].
1. Waylen A, Mahmoud O, Wills AK, Sell D, Sandy JR, Ness AR. Centre-level variation
in behaviour and the predictors of behaviour in 5-year-old children with non-
syndromic unilateral cleft lip: The Cleft Care UK study. Part 5. Orthodontics &
Craniofacial Research. 2017;20(S2):40–7.
2. Cleft lip and palate [Internet]. nhs.uk. 2017 [cited 2019 Apr 2]. Available from:
https://www.nhs.uk/conditions/cleft-lip-and-palate/
3. Hunt O, Burden D, Hepper P, Johnston C. The psychosocial effects of cleft lip and
palate: a systematic review. Eur J Orthod. 2005 Jun;27(3):274–85.
4. Bjerke SM, Feragen KB, Bergvik S. Strengths and Difficulties Questionnaire
(SDQ): Informant Agreement Between Children Born With Cleft Lip and/or
Palate and Their Parents. Cleft Palate Craniofac J. 2018;55(2):204–12.

This project is linked to dataset B2857

Attention deficit hyperactivity disorder (ADHD) is a common childhood neuropsychiatric disorder characterised by impaired levels of inattention, hyperactivity, and impulsivity (American Psychiatric Association, 2013). Meta-analyses estimate the global pooled prevalence of ADHD to be 7.2% in children and adolescents (Thomas et al., 2015) and 3.4% in adults (Fayyad et al., 2007). Cross-sectional studies have shown anxiety disorders are more prevalent in individuals with ADHD compared to the general population (Van Ameringen, Mancini, Simpson, & Patterson, 2010) and the rates increase with age; up to 30% of young people and 50% of adults (Kooji et al., 2012) with ADHD meet the diagnostic criteria for an anxiety disorder.
Although anxiety is highly prevalent in those with ADHD, much of the longitudinal research focuses on whether ADHD is associated with subsequent behaviour disorders and substance misuse. A 2008 systematic review by Jarret and Ollendick specifically identified a lack of longitudinal research on ADHD and subsequent anxiety; this finding still applies today. Longitudinal research on the matter is of importance to see whether ADHD symptoms predispose an individual to the development of anxiety. A recent study examined the association between co-occurring ADHD and anxiety from early to late adolescence and identified a bidirectional relationship between ADHD symptoms and anxiety (Murray et al., 2020) however, no study has examined longitudinal associations between childhood ADHD symptoms and anxiety in adolescence. This would provide a fuller picture of the association between ADHD and anxiety considering the onset of ADHD is often in childhood.

This project is linked to B2857.

Around 40% of the EU population suffers from a mental disorder. Healthy development can be derailed by excessive or prolonged activation of stress response systems in the body and brain during fetal life. Such toxic stress exposure can have damaging effects on learning, behavior, and mental health across the lifespan. Our ERA-NET consortium (Project EMBED) focuses on two cohorts (offspring of obese or stressed mothers), aiming to address specific questions on mental health risk factors. This might be then used in the clinic for disease prevention and health promotion during pregnancy.

Our hypothesis is that maternal obesity and inadequate nutrition during prenatal life can trigger similar responses to maternal stress, altering developmental trajectories and increasing the risk for mental health in adulthood. These adverse experiences can increase the likelihood of developmental delays and later health problems.

Our consortium analyzes epigenetic modifications from the abovementioned cohorts, assessing whether common biological signals characterize early exposure to metabolic and psychological stress, affecting the long-lasting expression and methylation of genes involved in depression, obesity, and immune-metabolic function. We propose to use the ALSPAC data to compare and validate the findings from our consortium-generated data, in a larger/complementary context.