Reciprocal duplication of the williams-beuren syndrome deletion on chromosome 7q11.23 is associated with schizophrenia

Jennifer Gladys Mulle, Ann E. Pulver, John A. McGrath, Paula S. Wolyniec, Anne F. Dodd, David J. Cutler, Jonathan Sebat, Dheeraj Malhotra, Gerald Nestadt, Donald F. Conrad, Matthew Hurles, Chris P. Barnes, Masashi Ikeda, Nakao Iwata, Douglas F. Levinson, Pablo V. Gejman, Alan R. Sanders, Jubao Duan, Adele A. Mitchell, Inga PeterPamela Sklar, Colm T. O'Dushlaine, Detelina Grozeva, Michael C. O'Donovan, Michael J. Owen, Christina M. Hultman, Anna K. Kähler, Patrick F. Sullivan, George Kirov, Stephen T. Warren

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Abstract

Background Several copy number variants (CNVs) have been implicated as susceptibility factors for schizophrenia (SZ). Some of these same CNVs also increase risk for autism spectrum disorders, suggesting an etiologic overlap between these conditions. Recently, de novo duplications of a region on chromosome 7q11.23 were associated with autism spectrum disorders. The reciprocal deletion of this region causes Williams-Beuren syndrome. Methods We assayed an Ashkenazi Jewish cohort of 554 SZ cases and 1014 controls for genome-wide CNV. An excess of large rare and de novo CNVs were observed, including a 1.4 Mb duplication on chromosome 7q11.23 identified in two unrelated patients. To test whether this 7q11.23 duplication is also associated with SZ, we obtained data for 14,387 SZ cases and 28,139 controls from seven additional studies with high-resolution genome-wide CNV detection. We performed a meta-analysis, correcting for study population of origin, to assess whether the duplication is associated with SZ. Results We found duplications at 7q11.23 in 11 of 14,387 SZ cases with only 1 in 28,139 control subjects (unadjusted odds ratio 21.52, 95% confidence interval: 3.13-922.6, p value 5.5 × 10 -5; adjusted odds ratio 10.8, 95% confidence interval: 1.46-79.62, p value.007). Of three SZ duplication carriers with detailed retrospective data, all showed social anxiety and language delay premorbid to SZ onset, consistent with both human studies and animal models of the 7q11.23 duplication. Conclusions We have identified a new CNV associated with SZ. Reciprocal duplication of the Williams-Beuren syndrome deletion at chromosome 7q11.23 confers an approximately tenfold increase in risk for SZ.

Original languageEnglish
Pages (from-to)371-377
Number of pages7
JournalBiological Psychiatry
Volume75
Issue number5
DOIs
Publication statusPublished - 01-03-2014

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Williams Syndrome
Chromosome Deletion
Schizophrenia
Odds Ratio
Chromosome Duplication
Genome
Confidence Intervals
Language Development Disorders
Meta-Analysis
Anxiety
Animal Models
Chromosomes

