Aims and hypothesis

The impact of rare copy number variants (CNVs) has almost exclusively been evaluated using clinical cohorts; it is thus unclear how these variants affect health in the general population. Our aim is to assess the genome-wide burden of rare CNVs on carriers' health and life quality in general population. We have conducted genotype and phenotype analyses of a random sample of 7877 adult individuals from the population biobank of Estonia (Estonian Genome Center, University of Tartu; Tartu, Estonia). Using this set we generated a genome-wide map of rare autosomal CNVs and identified 10.5% of the screened adult general population (n=831) as carriers of CNVs >=250kb with frequency <=0.05%. We found that when compared to the population, carriers of deletions >=250kb and duplications >=1Mb show lower education achievements (a proxy for intelligence) and a greater prevalence of intellectual disability. These effects are associated with the number and functions of contained genes, e.g. rare deletions are significantly enriched for genes with a role in neurogenesis, cognition, learning, memory and behavior. Interestingly, the effect on education attainment was more pronounced in female carriers of rare deletions in general population, who were also overrepresented amongst carriers.

Our results suggesting that rare CNVs contribute to a substantial portion of the population variance of educational attainment need to be replicated in a geographically independent cohort. The ALSPAC cohort of mothers and children would provide us, in collaboration with group of Dr. Nicholas Timpson, a valuable result as (i) ethnically unrelated to the discovery cohort; (ii) sufficient sample size of individuals with CNVs calls; (iii) the cognitive information of children is unbiased by preselection; (iii) large number of uniformly recruited females provides a possibility to validate the female effect of rare CNVs.