Implication of a rare deletion at distal 16p11.2 in schizophrenia

Saurav Guha, Elliott Rees, Ariel Darvasi, Dobril Ivanov, Masashi Ikeda, Sarah E. Bergen, Patrik K. Magnusson, Paul Cormican, Derek Morris, Michael Gill, Sven Cichon, Jeffrey A. Rosenfeld, Annette Lee, Peter K. Gregersen, John M. Kane, Anil K. Malhotra, Marcella Rietschel, Markus M. Nöthen, Franziska Degenhardt, Lutz PriebeRené Breuer, Jana Strohmaier, Douglas M. Ruderfer, Jennifer L. Moran, Kimberly D. Chambert, Alan R. Sanders, Jianxin Shi, Kenneth Kendler, Brien Riley, Tony O'Neill, Dermot Walsh, Dheeraj Malhotra, Aiden Corvin, Shaun Purcell, Pamela Sklar, Nakao Iwata, Christina M. Hultman, Patrick F. Sullivan, Jonathan Sebat, Shane McCarthy, Pablo V. Gejman, Douglas F. Levinson, Michael J. Owen, Michael C. O'Donovan, Todd Lencz, George Kirov

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

Context: Large genomic copy number variations have been implicated as strong risk factors for schizophrenia. However, the rarity of these events has created challenges for the identification of further pathogenic loci, and extremely large samples are required to provide convincing replication. Objective: To detect novel copy number variations that increase the susceptibility to schizophrenia by using 2 ethnically homogeneous discovery cohorts and replication in large samples. Design: Genetic association study of microarray data. Setting: Samples of DNA were collected at 9 sites from different countries. Participants: Two discovery cohorts consisted of 790 cases with schizophrenia and schizoaffective disorder and 1347 controls of Ashkenazi Jewish descent and 662 parentoffspring trios from Bulgaria, of which the offspring had schizophrenia or schizoaffective disorder. Replication data sets consisted of 12 398 cases and 17 945 controls. Main Outcome Measures: Statistically increased rate of specific copy number variations in cases vs controls. Results: One novel locus was implicated: a deletion at distal 16p11.2, which does not overlap the proximal 16p11.2 locus previously reported in schizophrenia and autism. Deletions at this locus were found in 13 of 13 850 cases (0.094%) and 3 of 19 954 controls (0.015%) (odds ratio, 6.25 [95% CI, 1.78-21.93]; P=.001, Fisher exact test). Conclusions: Deletions at distal 16p11.2 have been previously implicated in developmental delay and obesity. The region contains 9 genes, several of which are implicated in neurological diseases, regulation of body weight, and glucose homeostasis. A telomeric extension of the deletion, observed in about half the cases but no controls, potentially implicates an additional 8 genes. Our findings add a new locus to the list of copy number variations that increase the risk for development of schizophrenia.

Original languageEnglish
Pages (from-to)253-260
Number of pages8
JournalJAMA Psychiatry
Volume70
Issue number3
DOIs
Publication statusPublished - 03-2013

Fingerprint

Schizophrenia
Psychotic Disorders
Bulgaria
Genetic Association Studies
Autistic Disorder
Genes
Homeostasis
Obesity
Odds Ratio
Body Weight
Outcome Assessment (Health Care)
Glucose
DNA

