Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder

I. Jarick; A. L. Volckmar; C. Pütter; S. Pechlivanis; T. T. Nguyen; M. R. Dauvermann; S. Beck; Ö Albayrak; S. Scherag; S. Gilsbach; S. Cichon; P. Hoffmann; F. Degenhardt; M. M. Nöthen; S. Schreiber; H. E. Wichmann; K. H. Jöckel; J. Heinrich; C. M.T. Tiesler; S. V. Faraone; S. Walitza; J. Sinzig; C. Freitag; J. Meyer; B. Herpertz-Dahlmann; G. Lehmkuhl; T. J. Renner; A. Warnke; M. Romanos; K. P. Lesch; A. Reif; B. G. Schimmelmann; J. Hebebrand; A. Scherag; A. Hinney

doi:10.1038/mp.2012.161

Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder

I. Jarick, A. L. Volckmar, C. Pütter, S. Pechlivanis, T. T. Nguyen, M. R. Dauvermann, S. Beck, Ö Albayrak, S. Scherag, S. Gilsbach, S. Cichon, P. Hoffmann, F. Degenhardt, M. M. Nöthen, S. Schreiber, H. E. Wichmann, K. H. Jöckel, J. Heinrich, C. M.T. Tiesler, S. V. FaraoneS. Walitza, J. Sinzig, C. Freitag, J. Meyer, B. Herpertz-Dahlmann, G. Lehmkuhl, T. J. Renner, A. Warnke, M. Romanos, K. P. Lesch, A. Reif, B. G. Schimmelmann, J. Hebebrand, A. Scherag, A. Hinney^*

^*Corresponding author for this work

Psychology

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Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder. Genetic loci have not yet been identified by genome-wide association studies. Rare copy number variations (CNVs), such as chromosomal deletions or duplications, have been implicated in ADHD and other neurodevelopmental disorders. To identify rare (frequency ≤1%) CNVs that increase the risk of ADHD, we performed a whole-genome CNV analysis based on 489 young ADHD patients and 1285 adult population-based controls and identified one significantly associated CNV region. In tests for a global burden of large (>500 kb) rare CNVs, we observed a nonsignificant (P=0.271) 1.126-fold enriched rate of subjects carrying at least one such CNV in the group of ADHD cases. Locus-specific tests of association were used to assess if there were more rare CNVs in cases compared with controls. Detected CNVs, which were significantly enriched in the ADHD group, were validated by quantitative (q)PCR. Findings were replicated in an independent sample of 386 young patients with ADHD and 781 young population-based healthy controls. We identified rare CNVs within the parkinson protein 2 gene (PARK2) with a significantly higher prevalence in ADHD patients than in controls (P=2.8 × 10 -4 after empirical correction for genome-wide testing). In total, the PARK2 locus (chr 6: 162 659 756-162 767 019) harboured three deletions and nine duplications in the ADHD patients and two deletions and two duplications in the controls. By qPCR analysis, we validated 11 of the 12 CNVs in ADHD patients (P=1.2 × 10 -3 after empirical correction for genome-wide testing). In the replication sample, CNVs at the PARK2 locus were found in four additional ADHD patients and one additional control (P=4.3 × 10 -2). Our results suggest that copy number variants at the PARK2 locus contribute to the genetic susceptibility of ADHD. Mutations and CNVs in PARK2 are known to be associated with Parkinson disease.

Original language	English
Pages (from-to)	115-121
Number of pages	7
Journal	Molecular Psychiatry
Volume	19
Issue number	1
Early online date	20 Nov 2012
DOIs	https://doi.org/10.1038/mp.2012.161
Publication status	Published - Jan 2014

