Singleton deletions throughout the genome increase risk of bipolar disorder

D. Zhang; L. Cheng; Y. Qian; N. Alliey-Rodriguez; J. R. Kelsoe; T. Greenwood; C. Nievergelt; T. B. Barrett; R. McKinney; N. Schork; E. N. Smith; C. Bloss; J. Nurnberger; H. J. Edenberg; T. Foroud; W. Sheftner; W. B. Lawson; E. A. Nwulia; M. Hipolito; W. Coryell; J. Rice; W. Byerley; Francis Joseph McMahon; T. G. Schulze; W. Berrettini; J. B. Potash; Pamela Lynn Belmonte Mahon; P. P. Zandi; Melvin Mcinnis; S. Zöllner; D. Craig; S. Szelinger; D. Koller; S. L. Christian; C. Liu; E. S. Gershon

doi:10.1038/mp.2008.144

Singleton deletions throughout the genome increase risk of bipolar disorder

D. Zhang, L. Cheng, Y. Qian, N. Alliey-Rodriguez, J. R. Kelsoe, T. Greenwood, C. Nievergelt, T. B. Barrett, R. McKinney, N. Schork, E. N. Smith, C. Bloss, J. Nurnberger, H. J. Edenberg, T. Foroud, W. Sheftner, W. B. Lawson, E. A. Nwulia, M. Hipolito, W. CoryellJ. Rice, W. Byerley, Francis Joseph McMahon, T. G. Schulze, W. Berrettini, J. B. Potash, Pamela Lynn Belmonte Mahon, P. P. Zandi, Melvin Mcinnis, S. Zöllner, D. Craig, S. Szelinger, D. Koller, S. L. Christian, C. Liu, E. S. Gershon

School of Medicine

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114 Scopus citations

Abstract

An overall burden of rare structural genomic variants has not been reported in bipolar disorder (BD), although there have been reports of cases with microduplication and microdeletion. Here, we present a genome-wide copy number variant (CNV) survey of 1001 cases and 1034 controls using the Affymetrix single nucleotide polymorphism (SNP) 6.0 SNP and CNV platform. Singleton deletions (deletions that appear only once in the dataset) more than 100 kb in length are present in 16.2% of BD cases in contrast to 12.3% of controls (permutation P=0.007). This effect was more pronounced for age at onset of mania ≤18 years old. Our results strongly suggest that BD can result from the effects of multiple rare structural variants.

Original language	English (US)
Pages (from-to)	376-380
Number of pages	5
Journal	Molecular psychiatry
Volume	14
Issue number	4
DOIs	https://doi.org/10.1038/mp.2008.144
State	Published - Apr 2009

Keywords

Bipolar disorder
Copy number variation
Genetics
Singleton

ASJC Scopus subject areas

Molecular Biology
Cellular and Molecular Neuroscience
Psychiatry and Mental health

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10.1038/mp.2008.144

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Zhang, D., Cheng, L., Qian, Y., Alliey-Rodriguez, N., Kelsoe, J. R., Greenwood, T., Nievergelt, C., Barrett, T. B., McKinney, R., Schork, N., Smith, E. N., Bloss, C., Nurnberger, J., Edenberg, H. J., Foroud, T., Sheftner, W., Lawson, W. B., Nwulia, E. A., Hipolito, M., ... Gershon, E. S. (2009). Singleton deletions throughout the genome increase risk of bipolar disorder. Molecular psychiatry, 14(4), 376-380. https://doi.org/10.1038/mp.2008.144

Zhang, D, Cheng, L, Qian, Y, Alliey-Rodriguez, N, Kelsoe, JR, Greenwood, T, Nievergelt, C, Barrett, TB, McKinney, R, Schork, N, Smith, EN, Bloss, C, Nurnberger, J, Edenberg, HJ, Foroud, T, Sheftner, W, Lawson, WB, Nwulia, EA, Hipolito, M, Coryell, W, Rice, J, Byerley, W, McMahon, FJ, Schulze, TG, Berrettini, W, Potash, JB, Mahon, PLB, Zandi, PP, Mcinnis, M, Zöllner, S, Craig, D, Szelinger, S, Koller, D, Christian, SL, Liu, C & Gershon, ES 2009, 'Singleton deletions throughout the genome increase risk of bipolar disorder', Molecular psychiatry, vol. 14, no. 4, pp. 376-380. https://doi.org/10.1038/mp.2008.144

