A genome-wide investigation of SNPs and CNVs in schizophrenia

Anna C Need, Dongliang Ge, Michael E Weale, Jessica Maia, Sheng Feng, Erin L Heinzen, Kevin V Shianna, Woohyun Yoon, Dalia Kasperaviciute, Massimo Gennarelli, Warren J Strittmatter, Cristian Bonvicini, Giuseppe Rossi, Karu Jayathilake, Philip A Cola, Joseph P McEvoy, Richard S E Keefe, Elizabeth M C Fisher, Pamela L St Jean, Ina Giegling & 13 others Annette M Hartmann, Hans-Jürgen Möller, Andreas Ruppert, Gillian Fraser, Caroline Crombie, Lefkos T Middleton, David St Clair, Allen D Roses, Pierandrea Muglia, Clyde Francks, Dan Rujescu, Herbert Y Meltzer, David B Goldstein

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Abstract

We report a genome-wide assessment of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) in schizophrenia. We investigated SNPs using 871 patients and 863 controls, following up the top hits in four independent cohorts comprising 1,460 patients and 12,995 controls, all of European origin. We found no genome-wide significant associations, nor could we provide support for any previously reported candidate gene or genome-wide associations. We went on to examine CNVs using a subset of 1,013 cases and 1,084 controls of European ancestry, and a further set of 60 cases and 64 controls of African ancestry. We found that eight cases and zero controls carried deletions greater than 2 Mb, of which two, at 8p22 and 16p13.11-p12.4, are newly reported here. A further evaluation of 1,378 controls identified no deletions greater than 2 Mb, suggesting a high prior probability of disease involvement when such deletions are observed in cases. We also provide further evidence for some smaller, previously reported, schizophrenia-associated CNVs, such as those in NRXN1 and APBA2. We could not provide strong support for the hypothesis that schizophrenia patients have a significantly greater "load" of large (>100 kb), rare CNVs, nor could we find common CNVs that associate with schizophrenia. Finally, we did not provide support for the suggestion that schizophrenia-associated CNVs may preferentially disrupt genes in neurodevelopmental pathways. Collectively, these analyses provide the first integrated study of SNPs and CNVs in schizophrenia and support the emerging view that rare deleterious variants may be more important in schizophrenia predisposition than common polymorphisms. While our analyses do not suggest that implicated CNVs impinge on particular key pathways, we do support the contribution of specific genomic regions in schizophrenia, presumably due to recurrent mutation. On balance, these data suggest that very few schizophrenia patients share identical genomic causation, potentially complicating efforts to personalize treatment regimens.
Original languageEnglish
Article numbere1000373
Number of pages19
JournalPLoS Genetics
Volume5
Issue number2
DOIs
Publication statusPublished - 6 Feb 2009

Fingerprint

single nucleotide polymorphism
Single Nucleotide Polymorphism
Schizophrenia
polymorphism
genome
Genome
ancestry
genomics
gene
mutation
schizophrenia
Causality
Genes
genes
genetic polymorphism
Mutation

Keywords

  • alternative splicing
  • cohort studies
  • gene dosage
  • genetic variation
  • genome, human
  • humans
  • polymorphism, single nucleotide
  • schizophrenia

Cite this

Need, A. C., Ge, D., Weale, M. E., Maia, J., Feng, S., Heinzen, E. L., ... Goldstein, D. B. (2009). A genome-wide investigation of SNPs and CNVs in schizophrenia. PLoS Genetics, 5(2), [e1000373]. https://doi.org/10.1371/journal.pgen.1000373

A genome-wide investigation of SNPs and CNVs in schizophrenia. / Need, Anna C; Ge, Dongliang; Weale, Michael E; Maia, Jessica; Feng, Sheng; Heinzen, Erin L; Shianna, Kevin V; Yoon, Woohyun; Kasperaviciute, Dalia; Gennarelli, Massimo; Strittmatter, Warren J; Bonvicini, Cristian; Rossi, Giuseppe; Jayathilake, Karu; Cola, Philip A; McEvoy, Joseph P; Keefe, Richard S E; Fisher, Elizabeth M C; St Jean, Pamela L; Giegling, Ina; Hartmann, Annette M; Möller, Hans-Jürgen; Ruppert, Andreas; Fraser, Gillian ; Crombie, Caroline; Middleton, Lefkos T; St Clair, David; Roses, Allen D; Muglia, Pierandrea; Francks, Clyde; Rujescu, Dan; Meltzer, Herbert Y; Goldstein, David B.

In: PLoS Genetics, Vol. 5, No. 2, e1000373, 06.02.2009.

