Identification of putative second genetic hits in schizophrenia carriers of high-risk copy number variants and resequencing in additional samples

  • Julio Rodríguez-López
  • Beatriz Sobrino
  • Jorge Amigo
  • Noa Carrera
  • Julio Brenlla
  • Santiago Agra
  • Eduardo Paz
  • Ángel Carracedo
  • Mario Páramo
  • Manuel Arrojo
  • Javier CostasEmail author
Original Paper


Copy number variants (CNVs) conferring risk of schizophrenia present incomplete penetrance, suggesting the existence of second genetic hits. Identification of second hits may help to find genes with rare variants of susceptibility to schizophrenia. The aim of this work was to search for second hits of moderate/high risk in schizophrenia carriers of risk CNVs and resequencing of the relevant genes in additional samples. To this end, ten patients with risk CNVs at cytobands 15q11.2, 15q11.2-13.1, 16p11.2, or 16p13.11, were subjected to whole-exome sequencing. Rare single nucleotide variants, defined as those absent from main public databases, were classified according to bioinformatic prediction of pathogenicity by CADD scores. The average number of rare predicted pathogenic variants per sample was 13.6 (SD 2.01). Two genes, BFAR and SYNJ1, presented rare predicted pathogenic variants in more than one sample. Follow-up resequencing of these genes in 432 additional cases and 432 controls identified a significant excess of rare predicted pathogenic variants in case samples at SYNJ1. Taking into account its function in clathrin-mediated synaptic vesicle endocytosis at presynaptic terminals, our results suggest an impairment of this process in schizophrenia.


High-throughput nucleotide sequencing Exome DNA copy number variations Psychosis Rare variant 



This work was supported by Grant CP11/00163 from Instituto de Salud Carlos III, cofounded by FEDER; to JC, by agreement between SERGAS and Fundación Pública Galega de Medicina Xenómica, and by the Innopharma project (USC). The founders had no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. The genotyping service was carried out at CEGEN-PRB2-ISCIII; it is supported by Grant PT13/0001, ISCIII-SGEFI/FEDER. The authors would like to thank Centro de Supercomputación de Galicia (CESGA) for the use of their computing facilities and the NHLBI GO Exome Sequencing Project and its ongoing studies which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926), and the Heart GO Sequencing Project (HL-103010).

Compliance with ethical standards

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Supplementary material

406_2017_799_MOESM1_ESM.pdf (156 kb)
Supplementary Figure 1. Schematic representation of the study. Each color represents the different steps carried out in the study. Circles represent the subset of samples of the initial cohort used in each step, hexagons represent the specific assay, and rectangles represent the objective pursued in each step of the study (PDF 155 kb)
406_2017_799_MOESM2_ESM.xlsx (16 kb)
Supplementary Table 1. Main clinical characteristics and genetic findings of the ten schizophrenic CNV carriers (XLSX 15 kb)
406_2017_799_MOESM3_ESM.xlsx (23 kb)
Supplementary Table 2. Putative second hit SNVs identified in the present study (XLSX 23 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Julio Rodríguez-López
    • 1
  • Beatriz Sobrino
    • 1
    • 2
    • 3
  • Jorge Amigo
    • 1
    • 2
    • 3
  • Noa Carrera
    • 1
    • 3
    • 5
  • Julio Brenlla
    • 1
    • 4
  • Santiago Agra
    • 1
    • 4
  • Eduardo Paz
    • 1
    • 4
  • Ángel Carracedo
    • 1
    • 2
    • 3
  • Mario Páramo
    • 1
    • 4
  • Manuel Arrojo
    • 1
    • 4
  • Javier Costas
    • 1
    Email author
  1. 1.Instituto de Investigación Sanitaria (IDIS) de Santiago de CompostelaComplexo Hospitalario Universitario de Santiago de Compostela (CHUS), Servizo Galego de Saúde (SERGAS)Santiago de CompostelaSpain
  2. 2.Grupo de Medicina XenómicaUniversidade de Santiago de Compostela (USC)Santiago de CompostelaSpain
  3. 3.Fundación Pública Galega de Medicina XenómicaComplexo Hospitalario Universitario de Santiago (CHUS), Servizo Galego de Saúde (SERGAS)Santiago de CompostelaSpain
  4. 4.Servizo de PsiquiatríaComplexo Hospitalario Universitario de Santiago de Compostela, Servizo Galego de Saúde (SERGAS)Santiago de CompostelaSpain
  5. 5.Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical NeurosciencesCardiff UniversityCardiffUK

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