Priority Communication| Volume 70, ISSUE 12, P1109-1114, December 15, 2011

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De Novo Rates and Selection of Schizophrenia-Associated Copy Number Variants

  • Elliott Rees
    Department of Psychological Medicine and Neurology, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom
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  • Valentina Moskvina
    Department of Psychological Medicine and Neurology, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom
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  • Michael J. Owen
    Department of Psychological Medicine and Neurology, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom
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  • Michael C. O'Donovan
    Department of Psychological Medicine and Neurology, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom
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  • George Kirov
    Address correspondence to George Kirov, Ph.D., MRCPsych, Department of Psychological Medicine and Neurology, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Henry Wellcome Building, Heath Park, Cardiff, United Kingdom
    Department of Psychological Medicine and Neurology, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom
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      At least 10 large and rare recurrent DNA copy number variants (CNVs) have been identified as risk factors for schizophrenia and other neurodevelopmental disorders. Because such conditions are associated with reduced fecundity, these pathogenic CNVs should be filtered out from the population by selection and must be replenished by de novo events.


      To estimate the mutation rate (μ) for these CNVs and the selection pressure (s) against them, we first conducted a literature review on the rate of each of these CNVs in the population and the rate of their de novo occurrence. In each generation, the number of CNVs lost because of reduced fertility must be replenished by the same number of de novo CNVs. Therefore, the observed ratio of de novo versus all (inherited + de novo) CNVs approximates the selection coefficient (s) of that CNV. The mutation rate approximates to μ = s × q, where q is the frequency of the CNV in the population.


      High selection pressure operates at all these loci (s = .12 – .88), suggesting that following de novo occurrence, each of these CNVs persists in the population in only a few generations. The mutation rate for each CNV is high, affecting between 1:3500 and 1:30,000 individuals. The rarest CNVs have the highest selection coefficients.


      The CNVs that increase risk to develop schizophrenia are caused by recent de novo mutations and are under strong selection pressure. They persist in the population because of high mutation rates.

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      Linked Article

      • Rare Variants and Risk for Schizophrenia: More Support
        Biological PsychiatryVol. 70Issue 12
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          Copy number variants (CNVs) have a fundamental role in human disease and population diversity (1-3). Exploration of rare CNVs with genomic microarrays has allowed rapid assessment of structural variation at high resolution and low cost. Studies have implicated various schizophrenia associated CNVs, including deletions on 22q11, 15q13, 1q21.1, 2p16.3, and 15q11.2 and the duplications of 16p11.2. CNVs vary in frequency and with larger sample sizes and greater power. CNVs that are more rare and with less effect are continually being updated.
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