Genetic Overlap Between Attention-Deficit/Hyperactivity Disorder and Bipolar Disorder: Evidence From Genome-wide Association Study Meta-analysis

PGC ADHD Working Group; PGC Bipolar Disorder Working Group; Kimm J.E. van Hulzen; Claus J. Scholz; Barbara Franke; Stephan Ripke; Marieke Klein; Andrew McQuillin; Edmund J.S. Sonuga-Barke; John R. Kelsoe; Mikael Landén; Ole A. Andreassen; Klaus Peter Lesch; Heike Weber; Stephen V. Faraone; Alejandro Arias-Vasquez; Andreas Reif; Richard J.L. Anney; Alejandro Arias Vasquez; Maria J. Arranz; Philip Asherson; Tobias J. Banaschewski; Mònica Bayés; Joseph Biederman; Jan K. Buitelaar; Miguel Casas; Alice Charach; Bru Cormand; Jennifer Crosbie; Søren Dalsgaard; Mark J. Daly; Alysa E. Doyle; Richard P. Ebstein; Josephine Elia; Christine Freitag; Michael Gill; Hakon Hakonarson; Amaia Hervas; Peter Holmans; Lindsey Kent; Jonna Kuntsi; Nanda Lambregts-Rommelse; Kate Langley; Sandra K. Loo; Joanna Martin; James J. McGough; Sarah E. Medland; Jobst Meyer; Eric Mick; Ana Miranda; Fernando Mulas; Benjamin M. Neale; Stan F. Nelson; Michael C. O’Donovan; Robert D. Oades; Michael J. Owen; Haukur Palmason; Josep A. Ramos-Quiroga; Marta Ribasés; Herbert Roeyers; Jasmin Romanos; Marcel Romanos; Aribert Rothenberger; Cristina Sánchez-Mora; Russell Schachar; Joseph Sergeant; Susan L. Smalley; Hans Christoph Steinhausen; Anita Thapar; Alexandre Todorov; Susanne Walitza; Yufeng Wang; Andreas Warnke; Nigel Williams; Yanli Zhang-James; Devin Absher; Huda Akil; Adebayo Anjorin; Lena Backlund; Judith A. Badner; Jack D. Barchas; Thomas B. Barrett; Nick Bass; Michael Bauer; Frank Bellivier; Sarah E. Bergen; Wade Berrettini; Douglas Blackwood; Cinnamon S. Bloss; Michael Boehnke; Gerome Breen; René Breuer; William E. Bunney; Margit Burmeister; William Byerley; Sian Caesar; Kim Chambert; Sven Cichon; David A. Collier; Aiden Corvin; William Coryell; Nick Craddock; David W. Craig; Mark Daly; Richard Day; Franziska Degenhardt; Srdjan Djurovic; Frank Dudbridge; Howard J. Edenberg; Amanda Elkin; Bruno Etain; Anne Farmer; Manuel Ferreira; I. Nicol Ferrier; Matthew Flickinger; Tatiana Foroud; Josef Frank; Christine Fraser; Louise Frisén; Janice Fullerton; Elliot S. Gershon; Katherine Gordon-Smith; Elaine K. Green; Tiffany A. Greenwood; Detelina Grozeva; Weihua Guan; Hugh Gurling; Ómar Gustafsson; Marian L. Hamshere; Martin Hautzinger; Chantal Henry; Stefan Herms; Maria M. Hipolito; Christina Hultman; Stéphane Jamain; Edward G. Jones; Ian R. Jones; Lisa Jones; Jean Pierre Kahn; Radhika Kandaswamy; James L. Kennedy; George Kirov; Daniel L. Koller; Phoenix Kwan; Niklas Langstrom; Mark Lathrop; Jacob Lawrence; William B. Lawson; Marion Leboyer; Phil H. Lee; Jun Li; Paul Lichtenstein; Danyu Lin; Chunyu Liu; Falk W. Lohoff; Susanne Lucae; Pamela B. Mahon; Sandra Maier; Wolfgang Maier; Nick Martin; Manuel Mattheisen; Keith Matthews; Morten Mattingsdal; Kevin McGhee; Peter McGuffin; Melvin G. McInnis; Andrew McIntosh; Rebecca McKinney; Alan W. McLean; Francis J. McMahon; Ingrid Melle; Fan Guo Meng; Philip B. Mitchell; Grant W. Montgomery; Jennifer Moran; Gunnar Morken; Derek Morris; Valentina Moskvina; Pierandrea Muglia; Thomas W. Mühleisen; Walter J. Muir; Bertram Müller-Mysok; Richard M. Myers; Caroline M. Nievergelt; Ivan Nikolov; Vishwajit Nimgaonkar; Markus M. Nöthen; John I. Nurnberger; Evaristus A. Nwulia; Colm O'Dushlaine; Urban Osby; Högni Óskarsson; Roy Perlis; Hannes Petursson; Benjamin S. Pickard; James B. Potash; Peter Propping; Shaun Purcell; Emma Quinn; Soumya Raychaudhuri; John Rice; Marcella Rietschel

