Schizophrenia is associated with reduced fecundity, ∼40% that of the general population,20 or even lower according to the largest population-based study.21 It follows that schizophrenia-related mutations of large effect should be rare because of intense purifying selection, and those that occur in multiple unrelated individuals are likely to do so through independent de novo mutations.7, 22, 23, 24 One study on de novo CNV mutation in schizophrenia24 showed that the rate of de novo CNV mutation in probands with no family history was 8 times higher in cases than in controls. This marked elevation in the rate of de novo CNVs contrasts with the relatively modest elevation in the rate of CNVs seen in case–control studies,2, 4 and suggests that sets of de novos might be more informative for gene-set enrichment analyses.