All Science Journal Classification (ASJC) codes

  • Biological Psychiatry

Cite this

Mulle, J. G., Pulver, A. E., McGrath, J. A., Wolyniec, P. S., Dodd, A. F., Cutler, D. J., ... Warren, S. T. (2014). Reciprocal duplication of the williams-beuren syndrome deletion on chromosome 7q11.23 is associated with schizophrenia. Biological Psychiatry, 75(5), 371-377. https://doi.org/10.1016/j.biopsych.2013.05.040
Mulle, Jennifer Gladys ; Pulver, Ann E. ; McGrath, John A. ; Wolyniec, Paula S. ; Dodd, Anne F. ; Cutler, David J. ; Sebat, Jonathan ; Malhotra, Dheeraj ; Nestadt, Gerald ; Conrad, Donald F. ; Hurles, Matthew ; Barnes, Chris P. ; Ikeda, Masashi ; Iwata, Nakao ; Levinson, Douglas F. ; Gejman, Pablo V. ; Sanders, Alan R. ; Duan, Jubao ; Mitchell, Adele A. ; Peter, Inga ; Sklar, Pamela ; O'Dushlaine, Colm T. ; Grozeva, Detelina ; O'Donovan, Michael C. ; Owen, Michael J. ; Hultman, Christina M. ; Kähler, Anna K. ; Sullivan, Patrick F. ; Kirov, George ; Warren, Stephen T. / Reciprocal duplication of the williams-beuren syndrome deletion on chromosome 7q11.23 is associated with schizophrenia. In: Biological Psychiatry. 2014 ; Vol. 75, No. 5. pp. 371-377.
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title = "Reciprocal duplication of the williams-beuren syndrome deletion on chromosome 7q11.23 is associated with schizophrenia",
abstract = "Background Several copy number variants (CNVs) have been implicated as susceptibility factors for schizophrenia (SZ). Some of these same CNVs also increase risk for autism spectrum disorders, suggesting an etiologic overlap between these conditions. Recently, de novo duplications of a region on chromosome 7q11.23 were associated with autism spectrum disorders. The reciprocal deletion of this region causes Williams-Beuren syndrome. Methods We assayed an Ashkenazi Jewish cohort of 554 SZ cases and 1014 controls for genome-wide CNV. An excess of large rare and de novo CNVs were observed, including a 1.4 Mb duplication on chromosome 7q11.23 identified in two unrelated patients. To test whether this 7q11.23 duplication is also associated with SZ, we obtained data for 14,387 SZ cases and 28,139 controls from seven additional studies with high-resolution genome-wide CNV detection. We performed a meta-analysis, correcting for study population of origin, to assess whether the duplication is associated with SZ. Results We found duplications at 7q11.23 in 11 of 14,387 SZ cases with only 1 in 28,139 control subjects (unadjusted odds ratio 21.52, 95{\%} confidence interval: 3.13-922.6, p value 5.5 × 10 -5; adjusted odds ratio 10.8, 95{\%} confidence interval: 1.46-79.62, p value.007). Of three SZ duplication carriers with detailed retrospective data, all showed social anxiety and language delay premorbid to SZ onset, consistent with both human studies and animal models of the 7q11.23 duplication. Conclusions We have identified a new CNV associated with SZ. Reciprocal duplication of the Williams-Beuren syndrome deletion at chromosome 7q11.23 confers an approximately tenfold increase in risk for SZ.",
author = "Mulle, {Jennifer Gladys} and Pulver, {Ann E.} and McGrath, {John A.} and Wolyniec, {Paula S.} and Dodd, {Anne F.} and Cutler, {David J.} and Jonathan Sebat and Dheeraj Malhotra and Gerald Nestadt and Conrad, {Donald F.} and Matthew Hurles and Barnes, {Chris P.} and Masashi Ikeda and Nakao Iwata and Levinson, {Douglas F.} and Gejman, {Pablo V.} and Sanders, {Alan R.} and Jubao Duan and Mitchell, {Adele A.} and Inga Peter and Pamela Sklar and O'Dushlaine, {Colm T.} and Detelina Grozeva and O'Donovan, {Michael C.} and Owen, {Michael J.} and Hultman, {Christina M.} and K{\"a}hler, {Anna K.} and Sullivan, {Patrick F.} and George Kirov and Warren, {Stephen T.}",
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Mulle, JG, Pulver, AE, McGrath, JA, Wolyniec, PS, Dodd, AF, Cutler, DJ, Sebat, J, Malhotra, D, Nestadt, G, Conrad, DF, Hurles, M, Barnes, CP, Ikeda, M, Iwata, N, Levinson, DF, Gejman, PV, Sanders, AR, Duan, J, Mitchell, AA, Peter, I, Sklar, P, O'Dushlaine, CT, Grozeva, D, O'Donovan, MC, Owen, MJ, Hultman, CM, Kähler, AK, Sullivan, PF, Kirov, G & Warren, ST 2014, 'Reciprocal duplication of the williams-beuren syndrome deletion on chromosome 7q11.23 is associated with schizophrenia', Biological Psychiatry, vol. 75, no. 5, pp. 371-377. https://doi.org/10.1016/j.biopsych.2013.05.040

Reciprocal duplication of the williams-beuren syndrome deletion on chromosome 7q11.23 is associated with schizophrenia. / Mulle, Jennifer Gladys; Pulver, Ann E.; McGrath, John A.; Wolyniec, Paula S.; Dodd, Anne F.; Cutler, David J.; Sebat, Jonathan; Malhotra, Dheeraj; Nestadt, Gerald; Conrad, Donald F.; Hurles, Matthew; Barnes, Chris P.; Ikeda, Masashi; Iwata, Nakao; Levinson, Douglas F.; Gejman, Pablo V.; Sanders, Alan R.; Duan, Jubao; Mitchell, Adele A.; Peter, Inga; Sklar, Pamela; O'Dushlaine, Colm T.; Grozeva, Detelina; O'Donovan, Michael C.; Owen, Michael J.; Hultman, Christina M.; Kähler, Anna K.; Sullivan, Patrick F.; Kirov, George; Warren, Stephen T.