doi:10.1016/j.biopsych.2016.08.040

Genetic Overlap Between Attention-Deficit/Hyperactivity Disorder and Bipolar Disorder: Evidence From Genome-wide Association Study Meta-analysis

PGC ADHD Working Group, PGC Bipolar Disorder Working Group, Kimm J.E. van Hulzen, Claus J. Scholz, Barbara Franke, Stephan Ripke, Marieke Klein, Andrew McQuillin, Edmund J.S. Sonuga-Barke, John R. Kelsoe, Mikael Landén, Ole A. Andreassen, Klaus Peter Lesch, Heike Weber, Stephen V. Faraone, Alejandro Arias-Vasquez, Andreas Reif, Richard J.L. Anney, Alejandro Arias Vasquez, Maria J. ArranzPhilip Asherson, Tobias J. Banaschewski, Mònica Bayés, Joseph Biederman, Jan K. Buitelaar, Miguel Casas, Alice Charach, Bru Cormand, Jennifer Crosbie, Søren Dalsgaard, Mark J. Daly, Alysa E. Doyle, Richard P. Ebstein, Josephine Elia, Christine Freitag, Michael Gill, Hakon Hakonarson, Amaia Hervas, Peter Holmans, Lindsey Kent, Jonna Kuntsi, Nanda Lambregts-Rommelse, Kate Langley, Sandra K. Loo, Joanna Martin, James J. McGough, Sarah E. Medland, Jobst Meyer, Eric Mick, Ana Miranda, Fernando Mulas, Benjamin M. Neale, Stan F. Nelson, Michael C. O’Donovan, Robert D. Oades, Michael J. Owen, Haukur Palmason, Josep A. Ramos-Quiroga, Marta Ribasés, Herbert Roeyers, Jasmin Romanos, Marcel Romanos, Aribert Rothenberger, Cristina Sánchez-Mora, Russell Schachar, Joseph Sergeant, Susan L. Smalley, Hans Christoph Steinhausen, Anita Thapar, Alexandre Todorov, Susanne Walitza, Yufeng Wang, Andreas Warnke, Nigel Williams, Yanli Zhang-James, Devin Absher, Huda Akil, Adebayo Anjorin, Lena Backlund, Judith A. Badner, Jack D. Barchas, Thomas B. Barrett, Nick Bass, Michael Bauer, Frank Bellivier, Sarah E. Bergen, Wade Berrettini, Douglas Blackwood, Cinnamon S. Bloss, Michael Boehnke, Gerome Breen, René Breuer, William E. Bunney, Margit Burmeister, William Byerley, Sian Caesar, Kim Chambert, Sven Cichon, David A. Collier, Aiden Corvin, William Coryell, Nick Craddock, David W. Craig, Mark Daly, Richard Day, Franziska Degenhardt, Srdjan Djurovic, Frank Dudbridge, Howard J. Edenberg, Amanda Elkin, Bruno Etain, Anne Farmer, Manuel Ferreira, I. Nicol Ferrier, Matthew Flickinger, Tatiana Foroud, Josef Frank, Christine Fraser, Louise Frisén, Janice Fullerton, Elliot S. Gershon, Katherine Gordon-Smith, Elaine K. Green, Tiffany A. Greenwood, Detelina Grozeva, Weihua Guan, Hugh Gurling, Ómar Gustafsson, Marian L. Hamshere, Martin Hautzinger, Chantal Henry, Stefan Herms, Maria M. Hipolito, Christina Hultman, Stéphane Jamain, Edward G. Jones, Ian R. Jones, Lisa Jones, Jean Pierre Kahn, Radhika Kandaswamy, James L. Kennedy, George Kirov, Daniel L. Koller, Phoenix Kwan, Niklas Langstrom, Mark Lathrop, Jacob Lawrence, William B. Lawson, Marion Leboyer, Phil H. Lee, Jun Li, Paul Lichtenstein, Danyu Lin, Chunyu Liu, Falk W. Lohoff, Susanne Lucae, Pamela B. Mahon, Sandra Maier, Wolfgang Maier, Nick Martin, Manuel Mattheisen, Keith Matthews, Morten Mattingsdal, Kevin McGhee, Peter McGuffin, Melvin G. McInnis, Andrew McIntosh, Rebecca McKinney, Alan W. McLean, Francis J. McMahon, Ingrid Melle, Fan Guo Meng, Philip B. Mitchell, Grant W. Montgomery, Jennifer Moran, Gunnar Morken, Derek Morris, Valentina Moskvina, Pierandrea Muglia, Thomas W. Mühleisen, Walter J. Muir, Bertram Müller-Mysok, Richard M. Myers, Caroline M. Nievergelt, Ivan Nikolov, Vishwajit Nimgaonkar, Markus M. Nöthen, John I. Nurnberger, Evaristus A. Nwulia, Colm O'Dushlaine, Urban Osby, Högni Óskarsson, Roy Perlis, Hannes Petursson, Benjamin S. Pickard, James B. Potash, Peter Propping, Shaun Purcell, Emma Quinn, Soumya Raychaudhuri, John Rice, Marcella Rietschel