Bibliographical note

Funding Information:
KH Jöckel and A Scherag are responsible statisticians in several clinical trials and in this position they receive support money from various pharmaceutical companies, among them MEDICE Arzneimittel Pütter GmbH and KG. In the past year, Dr Faraone received consulting income and research support from Shire and Alcobra and research support from the National Institutes of Health. In previous years, he received consulting fees or was on Advisory Boards or participated in continuing medical education programs sponsored by: Shire, McNeil, Janssen, Novartis, Pfizer and Eli Lilly. Dr Faraone receives royalties from books published by Guilford Press: Straight Talk about Your Child’s Mental Health and Oxford University Press: Schizophrenia: The Facts. S Walitza recieves industry funding research from Vifor Pharma, Switzerland and was on the speakers’ bureau of Eli Lilly, Jannssen-Cilag and Astra Zeneca. SW receives research funding from DFG, SNF, BMFFSJ and FP7. CM Freitag was on the speakers’ bureau of Eli Lilly and Novartis, and was an expert consultant for Desitin. Dr Herpertz-Dahlmann receives industry research funding from Vifor Pharma, Schweiz. In previous years, she was on the Advisory Board of Eli Lilly and received sponsoring by AstraZeneca, Eli Lilly, Novartis and Janssen Cilag. She received research support from the Federal Ministry of Education and Research and the German Research Society (Deutsche Forschungsgemeinschaft). G Lehmkuhl receives industry research funding from Lilly Deutschland GmbH, Germany. A Warnke recieves industry research funding from Shire and in previous years from Eli Lilly. B Schimmelmann is a member of the speakers’ bureau of Eli Lilly, BMS, Janssen and Novartis. The other authors declare no conflict of interest.

We thank the children and their families for their participation and support to this study. We are also grateful to all probands from the community-based cohorts of PopGen, KORA, those from the Heinz Nixdorf RECALL (HNR) study, and the GINIplus and LISAplus cohorts. We thank the Heinz Nixdorf Foundation, Germany, for the generous support of the HNR study. We thank the German Research Association (DFG) who funded the GWAS analyses and confirmatory studies (He1446/9-1 to J Hebebrand, KP Lesch, A Hinney and T Renner, KFO 125, SFB 581, SFB TRR 58/A5, GRK 1253 to KP Lesch; ME 1923/5-1, ME 1923/5-3 to J Meyer and CM Freitag, GRK 1389 to J Meyer, SCHA 542/10-3 to H Schäfer) and the Bundesministerium für Bildung und Forschung (BMBF 01GV0605 to KP Lesch). We thank the START-Program EK 119/05 of the Medical Faculty, RWTH Aachen, Germany. The European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 245009 supported this study.

Keywords

ADHD
children
CNVs
GWAS
PARK2

ASJC Scopus subject areas

Molecular Biology
Cellular and Molecular Neuroscience
Psychiatry and Mental health

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cite this

Jarick, I., Volckmar, A. L., Pütter, C., Pechlivanis, S., Nguyen, T. T., Dauvermann, M. R., Beck, S., Albayrak, Ö., Scherag, S., Gilsbach, S., Cichon, S., Hoffmann, P., Degenhardt, F., Nöthen, M. M., Schreiber, S., Wichmann, H. E., Jöckel, K. H., Heinrich, J., Tiesler, C. M. T., ... Hinney, A. (2014). Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder. Molecular Psychiatry, 19(1), 115-121. https://doi.org/10.1038/mp.2012.161

@article{709df89fc5944263b1390c1faf51ca69,

title = "Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder",

abstract = "Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder. Genetic loci have not yet been identified by genome-wide association studies. Rare copy number variations (CNVs), such as chromosomal deletions or duplications, have been implicated in ADHD and other neurodevelopmental disorders. To identify rare (frequency ≤1%) CNVs that increase the risk of ADHD, we performed a whole-genome CNV analysis based on 489 young ADHD patients and 1285 adult population-based controls and identified one significantly associated CNV region. In tests for a global burden of large (>500 kb) rare CNVs, we observed a nonsignificant (P=0.271) 1.126-fold enriched rate of subjects carrying at least one such CNV in the group of ADHD cases. Locus-specific tests of association were used to assess if there were more rare CNVs in cases compared with controls. Detected CNVs, which were significantly enriched in the ADHD group, were validated by quantitative (q)PCR. Findings were replicated in an independent sample of 386 young patients with ADHD and 781 young population-based healthy controls. We identified rare CNVs within the parkinson protein 2 gene (PARK2) with a significantly higher prevalence in ADHD patients than in controls (P=2.8 × 10 -4 after empirical correction for genome-wide testing). In total, the PARK2 locus (chr 6: 162 659 756-162 767 019) harboured three deletions and nine duplications in the ADHD patients and two deletions and two duplications in the controls. By qPCR analysis, we validated 11 of the 12 CNVs in ADHD patients (P=1.2 × 10 -3 after empirical correction for genome-wide testing). In the replication sample, CNVs at the PARK2 locus were found in four additional ADHD patients and one additional control (P=4.3 × 10 -2). Our results suggest that copy number variants at the PARK2 locus contribute to the genetic susceptibility of ADHD. Mutations and CNVs in PARK2 are known to be associated with Parkinson disease.",

