Large recurrent microdeletions associated with schizophrenia

By Hreinn Stefansson, D. Rujescu, S. Cichon, O. Pietiläinen, A. Ingason, S. Steinberg, R. Fossdal, E. Sigurdsson, T. Sigmundsson, J. Buizer-Voskamp and 74 more. Nature, 2008

1,814 citations recorded by the source corpus.

Reduced fecundity, associated with severe mental disorders, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk of disorders such as autism, schizophrenia and mental retardation. Thus, rare variants may account for a larger fraction of the overall genetic risk than previously assumed. In contrast to rare single nucleotide mutations, rare copy number variations (CNVs) can be detected using genome-wide single nucleotide polymorphism arrays. This has led to the identification of CNVs associated with mental retardation and autism. In a genome-wide search for CNVs associating with schizophrenia, we used a population-based sample to identify de novo CNVs by analysing 9,878 transmissions from parents to offspring. The 66 de novo CNVs identified were tested for association in a sample of 1,433 schizophrenia cases and 33,250 controls. Three deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II). All three deletions significantly associate with schizophrenia and related psychoses in the combined sample. The identification of these rare, recurrent risk variants, having occurred independently in multiple founders and being subject to negative selection, is important in itself. CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia.

Subfields: Genetics, Molecular Biology, Pediatrics, Perinatology and Child Health

View Paper: https://www.semanticscholar.org/paper/618e8468f9d4ccfa87d1169fda99e72cb2f7641d

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In Pediatrics, Perinatology and Child Health

Citations in the corpus

Heritability in the Era of Molecular Genetics: Some Thoughts for Understanding Genetic Influences on Behavioural Traits (2011, background): “Their involvement is increasingly suspected in major behavioural disorders such as schizophrenia and autism (Sebat et al., 2007; International Schizophrenia Consortium, 2008; Kumar et al., 2008; Morrow et al., 2008; Stefansson et al., 2008; Walsh et al., 2008; Xu et al., 2008).”
De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia (2011, neutral): “1 schizophrenia locus 2,7 ).”
Rare Variants Create Synthetic Genome-Wide Associations (2010, background): “Second, it is now known that rare variants contribute to common diseases, and that cases that carry the rare high-penetrant contributors to disease often have ‘‘typical’’ clinical presentations [19–21].”
Rare and Common Variants: Twenty arguments (2011, background): “Five per cent of cases of schizophrenia and of autism have each been attributed to CNVs at fewer than half a dozen genomic location”
Long-read human genome sequencing and its applications (2020, neutral): “The presence of these duplications was used to predict and discover recurrent rearrangements associated with developmental delay, microcephaly and macrocephaly 68,118,119 and later schizophrenia 67 (Fig.”