Research output: Contribution to journalArticle

Need, AC, Ge, D, Weale, ME, Maia, J, Feng, S, Heinzen, EL, Shianna, KV, Yoon, W, Kasperaviciute, D, Gennarelli, M, Strittmatter, WJ, Bonvicini, C, Rossi, G, Jayathilake, K, Cola, PA, McEvoy, JP, Keefe, RSE, Fisher, EMC, St Jean, PL, Giegling, I, Hartmann, AM, Möller, H-J, Ruppert, A, Fraser, G, Crombie, C, Middleton, LT, St Clair, D, Roses, AD, Muglia, P, Francks, C, Rujescu, D, Meltzer, HY & Goldstein, DB 2009, 'A genome-wide investigation of SNPs and CNVs in schizophrenia', PLoS Genetics, vol. 5, no. 2, e1000373. https://doi.org/10.1371/journal.pgen.1000373
Need AC, Ge D, Weale ME, Maia J, Feng S, Heinzen EL et al. A genome-wide investigation of SNPs and CNVs in schizophrenia. PLoS Genetics. 2009 Feb 6;5(2). e1000373. https://doi.org/10.1371/journal.pgen.1000373
Need, Anna C ; Ge, Dongliang ; Weale, Michael E ; Maia, Jessica ; Feng, Sheng ; Heinzen, Erin L ; Shianna, Kevin V ; Yoon, Woohyun ; Kasperaviciute, Dalia ; Gennarelli, Massimo ; Strittmatter, Warren J ; Bonvicini, Cristian ; Rossi, Giuseppe ; Jayathilake, Karu ; Cola, Philip A ; McEvoy, Joseph P ; Keefe, Richard S E ; Fisher, Elizabeth M C ; St Jean, Pamela L ; Giegling, Ina ; Hartmann, Annette M ; Möller, Hans-Jürgen ; Ruppert, Andreas ; Fraser, Gillian ; Crombie, Caroline ; Middleton, Lefkos T ; St Clair, David ; Roses, Allen D ; Muglia, Pierandrea ; Francks, Clyde ; Rujescu, Dan ; Meltzer, Herbert Y ; Goldstein, David B. / A genome-wide investigation of SNPs and CNVs in schizophrenia. In: PLoS Genetics. 2009 ; Vol. 5, No. 2.
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AU - Heinzen, Erin L

AU - Shianna, Kevin V

AU - Yoon, Woohyun

AU - Kasperaviciute, Dalia

AU - Gennarelli, Massimo

AU - Strittmatter, Warren J

AU - Bonvicini, Cristian

AU - Rossi, Giuseppe

AU - Jayathilake, Karu

AU - Cola, Philip A

AU - McEvoy, Joseph P

AU - Keefe, Richard S E

AU - Fisher, Elizabeth M C

AU - St Jean, Pamela L

AU - Giegling, Ina

AU - Hartmann, Annette M

AU - Möller, Hans-Jürgen

AU - Ruppert, Andreas

AU - Fraser, Gillian

AU - Crombie, Caroline

AU - Middleton, Lefkos T

AU - St Clair, David

AU - Roses, Allen D

AU - Muglia, Pierandrea

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AU - Meltzer, Herbert Y

AU - Goldstein, David B

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N2 - We report a genome-wide assessment of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) in schizophrenia. We investigated SNPs using 871 patients and 863 controls, following up the top hits in four independent cohorts comprising 1,460 patients and 12,995 controls, all of European origin. We found no genome-wide significant associations, nor could we provide support for any previously reported candidate gene or genome-wide associations. We went on to examine CNVs using a subset of 1,013 cases and 1,084 controls of European ancestry, and a further set of 60 cases and 64 controls of African ancestry. We found that eight cases and zero controls carried deletions greater than 2 Mb, of which two, at 8p22 and 16p13.11-p12.4, are newly reported here. A further evaluation of 1,378 controls identified no deletions greater than 2 Mb, suggesting a high prior probability of disease involvement when such deletions are observed in cases. We also provide further evidence for some smaller, previously reported, schizophrenia-associated CNVs, such as those in NRXN1 and APBA2. We could not provide strong support for the hypothesis that schizophrenia patients have a significantly greater "load" of large (>100 kb), rare CNVs, nor could we find common CNVs that associate with schizophrenia. Finally, we did not provide support for the suggestion that schizophrenia-associated CNVs may preferentially disrupt genes in neurodevelopmental pathways. Collectively, these analyses provide the first integrated study of SNPs and CNVs in schizophrenia and support the emerging view that rare deleterious variants may be more important in schizophrenia predisposition than common polymorphisms. While our analyses do not suggest that implicated CNVs impinge on particular key pathways, we do support the contribution of specific genomic regions in schizophrenia, presumably due to recurrent mutation. On balance, these data suggest that very few schizophrenia patients share identical genomic causation, potentially complicating efforts to personalize treatment regimens.

AB - We report a genome-wide assessment of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) in schizophrenia. We investigated SNPs using 871 patients and 863 controls, following up the top hits in four independent cohorts comprising 1,460 patients and 12,995 controls, all of European origin. We found no genome-wide significant associations, nor could we provide support for any previously reported candidate gene or genome-wide associations. We went on to examine CNVs using a subset of 1,013 cases and 1,084 controls of European ancestry, and a further set of 60 cases and 64 controls of African ancestry. We found that eight cases and zero controls carried deletions greater than 2 Mb, of which two, at 8p22 and 16p13.11-p12.4, are newly reported here. A further evaluation of 1,378 controls identified no deletions greater than 2 Mb, suggesting a high prior probability of disease involvement when such deletions are observed in cases. We also provide further evidence for some smaller, previously reported, schizophrenia-associated CNVs, such as those in NRXN1 and APBA2. We could not provide strong support for the hypothesis that schizophrenia patients have a significantly greater "load" of large (>100 kb), rare CNVs, nor could we find common CNVs that associate with schizophrenia. Finally, we did not provide support for the suggestion that schizophrenia-associated CNVs may preferentially disrupt genes in neurodevelopmental pathways. Collectively, these analyses provide the first integrated study of SNPs and CNVs in schizophrenia and support the emerging view that rare deleterious variants may be more important in schizophrenia predisposition than common polymorphisms. While our analyses do not suggest that implicated CNVs impinge on particular key pathways, we do support the contribution of specific genomic regions in schizophrenia, presumably due to recurrent mutation. On balance, these data suggest that very few schizophrenia patients share identical genomic causation, potentially complicating efforts to personalize treatment regimens.

KW - alternative splicing

KW - cohort studies

KW - gene dosage

KW - genetic variation

KW - genome, human

KW - humans

KW - polymorphism, single nucleotide

KW - schizophrenia

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DO - 10.1371/journal.pgen.1000373

M3 - Article

VL - 5

JO - PLoS Genetics

JF - PLoS Genetics

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