keywords = "ADHD, children, CNVs, GWAS, PARK2",

author = "I. Jarick and Volckmar, {A. L.} and C. P{\"u}tter and S. Pechlivanis and Nguyen, {T. T.} and Dauvermann, {M. R.} and S. Beck and {\"O} Albayrak and S. Scherag and S. Gilsbach and S. Cichon and P. Hoffmann and F. Degenhardt and N{\"o}then, {M. M.} and S. Schreiber and Wichmann, {H. E.} and J{\"o}ckel, {K. H.} and J. Heinrich and Tiesler, {C. M.T.} and Faraone, {S. V.} and S. Walitza and J. Sinzig and C. Freitag and J. Meyer and B. Herpertz-Dahlmann and G. Lehmkuhl and Renner, {T. J.} and A. Warnke and M. Romanos and Lesch, {K. P.} and A. Reif and Schimmelmann, {B. G.} and J. Hebebrand and A. Scherag and A. Hinney",

note = "Funding Information: KH J{\"o}ckel and A Scherag are responsible statisticians in several clinical trials and in this position they receive support money from various pharmaceutical companies, among them MEDICE Arzneimittel P{\"u}tter GmbH and KG. In the past year, Dr Faraone received consulting income and research support from Shire and Alcobra and research support from the National Institutes of Health. In previous years, he received consulting fees or was on Advisory Boards or participated in continuing medical education programs sponsored by: Shire, McNeil, Janssen, Novartis, Pfizer and Eli Lilly. Dr Faraone receives royalties from books published by Guilford Press: Straight Talk about Your Child{\textquoteright}s Mental Health and Oxford University Press: Schizophrenia: The Facts. S Walitza recieves industry funding research from Vifor Pharma, Switzerland and was on the speakers{\textquoteright} bureau of Eli Lilly, Jannssen-Cilag and Astra Zeneca. SW receives research funding from DFG, SNF, BMFFSJ and FP7. CM Freitag was on the speakers{\textquoteright} bureau of Eli Lilly and Novartis, and was an expert consultant for Desitin. Dr Herpertz-Dahlmann receives industry research funding from Vifor Pharma, Schweiz. In previous years, she was on the Advisory Board of Eli Lilly and received sponsoring by AstraZeneca, Eli Lilly, Novartis and Janssen Cilag. She received research support from the Federal Ministry of Education and Research and the German Research Society (Deutsche Forschungsgemeinschaft). G Lehmkuhl receives industry research funding from Lilly Deutschland GmbH, Germany. A Warnke recieves industry research funding from Shire and in previous years from Eli Lilly. B Schimmelmann is a member of the speakers{\textquoteright} bureau of Eli Lilly, BMS, Janssen and Novartis. The other authors declare no conflict of interest. We thank the children and their families for their participation and support to this study. We are also grateful to all probands from the community-based cohorts of PopGen, KORA, those from the Heinz Nixdorf RECALL (HNR) study, and the GINIplus and LISAplus cohorts. We thank the Heinz Nixdorf Foundation, Germany, for the generous support of the HNR study. We thank the German Research Association (DFG) who funded the GWAS analyses and confirmatory studies (He1446/9-1 to J Hebebrand, KP Lesch, A Hinney and T Renner, KFO 125, SFB 581, SFB TRR 58/A5, GRK 1253 to KP Lesch; ME 1923/5-1, ME 1923/5-3 to J Meyer and CM Freitag, GRK 1389 to J Meyer, SCHA 542/10-3 to H Sch{\"a}fer) and the Bundesministerium f{\"u}r Bildung und Forschung (BMBF 01GV0605 to KP Lesch). We thank the START-Program EK 119/05 of the Medical Faculty, RWTH Aachen, Germany. The European Community{\textquoteright}s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 245009 supported this study.",