@article{99c087075adf43ca8835e3fa6bd6060e,

title = "Singleton deletions throughout the genome increase risk of bipolar disorder",

abstract = "An overall burden of rare structural genomic variants has not been reported in bipolar disorder (BD), although there have been reports of cases with microduplication and microdeletion. Here, we present a genome-wide copy number variant (CNV) survey of 1001 cases and 1034 controls using the Affymetrix single nucleotide polymorphism (SNP) 6.0 SNP and CNV platform. Singleton deletions (deletions that appear only once in the dataset) more than 100 kb in length are present in 16.2% of BD cases in contrast to 12.3% of controls (permutation P=0.007). This effect was more pronounced for age at onset of mania ≤18 years old. Our results strongly suggest that BD can result from the effects of multiple rare structural variants.",

keywords = "Bipolar disorder, Copy number variation, Genetics, Singleton",

author = "D. Zhang and L. Cheng and Y. Qian and N. Alliey-Rodriguez and Kelsoe, {J. R.} and T. Greenwood and C. Nievergelt and Barrett, {T. B.} and R. McKinney and N. Schork and Smith, {E. N.} and C. Bloss and J. Nurnberger and Edenberg, {H. J.} and T. Foroud and W. Sheftner and Lawson, {W. B.} and Nwulia, {E. A.} and M. Hipolito and W. Coryell and J. Rice and W. Byerley and McMahon, {Francis Joseph} and Schulze, {T. G.} and W. Berrettini and Potash, {J. B.} and Mahon, {Pamela Lynn Belmonte} and Zandi, {P. P.} and Melvin Mcinnis and S. Z{\"o}llner and D. Craig and S. Szelinger and D. Koller and Christian, {S. L.} and C. Liu and Gershon, {E. S.}",

note = "Funding Information: This paper was prepared as part of the bipolar collaboration of the GAIN, and was submitted before the end of the publication embargo for non-GAIN scientists. We acknowledge Dr Dan Nicolae (University of Chicago) for extensive statistical discussion and advice, Mr Xiaotong Zhang (University of Chicago) for his excellent software support and Ms Kay Grennan (University of Chicago) for her technical assistance. This work was supported by grants from 1R01MH081804-01 (NIMH), NARSAD, the Eklund family and the Geraldi Norton Foundation.",

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doi = "10.1038/mp.2008.144",

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T1 - Singleton deletions throughout the genome increase risk of bipolar disorder

AU - Zhang, D.

AU - Cheng, L.

AU - Qian, Y.

AU - Alliey-Rodriguez, N.

AU - Kelsoe, J. R.

AU - Greenwood, T.

AU - Nievergelt, C.

AU - Barrett, T. B.

AU - McKinney, R.

AU - Schork, N.

AU - Smith, E. N.

AU - Bloss, C.

AU - Nurnberger, J.

AU - Edenberg, H. J.

AU - Foroud, T.

AU - Sheftner, W.

AU - Lawson, W. B.

AU - Nwulia, E. A.

AU - Hipolito, M.

AU - Coryell, W.

AU - Rice, J.

AU - Byerley, W.

AU - McMahon, Francis Joseph

AU - Schulze, T. G.

AU - Berrettini, W.

AU - Potash, J. B.

AU - Mahon, Pamela Lynn Belmonte

AU - Zandi, P. P.

AU - Mcinnis, Melvin

AU - Zöllner, S.

AU - Craig, D.

AU - Szelinger, S.

AU - Koller, D.

AU - Christian, S. L.

AU - Liu, C.

AU - Gershon, E. S.

N1 - Funding Information: This paper was prepared as part of the bipolar collaboration of the GAIN, and was submitted before the end of the publication embargo for non-GAIN scientists. We acknowledge Dr Dan Nicolae (University of Chicago) for extensive statistical discussion and advice, Mr Xiaotong Zhang (University of Chicago) for his excellent software support and Ms Kay Grennan (University of Chicago) for her technical assistance. This work was supported by grants from 1R01MH081804-01 (NIMH), NARSAD, the Eklund family and the Geraldi Norton Foundation.

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N2 - An overall burden of rare structural genomic variants has not been reported in bipolar disorder (BD), although there have been reports of cases with microduplication and microdeletion. Here, we present a genome-wide copy number variant (CNV) survey of 1001 cases and 1034 controls using the Affymetrix single nucleotide polymorphism (SNP) 6.0 SNP and CNV platform. Singleton deletions (deletions that appear only once in the dataset) more than 100 kb in length are present in 16.2% of BD cases in contrast to 12.3% of controls (permutation P=0.007). This effect was more pronounced for age at onset of mania ≤18 years old. Our results strongly suggest that BD can result from the effects of multiple rare structural variants.

AB - An overall burden of rare structural genomic variants has not been reported in bipolar disorder (BD), although there have been reports of cases with microduplication and microdeletion. Here, we present a genome-wide copy number variant (CNV) survey of 1001 cases and 1034 controls using the Affymetrix single nucleotide polymorphism (SNP) 6.0 SNP and CNV platform. Singleton deletions (deletions that appear only once in the dataset) more than 100 kb in length are present in 16.2% of BD cases in contrast to 12.3% of controls (permutation P=0.007). This effect was more pronounced for age at onset of mania ≤18 years old. Our results strongly suggest that BD can result from the effects of multiple rare structural variants.

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JF - Molecular psychiatry

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Singleton deletions throughout the genome increase risk of bipolar disorder

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