Abstract
Several recurrent copy number variants (CNVs) have been shown to increase the risk of developing schizophrenia (SCZ), developmental delay (DD), autism spectrum disorders (ASD), and various congenital malformations (CM). Their penetrance for SCZ has been estimated to be modest. However, comparisons between their penetrance for SCZ or DD/ASD/CM, or estimates of the total penetrance for any of these disorders have not yet been made. We use data from the largest available studies on SCZ and DD/ASD/CM, including a new sample of 6882 cases and 6316 controls, to estimate the frequencies of 70 implicated CNVs in carriers with these disorders, healthy control subjects, and the general population. On the basis of these frequencies, we estimate their penetrance. We also estimate the strength of the selection pressure against CNVs and correlate this against their overall penetrance. The rates of nearly all CNVs are higher in DD/ASD/CM compared with SCZ. The penetrance of CNVs is at least several times higher for the development of a disorder from the group of DD/ASD/CM. The overall penetrance of SCZ-associated CNVs for developing any disorder is high, ranging between 10.6% and 100%. CNVs associated with SCZ have high pathogenicity. The majority of the increased risk conferred by CNVs is toward the development of an earlier-onset disorder, such as DD/ASD/CM, rather than SCZ. The penetrance of CNVs correlates strongly with their selection coefficients. The improved estimates of penetrance will provide crucial information for genetic counselling.
Highlights
Several recurrent copy number variants (CNVs) have been shown to increase the risk of developing schizophrenia (SCZ), developmental delay (DD), autism spectrum disorders (ASD), and various congenital malformations (CM)
The rates of most CNVs are higher in DD/ASD/CM compared with SCZ
The penetrance of CNVs is at least several times higher for the development of a disorder from the group of DD/ASD/CM
Summary
We use data from the largest available studies on SCZ and DD/ASD/CM, including a new sample of 6882 cases and 6316 controls, to estimate the frequencies of 70 implicated CNVs in carriers with these disorders, healthy control subjects, and the general population. Choice of CNVs We analyzed CNVs previously associated with SCZ or severe neurodevelopmental phenotypes. These were taken from the list of CNV regions proposed by Girirajan et al [7]: 37 deletions and 32 reciprocal duplications, after excluding an overlapping segment at 17p13.3 and a CNV on the X chromosome because the X chromosome was not analyzed in our samples. Estimating the Rate of CNVs in Different Disorders We only included data from the largest studies/samples available to simplify the presentation. In the case of loci that include only single genes (NRXN1, SIM1, YWHAE, PAFAH1B1, and NF1), we accepted CNVs that intersected at least one exon of the gene
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