Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder

Josephine Elia; Joseph T Glessner; Kai Wang; Nagahide Takahashi; Corina J Shtir; Dexter Hadley; Patrick M A Sleiman; Haitao Zhang; Cecilia E Kim; Reid Robison; Gholson J Lyon; James H Flory; Jonathan P Bradfield; Marcin Imielinski; Cuiping Hou; Edward C Frackelton; Rosetta M Chiavacci; Takeshi Sakurai; Cara Rabin; Frank A Middleton; Kelly A Thomas; Maria Garris; Frank Mentch; Christine M Freitag; Hans-Christoph Steinhausen; Alexandre A Todorov; Andreas Reif; Aribert Rothenberger; Barbara Franke; Eric O Mick; Herbert Roeyers; Jan Buitelaar; Klaus-Peter Lesch; Tobias Banaschewski; Richard P Ebstein; Fernando Mulas; Robert D Oades; Joseph Sergeant; Edmund Sonuga-Barke; Tobias J Renner; Marcel Romanos; Jasmin Romanos; Andreas Warnke; Susanne Walitza; Jobst Meyer; Haukur Pálmason; Christiane Seitz; Sandra K Loo; Susan L Smalley; Joseph Biederman; Lindsey Kent; Philip Asherson; Richard J L Anney; J William Gaynor; Philip Shaw; Marcella Devoto; Peter S White; Struan F A Grant; Joseph D Buxbaum; Judith L Rapoport; Nigel M Williams; Stanley F Nelson; Stephen V Faraone; Hakon Hakonarson

doi:10.1038/ng.1013

Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder

Josephine Elia, Joseph T Glessner, Kai Wang, Nagahide Takahashi, Corina J Shtir, Dexter Hadley, Patrick M A Sleiman, Haitao Zhang, Cecilia E Kim, Reid Robison, Gholson J Lyon, James H Flory, Jonathan P Bradfield, Marcin Imielinski, Cuiping Hou, Edward C Frackelton, Rosetta M Chiavacci, Takeshi Sakurai, Cara Rabin, Frank A MiddletonKelly A Thomas, Maria Garris, Frank Mentch, Christine M Freitag, Hans-Christoph Steinhausen, Alexandre A Todorov, Andreas Reif, Aribert Rothenberger, Barbara Franke, Eric O Mick, Herbert Roeyers, Jan Buitelaar, Klaus-Peter Lesch, Tobias Banaschewski, Richard P Ebstein, Fernando Mulas, Robert D Oades, Joseph Sergeant, Edmund Sonuga-Barke, Tobias J Renner, Marcel Romanos, Jasmin Romanos, Andreas Warnke, Susanne Walitza, Jobst Meyer, Haukur Pálmason, Christiane Seitz, Sandra K Loo, Susan L Smalley, Joseph Biederman, Lindsey Kent, Philip Asherson, Richard J L Anney, J William Gaynor, Philip Shaw, Marcella Devoto, Peter S White, Struan F A Grant, Joseph D Buxbaum, Judith L Rapoport, Nigel M Williams, Stanley F Nelson, Stephen V Faraone, Hakon Hakonarson

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Abstract

Attention deficit hyperactivity disorder (ADHD) is a common, heritable neuropsychiatric disorder of unknown etiology. We performed a whole-genome copy number variation (CNV) study on 1,013 cases with ADHD and 4,105 healthy children of European ancestry using 550,000 SNPs. We evaluated statistically significant findings in multiple independent cohorts, with a total of 2,493 cases with ADHD and 9,222 controls of European ancestry, using matched platforms. CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts (P = 2.1 × 10(-9)). We saw GRM5 (encoding glutamate receptor, metabotropic 5) deletions in ten cases and one control (P = 1.36 × 10(-6)). We saw GRM7 deletions in six cases, and we saw GRM8 deletions in eight cases and no controls. GRM1 was duplicated in eight cases. We experimentally validated the observed variants using quantitative RT-PCR. A gene network analysis showed that genes interacting with the genes in the GRM family are enriched for CNVs in ∼10% of the cases (P = 4.38 × 10(-10)) after correction for occurrence in the controls. We identified rare recurrent CNVs affecting glutamatergic neurotransmission genes that were overrepresented in multiple ADHD cohorts.

