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Girard SL, Gauthier J, Noreau A, Xiong L, Zhou S, Jouan L, Dionne-Laporte A, Spiegelman D, Henrion E, Diallo O, Thibodeau P, Bachand I, Bao JY, Tong AH, Lin CH, Millet B, Jaafari N, Joober R, Dion PA, Lok S, Krebs MO, Rouleau GA. Increased exonic de novo mutation rate in individuals with schizophrenia. Nat Genet . 2011 Sep ; 43(9):860-3. PubMed Abstract

Comments on Paper and Primary News
Comment by:  Daniel Weinberger, SRF Advisor
Submitted 14 July 2011 Posted 14 July 2011

The paper by Girard et al. is the first of a number of papers that will soon appear searching for rare single nucleotide DNA sequence variants in patients with schizophrenia. It marches to the popular drumbeat that rare single nucleotide variants, like rare CNVs, represent part of the complex genetic architecture of the population of individuals with the diagnosis of schizophrenia. While this is likely to be true, de-novo variants in particular (i.e., those not inherited) cannot account for the “missing heritability” that has so far not been accounted for by common variant association studies, unless for some improbable reason the genetics of the machinery that leads to DNA replication errors is associated with risk for schizophrenia. The findings of Girard et al.—that there is an increased burden of coding, likely functional, de-novo mutations in individuals with schizophrenia—are based on a very small sample (n = 14 patients). The reference sequence data to which they compare their results are based on even smaller numbers of fully sequenced individuals.

I...  Read more

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Comment by:  Patrick Sullivan, SRF AdvisorJin Szatkiewicz
Submitted 17 August 2011 Posted 19 August 2011

Girard et al. sequenced the exomes of 14 parent-child trios, each comprising an individual with sporadic schizophrenia and his or her unaffected parents. They found 15 de-novo mutations from eight probands, and suggest that individuals with schizophrenia are more likely to have de-novo and deleterious mutations specific to coding sequences. This is the first paper in this area, and the third in neuropsychiatric disorders following mental retardation (Vissers et al., 2010) and sporadic autism spectrum disorders (O'roak et al., 2011).

However, some major issues complicate interpretation of the results reported in Girard et al. and weaken the conclusions the authors wish to draw.

First, regarding sequencing coverage, mutation discovery from exome data is a challenging problem, and identifying de-novo mutations is particularly enriched by technical errors. The authors reported that the exome capture resulted in an average of 72 percent targeted regions covered with read depth...  Read more

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