B4537 - Rare and common genetic influences on cognitive and behavioural phenotypes in ALSPAC - 04/03/2024

B number: 
B4537
Principal applicant name: 
Hilary Martin | Wellcome Sanger Institute
Co-applicants: 
Emma Wade
Title of project: 
Rare and common genetic influences on cognitive and behavioural phenotypes in ALSPAC
Proposal summary: 

Emma will be re-using the existing dataset from B3565, no additional data will be required for her student project.
Emma will study rare and common genetic influences on cognitive and behavioural phenotypes in particular, as measured by the Strengths and Difficulties questionnaire across childhood and adolescence. She will analyse exome sequencing and genotyping array data from ALSPAC as well as the Millennium Cohort Study. Her project aims to understand the contribution of genetic effects on cognitive development.

We wish to sequence the genes of ~7,000
ALSPAC children and parents for ~2,000 of them. We will use these data to
identify rare genetic variants, combine these with existing data on common genetic
variants, and then investigate the effects of these variants on the cognitive and
behavioural development of ALSPAC children.
The rationale for this project comes from previous work which has shown that rare
genetic variants in some genes affect children's risk of severe neurodevelopmental
disorders (e.g. intellectual disability, autism), but these variants are often inherited
from parents who appear to have normal cognitive functioning. We have shown
that, on average, these variants affect the normal spectrum of cognition in adults,
as well as mental health traits and reproductive success. We suspect that the effect
of these rare genetic variants might be modified by other more common variants in
individuals’ genomes, which have also been shown to affect cognitive ability, as
well as environmental factors. Furthermore, these effects may change across a
person’s lifetime, and may be modified by the parents’ behaviour and genes.
We wish to use the rich longitudinal data on cognitive development, behaviour and
educational achievement of ALSPAC children at different ages to investigate the
joint impact of rare and common genetic variants on cognitive development, and
whether these are modified by the parents’ behaviour. We will also look at genetic
effects on mental health, as well as behavioural and personality traits relevant to
reproductive success.

Impact of research: 
Our research will lead to a greater understanding of how different types of genetic factors affect cognitive development, and the extent to which these are modified by parental phenotypes. This may help to understand the conundrum of incomplete penetrance in the context of neurodevelopmental disorders and ultimately may lead to improvements in genetic counselling for these disorders. Furthermore, our research will increase our understanding of the mechanisms by which rare, damaging genetic variants affect fertility, and hence the nature of negative selection acting on these variants.
Date proposal received: 
Thursday, 8 February, 2024
Date proposal approved: 
Tuesday, 20 February, 2024
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Developmental disorders - autism, Cognitive impairment, Epilepsy, Learning difficulty, Mental health, Speech/language problem, DNA sequencing, GWAS, Statistical methods, Birth outcomes, Cohort studies - attrition, bias, participant engagement, ethics, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc., Speech and language, Statistical methods, Childhood - childcare, childhood adversity, Cognition - cognitive function, Development, Genetic epidemiology, Genetics, Genome wide association study, Intelligence - memory, Mendelian randomisation