Background
Mastering motor milestones and social personal skills may lead to a developmental transition that initiates a cascade of developmental changes, including social interaction and language learning(1). For example, the onset of walking(1,2) and sitting skills(3) but also social-personal skills can predict children's vocabulary size, which may potentially affect literacy-related abilities in later life. Similarly, early abilities to distinguish prosody and rhythm may affect children’s progress in learning language and (social) communication. For example, musical rhythmicity is strongly linked to cognition due to the synchronization of the partner's language expression in social communication(4).
Various studies have shown the genetic overlap between interpersonal milestone development and neurodevelopmental disorders. For example, individuals diagnosed with Autism Spectrum Disorder (ASD) show delayed development of cognitive and social functioning and, therefore, may reach early developmental milestones later (smiling, walking, spoon feeding themselves, crawling) or not at all(5).

This project will use data from ALSPAC and other large cohorts to investigate the genetic architecture of early social/communicative/language abilities as well as social /social communication abilities during the life course within large consortia (e.g. meta-Genome Wide Association Analyses (GWAS) within the EAGLE consortium) including in-depth structural models of genetic factors. The study will biologically annotate the genetic architecture of early social/communicative abilities as well as social abilities through genetic enrichment and variance partitioning analyses. Once social behaviour has been modelled genetically, we will derive genetic tools to identify genetic overlap with neuro-developmental disorders and other health-related, educational and (social) behavioural outcomes in later life, as well as brain-related encodings (e.g. brain structure and function). The project will finally assess evidence for correlation and causal mechanisms linking precursors of social/communicative abilities (e.g. musicality, motor behaviour and temperament) to social performance and, in turn, social behaviour and social communication skills to later-life outcomes (e.g. health, education, behaviour).

1. Walle, E. A. Infant Social Development across the Transition from Crawling to Walking. Front. Psychol. 7, (2016).
2. Walle, E. A. & Campos, J. J. Infant language development is related to the acquisition of walking. Dev. Psychol. 50, 336–348 (2014).
3. Libertus, K. & Violi, D. A. Sit to Talk: Relation between Motor Skills and Language Development in Infancy. Front. Psychol. 7, (2016).
4. Ravignani, A., Honing, H. & Kotz, S. A. Editorial: The Evolution of Rhythm Cognition: Timing in Music and Speech. Front. Hum. Neurosci. 11, 303 (2017).
5. Kuo, S. S. et al. Developmental Variability in Autism Across 17 000 Autistic Individuals and 4000 Siblings Without an Autism Diagnosis: Comparisons by Cohort, Intellectual Disability, Genetic Etiology, and Age at Diagnosis. JAMA Pediatr. 176, 915–923 (2022).

Around one-quarter of young people in the UK report intimate partner violence and abuse (IPVA, that is, physical or sexual violence, or emotional abuse) among their parents by age 16. Research in US student samples suggests that for these young people, they are more likely to be victimised in their own intimate relationships as adolescents and young adults, this association my vary according to the timing of exposure to parental IPVA, and may be even higher for those with other adverse childhood experiences, such as maltreatment or parental mental illness. However, this has rarely been studied in a general population sample, or in the UK. Further, little is known about the burden
of continued IPVA over the life-course on later health, that is, witnessing IPVA among parents to then experiencing IPVA in one’s own relationship. However, IPVA among parents does not guarantee future IPVA, and many go on to not to experience this in their own intimate relationships. Understanding what factors (e.g. parent-child relationships, school, peers) help to break the cycle of intimate partner violence, can inform policies and interventions to prevent further violence and improve quality of life in these families.

