title: The penetrance of copy number variations for schizophrenia and developmental delay.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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%.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom. Electronic address: kirov@cardiff.ac.uk.
authors.forename: George
authors.initials: G
authors.lastname: Kirov
authors.affiliation: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: Elliott
authors.initials: E
authors.lastname: Rees
authors.affiliation: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: James T R
authors.initials: JT
authors.lastname: Walters
authors.affiliation: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: Valentina
authors.initials: V
authors.lastname: Escott-Price
authors.affiliation: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: Lyudmila
authors.initials: L
authors.lastname: Georgieva
authors.affiliation: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Richards
authors.affiliation: Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors.forename: Kimberly D
authors.initials: KD
authors.lastname: Chambert
authors.affiliation: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: Gerwyn
authors.initials: G
authors.lastname: Davies
authors.affiliation: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: Sophie E
authors.initials: SE
authors.lastname: Legge
authors.affiliation: Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Moran
authors.affiliation: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: Steven A
authors.initials: SA
authors.lastname: McCarroll
authors.affiliation: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: Michael C
authors.initials: MC
authors.lastname: O'Donovan
authors.affiliation: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owen
mesh_terms: D002869:Chromosome Aberrations; D056915:DNA Copy Number Variations / Q000235:genetics*; D002658:Developmental Disabilities / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D019683:Penetrance; D012559:Schizophrenia / Q000235:genetics*
keywords: Autism spectrum disorder; CNV; developmental delay; penetrance; schizophrenia; selection