Original language	English
Journal	Nature Genetics
Volume	44
Pages (from-to)	78-84
Number of pages	7
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.1013
Publication status	Published - 2012
Externally published	Yes

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Elia, J., Glessner, J. T., Wang, K., Takahashi, N., Shtir, C. J., Hadley, D., Sleiman, P. M. A., Zhang, H., Kim, C. E., Robison, R., Lyon, G. J., Flory, J. H., Bradfield, J. P., Imielinski, M., Hou, C., Frackelton, E. C., Chiavacci, R. M., Sakurai, T., Rabin, C., ... Hakonarson, H. (2012). Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder. Nature Genetics, 44, 78-84. https://doi.org/10.1038/ng.1013

@article{86130434ffde433d927751511d26dd49,

title = "Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder",

abstract = "Attention deficit hyperactivity disorder (ADHD) is a common, heritable neuropsychiatric disorder of unknown etiology. We performed a whole-genome copy number variation (CNV) study on 1,013 cases with ADHD and 4,105 healthy children of European ancestry using 550,000 SNPs. We evaluated statistically significant findings in multiple independent cohorts, with a total of 2,493 cases with ADHD and 9,222 controls of European ancestry, using matched platforms. CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts (P = 2.1 × 10(-9)). We saw GRM5 (encoding glutamate receptor, metabotropic 5) deletions in ten cases and one control (P = 1.36 × 10(-6)). We saw GRM7 deletions in six cases, and we saw GRM8 deletions in eight cases and no controls. GRM1 was duplicated in eight cases. We experimentally validated the observed variants using quantitative RT-PCR. A gene network analysis showed that genes interacting with the genes in the GRM family are enriched for CNVs in ∼10% of the cases (P = 4.38 × 10(-10)) after correction for occurrence in the controls. We identified rare recurrent CNVs affecting glutamatergic neurotransmission genes that were overrepresented in multiple ADHD cohorts.",

author = "Josephine Elia and Glessner, {Joseph T} and Kai Wang and Nagahide Takahashi and Shtir, {Corina J} and Dexter Hadley and Sleiman, {Patrick M A} and Haitao Zhang and Kim, {Cecilia E} and Reid Robison and Lyon, {Gholson J} and Flory, {James H} and Bradfield, {Jonathan P} and Marcin Imielinski and Cuiping Hou and Frackelton, {Edward C} and Chiavacci, {Rosetta M} and Takeshi Sakurai and Cara Rabin and Middleton, {Frank A} and Thomas, {Kelly A} and Maria Garris and Frank Mentch and Freitag, {Christine M} and Hans-Christoph Steinhausen and Todorov, {Alexandre A} and Andreas Reif and Aribert Rothenberger and Barbara Franke and Mick, {Eric O} and Herbert Roeyers and Jan Buitelaar and Klaus-Peter Lesch and Tobias Banaschewski and Ebstein, {Richard P} and Fernando Mulas and Oades, {Robert D} and Joseph Sergeant and Edmund Sonuga-Barke and Renner, {Tobias J} and Marcel Romanos and Jasmin Romanos and Andreas Warnke and Susanne Walitza and Jobst Meyer and Haukur P{\'a}lmason and Christiane Seitz and Loo, {Sandra K} and Smalley, {Susan L} and Joseph Biederman and Lindsey Kent and Philip Asherson and Anney, {Richard J L} and Gaynor, {J William} and Philip Shaw and Marcella Devoto and White, {Peter S} and Grant, {Struan F A} and Buxbaum, {Joseph D} and Rapoport, {Judith L} and Williams, {Nigel M} and Nelson, {Stanley F} and Faraone, {Stephen V} and Hakon Hakonarson",

year = "2012",

doi = "10.1038/ng.1013",

language = "English",

volume = "44",

pages = "78--84",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

}

Elia, J, Glessner, JT, Wang, K, Takahashi, N, Shtir, CJ, Hadley, D, Sleiman, PMA, Zhang, H, Kim, CE, Robison, R, Lyon, GJ, Flory, JH, Bradfield, JP, Imielinski, M, Hou, C, Frackelton, EC, Chiavacci, RM, Sakurai, T, Rabin, C, Middleton, FA, Thomas, KA, Garris, M, Mentch, F, Freitag, CM, Steinhausen, H-C, Todorov, AA, Reif, A, Rothenberger, A, Franke, B, Mick, EO, Roeyers, H, Buitelaar, J, Lesch, K-P, Banaschewski, T, Ebstein, RP, Mulas, F, Oades, RD, Sergeant, J, Sonuga-Barke, E, Renner, TJ, Romanos, M, Romanos, J, Warnke, A, Walitza, S, Meyer, J, Pálmason, H, Seitz, C, Loo, SK, Smalley, SL, Biederman, J, Kent, L, Asherson, P, Anney, RJL, Gaynor, JW, Shaw, P, Devoto, M, White, PS, Grant, SFA, Buxbaum, JD, Rapoport, JL, Williams, NM, Nelson, SF, Faraone, SV & Hakonarson, H 2012, 'Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder', Nature Genetics, vol. 44, pp. 78-84. https://doi.org/10.1038/ng.1013

