Rare genome-wide copy number variation and expression of schizophrenia in 22q11.2 deletion syndrome

Anne S. Bassett, Chelsea Lowther, Daniele Merico, Gregory Costain, Eva W.C. Chow, Therese Van Amelsvoort, Donna McDonald-McGinn, Raquel E. Gur, Ann Swillen, Marianne Van Den Bree, Kieran Murphy, Doron Gothelf, Carrie E. Bearden, Stephan Eliez, Wendy Kates, Nicole Philip, Vandana Sashi, Linda Campbell, Jacob Vorstman, Joseph Cubells & 30 others Gabriela M. Repetto, Tony Simon, Erik Boot, Tracy Heung, Rens Evers, Claudia Vingerhoets, Esther Van Duin, Elaine Zackai, Elfi Vergaelen, Koen Devriendt, Joris R. Vermeesch, Michael Owen, Clodagh Murphy, Elena Michaelovosky, Leila Kushan, Maude Schneider, Wanda Fremont, Tiffany Busa, Stephen Hooper, Kathryn McCabe, Sasja Duijff, Karin Isaev, Giovanna Pellecchia, John Wei, Matthew J. Gazzellone, Stephen W. Scherer, Beverly S. Emanuel, Tingwei Guo, Bernice E. Morrow, Christian R. Marshall

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Objective: Chromosome 22q11.2 deletion syndrome (22q11.2DS) is associated with a more than 20-fold increased risk for developing schizophrenia. The aim of this studywas to identify additional genetic factors (i.e., "second hits") that may contribute to schizophrenia expression. Method: Through an international consortium, the authors obtained DNA samples from 329 psychiatrically phenotyped subjects with 22q11.2DS. Using a high-resolution microarray platform and established methods to assess copy number variation (CNV), the authors compared the genome-wide burden of rare autosomal CNV, outside of the 22q11.2 deletion region, between two groups: A schizophrenia group and those with no psychotic disorder at age≥25 years. The authors assessedwhether genes overlapped by rare CNVs were overrepresented in functional pathways relevant to schizophrenia. Results: Rare CNVs overlapping one or more protein-coding genes revealed significant between-group differences. For rare exonic duplications, six of 19 gene sets tested were enriched in the schizophrenia group; genes associated with abnormal nervous system phenotypes remained significant in a stepwise logistic regression model and showed significant interactions with 22q11.2 deletion region genes in a connectivity analysis. For rare exonic deletions, the schizophrenia group had, on average, more genes overlapped. The additional rare CNVs implicated known (e.g., GRM7, 15q13.3, 16p12.2) and novel schizophrenia risk genes and loci. Conclusions: The results suggest that additional rare CNVs overlapping genes outside of the 22q11.2 deletion region contribute to schizophrenia risk in 22q11.2DS, supporting a multigenic hypothesis for schizophrenia. The findings have implications for understanding expression of psychotic illness and herald the importance of whole-genome sequencing to appreciate the overall genomic architecture of schizophrenia.

Original languageEnglish (US)
Pages (from-to)1054-1063
Number of pages10
JournalAmerican Journal of Psychiatry
Volume174
Issue number11
DOIs
StatePublished - Nov 1 2017
Externally publishedYes

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DiGeorge Syndrome
Schizophrenia
Genome
Genes
Logistic Models
Overlapping Genes
Chromosome Deletion
Gene Deletion
Psychotic Disorders
Nervous System

ASJC Scopus subject areas

  • Psychiatry and Mental health

Cite this

Bassett, A. S., Lowther, C., Merico, D., Costain, G., Chow, E. W. C., Van Amelsvoort, T., ... Marshall, C. R. (2017). Rare genome-wide copy number variation and expression of schizophrenia in 22q11.2 deletion syndrome. American Journal of Psychiatry, 174(11), 1054-1063. https://doi.org/10.1176/appi.ajp.2017.16121417