Female reproductive longevity, controlled by the timing of menarche and menopause, can vary greatly depending on genetics, lifestyle, and environmental exposures. While variations in age at menarche (AAM) and age at natural menopause (ANM) have a complex multi-factorial aetiology, the biological mechanisms underlying these variations are still not fully understood. Identifying biomarkers allows for a better understanding of the pathophysiology underpinning variations in AAM and ANM and their interconnection, while the same molecules could represent potential targets to pharmacologically modify timing of these events. High-throughput metabolomics studies have led to the discovery of a number of candidate biomarkers for a variety of traits. However, simultaneous measurement of hundreds of circulating metabolites in case-control studies is cost prohibitive and subject to confounding and reverse causation. Large genome-wide association studies (GWAS) have become available for both metabolites and AAM and ANM, advancing our knowledge on the genetic determinants of these traits. Mendelian randomisation (MR) is an established method in genetic epidemiology that explores whether a modifiable exposure is causally linked to an outcome by using genetic variants for this exposure as instrumental variables. The MR design can avoid potential bias from confounding that are typical in conventional observational studies by taking advantage of the fact that inherent genetic variants are not susceptible to environmental risk factors and reverse causation. In a setting known as two-sample MR, GWAS data for an exposure and an outcome measured in independent populations can be used to test causality of risk factors on complex health outcomes.
By employing two-sample MR, we screened hundreds of previously measured circulating metabolites for causal association with AAM and ANM. Genetic variants associated with each metabolite were extracted from four large metabolomic GWAS and effects of these variants on AAM and ANM were retrieved from the largest GWAS conducted for AAM (N = 329,345), and ANM (N = 200,000). We discovered 12 blood metabolites with evidence of a causal relationship with the AAM and 114 metabolites associated with ANM. Using multivariable MR, we found that the majority of these metabolites affect the timing of AAM or ANM regardless of body mass index (BMI). These molecules cluster in specific pathways, such as that of amino acid synthesis and glycerophosphocholine synthesis. We identified two of the candidate metabolites for AAM as significantly associated with ANM in ALSPAC participants (data requested as part of a separate project [B3667], aiming to predict AAM using a combination of genetic and non-genetic risk factors). Specifically we found an association between higher phosphatidylcholine levels and a later onset of AAM, and a link between lower isoleucine levels and an earlier onset of AAM, and the magnitude of the effects were comparable with those of the MR study. In this proposal, we request data on metabolites levels and AAM of ALSPAC mothers, in order to seek validation for a portion of the 114 candidate metabolites for ANM prioritized by our MR study, which have been measured in ALSPAC. This validation will provide further support to our MR findings, suggesting a causal role of the above metabolites in ANM.

Birth weight (BW) and placental weight (PW) have been associated with adult health outcomes, and a genetic component for this relationship has been established. Similar associations between offspring BW and PW and parental health have been found in observational studies. We aim to investigate the association of parental diabetes and cardiovascular disease risk variants with offspring BW and PW.

Epilepsy is the most common primary neurological disorder worldwide, with 10% of people experiencing a seizure during their life. Seizures often occur in combination with other neurological or behavioural traits indicating altered brain development. Seizures might also themselves negatively impact the neurocognitive development in early life. Understanding the links between epilepsy and other neurodevelopmental and neurological conditions is key to understanding the mechanism and impact of the disease. Large genome-wide association studies of epilepsy have found specific genes that are linked to brain function and might therefore explain the vulnerability of specific brain circuits in people experiencing seizures. It is not clear though how these genetic predispositions to epilepsy would affect other brain properties, for instance neurocognitive development. Therefore, we propose to investigate the molecular, neurodevelopmental and cognitive outcomes of having a genetic predisposition for epilepsy in the ALSPAC children.

We and others have identified numerous factors that influence mental health in young adults and early adulthood. These include obstetric complications, adversity, cannabis use, population density, immigrant status (PMID: 29352556, 12091183, 31563981) and most recently exposure to COVID (PMID: 35987197). Additionally, in the ALSPAC cohort, we recently identified that suicidal ideation at age 17 is associated with 7-fold increased odds of psychotic disorder, and with depressive disorder and generalised anxiety disorder at age 24. Indeed, over 40% of those with psychotic disorder in early adulthood had experienced this symptom in late adolescence (Mongan et al, 2022, unpublished).

We and others have also identified evidence for inflammatory marker
dysregulation both preceding and in association with psychiatric disorders
including psychosis, depression and recently, long COVID (PMID: 36085284 ,
35472304). Dysregulation of acute inflammatory markers [such as Interleukin
(IL)-6 and C-Reactive Protein] and complement proteins has been reported prior to
and in association with these outcomes (PMID: 25133871, PMID: 32857162).

