Rare chromosomal deletions and duplications increase risk of schizophrenia

Jennifer L. Stone, Michael C. O'Donovan, Hugh Gurling, George K. Kirov, Douglas H. R. Blackwood, Aiden Corvin, Nick J. Craddock, Michael Gill, Christina M. Hultman, Paul Lichtenstein, Andrew McQuillin, Carlos N. Pato, Douglas M. Ruderfer, Michael J. Owen, David St Clair, Patrick F. Sullivan, Pamela Sklar, Shaun M. Purcell, E. M. Scolnick, P. A. Holmans & 31 others L. Georgieva, I. Nikolov, N. Norton, H. Williams, N. M. Williams, D. Toncheva, V. Milanova, E. F. Thelander, D. W. Morris, C. T. O'Dushlaine, E. Kenny, J. L. Waddington, K. Choudhury, S. Datta, J. Pimm, S. Thirumalai, V. Puri, R. Krasucki, J. Lawrence, D. Quested, N. Bass, D. Curtis, C. Crombie, G. Fraser, S. L. Kwan, W. J. Muir, K. A. McGhee, B. Pickard, P. Malloy, A. W. Maclean, The International Schizophrenia Consortium (ISC)

Research output: Contribution to journalLetter

1130 Citations (Scopus)

Abstract

Schizophrenia is a severe mental disorder marked by hallucinations, delusions, cognitive deficits and apathy, with a heritability estimated at 73 - 90% ( ref. 1). Inheritance patterns are complex, and the number and type of genetic variants involved are not understood. Copy number variants ( CNVs) have been identified in individual patients with schizophrenia(2-7) and also in neurodevelopmental disorders(8-11), but large- scale genome- wide surveys have not been performed. Here we report a genome- wide survey of rare CNVs in 3,391 patients with schizophrenia and 3,181 ancestrally matched controls, using high- density microarrays. For CNVs that were observed in less than 1% of the sample and were more than 100 kilobases in length, the total burden is increased 1.15- fold in patients with schizophrenia in comparison with controls. This effect was more pronounced for rarer, single- occurrence CNVs and for those that involved genes as opposed to those that did not. As expected, deletions were found within the region critical for velo- cardio- facial syndrome, which includes psychotic symptoms in 30% of patients(12). Associations with schizophrenia were also found for large deletions on chromosome 15q13.3 and 1q21.1. These associations have not previously been reported, and they remained significant after genome- wide correction. Our results provide strong support for a model of schizophrenia pathogenesis that includes the effects of multiple rare structural variants, both genome- wide and at specific loci.

Original languageEnglish
Pages (from-to)237-241
Number of pages5
JournalNature
Volume455
Issue number7210
Early online date30 Jul 2008
DOIs
Publication statusPublished - 11 Sep 2008

Keywords

  • comparative genomic hybridization
  • low copy repeats
  • disorders
  • rearrangements
  • association
  • linkage
  • number
  • locus
  • microdeletion
  • architecture

Cite this

Stone, J. L., O'Donovan, M. C., Gurling, H., Kirov, G. K., Blackwood, D. H. R., Corvin, A., ... The International Schizophrenia Consortium (ISC) (2008). Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature, 455(7210), 237-241. https://doi.org/10.1038/nature07239

Rare chromosomal deletions and duplications increase risk of schizophrenia. / Stone, Jennifer L.; O'Donovan, Michael C.; Gurling, Hugh; Kirov, George K.; Blackwood, Douglas H. R.; Corvin, Aiden; Craddock, Nick J.; Gill, Michael; Hultman, Christina M.; Lichtenstein, Paul; McQuillin, Andrew; Pato, Carlos N.; Ruderfer, Douglas M.; Owen, Michael J.; St Clair, David; Sullivan, Patrick F.; Sklar, Pamela; Purcell, Shaun M.; Scolnick, E. M.; Holmans, P. A.; Georgieva, L.; Nikolov, I.; Norton, N.; Williams, H.; Williams, N. M.; Toncheva, D.; Milanova, V.; Thelander, E. F.; Morris, D. W.; O'Dushlaine, C. T.; Kenny, E.; Waddington, J. L.; Choudhury, K.; Datta, S.; Pimm, J.; Thirumalai, S.; Puri, V.; Krasucki, R.; Lawrence, J.; Quested, D.; Bass, N.; Curtis, D.; Crombie, C.; Fraser, G.; Kwan, S. L.; Muir, W. J.; McGhee, K. A.; Pickard, B.; Malloy, P.; Maclean, A. W.; The International Schizophrenia Consortium (ISC).

In: Nature, Vol. 455, No. 7210, 11.09.2008, p. 237-241.