Rare genome-wide copy number variation and expression of schizophrenia in 22q11.2 deletion syndrome. / Bassett, Anne S.; Lowther, Chelsea; Merico, Daniele; Costain, Gregory; Chow, Eva W.C.; Van Amelsvoort, Therese; McDonald-McGinn, Donna; Gur, Raquel E.; Swillen, Ann; Van Den Bree, Marianne; Murphy, Kieran; Gothelf, Doron; Bearden, Carrie E.; Eliez, Stephan; Kates, Wendy; Philip, Nicole; Sashi, Vandana; Campbell, Linda; Vorstman, Jacob; Cubells, Joseph; Repetto, Gabriela M.; Simon, Tony; Boot, Erik; Heung, Tracy; Evers, Rens; Vingerhoets, Claudia; Van Duin, Esther; Zackai, Elaine; Vergaelen, Elfi; Devriendt, Koen; Vermeesch, Joris R.; Owen, Michael; Murphy, Clodagh; Michaelovosky, Elena; Kushan, Leila; Schneider, Maude; Fremont, Wanda; Busa, Tiffany; Hooper, Stephen; McCabe, Kathryn; Duijff, Sasja; Isaev, Karin; Pellecchia, Giovanna; Wei, John; Gazzellone, Matthew J.; Scherer, Stephen W.; Emanuel, Beverly S.; Guo, Tingwei; Morrow, Bernice E.; Marshall, Christian R.

In: American Journal of Psychiatry, Vol. 174, No. 11, 01.11.2017, p. 1054-1063.

