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CNVs conferring risk of autism or schizophrenia affect cognition in controls

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In a small fraction of patients with schizophrenia or autism, alleles of copy-number variants (CNVs) in their genomes are probably the strongest factors contributing to the pathogenesis of the disease. These CNVs may provide an entry point for investigations into the mechanisms of brain function and dysfunction alike. They are not fully penetrant and offer an opportunity to study their effects separate from that of manifest disease. Here we show in an Icelandic sample that a few of the CNVs clearly alter fecundity (measured as the number of children by age 45). Furthermore, we use various tests of cognitive function to demonstrate that control subjects carrying the CNVs perform at a level that is between that of schizophrenia patients and population controls. The CNVs do not all affect the same cognitive domains, hence the cognitive deficits that drive or accompany the pathogenesis vary from one CNV to another. Controls carrying the chromosome 15q11.2 deletion between breakpoints 1 and 2 (15q11.2(BP1-BP2) deletion) have a history of dyslexia and dyscalculia, even after adjusting for IQ in the analysis, and the CNV only confers modest effects on other cognitive traits. The 15q11.2(BP1-BP2) deletion affects brain structure in a pattern consistent with both that observed during first-episode psychosis in schizophrenia and that of structural correlates in dyslexia.

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Figure 1: Association of CNV groups with cognitive traits, GAF, ARHQ and AMHQ scores.
Figure 2: Association of CNVs with cognitive traits, GAF, ARHQ and AMHQ scores.
Figure 3: Dose-dependent alterations in brain structure in 15q11.2(BP1-BP2) CNV carriers.

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  • 15 January 2014

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The authors are grateful to the participants and we thank the research nurses and staff at the Krókháls recruitment centre and roentgentechnicians at Röntgen Domus. We also thank the staff at deCODE genetics core facilities and all our colleagues for their important contribution to this work. The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115008 of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EU funded FP7-People-2011-IAPP grant PsychDPC (GA 286213).

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H.St., A.M-L., S.S., B.M., S.A., G.B., G.B.W., M.D., T.B.S., M.B., S. Ka., J.H., S.H., E.Sa., E.Si. and K.S. were involved in study design. B.M., S.A., G.A.J., S. Kr., H.Sn., S.R.D., B.S., I.H., M.H., B.J., J.G.H., S.H., E.Sa. and E.Si. were involved with cohort ascertainment, phenotypic characterization and recruitment. H.St., K.M., G.B., G.B.W., O.M.D., H.T., O.G., G.F.J., J.H.T and L.J.G. were involved with informatics and data management. H.St., A.M-L., S.S., K.M., G.B., G.B.W., O.M.D., H.T., O.G., M.B. and A.J.S. carried out statistical analysis. H.St., A.M-L., S.S., B.M., K.M., S.A., G.B., G.B.W., G.A.J., O.M.D., H.T., O.G., S. Kr., H.Sn., S.R.D., L.J.G., G.F.J., B.S., I.H., M.H., B.J., J.H.T., M.D., T.B.S., M.B., S. Ka., J.G.H., S.H., E.Sa., E.Si. and K.S. wrote the manuscript.

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Correspondence to Andreas Meyer-Lindenberg or Kari Stefansson.

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Competing interests

H.St., S.S., S.A., G.B., G.B.W., G.J., S. Kr., H.Sn., S.R.D., L.J.G., G.F.J., B.S. and K.S. are employees of deCODE genetics/Amgen. B.J. is an employee of Röntgen domus. A.J.S. is an employee of Eli Lilly and Company. M.D. and T.B.S. are employees of H. Lundbeck A/S.

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The authors declare competing financial interests: details are available in the online version of the paper.

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Stefansson, H., Meyer-Lindenberg, A., Steinberg, S. et al. CNVs conferring risk of autism or schizophrenia affect cognition in controls. Nature 505, 361–366 (2014).

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