Research output: Contribution to journal › Article › peer-review

94 Scopus citations

Abstract

Background Attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder (BPD) are frequently co-occurring and highly heritable mental health conditions. We hypothesized that BPD cases with an early age of onset (≤21 years old) would be particularly likely to show genetic covariation with ADHD. Methods Genome-wide association study data were available for 4609 individuals with ADHD, 9650 individuals with BPD (5167 thereof with early-onset BPD), and 21,363 typically developing controls. We conducted a cross-disorder genome-wide association study meta-analysis to identify whether the observed comorbidity between ADHD and BPD could be due to shared genetic risks. Results We found a significant single nucleotide polymorphism–based genetic correlation between ADHD and BPD in the full and age-restricted samples (r_Gfull =.64, p = 3.13 × 10^–14; r_Grestricted =.71, p = 4.09 × 10^–16). The meta-analysis between the full BPD sample identified two genome-wide significant (p_rs7089973 = 2.47 × 10^–8; p_rs11756438 = 4.36 × 10^–8) regions located on chromosomes 6 (CEP85L) and 10 (TAF9BP2). Restricting the analyses to BPD cases with an early onset yielded one genome-wide significant association (p_rs58502974 = 2.11 × 10^–8) on chromosome 5 in the ADCY2 gene. Additional nominally significant regions identified contained known expression quantitative trait loci with putative functional consequences for NT5DC1, NT5DC2, and CACNB3 expression, whereas functional predictions implicated ABLIM1 as an allele-specific expressed gene in neuronal tissue. Conclusions The single nucleotide polymorphism–based genetic correlation between ADHD and BPD is substantial, significant, and consistent with the existence of genetic overlap between ADHD and BPD, with potential differential genetic mechanisms involved in early and later BPD onset.

Original language	English
Pages (from-to)	634-641
Number of pages	8
Journal	Biological Psychiatry
Volume	82
Issue number	9
DOIs	https://doi.org/10.1016/j.biopsych.2016.08.040
State	Published - Nov 1 2017

Keywords

Attention-deficit/hyperactivity disorder
GWAS
bipolar disorder
cross-disorder meta-analysis
genetic correlation
genetic overlap

Access to Document

10.1016/j.biopsych.2016.08.040

Cite this

PGC ADHD Working Group, PGC Bipolar Disorder Working Group, van Hulzen, K. J. E., Scholz, C. J., Franke, B., Ripke, S., Klein, M., McQuillin, A., Sonuga-Barke, E. J. S., Kelsoe, J. R., Landén, M., Andreassen, O. A., Lesch, K. P., Weber, H., Faraone, S. V., Arias-Vasquez, A., Reif, A., Anney, R. J. L., Vasquez, A. A., ... Rietschel, M. (2017). Genetic Overlap Between Attention-Deficit/Hyperactivity Disorder and Bipolar Disorder: Evidence From Genome-wide Association Study Meta-analysis. Biological Psychiatry, 82(9), 634-641. https://doi.org/10.1016/j.biopsych.2016.08.040

