High frequencies of de novo cnvs in bipolar disorder and schizophrenia

Dheeraj Malhotra; Shane McCarthy; Jacob J. Michaelson; Vladimir Vacic; Katherine E. Burdick; Seungtai Yoon; Sven Cichon; Aiden Corvin; Sydney Gary; Elliot S. Gershon; Michael Gill; Maria Karayiorgou; John R. Kelsoe; Olga Krastoshevsky; Verena Krause; Ellen Leibenluft; Deborah L. Levy; Vladimir Makarov; Abhishek Bhandari; Anil K. Malhotra; Francis J. McMahon; Markus M. Nöthen; James B. Potash; Marcella Rietschel; Thomas G. Schulze; Jonathan Sebat

doi:10.1016/j.neuron.2011.11.007

High frequencies of de novo cnvs in bipolar disorder and schizophrenia

Dheeraj Malhotra, Shane McCarthy, Jacob J. Michaelson, Vladimir Vacic, Katherine E. Burdick, Seungtai Yoon, Sven Cichon, Aiden Corvin, Sydney Gary, Elliot S. Gershon, Michael Gill, Maria Karayiorgou, John R. Kelsoe, Olga Krastoshevsky, Verena Krause, Ellen Leibenluft, Deborah L. Levy, Vladimir Makarov, Abhishek Bhandari, Anil K. MalhotraFrancis J. McMahon, Markus M. Nöthen, James B. Potash, Marcella Rietschel, Thomas G. Schulze, Jonathan Sebat

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Abstract

While it is known that rare copy-number variants (CNVs) contribute to risk for some neuropsychiatric disorders, the role of CNVs in bipolar disorder is unclear. Here, we reasoned that a contribution of CNVs to mood disorders might be most evident for de novo mutations. We performed a genome-wide analysis of de novo CNVs in a cohort of 788 trios. Diagnoses of offspring included bipolar disorder (n = 185), schizophrenia (n = 177), and healthy controls (n = 426). Frequencies of de novo CNVs were significantly higher in bipolar disorder as compared with controls (OR = 4.8 [1.4,16.0], p = 0.009). De novo CNVs were particularly enriched among cases with an age at onset younger than 18 (OR = 6.3 [1.7,22.6], p = 0.006). We also confirmed a significant enrichment of de novo CNVs in schizophrenia (OR = 5.0 [1.5,16.8], p = 0.007). Our results suggest that rare spontaneous mutations are an important contributor to risk for bipolar disorder and other major neuropsychiatric diseases.

Original language	English (US)
Pages (from-to)	951-963
Number of pages	13
Journal	Neuron
Volume	72
Issue number	6
DOIs	https://doi.org/10.1016/j.neuron.2011.11.007
State	Published - Dec 22 2011
Externally published	Yes

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Neuroscience(all)

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10.1016/j.neuron.2011.11.007

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Malhotra, D., McCarthy, S., Michaelson, J. J., Vacic, V., Burdick, K. E., Yoon, S., Cichon, S., Corvin, A., Gary, S., Gershon, E. S., Gill, M., Karayiorgou, M., Kelsoe, J. R., Krastoshevsky, O., Krause, V., Leibenluft, E., Levy, D. L., Makarov, V., Bhandari, A., ... Sebat, J. (2011). High frequencies of de novo cnvs in bipolar disorder and schizophrenia. Neuron, 72(6), 951-963. https://doi.org/10.1016/j.neuron.2011.11.007

Malhotra, D, McCarthy, S, Michaelson, JJ, Vacic, V, Burdick, KE, Yoon, S, Cichon, S, Corvin, A, Gary, S, Gershon, ES, Gill, M, Karayiorgou, M, Kelsoe, JR, Krastoshevsky, O, Krause, V, Leibenluft, E, Levy, DL, Makarov, V, Bhandari, A, Malhotra, AK, McMahon, FJ, Nöthen, MM, Potash, JB, Rietschel, M, Schulze, TG & Sebat, J 2011, 'High frequencies of de novo cnvs in bipolar disorder and schizophrenia', Neuron, vol. 72, no. 6, pp. 951-963. https://doi.org/10.1016/j.neuron.2011.11.007

@article{fa243e65328b4f768e9f60b6c464ac7a,

title = "High frequencies of de novo cnvs in bipolar disorder and schizophrenia",

abstract = "While it is known that rare copy-number variants (CNVs) contribute to risk for some neuropsychiatric disorders, the role of CNVs in bipolar disorder is unclear. Here, we reasoned that a contribution of CNVs to mood disorders might be most evident for de novo mutations. We performed a genome-wide analysis of de novo CNVs in a cohort of 788 trios. Diagnoses of offspring included bipolar disorder (n = 185), schizophrenia (n = 177), and healthy controls (n = 426). Frequencies of de novo CNVs were significantly higher in bipolar disorder as compared with controls (OR = 4.8 [1.4,16.0], p = 0.009). De novo CNVs were particularly enriched among cases with an age at onset younger than 18 (OR = 6.3 [1.7,22.6], p = 0.006). We also confirmed a significant enrichment of de novo CNVs in schizophrenia (OR = 5.0 [1.5,16.8], p = 0.007). Our results suggest that rare spontaneous mutations are an important contributor to risk for bipolar disorder and other major neuropsychiatric diseases.",