Using ALSPAC data we identified for the first time the cross-sectional association of suPAR (soluble urokinase plasminogen activator receptor- an established marker of chronic inflammation) and IL-6 (an established marker of primarily acute inflammation) with psychotic disorder in young adults (Mongan et al 2022, under review). We previously found an inverse association between the anti-inflammatory marker n-3 fatty acid docosahexaenoic acid (DHA) at age 17 and psychotic disorder at age 24 in the ALSPAC cohort (PMID 34059620). Using ALSPAC data we have also shown for the first time that elevated suPAR is associated cross-sectionally with cannabis exposure, itself a marker for mental illhealth (Power et al 2022 (under review)).

We now seek to expand our knowledge to mental health outcomes in early adulthood (at age 24 and also at age 30 (when available)). We wish to examine not only associations between risk factors and inflammation in relation to clinical thresholds of psychiatric disorders, but also in relation to specific symptoms and symptom severity.

We hypothesise that exposure to environmental risk factors and early-life adversity is associated with chronic inflammatory dysregulation, in line with recent evidence (PMID: 31682707, 26033244, 34990745). We also hypothesise that inflammatory dysregulation will be more common in those who go on to report mental disorders in adulthood (PMID: 25133871, PMID: 32857162). Crucially, we hypothesise that inflammatory dysregulation mediates the relationship between environmental exposures and adult mental disorders, which could provide evidence for a
biological mechanism by which environmental exposures influences the risk of adult mental disorder. Alternatively, environmental exposures and biological risk factors may operate independently, but have a cumulative effect on the risk of mental disorders.

We propose to investigate this using a combination of existing ALSPAC data, and new data derived from assays undertaken by us which assessed levels of the robust marker of chronic inflammation, suPAR, in age 24 plasma samples donated by ALSPAC participants.

Only data from B4168 will be used

A large literature has explored the implications of allomaternal care (care of children by people other than their mother) on child human capital development. This project will describe parental network of help in a developed country setting, and how help received with childcare from different caregivers influence child outcomes. We will also explore how such networks predict mother return to work decisions and wellbeing. Our findings will have implications to understand how social support networks influence child and maternal outcomes.

Problematic menstrual symptoms, such as pain, heavy bleeding, and irregular cycles, impact a high proportion of women and people who menstruate and are associated with multiple adverse physical and mental health outcomes, as well as reduced attendance and productivity at school/work. Despite this, little research has sought to identify the causes and risk factors associated with such menstrual symptoms. Socioeconomic disadvantage is one factor that has been associated with worse menstrual symptoms; however, the current evidence is mixed and unable to understand causality. It is possible that socioeconomic position (SEP) causally impacts menstrual symptoms due to early life stressors and associated lifestyle factors adversely impacting the development of the brain, the nervous system, and hormone production systems. Additionally, menstrual symptoms could negatively impact SEP through their impacts on school and work thus restricting the ability of women suffering with such symptoms to reach their fully academic and career potential. Therefore, this project aims to understand the causal, bidirectional relationship between SEP and menstrual symptoms by combining observational and genetic methods in multiple UK-based cohorts. Robust evidence that SEP and menstrual symptoms are causally related may support the need for additional support or treatment for individuals from disadvantaged backgrounds and/or provide rationale for improving school and work environments to enable women to better manage problematic menstrual symptoms.

Several leading theories of suicide propose that capability for suicide is acquired across development, in part through exposure to physically painful and/or fear-inducing experiences, collectively referred to as painful and provocative events (PPEs). However, studies investigating the association between exposure to PPEs and risk for suicide attempt are usually cross-sectional (the exposure and outcome are measured at the same time) and do not employ a genetically-informed approach. In this project, we will use data from the ALSPAC study to further characterize the association between PPE exposure and risk for suicide attempt. First, we will test whether the association between genetic liability and risk for suicide attempt is mediated by impulsivity and exposure to PPEs, such as aches and pains, injuries, accidents, and traumatic events. Second, we will investigate whether the magnitude of the association between PPE exposure and risk for suicide attempt in adolescence varies based on parenting behaviors, as positive parenting behaviors may buffer risk associated with exposure to PPEs.