@article{7d7c607dbdbf4e6b9df12a28bb127ea1,

title = "Genetic Overlap Between Attention-Deficit/Hyperactivity Disorder and Bipolar Disorder: Evidence From Genome-wide Association Study Meta-analysis",

abstract = "Background Attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder (BPD) are frequently co-occurring and highly heritable mental health conditions. We hypothesized that BPD cases with an early age of onset (≤21 years old) would be particularly likely to show genetic covariation with ADHD. Methods Genome-wide association study data were available for 4609 individuals with ADHD, 9650 individuals with BPD (5167 thereof with early-onset BPD), and 21,363 typically developing controls. We conducted a cross-disorder genome-wide association study meta-analysis to identify whether the observed comorbidity between ADHD and BPD could be due to shared genetic risks. Results We found a significant single nucleotide polymorphism–based genetic correlation between ADHD and BPD in the full and age-restricted samples (rGfull =.64, p = 3.13 × 10–14; rGrestricted =.71, p = 4.09 × 10–16). The meta-analysis between the full BPD sample identified two genome-wide significant (prs7089973 = 2.47 × 10–8; prs11756438 = 4.36 × 10–8) regions located on chromosomes 6 (CEP85L) and 10 (TAF9BP2). Restricting the analyses to BPD cases with an early onset yielded one genome-wide significant association (prs58502974 = 2.11 × 10–8) on chromosome 5 in the ADCY2 gene. Additional nominally significant regions identified contained known expression quantitative trait loci with putative functional consequences for NT5DC1, NT5DC2, and CACNB3 expression, whereas functional predictions implicated ABLIM1 as an allele-specific expressed gene in neuronal tissue. Conclusions The single nucleotide polymorphism–based genetic correlation between ADHD and BPD is substantial, significant, and consistent with the existence of genetic overlap between ADHD and BPD, with potential differential genetic mechanisms involved in early and later BPD onset.",

keywords = "Attention-deficit/hyperactivity disorder, GWAS, bipolar disorder, cross-disorder meta-analysis, genetic correlation, genetic overlap",

