B3565 - Exome sequencing of ALSPAC children and parents - 14/07/2020

B number: 
Principal applicant name: 
Hilary Martin | Wellcome Sanger Institute
Prof Matthew Hurles
Title of project: 
Exome sequencing of ALSPAC children and parents
Proposal summary: 

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, 2 July, 2020
Date proposal approved: 
Thursday, 2 July, 2020
Genetic epidemiology (including association studies and mendelian randomisation), Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Developmental disorders - autism, Cognitive impairment, Congenital abnormalities, Fertility/infertility, Learning difficulty, Mental health, Speech/language problem, DNA sequencing, GWAS, Childhood - childcare, childhood adversity, Cognition - cognitive function, Development, Genetic epidemiology, Genetics, Genomics, Genome wide association study, Sex differences, Speech and language