TY - JOUR

T1 - Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder

AU - Elia, Josephine

AU - Glessner, Joseph T

AU - Wang, Kai

AU - Takahashi, Nagahide

AU - Shtir, Corina J

AU - Hadley, Dexter

AU - Sleiman, Patrick M A

AU - Zhang, Haitao

AU - Kim, Cecilia E

AU - Robison, Reid

AU - Lyon, Gholson J

AU - Flory, James H

AU - Bradfield, Jonathan P

AU - Imielinski, Marcin

AU - Hou, Cuiping

AU - Frackelton, Edward C

AU - Chiavacci, Rosetta M

AU - Sakurai, Takeshi

AU - Rabin, Cara

AU - Middleton, Frank A

AU - Thomas, Kelly A

AU - Garris, Maria

AU - Mentch, Frank

AU - Freitag, Christine M

AU - Steinhausen, Hans-Christoph

AU - Todorov, Alexandre A

AU - Reif, Andreas

AU - Rothenberger, Aribert

AU - Franke, Barbara

AU - Mick, Eric O

AU - Roeyers, Herbert

AU - Buitelaar, Jan

AU - Lesch, Klaus-Peter

AU - Banaschewski, Tobias

AU - Ebstein, Richard P

AU - Mulas, Fernando

AU - Oades, Robert D

AU - Sergeant, Joseph

AU - Sonuga-Barke, Edmund

AU - Renner, Tobias J

AU - Romanos, Marcel

AU - Romanos, Jasmin

AU - Warnke, Andreas

AU - Walitza, Susanne

AU - Meyer, Jobst

AU - Pálmason, Haukur

AU - Seitz, Christiane

AU - Loo, Sandra K

AU - Smalley, Susan L

AU - Biederman, Joseph

AU - Kent, Lindsey

AU - Asherson, Philip

AU - Anney, Richard J L

AU - Gaynor, J William

AU - Shaw, Philip

AU - Devoto, Marcella

AU - White, Peter S

AU - Grant, Struan F A

AU - Buxbaum, Joseph D

AU - Rapoport, Judith L

AU - Williams, Nigel M

AU - Nelson, Stanley F

AU - Faraone, Stephen V

AU - Hakonarson, Hakon

PY - 2012

Y1 - 2012

N2 - Attention deficit hyperactivity disorder (ADHD) is a common, heritable neuropsychiatric disorder of unknown etiology. We performed a whole-genome copy number variation (CNV) study on 1,013 cases with ADHD and 4,105 healthy children of European ancestry using 550,000 SNPs. We evaluated statistically significant findings in multiple independent cohorts, with a total of 2,493 cases with ADHD and 9,222 controls of European ancestry, using matched platforms. CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts (P = 2.1 × 10(-9)). We saw GRM5 (encoding glutamate receptor, metabotropic 5) deletions in ten cases and one control (P = 1.36 × 10(-6)). We saw GRM7 deletions in six cases, and we saw GRM8 deletions in eight cases and no controls. GRM1 was duplicated in eight cases. We experimentally validated the observed variants using quantitative RT-PCR. A gene network analysis showed that genes interacting with the genes in the GRM family are enriched for CNVs in ∼10% of the cases (P = 4.38 × 10(-10)) after correction for occurrence in the controls. We identified rare recurrent CNVs affecting glutamatergic neurotransmission genes that were overrepresented in multiple ADHD cohorts.

AB - Attention deficit hyperactivity disorder (ADHD) is a common, heritable neuropsychiatric disorder of unknown etiology. We performed a whole-genome copy number variation (CNV) study on 1,013 cases with ADHD and 4,105 healthy children of European ancestry using 550,000 SNPs. We evaluated statistically significant findings in multiple independent cohorts, with a total of 2,493 cases with ADHD and 9,222 controls of European ancestry, using matched platforms. CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts (P = 2.1 × 10(-9)). We saw GRM5 (encoding glutamate receptor, metabotropic 5) deletions in ten cases and one control (P = 1.36 × 10(-6)). We saw GRM7 deletions in six cases, and we saw GRM8 deletions in eight cases and no controls. GRM1 was duplicated in eight cases. We experimentally validated the observed variants using quantitative RT-PCR. A gene network analysis showed that genes interacting with the genes in the GRM family are enriched for CNVs in ∼10% of the cases (P = 4.38 × 10(-10)) after correction for occurrence in the controls. We identified rare recurrent CNVs affecting glutamatergic neurotransmission genes that were overrepresented in multiple ADHD cohorts.

U2 - 10.1038/ng.1013

DO - 10.1038/ng.1013

M3 - Journal article

SN - 1061-4036

VL - 44

SP - 78

EP - 84

JO - Nature Genetics

JF - Nature Genetics

ER -

Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder

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