Research output: Contribution to journalLetter

Stone, JL, O'Donovan, MC, Gurling, H, Kirov, GK, Blackwood, DHR, Corvin, A, Craddock, NJ, Gill, M, Hultman, CM, Lichtenstein, P, McQuillin, A, Pato, CN, Ruderfer, DM, Owen, MJ, St Clair, D, Sullivan, PF, Sklar, P, Purcell, SM, Scolnick, EM, Holmans, PA, Georgieva, L, Nikolov, I, Norton, N, Williams, H, Williams, NM, Toncheva, D, Milanova, V, Thelander, EF, Morris, DW, O'Dushlaine, CT, Kenny, E, Waddington, JL, Choudhury, K, Datta, S, Pimm, J, Thirumalai, S, Puri, V, Krasucki, R, Lawrence, J, Quested, D, Bass, N, Curtis, D, Crombie, C, Fraser, G, Kwan, SL, Muir, WJ, McGhee, KA, Pickard, B, Malloy, P, Maclean, AW & The International Schizophrenia Consortium (ISC) 2008, 'Rare chromosomal deletions and duplications increase risk of schizophrenia', Nature, vol. 455, no. 7210, pp. 237-241. https://doi.org/10.1038/nature07239
Stone JL, O'Donovan MC, Gurling H, Kirov GK, Blackwood DHR, Corvin A et al. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature. 2008 Sep 11;455(7210):237-241. https://doi.org/10.1038/nature07239
Stone, Jennifer L. ; O'Donovan, Michael C. ; Gurling, Hugh ; Kirov, George K. ; Blackwood, Douglas H. R. ; Corvin, Aiden ; Craddock, Nick J. ; Gill, Michael ; Hultman, Christina M. ; Lichtenstein, Paul ; McQuillin, Andrew ; Pato, Carlos N. ; Ruderfer, Douglas M. ; Owen, Michael J. ; St Clair, David ; Sullivan, Patrick F. ; Sklar, Pamela ; Purcell, Shaun M. ; Scolnick, E. M. ; Holmans, P. A. ; Georgieva, L. ; Nikolov, I. ; Norton, N. ; Williams, H. ; Williams, N. M. ; Toncheva, D. ; Milanova, V. ; Thelander, E. F. ; Morris, D. W. ; O'Dushlaine, C. T. ; Kenny, E. ; Waddington, J. L. ; Choudhury, K. ; Datta, S. ; Pimm, J. ; Thirumalai, S. ; Puri, V. ; Krasucki, R. ; Lawrence, J. ; Quested, D. ; Bass, N. ; Curtis, D. ; Crombie, C. ; Fraser, G. ; Kwan, S. L. ; Muir, W. J. ; McGhee, K. A. ; Pickard, B. ; Malloy, P. ; Maclean, A. W. ; The International Schizophrenia Consortium (ISC). / Rare chromosomal deletions and duplications increase risk of schizophrenia. In: Nature. 2008 ; Vol. 455, No. 7210. pp. 237-241.
@article{14bc09f977e64569a81924de7a3650df,
title = "Rare chromosomal deletions and duplications increase risk of schizophrenia",
abstract = "Schizophrenia is a severe mental disorder marked by hallucinations, delusions, cognitive deficits and apathy, with a heritability estimated at 73 - 90{\%} ( ref. 1). Inheritance patterns are complex, and the number and type of genetic variants involved are not understood. Copy number variants ( CNVs) have been identified in individual patients with schizophrenia(2-7) and also in neurodevelopmental disorders(8-11), but large- scale genome- wide surveys have not been performed. Here we report a genome- wide survey of rare CNVs in 3,391 patients with schizophrenia and 3,181 ancestrally matched controls, using high- density microarrays. For CNVs that were observed in less than 1{\%} of the sample and were more than 100 kilobases in length, the total burden is increased 1.15- fold in patients with schizophrenia in comparison with controls. This effect was more pronounced for rarer, single- occurrence CNVs and for those that involved genes as opposed to those that did not. As expected, deletions were found within the region critical for velo- cardio- facial syndrome, which includes psychotic symptoms in 30{\%} of patients(12). Associations with schizophrenia were also found for large deletions on chromosome 15q13.3 and 1q21.1. These associations have not previously been reported, and they remained significant after genome- wide correction. Our results provide strong support for a model of schizophrenia pathogenesis that includes the effects of multiple rare structural variants, both genome- wide and at specific loci.",
keywords = "comparative genomic hybridization, low copy repeats, disorders, rearrangements, association, linkage, number, locus, microdeletion, architecture",
author = "Stone, {Jennifer L.} and O'Donovan, {Michael C.} and Hugh Gurling and Kirov, {George K.} and Blackwood, {Douglas H. R.} and Aiden Corvin and Craddock, {Nick J.} and Michael Gill and Hultman, {Christina M.} and Paul Lichtenstein and Andrew McQuillin and Pato, {Carlos N.} and Ruderfer, {Douglas M.} and Owen, {Michael J.} and {St Clair}, David and Sullivan, {Patrick F.} and Pamela Sklar and Purcell, {Shaun M.} and Scolnick, {E. M.} and Holmans, {P. A.} and L. Georgieva and I. Nikolov and N. Norton and H. Williams and Williams, {N. M.} and D. Toncheva and V. Milanova and Thelander, {E. F.} and Morris, {D. W.} and O'Dushlaine, {C. T.} and E. Kenny and Waddington, {J. L.} and K. Choudhury and S. Datta and J. Pimm and S. Thirumalai and V. Puri and R. Krasucki and J. Lawrence and D. Quested and N. Bass and D. Curtis and C. Crombie and G. Fraser and Kwan, {S. L.} and Muir, {W. J.} and McGhee, {K. A.} and B. Pickard and P. Malloy and Maclean, {A. W.} and {The International Schizophrenia Consortium (ISC)}",
year = "2008",
month = "9",
day = "11",
doi = "10.1038/nature07239",
language = "English",
volume = "455",
pages = "237--241",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7210",

}

TY - JOUR

T1 - Rare chromosomal deletions and duplications increase risk of schizophrenia

AU - Stone, Jennifer L.