year = "2014",

month = jan,

doi = "10.1038/mp.2012.161",

language = "English",

volume = "19",

pages = "115--121",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Nature Publishing Group",

number = "1",

}

Jarick, I, Volckmar, AL, Pütter, C, Pechlivanis, S, Nguyen, TT, Dauvermann, MR, Beck, S, Albayrak, Ö, Scherag, S, Gilsbach, S, Cichon, S, Hoffmann, P, Degenhardt, F, Nöthen, MM, Schreiber, S, Wichmann, HE, Jöckel, KH, Heinrich, J, Tiesler, CMT, Faraone, SV, Walitza, S, Sinzig, J, Freitag, C, Meyer, J, Herpertz-Dahlmann, B, Lehmkuhl, G, Renner, TJ, Warnke, A, Romanos, M, Lesch, KP, Reif, A, Schimmelmann, BG, Hebebrand, J, Scherag, A & Hinney, A 2014, 'Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder', Molecular Psychiatry, vol. 19, no. 1, pp. 115-121. https://doi.org/10.1038/mp.2012.161

TY - JOUR

T1 - Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder

AU - Jarick, I.

AU - Volckmar, A. L.

AU - Pütter, C.

AU - Pechlivanis, S.

AU - Nguyen, T. T.

AU - Dauvermann, M. R.

AU - Beck, S.

AU - Albayrak, Ö

AU - Scherag, S.

AU - Gilsbach, S.

AU - Cichon, S.

AU - Hoffmann, P.

AU - Degenhardt, F.

AU - Nöthen, M. M.

AU - Schreiber, S.

AU - Wichmann, H. E.

AU - Jöckel, K. H.

AU - Heinrich, J.

AU - Tiesler, C. M.T.

AU - Faraone, S. V.

AU - Walitza, S.

AU - Sinzig, J.

AU - Freitag, C.

AU - Meyer, J.

AU - Herpertz-Dahlmann, B.

AU - Lehmkuhl, G.

AU - Renner, T. J.

AU - Warnke, A.

AU - Romanos, M.

AU - Lesch, K. P.

AU - Reif, A.

AU - Schimmelmann, B. G.

AU - Hebebrand, J.

AU - Scherag, A.

AU - Hinney, A.

N1 - Funding Information: KH Jöckel and A Scherag are responsible statisticians in several clinical trials and in this position they receive support money from various pharmaceutical companies, among them MEDICE Arzneimittel Pütter GmbH and KG. In the past year, Dr Faraone received consulting income and research support from Shire and Alcobra and research support from the National Institutes of Health. In previous years, he received consulting fees or was on Advisory Boards or participated in continuing medical education programs sponsored by: Shire, McNeil, Janssen, Novartis, Pfizer and Eli Lilly. Dr Faraone receives royalties from books published by Guilford Press: Straight Talk about Your Child’s Mental Health and Oxford University Press: Schizophrenia: The Facts. S Walitza recieves industry funding research from Vifor Pharma, Switzerland and was on the speakers’ bureau of Eli Lilly, Jannssen-Cilag and Astra Zeneca. SW receives research funding from DFG, SNF, BMFFSJ and FP7. CM Freitag was on the speakers’ bureau of Eli Lilly and Novartis, and was an expert consultant for Desitin. Dr Herpertz-Dahlmann receives industry research funding from Vifor Pharma, Schweiz. In previous years, she was on the Advisory Board of Eli Lilly and received sponsoring by AstraZeneca, Eli Lilly, Novartis and Janssen Cilag. She received research support from the Federal Ministry of Education and Research and the German Research Society (Deutsche Forschungsgemeinschaft). G Lehmkuhl receives industry research funding from Lilly Deutschland GmbH, Germany. A Warnke recieves industry research funding from Shire and in previous years from Eli Lilly. B Schimmelmann is a member of the speakers’ bureau of Eli Lilly, BMS, Janssen and Novartis. The other authors declare no conflict of interest. We thank the children and their families for their participation and support to this study. We are also grateful to all probands from the community-based cohorts of PopGen, KORA, those from the Heinz Nixdorf RECALL (HNR) study, and the GINIplus and LISAplus cohorts. We thank the Heinz Nixdorf Foundation, Germany, for the generous support of the HNR study. We thank the German Research Association (DFG) who funded the GWAS analyses and confirmatory studies (He1446/9-1 to J Hebebrand, KP Lesch, A Hinney and T Renner, KFO 125, SFB 581, SFB TRR 58/A5, GRK 1253 to KP Lesch; ME 1923/5-1, ME 1923/5-3 to J Meyer and CM Freitag, GRK 1389 to J Meyer, SCHA 542/10-3 to H Schäfer) and the Bundesministerium für Bildung und Forschung (BMBF 01GV0605 to KP Lesch). We thank the START-Program EK 119/05 of the Medical Faculty, RWTH Aachen, Germany. The European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 245009 supported this study.