author = "{PGC ADHD Working Group} and {PGC Bipolar Disorder Working Group} and {van Hulzen}, {Kimm J.E.} and Scholz, {Claus J.} and Barbara Franke and Stephan Ripke and Marieke Klein and Andrew McQuillin and Sonuga-Barke, {Edmund J.S.} and Kelsoe, {John R.} and Mikael Land{\'e}n and Andreassen, {Ole A.} and Lesch, {Klaus Peter} and Heike Weber and Faraone, {Stephen V.} and Alejandro Arias-Vasquez and Andreas Reif and Anney, {Richard J.L.} and Vasquez, {Alejandro Arias} and Arranz, {Maria J.} and Philip Asherson and Banaschewski, {Tobias J.} and M{\`o}nica Bay{\'e}s and Joseph Biederman and Buitelaar, {Jan K.} and Miguel Casas and Alice Charach and Bru Cormand and Jennifer Crosbie and S{\o}ren Dalsgaard and Daly, {Mark J.} and Doyle, {Alysa E.} and Ebstein, {Richard P.} and Josephine Elia and Christine Freitag and Michael Gill and Hakon Hakonarson and Amaia Hervas and Peter Holmans and Lindsey Kent and Jonna Kuntsi and Nanda Lambregts-Rommelse and Kate Langley and Loo, {Sandra K.} and Joanna Martin and McGough, {James J.} and Medland, {Sarah E.} and Jobst Meyer and Eric Mick and Ana Miranda and Fernando Mulas and Neale, {Benjamin M.} and Nelson, {Stan F.} and O{\textquoteright}Donovan, {Michael C.} and Oades, {Robert D.} and Owen, {Michael J.} and Haukur Palmason and Ramos-Quiroga, {Josep A.} and Marta Ribas{\'e}s and Herbert Roeyers and Jasmin Romanos and Marcel Romanos and Aribert Rothenberger and Cristina S{\'a}nchez-Mora and Russell Schachar and Joseph Sergeant and Smalley, {Susan L.} and Steinhausen, {Hans Christoph} and Anita Thapar and Alexandre Todorov and Susanne Walitza and Yufeng Wang and Andreas Warnke and Nigel Williams and Yanli Zhang-James and Devin Absher and Huda Akil and Adebayo Anjorin and Lena Backlund and Badner, {Judith A.} and Barchas, {Jack D.} and Barrett, {Thomas B.} and Nick Bass and Michael Bauer and Frank Bellivier and Bergen, {Sarah E.} and Wade Berrettini and Douglas Blackwood and Bloss, {Cinnamon S.} and Michael Boehnke and Gerome Breen and Ren{\'e} Breuer and Bunney, {William E.} and Margit Burmeister and William Byerley and Sian Caesar and Kim Chambert and Sven Cichon and Collier, {David A.} and Aiden Corvin and William Coryell and Nick Craddock and Craig, {David W.} and Mark Daly and Richard Day and Franziska Degenhardt and Srdjan Djurovic and Frank Dudbridge and Edenberg, {Howard J.} and Amanda Elkin and Bruno Etain and Anne Farmer and Manuel Ferreira and Ferrier, {I. Nicol} and Matthew Flickinger and Tatiana Foroud and Josef Frank and Christine Fraser and Louise Fris{\'e}n and Janice Fullerton and Gershon, {Elliot S.} and Katherine Gordon-Smith and Green, {Elaine K.} and Greenwood, {Tiffany A.} and Detelina Grozeva and Weihua Guan and Hugh Gurling and {\'O}mar Gustafsson and Hamshere, {Marian L.} and Martin Hautzinger and Chantal Henry and Stefan Herms and Hipolito, {Maria M.} and Christina Hultman and St{\'e}phane Jamain and Jones, {Edward G.} and Jones, {Ian R.} and Lisa Jones and Kahn, {Jean Pierre} and Radhika Kandaswamy and Kennedy, {James L.} and George Kirov and Koller, {Daniel L.} and Phoenix Kwan and Niklas Langstrom and Mark Lathrop and Jacob Lawrence and Lawson, {William B.} and Marion Leboyer and Lee, {Phil H.} and Jun Li and Paul Lichtenstein and Danyu Lin and Chunyu Liu and Lohoff, {Falk W.} and Susanne Lucae and Mahon, {Pamela B.} and Sandra Maier and Wolfgang Maier and Nick Martin and Manuel Mattheisen and Keith Matthews and Morten Mattingsdal and Kevin McGhee and Peter McGuffin and McInnis, {Melvin G.} and Andrew McIntosh and Rebecca McKinney and McLean, {Alan W.} and McMahon, {Francis J.} and Ingrid Melle and {Guo Meng}, Fan and Mitchell, {Philip B.} and Montgomery, {Grant W.} and Jennifer Moran and Gunnar Morken and Derek Morris and Valentina Moskvina and Pierandrea Muglia and M{\"u}hleisen, {Thomas W.} and Muir, {Walter J.} and Bertram M{\"u}ller-Mysok and Myers, {Richard M.} and Nievergelt, {Caroline M.} and Ivan Nikolov and Vishwajit Nimgaonkar and N{\"o}then, {Markus M.} and Nurnberger, {John I.} and Nwulia, {Evaristus A.} and Colm O'Dushlaine and Urban Osby and H{\"o}gni {\'O}skarsson and Roy Perlis and Hannes Petursson and Pickard, {Benjamin S.} and Potash, {James B.} and Peter Propping and Shaun Purcell and Emma Quinn and Soumya Raychaudhuri and John Rice and Marcella Rietschel",

note = "Publisher Copyright: {\textcopyright} 2016 Society of Biological Psychiatry",