All Science Journal Classification (ASJC) codes

  • Psychiatry and Mental health

Cite this

Guha, S., Rees, E., Darvasi, A., Ivanov, D., Ikeda, M., Bergen, S. E., ... Kirov, G. (2013). Implication of a rare deletion at distal 16p11.2 in schizophrenia. JAMA Psychiatry, 70(3), 253-260. https://doi.org/10.1001/2013.jamapsychiatry.71
Guha, Saurav ; Rees, Elliott ; Darvasi, Ariel ; Ivanov, Dobril ; Ikeda, Masashi ; Bergen, Sarah E. ; Magnusson, Patrik K. ; Cormican, Paul ; Morris, Derek ; Gill, Michael ; Cichon, Sven ; Rosenfeld, Jeffrey A. ; Lee, Annette ; Gregersen, Peter K. ; Kane, John M. ; Malhotra, Anil K. ; Rietschel, Marcella ; Nöthen, Markus M. ; Degenhardt, Franziska ; Priebe, Lutz ; Breuer, René ; Strohmaier, Jana ; Ruderfer, Douglas M. ; Moran, Jennifer L. ; Chambert, Kimberly D. ; Sanders, Alan R. ; Shi, Jianxin ; Kendler, Kenneth ; Riley, Brien ; O'Neill, Tony ; Walsh, Dermot ; Malhotra, Dheeraj ; Corvin, Aiden ; Purcell, Shaun ; Sklar, Pamela ; Iwata, Nakao ; Hultman, Christina M. ; Sullivan, Patrick F. ; Sebat, Jonathan ; McCarthy, Shane ; Gejman, Pablo V. ; Levinson, Douglas F. ; Owen, Michael J. ; O'Donovan, Michael C. ; Lencz, Todd ; Kirov, George. / Implication of a rare deletion at distal 16p11.2 in schizophrenia. In: JAMA Psychiatry. 2013 ; Vol. 70, No. 3. pp. 253-260.
@article{c35b2001b8504ec5817ecbf53dd00543,
title = "Implication of a rare deletion at distal 16p11.2 in schizophrenia",
abstract = "Context: Large genomic copy number variations have been implicated as strong risk factors for schizophrenia. However, the rarity of these events has created challenges for the identification of further pathogenic loci, and extremely large samples are required to provide convincing replication. Objective: To detect novel copy number variations that increase the susceptibility to schizophrenia by using 2 ethnically homogeneous discovery cohorts and replication in large samples. Design: Genetic association study of microarray data. Setting: Samples of DNA were collected at 9 sites from different countries. Participants: Two discovery cohorts consisted of 790 cases with schizophrenia and schizoaffective disorder and 1347 controls of Ashkenazi Jewish descent and 662 parentoffspring trios from Bulgaria, of which the offspring had schizophrenia or schizoaffective disorder. Replication data sets consisted of 12 398 cases and 17 945 controls. Main Outcome Measures: Statistically increased rate of specific copy number variations in cases vs controls. Results: One novel locus was implicated: a deletion at distal 16p11.2, which does not overlap the proximal 16p11.2 locus previously reported in schizophrenia and autism. Deletions at this locus were found in 13 of 13 850 cases (0.094{\%}) and 3 of 19 954 controls (0.015{\%}) (odds ratio, 6.25 [95{\%} CI, 1.78-21.93]; P=.001, Fisher exact test). Conclusions: Deletions at distal 16p11.2 have been previously implicated in developmental delay and obesity. The region contains 9 genes, several of which are implicated in neurological diseases, regulation of body weight, and glucose homeostasis. A telomeric extension of the deletion, observed in about half the cases but no controls, potentially implicates an additional 8 genes. Our findings add a new locus to the list of copy number variations that increase the risk for development of schizophrenia.",
author = "Saurav Guha and Elliott Rees and Ariel Darvasi and Dobril Ivanov and Masashi Ikeda and Bergen, {Sarah E.} and Magnusson, {Patrik K.} and Paul Cormican and Derek Morris and Michael Gill and Sven Cichon and Rosenfeld, {Jeffrey A.} and Annette Lee and Gregersen, {Peter K.} and Kane, {John M.} and Malhotra, {Anil K.} and Marcella Rietschel and N{\"o}then, {Markus M.} and Franziska Degenhardt and Lutz Priebe and Ren{\'e} Breuer and Jana Strohmaier and Ruderfer, {Douglas M.} and Moran, {Jennifer L.} and Chambert, {Kimberly D.} and Sanders, {Alan R.} and Jianxin Shi and Kenneth Kendler and Brien Riley and Tony O'Neill and Dermot Walsh and Dheeraj Malhotra and Aiden Corvin and Shaun Purcell and Pamela Sklar and Nakao Iwata and Hultman, {Christina M.} and Sullivan, {Patrick F.} and Jonathan Sebat and Shane McCarthy and Gejman, {Pablo V.} and Levinson, {Douglas F.} and Owen, {Michael J.} and O'Donovan, {Michael C.} and Todd Lencz and George Kirov",
year = "2013",
month = "3",
doi = "10.1001/2013.jamapsychiatry.71",
language = "English",
volume = "70",
pages = "253--260",
journal = "JAMA Psychiatry",
issn = "2168-622X",
publisher = "American Medical Association",
number = "3",

