B4112 - Exploring genetic architecture of developmental disorders using ALSPAC as controls - 22/12/2022

B number: 
Principal applicant name: 
Hilary Martin | University of Cambridge (UK)
Prof Matthew Hurles, Emilie Wigdor, Dr Qinqin Huang, Dr Klaudia Walter, Daniel Malawsky, Deborah Plowman, Dr Wei Huang, Dr Sana Amanat Ali, Davide Bonifanti, Ruth Eberhardt
Title of project: 
Exploring genetic architecture of developmental disorders using ALSPAC as controls
Proposal summary: 

About 1% of babies are born with a developmental disorder which affects mental or physical development, such as intellectual disability or congenital heart defects. Many of these disorders are at least partly genetic, often due to a rare change in a single gene. However, we also know that common genetic variants that influence cognitive ability, educational attainment and mental health traits in the general population affect risk of rare neurodevelopmental disorders too. We are exploring the genetic basis of rare neurodevelopmental disorders (NDDs) in two large cohorts of patients, Deciphering Developmental Disorders (DDD) and the Genomics England 100k Genomes project (GEL). We wish to use ALSPAC families as population-based controls in these analyses, since most of them do not have NDDs. We will calculate polygenic scores for different traits (including cognitive ability, educational attainment and schizophrenia), which summarise the level of genetic risk an individual has for a given trait based on the common genetic variants in their DNA, and compare these between NDD cases and ALSPAC participants. We will also make use of the trio data (children plus both parents) to investigate whether the genetic background of individuals’ parents influences the risk of NDDs independently of the individuals’ own genetic background (“genetic nurture”). Finally, we will compare the burden of rare genetic variants that affect gene function between NDD cases and ALSPAC controls.

Impact of research: 
Our research will lead to a greater understanding of how different types of genetic factors affect developmental disorder risk, and the extent to which these manifest directly on the child versus indirectly through the environment provided by their parents. 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.
Date proposal received: 
Tuesday, 19 July, 2022
Date proposal approved: 
Thursday, 22 December, 2022
Genetics, Developmental disorders - autism, Cognitive impairment, Congenital abnormalities, Learning difficulty, DNA sequencing, GWAS, Cognition - cognitive function, Genomics, Genome wide association study, Neurology