In: Biological Psychiatry, Vol. 75, No. 5, 01.03.2014, p. 371-377.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Reciprocal duplication of the williams-beuren syndrome deletion on chromosome 7q11.23 is associated with schizophrenia

AU - Mulle, Jennifer Gladys

AU - Pulver, Ann E.

AU - McGrath, John A.

AU - Wolyniec, Paula S.

AU - Dodd, Anne F.

AU - Cutler, David J.

AU - Sebat, Jonathan

AU - Malhotra, Dheeraj

AU - Nestadt, Gerald

AU - Conrad, Donald F.

AU - Hurles, Matthew

AU - Barnes, Chris P.

AU - Ikeda, Masashi

AU - Iwata, Nakao

AU - Levinson, Douglas F.

AU - Gejman, Pablo V.

AU - Sanders, Alan R.

AU - Duan, Jubao

AU - Mitchell, Adele A.

AU - Peter, Inga

AU - Sklar, Pamela

AU - O'Dushlaine, Colm T.

AU - Grozeva, Detelina

AU - O'Donovan, Michael C.

AU - Owen, Michael J.

AU - Hultman, Christina M.

AU - Kähler, Anna K.

AU - Sullivan, Patrick F.

AU - Kirov, George

AU - Warren, Stephen T.

PY - 2014/3/1

Y1 - 2014/3/1

N2 - Background Several copy number variants (CNVs) have been implicated as susceptibility factors for schizophrenia (SZ). Some of these same CNVs also increase risk for autism spectrum disorders, suggesting an etiologic overlap between these conditions. Recently, de novo duplications of a region on chromosome 7q11.23 were associated with autism spectrum disorders. The reciprocal deletion of this region causes Williams-Beuren syndrome. Methods We assayed an Ashkenazi Jewish cohort of 554 SZ cases and 1014 controls for genome-wide CNV. An excess of large rare and de novo CNVs were observed, including a 1.4 Mb duplication on chromosome 7q11.23 identified in two unrelated patients. To test whether this 7q11.23 duplication is also associated with SZ, we obtained data for 14,387 SZ cases and 28,139 controls from seven additional studies with high-resolution genome-wide CNV detection. We performed a meta-analysis, correcting for study population of origin, to assess whether the duplication is associated with SZ. Results We found duplications at 7q11.23 in 11 of 14,387 SZ cases with only 1 in 28,139 control subjects (unadjusted odds ratio 21.52, 95% confidence interval: 3.13-922.6, p value 5.5 × 10 -5; adjusted odds ratio 10.8, 95% confidence interval: 1.46-79.62, p value.007). Of three SZ duplication carriers with detailed retrospective data, all showed social anxiety and language delay premorbid to SZ onset, consistent with both human studies and animal models of the 7q11.23 duplication. Conclusions We have identified a new CNV associated with SZ. Reciprocal duplication of the Williams-Beuren syndrome deletion at chromosome 7q11.23 confers an approximately tenfold increase in risk for SZ.

AB - Background Several copy number variants (CNVs) have been implicated as susceptibility factors for schizophrenia (SZ). Some of these same CNVs also increase risk for autism spectrum disorders, suggesting an etiologic overlap between these conditions. Recently, de novo duplications of a region on chromosome 7q11.23 were associated with autism spectrum disorders. The reciprocal deletion of this region causes Williams-Beuren syndrome. Methods We assayed an Ashkenazi Jewish cohort of 554 SZ cases and 1014 controls for genome-wide CNV. An excess of large rare and de novo CNVs were observed, including a 1.4 Mb duplication on chromosome 7q11.23 identified in two unrelated patients. To test whether this 7q11.23 duplication is also associated with SZ, we obtained data for 14,387 SZ cases and 28,139 controls from seven additional studies with high-resolution genome-wide CNV detection. We performed a meta-analysis, correcting for study population of origin, to assess whether the duplication is associated with SZ. Results We found duplications at 7q11.23 in 11 of 14,387 SZ cases with only 1 in 28,139 control subjects (unadjusted odds ratio 21.52, 95% confidence interval: 3.13-922.6, p value 5.5 × 10 -5; adjusted odds ratio 10.8, 95% confidence interval: 1.46-79.62, p value.007). Of three SZ duplication carriers with detailed retrospective data, all showed social anxiety and language delay premorbid to SZ onset, consistent with both human studies and animal models of the 7q11.23 duplication. Conclusions We have identified a new CNV associated with SZ. Reciprocal duplication of the Williams-Beuren syndrome deletion at chromosome 7q11.23 confers an approximately tenfold increase in risk for SZ.

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U2 - 10.1016/j.biopsych.2013.05.040

DO - 10.1016/j.biopsych.2013.05.040

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