}

Guha, S, Rees, E, Darvasi, A, Ivanov, D, Ikeda, M, Bergen, SE, Magnusson, PK, Cormican, P, Morris, D, Gill, M, Cichon, S, Rosenfeld, JA, Lee, A, Gregersen, PK, Kane, JM, Malhotra, AK, Rietschel, M, Nöthen, MM, Degenhardt, F, Priebe, L, Breuer, R, Strohmaier, J, Ruderfer, DM, Moran, JL, Chambert, KD, Sanders, AR, Shi, J, Kendler, K, Riley, B, O'Neill, T, Walsh, D, Malhotra, D, Corvin, A, Purcell, S, Sklar, P, Iwata, N, Hultman, CM, Sullivan, PF, Sebat, J, McCarthy, S, Gejman, PV, Levinson, DF, Owen, MJ, O'Donovan, MC, Lencz, T & Kirov, G 2013, 'Implication of a rare deletion at distal 16p11.2 in schizophrenia', JAMA Psychiatry, vol. 70, no. 3, pp. 253-260. https://doi.org/10.1001/2013.jamapsychiatry.71

Implication of a rare deletion at distal 16p11.2 in schizophrenia. / Guha, Saurav; Rees, Elliott; Darvasi, Ariel; Ivanov, Dobril; Ikeda, Masashi; Bergen, Sarah E.; Magnusson, Patrik K.; Cormican, Paul; Morris, Derek; Gill, Michael; Cichon, Sven; Rosenfeld, Jeffrey A.; Lee, Annette; Gregersen, Peter K.; Kane, John M.; Malhotra, Anil K.; Rietschel, Marcella; Nöthen, Markus M.; Degenhardt, Franziska; Priebe, Lutz; Breuer, René; Strohmaier, Jana; Ruderfer, Douglas M.; Moran, Jennifer L.; Chambert, Kimberly D.; Sanders, Alan R.; Shi, Jianxin; Kendler, Kenneth; Riley, Brien; O'Neill, Tony; Walsh, Dermot; Malhotra, Dheeraj; Corvin, Aiden; Purcell, Shaun; Sklar, Pamela; Iwata, Nakao; Hultman, Christina M.; Sullivan, Patrick F.; Sebat, Jonathan; McCarthy, Shane; Gejman, Pablo V.; Levinson, Douglas F.; Owen, Michael J.; O'Donovan, Michael C.; Lencz, Todd; Kirov, George.

In: JAMA Psychiatry, Vol. 70, No. 3, 03.2013, p. 253-260.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Implication of a rare deletion at distal 16p11.2 in schizophrenia

AU - Guha, Saurav

AU - Rees, Elliott

AU - Darvasi, Ariel

AU - Ivanov, Dobril

AU - Ikeda, Masashi

AU - Bergen, Sarah E.

AU - Magnusson, Patrik K.

AU - Cormican, Paul

AU - Morris, Derek

AU - Gill, Michael

AU - Cichon, Sven

AU - Rosenfeld, Jeffrey A.

AU - Lee, Annette

AU - Gregersen, Peter K.

AU - Kane, John M.

AU - Malhotra, Anil K.

AU - Rietschel, Marcella

AU - Nöthen, Markus M.

AU - Degenhardt, Franziska

AU - Priebe, Lutz

AU - Breuer, René

AU - Strohmaier, Jana

AU - Ruderfer, Douglas M.

AU - Moran, Jennifer L.

AU - Chambert, Kimberly D.

AU - Sanders, Alan R.

AU - Shi, Jianxin

AU - Kendler, Kenneth

AU - Riley, Brien

AU - O'Neill, Tony

AU - Walsh, Dermot

AU - Malhotra, Dheeraj

AU - Corvin, Aiden

AU - Purcell, Shaun

AU - Sklar, Pamela

AU - Iwata, Nakao

AU - Hultman, Christina M.

