Common genetic variants contribute to risk of rare severe neurodevelopmental disorders

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Niemi, Mari Elisa Katariina   ORCID logo

Most known genetic causes of severe childhood developmental disorders are rare, deleterious, protein-coding changes that cause Mendelian disorders. Children with these disorders typically show early-onset impairment in growth, learning and adaptive behaviours. Linkage and whole exome sequencing studies on these patients have previously focused on identifying diagnostic rare variants that are solely responsible for the patient’s phenotype. In this thesis, I investigate whether common, inherited genetic variation also plays a modifying role in severe, presumably Mendelian neurodevelopmental disorders. In addition, I study the effects of common variants on the cognitive functioning of healthy individuals, who carry rare deleterious variants in genes that are intolerant to such variants in the general population. To test whether common variants contribute to neurodevelopmental disorders that are expected to be almost entirely monogenic, I conduct a genome-wide association study (GWAS) in nearly 7,000 patients from the Deciphering Developmental Disorders (DDD) Study and ancestry-matched controls. I show that common genetic variants explain almost 8% of variation in risk for these severe disorders. I also find genetic overlap between our study and GWAS for other cognitive and neuropsychiatric traits. This suggests that common variants individually have a small effect on brain development and functioning, influencing both risk for common diseases in the population and risk for severe disorders that affect only a small number of individuals. This polygenic burden in the DDD is also not confined to only patients who do not have diagnostic rare variants. Altogether, these results may have important implications for understanding variable clinical presentation of neurodevelopmental disorders and searching for secondary genetic modifiers. Finally, I assess the interplay between common and rare variants on the cognitive functioning of seemingly healthy individuals. Using data from the INTERVAL Study, I test whether common variants are protective of the deleterious rare variants in these individuals. Whilst these analyses are potentially currently underpowered, with additional samples in the future, we may be able to shed more light on expressivity and penetrance of deleterious variants in the general population.

Barrett, Jeffrey
Neurodevelopmental disorder, Developmental disorder, Genome-wide association study, GWAS, Polygenic score, Heritability, Neurodevelopmental, Genetic, Polygenic, Common genetic variation, Cognitive functioning, Sequencing, DNA, Genotyping, Mendelian disease, Genetic correlation
Doctor of Philosophy (PhD)
Awarding Institution
University of Cambridge
Wellcome Trust