PY - 2014/1

Y1 - 2014/1

N2 - Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder. Genetic loci have not yet been identified by genome-wide association studies. Rare copy number variations (CNVs), such as chromosomal deletions or duplications, have been implicated in ADHD and other neurodevelopmental disorders. To identify rare (frequency ≤1%) CNVs that increase the risk of ADHD, we performed a whole-genome CNV analysis based on 489 young ADHD patients and 1285 adult population-based controls and identified one significantly associated CNV region. In tests for a global burden of large (>500 kb) rare CNVs, we observed a nonsignificant (P=0.271) 1.126-fold enriched rate of subjects carrying at least one such CNV in the group of ADHD cases. Locus-specific tests of association were used to assess if there were more rare CNVs in cases compared with controls. Detected CNVs, which were significantly enriched in the ADHD group, were validated by quantitative (q)PCR. Findings were replicated in an independent sample of 386 young patients with ADHD and 781 young population-based healthy controls. We identified rare CNVs within the parkinson protein 2 gene (PARK2) with a significantly higher prevalence in ADHD patients than in controls (P=2.8 × 10 -4 after empirical correction for genome-wide testing). In total, the PARK2 locus (chr 6: 162 659 756-162 767 019) harboured three deletions and nine duplications in the ADHD patients and two deletions and two duplications in the controls. By qPCR analysis, we validated 11 of the 12 CNVs in ADHD patients (P=1.2 × 10 -3 after empirical correction for genome-wide testing). In the replication sample, CNVs at the PARK2 locus were found in four additional ADHD patients and one additional control (P=4.3 × 10 -2). Our results suggest that copy number variants at the PARK2 locus contribute to the genetic susceptibility of ADHD. Mutations and CNVs in PARK2 are known to be associated with Parkinson disease.

AB - Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder. Genetic loci have not yet been identified by genome-wide association studies. Rare copy number variations (CNVs), such as chromosomal deletions or duplications, have been implicated in ADHD and other neurodevelopmental disorders. To identify rare (frequency ≤1%) CNVs that increase the risk of ADHD, we performed a whole-genome CNV analysis based on 489 young ADHD patients and 1285 adult population-based controls and identified one significantly associated CNV region. In tests for a global burden of large (>500 kb) rare CNVs, we observed a nonsignificant (P=0.271) 1.126-fold enriched rate of subjects carrying at least one such CNV in the group of ADHD cases. Locus-specific tests of association were used to assess if there were more rare CNVs in cases compared with controls. Detected CNVs, which were significantly enriched in the ADHD group, were validated by quantitative (q)PCR. Findings were replicated in an independent sample of 386 young patients with ADHD and 781 young population-based healthy controls. We identified rare CNVs within the parkinson protein 2 gene (PARK2) with a significantly higher prevalence in ADHD patients than in controls (P=2.8 × 10 -4 after empirical correction for genome-wide testing). In total, the PARK2 locus (chr 6: 162 659 756-162 767 019) harboured three deletions and nine duplications in the ADHD patients and two deletions and two duplications in the controls. By qPCR analysis, we validated 11 of the 12 CNVs in ADHD patients (P=1.2 × 10 -3 after empirical correction for genome-wide testing). In the replication sample, CNVs at the PARK2 locus were found in four additional ADHD patients and one additional control (P=4.3 × 10 -2). Our results suggest that copy number variants at the PARK2 locus contribute to the genetic susceptibility of ADHD. Mutations and CNVs in PARK2 are known to be associated with Parkinson disease.

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JO - Molecular Psychiatry

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ER -

Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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