Research output: Contribution to journalArticle

Bassett, AS, Lowther, C, Merico, D, Costain, G, Chow, EWC, Van Amelsvoort, T, McDonald-McGinn, D, Gur, RE, Swillen, A, Van Den Bree, M, Murphy, K, Gothelf, D, Bearden, CE, Eliez, S, Kates, W, Philip, N, Sashi, V, Campbell, L, Vorstman, J, Cubells, J, Repetto, GM, Simon, T, Boot, E, Heung, T, Evers, R, Vingerhoets, C, Van Duin, E, Zackai, E, Vergaelen, E, Devriendt, K, Vermeesch, JR, Owen, M, Murphy, C, Michaelovosky, E, Kushan, L, Schneider, M, Fremont, W, Busa, T, Hooper, S, McCabe, K, Duijff, S, Isaev, K, Pellecchia, G, Wei, J, Gazzellone, MJ, Scherer, SW, Emanuel, BS, Guo, T, Morrow, BE & Marshall, CR 2017, 'Rare genome-wide copy number variation and expression of schizophrenia in 22q11.2 deletion syndrome', American Journal of Psychiatry, vol. 174, no. 11, pp. 1054-1063. https://doi.org/10.1176/appi.ajp.2017.16121417
Bassett, Anne S. ; Lowther, Chelsea ; Merico, Daniele ; Costain, Gregory ; Chow, Eva W.C. ; Van Amelsvoort, Therese ; McDonald-McGinn, Donna ; Gur, Raquel E. ; Swillen, Ann ; Van Den Bree, Marianne ; Murphy, Kieran ; Gothelf, Doron ; Bearden, Carrie E. ; Eliez, Stephan ; Kates, Wendy ; Philip, Nicole ; Sashi, Vandana ; Campbell, Linda ; Vorstman, Jacob ; Cubells, Joseph ; Repetto, Gabriela M. ; Simon, Tony ; Boot, Erik ; Heung, Tracy ; Evers, Rens ; Vingerhoets, Claudia ; Van Duin, Esther ; Zackai, Elaine ; Vergaelen, Elfi ; Devriendt, Koen ; Vermeesch, Joris R. ; Owen, Michael ; Murphy, Clodagh ; Michaelovosky, Elena ; Kushan, Leila ; Schneider, Maude ; Fremont, Wanda ; Busa, Tiffany ; Hooper, Stephen ; McCabe, Kathryn ; Duijff, Sasja ; Isaev, Karin ; Pellecchia, Giovanna ; Wei, John ; Gazzellone, Matthew J. ; Scherer, Stephen W. ; Emanuel, Beverly S. ; Guo, Tingwei ; Morrow, Bernice E. ; Marshall, Christian R. / Rare genome-wide copy number variation and expression of schizophrenia in 22q11.2 deletion syndrome. In: American Journal of Psychiatry. 2017 ; Vol. 174, No. 11. pp. 1054-1063.
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abstract = "Objective: Chromosome 22q11.2 deletion syndrome (22q11.2DS) is associated with a more than 20-fold increased risk for developing schizophrenia. The aim of this studywas to identify additional genetic factors (i.e., {"}second hits{"}) that may contribute to schizophrenia expression. Method: Through an international consortium, the authors obtained DNA samples from 329 psychiatrically phenotyped subjects with 22q11.2DS. Using a high-resolution microarray platform and established methods to assess copy number variation (CNV), the authors compared the genome-wide burden of rare autosomal CNV, outside of the 22q11.2 deletion region, between two groups: A schizophrenia group and those with no psychotic disorder at age≥25 years. The authors assessedwhether genes overlapped by rare CNVs were overrepresented in functional pathways relevant to schizophrenia. Results: Rare CNVs overlapping one or more protein-coding genes revealed significant between-group differences. For rare exonic duplications, six of 19 gene sets tested were enriched in the schizophrenia group; genes associated with abnormal nervous system phenotypes remained significant in a stepwise logistic regression model and showed significant interactions with 22q11.2 deletion region genes in a connectivity analysis. For rare exonic deletions, the schizophrenia group had, on average, more genes overlapped. The additional rare CNVs implicated known (e.g., GRM7, 15q13.3, 16p12.2) and novel schizophrenia risk genes and loci. Conclusions: The results suggest that additional rare CNVs overlapping genes outside of the 22q11.2 deletion region contribute to schizophrenia risk in 22q11.2DS, supporting a multigenic hypothesis for schizophrenia. The findings have implications for understanding expression of psychotic illness and herald the importance of whole-genome sequencing to appreciate the overall genomic architecture of schizophrenia.",
author = "Bassett, {Anne S.} and Chelsea Lowther and Daniele Merico and Gregory Costain and Chow, {Eva W.C.} and {Van Amelsvoort}, Therese and Donna McDonald-McGinn and Gur, {Raquel E.} and Ann Swillen and {Van Den Bree}, Marianne and Kieran Murphy and Doron Gothelf and Bearden, {Carrie E.} and Stephan Eliez and Wendy Kates and Nicole Philip and Vandana Sashi and Linda Campbell and Jacob Vorstman and Joseph Cubells and Repetto, {Gabriela M.} and Tony Simon and Erik Boot and Tracy Heung and Rens Evers and Claudia Vingerhoets and {Van Duin}, Esther and Elaine Zackai and Elfi Vergaelen and Koen Devriendt and Vermeesch, {Joris R.} and Michael Owen and Clodagh Murphy and Elena Michaelovosky and Leila Kushan and Maude Schneider and Wanda Fremont and Tiffany Busa and Stephen Hooper and Kathryn McCabe and Sasja Duijff and Karin Isaev and Giovanna Pellecchia and John Wei and Gazzellone, {Matthew J.} and Scherer, {Stephen W.} and Emanuel, {Beverly S.} and Tingwei Guo and Morrow, {Bernice E.} and Marshall, {Christian R.}",
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T1 - Rare genome-wide copy number variation and expression of schizophrenia in 22q11.2 deletion syndrome

AU - Bassett, Anne S.

AU - Lowther, Chelsea

AU - Merico, Daniele

AU - Costain, Gregory

AU - Chow, Eva W.C.

AU - Van Amelsvoort, Therese

AU - McDonald-McGinn, Donna

AU - Gur, Raquel E.

AU - Swillen, Ann

AU - Van Den Bree, Marianne

AU - Murphy, Kieran

AU - Gothelf, Doron

AU - Bearden, Carrie E.

AU - Eliez, Stephan

AU - Kates, Wendy

AU - Philip, Nicole

AU - Sashi, Vandana

AU - Campbell, Linda

AU - Vorstman, Jacob

AU - Cubells, Joseph

AU - Repetto, Gabriela M.

AU - Simon, Tony

AU - Boot, Erik

AU - Heung, Tracy

AU - Evers, Rens

AU - Vingerhoets, Claudia

AU - Van Duin, Esther

AU - Zackai, Elaine

AU - Vergaelen, Elfi

AU - Devriendt, Koen

AU - Vermeesch, Joris R.