AU - O'Donovan, Michael C.

AU - Gurling, Hugh

AU - Kirov, George K.

AU - Blackwood, Douglas H. R.

AU - Corvin, Aiden

AU - Craddock, Nick J.

AU - Gill, Michael

AU - Hultman, Christina M.

AU - Lichtenstein, Paul

AU - McQuillin, Andrew

AU - Pato, Carlos N.

AU - Ruderfer, Douglas M.

AU - Owen, Michael J.

AU - St Clair, David

AU - Sullivan, Patrick F.

AU - Sklar, Pamela

AU - Purcell, Shaun M.

AU - Scolnick, E. M.

AU - Holmans, P. A.

AU - Georgieva, L.

AU - Nikolov, I.

AU - Norton, N.

AU - Williams, H.

AU - Williams, N. M.

AU - Toncheva, D.

AU - Milanova, V.

AU - Thelander, E. F.

AU - Morris, D. W.

AU - O'Dushlaine, C. T.

AU - Kenny, E.

AU - Waddington, J. L.

AU - Choudhury, K.

AU - Datta, S.

AU - Pimm, J.

AU - Thirumalai, S.

AU - Puri, V.

AU - Krasucki, R.

AU - Lawrence, J.

AU - Quested, D.

AU - Bass, N.

AU - Curtis, D.

AU - Crombie, C.

AU - Fraser, G.

AU - Kwan, S. L.

AU - Muir, W. J.

AU - McGhee, K. A.

AU - Pickard, B.

AU - Malloy, P.

AU - Maclean, A. W.

AU - The International Schizophrenia Consortium (ISC)

PY - 2008/9/11

Y1 - 2008/9/11

N2 - Schizophrenia is a severe mental disorder marked by hallucinations, delusions, cognitive deficits and apathy, with a heritability estimated at 73 - 90% ( ref. 1). Inheritance patterns are complex, and the number and type of genetic variants involved are not understood. Copy number variants ( CNVs) have been identified in individual patients with schizophrenia(2-7) and also in neurodevelopmental disorders(8-11), but large- scale genome- wide surveys have not been performed. Here we report a genome- wide survey of rare CNVs in 3,391 patients with schizophrenia and 3,181 ancestrally matched controls, using high- density microarrays. For CNVs that were observed in less than 1% of the sample and were more than 100 kilobases in length, the total burden is increased 1.15- fold in patients with schizophrenia in comparison with controls. This effect was more pronounced for rarer, single- occurrence CNVs and for those that involved genes as opposed to those that did not. As expected, deletions were found within the region critical for velo- cardio- facial syndrome, which includes psychotic symptoms in 30% of patients(12). Associations with schizophrenia were also found for large deletions on chromosome 15q13.3 and 1q21.1. These associations have not previously been reported, and they remained significant after genome- wide correction. Our results provide strong support for a model of schizophrenia pathogenesis that includes the effects of multiple rare structural variants, both genome- wide and at specific loci.

AB - Schizophrenia is a severe mental disorder marked by hallucinations, delusions, cognitive deficits and apathy, with a heritability estimated at 73 - 90% ( ref. 1). Inheritance patterns are complex, and the number and type of genetic variants involved are not understood. Copy number variants ( CNVs) have been identified in individual patients with schizophrenia(2-7) and also in neurodevelopmental disorders(8-11), but large- scale genome- wide surveys have not been performed. Here we report a genome- wide survey of rare CNVs in 3,391 patients with schizophrenia and 3,181 ancestrally matched controls, using high- density microarrays. For CNVs that were observed in less than 1% of the sample and were more than 100 kilobases in length, the total burden is increased 1.15- fold in patients with schizophrenia in comparison with controls. This effect was more pronounced for rarer, single- occurrence CNVs and for those that involved genes as opposed to those that did not. As expected, deletions were found within the region critical for velo- cardio- facial syndrome, which includes psychotic symptoms in 30% of patients(12). Associations with schizophrenia were also found for large deletions on chromosome 15q13.3 and 1q21.1. These associations have not previously been reported, and they remained significant after genome- wide correction. Our results provide strong support for a model of schizophrenia pathogenesis that includes the effects of multiple rare structural variants, both genome- wide and at specific loci.

KW - comparative genomic hybridization

KW - low copy repeats

KW - disorders

KW - rearrangements

KW - association

KW - linkage

KW - number

KW - locus

KW - microdeletion

KW - architecture

U2 - 10.1038/nature07239

DO - 10.1038/nature07239

M3 - Letter

VL - 455

SP - 237

EP - 241

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7210

ER -