author = "Dheeraj Malhotra and Shane McCarthy and Michaelson, {Jacob J.} and Vladimir Vacic and Burdick, {Katherine E.} and Seungtai Yoon and Sven Cichon and Aiden Corvin and Sydney Gary and Gershon, {Elliot S.} and Michael Gill and Maria Karayiorgou and Kelsoe, {John R.} and Olga Krastoshevsky and Verena Krause and Ellen Leibenluft and Levy, {Deborah L.} and Vladimir Makarov and Abhishek Bhandari and Malhotra, {Anil K.} and McMahon, {Francis J.} and N{\"o}then, {Markus M.} and Potash, {James B.} and Marcella Rietschel and Schulze, {Thomas G.} and Jonathan Sebat",

note = "Funding Information: We thank all patients and their families for their participation in this genetic study. Special thanks to James Watson for helpful discussions and support. This study was supported by a gift from Ted and Vada Stanley to the Cold Spring Harbor Laboratory, a gift to J.S. from the Beyster family foundation, NIH grants to J.S. (MH076431, HG04222), D.L.L. (MH071523), and M.K. (MH061399), grants to J.S. and D.L.L. from NARSAD, grants to A.C. and M.G. from the Wellcome Trust (072894/Z/03/Z) and Science Foundation Ireland (08INIB1916), and grants to D.L.L. from the Sidney R. Baer, Jr. Foundation and Essel Foundation. We thank the Genetic Association Information Network (GAIN), Molecular Genetics of Schizophrenia (MGS), and the Bipolar Genome Study (BiGS) for providing data for this study. We thank Roche NimbleGen and Oxford Gene Technology for their expert technical assistance. We thank Lilia M. Iakoucheva and Roser Corominas for helpful discussions. ",

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doi = "10.1016/j.neuron.2011.11.007",

language = "English (US)",

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pages = "951--963",

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T1 - High frequencies of de novo cnvs in bipolar disorder and schizophrenia

AU - Malhotra, Dheeraj

AU - McCarthy, Shane

AU - Michaelson, Jacob J.

AU - Vacic, Vladimir

AU - Burdick, Katherine E.

AU - Yoon, Seungtai

AU - Cichon, Sven

AU - Corvin, Aiden

AU - Gary, Sydney

AU - Gershon, Elliot S.

AU - Gill, Michael

AU - Karayiorgou, Maria

AU - Kelsoe, John R.

AU - Krastoshevsky, Olga

AU - Krause, Verena

AU - Leibenluft, Ellen

AU - Levy, Deborah L.

AU - Makarov, Vladimir

AU - Bhandari, Abhishek

AU - Malhotra, Anil K.

AU - McMahon, Francis J.

AU - Nöthen, Markus M.

AU - Potash, James B.

AU - Rietschel, Marcella

AU - Schulze, Thomas G.

AU - Sebat, Jonathan

N1 - Funding Information: We thank all patients and their families for their participation in this genetic study. Special thanks to James Watson for helpful discussions and support. This study was supported by a gift from Ted and Vada Stanley to the Cold Spring Harbor Laboratory, a gift to J.S. from the Beyster family foundation, NIH grants to J.S. (MH076431, HG04222), D.L.L. (MH071523), and M.K. (MH061399), grants to J.S. and D.L.L. from NARSAD, grants to A.C. and M.G. from the Wellcome Trust (072894/Z/03/Z) and Science Foundation Ireland (08INIB1916), and grants to D.L.L. from the Sidney R. Baer, Jr. Foundation and Essel Foundation. We thank the Genetic Association Information Network (GAIN), Molecular Genetics of Schizophrenia (MGS), and the Bipolar Genome Study (BiGS) for providing data for this study. We thank Roche NimbleGen and Oxford Gene Technology for their expert technical assistance. We thank Lilia M. Iakoucheva and Roser Corominas for helpful discussions.

PY - 2011/12/22

Y1 - 2011/12/22

N2 - While it is known that rare copy-number variants (CNVs) contribute to risk for some neuropsychiatric disorders, the role of CNVs in bipolar disorder is unclear. Here, we reasoned that a contribution of CNVs to mood disorders might be most evident for de novo mutations. We performed a genome-wide analysis of de novo CNVs in a cohort of 788 trios. Diagnoses of offspring included bipolar disorder (n = 185), schizophrenia (n = 177), and healthy controls (n = 426). Frequencies of de novo CNVs were significantly higher in bipolar disorder as compared with controls (OR = 4.8 [1.4,16.0], p = 0.009). De novo CNVs were particularly enriched among cases with an age at onset younger than 18 (OR = 6.3 [1.7,22.6], p = 0.006). We also confirmed a significant enrichment of de novo CNVs in schizophrenia (OR = 5.0 [1.5,16.8], p = 0.007). Our results suggest that rare spontaneous mutations are an important contributor to risk for bipolar disorder and other major neuropsychiatric diseases.

AB - While it is known that rare copy-number variants (CNVs) contribute to risk for some neuropsychiatric disorders, the role of CNVs in bipolar disorder is unclear. Here, we reasoned that a contribution of CNVs to mood disorders might be most evident for de novo mutations. We performed a genome-wide analysis of de novo CNVs in a cohort of 788 trios. Diagnoses of offspring included bipolar disorder (n = 185), schizophrenia (n = 177), and healthy controls (n = 426). Frequencies of de novo CNVs were significantly higher in bipolar disorder as compared with controls (OR = 4.8 [1.4,16.0], p = 0.009). De novo CNVs were particularly enriched among cases with an age at onset younger than 18 (OR = 6.3 [1.7,22.6], p = 0.006). We also confirmed a significant enrichment of de novo CNVs in schizophrenia (OR = 5.0 [1.5,16.8], p = 0.007). Our results suggest that rare spontaneous mutations are an important contributor to risk for bipolar disorder and other major neuropsychiatric diseases.

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JO - Neuron

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High frequencies of de novo cnvs in bipolar disorder and schizophrenia

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