AU - Owen, Michael

AU - Murphy, Clodagh

AU - Michaelovosky, Elena

AU - Kushan, Leila

AU - Schneider, Maude

AU - Fremont, Wanda

AU - Busa, Tiffany

AU - Hooper, Stephen

AU - McCabe, Kathryn

AU - Duijff, Sasja

AU - Isaev, Karin

AU - Pellecchia, Giovanna

AU - Wei, John

AU - Gazzellone, Matthew J.

AU - Scherer, Stephen W.

AU - Emanuel, Beverly S.

AU - Guo, Tingwei

AU - Morrow, Bernice E.

AU - Marshall, Christian R.

PY - 2017/11/1

Y1 - 2017/11/1

N2 - Objective: Chromosome 22q11.2 deletion syndrome (22q11.2DS) is associated with a more than 20-fold increased risk for developing schizophrenia. The aim of this studywas to identify additional genetic factors (i.e., "second hits") that may contribute to schizophrenia expression. Method: Through an international consortium, the authors obtained DNA samples from 329 psychiatrically phenotyped subjects with 22q11.2DS. Using a high-resolution microarray platform and established methods to assess copy number variation (CNV), the authors compared the genome-wide burden of rare autosomal CNV, outside of the 22q11.2 deletion region, between two groups: A schizophrenia group and those with no psychotic disorder at age≥25 years. The authors assessedwhether genes overlapped by rare CNVs were overrepresented in functional pathways relevant to schizophrenia. Results: Rare CNVs overlapping one or more protein-coding genes revealed significant between-group differences. For rare exonic duplications, six of 19 gene sets tested were enriched in the schizophrenia group; genes associated with abnormal nervous system phenotypes remained significant in a stepwise logistic regression model and showed significant interactions with 22q11.2 deletion region genes in a connectivity analysis. For rare exonic deletions, the schizophrenia group had, on average, more genes overlapped. The additional rare CNVs implicated known (e.g., GRM7, 15q13.3, 16p12.2) and novel schizophrenia risk genes and loci. Conclusions: The results suggest that additional rare CNVs overlapping genes outside of the 22q11.2 deletion region contribute to schizophrenia risk in 22q11.2DS, supporting a multigenic hypothesis for schizophrenia. The findings have implications for understanding expression of psychotic illness and herald the importance of whole-genome sequencing to appreciate the overall genomic architecture of schizophrenia.

AB - Objective: Chromosome 22q11.2 deletion syndrome (22q11.2DS) is associated with a more than 20-fold increased risk for developing schizophrenia. The aim of this studywas to identify additional genetic factors (i.e., "second hits") that may contribute to schizophrenia expression. Method: Through an international consortium, the authors obtained DNA samples from 329 psychiatrically phenotyped subjects with 22q11.2DS. Using a high-resolution microarray platform and established methods to assess copy number variation (CNV), the authors compared the genome-wide burden of rare autosomal CNV, outside of the 22q11.2 deletion region, between two groups: A schizophrenia group and those with no psychotic disorder at age≥25 years. The authors assessedwhether genes overlapped by rare CNVs were overrepresented in functional pathways relevant to schizophrenia. Results: Rare CNVs overlapping one or more protein-coding genes revealed significant between-group differences. For rare exonic duplications, six of 19 gene sets tested were enriched in the schizophrenia group; genes associated with abnormal nervous system phenotypes remained significant in a stepwise logistic regression model and showed significant interactions with 22q11.2 deletion region genes in a connectivity analysis. For rare exonic deletions, the schizophrenia group had, on average, more genes overlapped. The additional rare CNVs implicated known (e.g., GRM7, 15q13.3, 16p12.2) and novel schizophrenia risk genes and loci. Conclusions: The results suggest that additional rare CNVs overlapping genes outside of the 22q11.2 deletion region contribute to schizophrenia risk in 22q11.2DS, supporting a multigenic hypothesis for schizophrenia. The findings have implications for understanding expression of psychotic illness and herald the importance of whole-genome sequencing to appreciate the overall genomic architecture of schizophrenia.

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