AU - Sullivan, Patrick F.

AU - Sebat, Jonathan

AU - McCarthy, Shane

AU - Gejman, Pablo V.

AU - Levinson, Douglas F.

AU - Owen, Michael J.

AU - O'Donovan, Michael C.

AU - Lencz, Todd

AU - Kirov, George

PY - 2013/3

Y1 - 2013/3

N2 - Context: Large genomic copy number variations have been implicated as strong risk factors for schizophrenia. However, the rarity of these events has created challenges for the identification of further pathogenic loci, and extremely large samples are required to provide convincing replication. Objective: To detect novel copy number variations that increase the susceptibility to schizophrenia by using 2 ethnically homogeneous discovery cohorts and replication in large samples. Design: Genetic association study of microarray data. Setting: Samples of DNA were collected at 9 sites from different countries. Participants: Two discovery cohorts consisted of 790 cases with schizophrenia and schizoaffective disorder and 1347 controls of Ashkenazi Jewish descent and 662 parentoffspring trios from Bulgaria, of which the offspring had schizophrenia or schizoaffective disorder. Replication data sets consisted of 12 398 cases and 17 945 controls. Main Outcome Measures: Statistically increased rate of specific copy number variations in cases vs controls. Results: One novel locus was implicated: a deletion at distal 16p11.2, which does not overlap the proximal 16p11.2 locus previously reported in schizophrenia and autism. Deletions at this locus were found in 13 of 13 850 cases (0.094%) and 3 of 19 954 controls (0.015%) (odds ratio, 6.25 [95% CI, 1.78-21.93]; P=.001, Fisher exact test). Conclusions: Deletions at distal 16p11.2 have been previously implicated in developmental delay and obesity. The region contains 9 genes, several of which are implicated in neurological diseases, regulation of body weight, and glucose homeostasis. A telomeric extension of the deletion, observed in about half the cases but no controls, potentially implicates an additional 8 genes. Our findings add a new locus to the list of copy number variations that increase the risk for development of schizophrenia.

AB - Context: Large genomic copy number variations have been implicated as strong risk factors for schizophrenia. However, the rarity of these events has created challenges for the identification of further pathogenic loci, and extremely large samples are required to provide convincing replication. Objective: To detect novel copy number variations that increase the susceptibility to schizophrenia by using 2 ethnically homogeneous discovery cohorts and replication in large samples. Design: Genetic association study of microarray data. Setting: Samples of DNA were collected at 9 sites from different countries. Participants: Two discovery cohorts consisted of 790 cases with schizophrenia and schizoaffective disorder and 1347 controls of Ashkenazi Jewish descent and 662 parentoffspring trios from Bulgaria, of which the offspring had schizophrenia or schizoaffective disorder. Replication data sets consisted of 12 398 cases and 17 945 controls. Main Outcome Measures: Statistically increased rate of specific copy number variations in cases vs controls. Results: One novel locus was implicated: a deletion at distal 16p11.2, which does not overlap the proximal 16p11.2 locus previously reported in schizophrenia and autism. Deletions at this locus were found in 13 of 13 850 cases (0.094%) and 3 of 19 954 controls (0.015%) (odds ratio, 6.25 [95% CI, 1.78-21.93]; P=.001, Fisher exact test). Conclusions: Deletions at distal 16p11.2 have been previously implicated in developmental delay and obesity. The region contains 9 genes, several of which are implicated in neurological diseases, regulation of body weight, and glucose homeostasis. A telomeric extension of the deletion, observed in about half the cases but no controls, potentially implicates an additional 8 genes. Our findings add a new locus to the list of copy number variations that increase the risk for development of schizophrenia.

UR - http://www.scopus.com/inward/record.url?scp=84874870865&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84874870865&partnerID=8YFLogxK

U2 - 10.1001/2013.jamapsychiatry.71

DO - 10.1001/2013.jamapsychiatry.71

M3 - Article

C2 - 23325106

AN - SCOPUS:84874870865

VL - 70

SP - 253

EP - 260

JO - JAMA Psychiatry

JF - JAMA Psychiatry

SN - 2168-622X

IS - 3

ER -