year = "2017",

month = nov,

day = "1",

doi = "10.1016/j.biopsych.2016.08.040",

language = "English",

volume = "82",

pages = "634--641",

journal = "Biological Psychiatry",

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PGC ADHD Working Group, PGC Bipolar Disorder Working Group, van Hulzen, KJE, Scholz, CJ, Franke, B, Ripke, S, Klein, M, McQuillin, A, Sonuga-Barke, EJS, Kelsoe, JR, Landén, M, Andreassen, OA, Lesch, KP, Weber, H, Faraone, SV, Arias-Vasquez, A, Reif, A, Anney, RJL, Vasquez, AA, Arranz, MJ, Asherson, P, Banaschewski, TJ, Bayés, M, Biederman, J, Buitelaar, JK, Casas, M, Charach, A, Cormand, B, Crosbie, J, Dalsgaard, S, Daly, MJ, Doyle, AE, Ebstein, RP, Elia, J, Freitag, C, Gill, M, Hakonarson, H, Hervas, A, Holmans, P, Kent, L, Kuntsi, J, Lambregts-Rommelse, N, Langley, K, Loo, SK, Martin, J, McGough, JJ, Medland, SE, Meyer, J, Mick, E, Miranda, A, Mulas, F, Neale, BM, Nelson, SF, O’Donovan, MC, Oades, RD, Owen, MJ, Palmason, H, Ramos-Quiroga, JA, Ribasés, M, Roeyers, H, Romanos, J, Romanos, M, Rothenberger, A, Sánchez-Mora, C, Schachar, R, Sergeant, J, Smalley, SL, Steinhausen, HC, Thapar, A, Todorov, A, Walitza, S, Wang, Y, Warnke, A, Williams, N, Zhang-James, Y, Absher, D, Akil, H, Anjorin, A, Backlund, L, Badner, JA, Barchas, JD, Barrett, TB, Bass, N, Bauer, M, Bellivier, F, Bergen, SE, Berrettini, W, Blackwood, D, Bloss, CS, Boehnke, M, Breen, G, Breuer, R, Bunney, WE, Burmeister, M, Byerley, W, Caesar, S, Chambert, K, Cichon, S, Collier, DA, Corvin, A, Coryell, W, Craddock, N, Craig, DW, Daly, M, Day, R, Degenhardt, F, Djurovic, S, Dudbridge, F, Edenberg, HJ, Elkin, A, Etain, B, Farmer, A, Ferreira, M, Ferrier, IN, Flickinger, M, Foroud, T, Frank, J, Fraser, C, Frisén, L, Fullerton, J, Gershon, ES, Gordon-Smith, K, Green, EK, Greenwood, TA, Grozeva, D, Guan, W, Gurling, H, Gustafsson, Ó, Hamshere, ML, Hautzinger, M, Henry, C, Herms, S, Hipolito, MM, Hultman, C, Jamain, S, Jones, EG, Jones, IR, Jones, L, Kahn, JP, Kandaswamy, R, Kennedy, JL, Kirov, G, Koller, DL, Kwan, P, Langstrom, N, Lathrop, M, Lawrence, J, Lawson, WB, Leboyer, M, Lee, PH, Li, J, Lichtenstein, P, Lin, D, Liu, C, Lohoff, FW, Lucae, S, Mahon, PB, Maier, S, Maier, W, Martin, N, Mattheisen, M, Matthews, K, Mattingsdal, M, McGhee, K, McGuffin, P, McInnis, MG, McIntosh, A, McKinney, R, McLean, AW, McMahon, FJ, Melle, I, Guo Meng, F, Mitchell, PB, Montgomery, GW, Moran, J, Morken, G, Morris, D, Moskvina, V, Muglia, P, Mühleisen, TW, Muir, WJ, Müller-Mysok, B, Myers, RM, Nievergelt, CM, Nikolov, I, Nimgaonkar, V, Nöthen, MM, Nurnberger, JI, Nwulia, EA, O'Dushlaine, C, Osby, U, Óskarsson, H, Perlis, R, Petursson, H, Pickard, BS, Potash, JB, Propping, P, Purcell, S, Quinn, E, Raychaudhuri, S, Rice, J & Rietschel, M 2017, 'Genetic Overlap Between Attention-Deficit/Hyperactivity Disorder and Bipolar Disorder: Evidence From Genome-wide Association Study Meta-analysis', Biological Psychiatry, vol. 82, no. 9, pp. 634-641. https://doi.org/10.1016/j.biopsych.2016.08.040

Genetic Overlap Between Attention-Deficit/Hyperactivity Disorder and Bipolar Disorder: Evidence From Genome-wide Association Study Meta-analysis. / PGC ADHD Working Group; PGC Bipolar Disorder Working Group; van Hulzen, Kimm J.E. et al.
In: Biological Psychiatry, Vol. 82, No. 9, 01.11.2017, p. 634-641.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Genetic Overlap Between Attention-Deficit/Hyperactivity Disorder and Bipolar Disorder

T2 - Evidence From Genome-wide Association Study Meta-analysis

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AU - Muglia, Pierandrea

AU - Mühleisen, Thomas W.

AU - Muir, Walter J.

AU - Müller-Mysok, Bertram

AU - Myers, Richard M.

AU - Nievergelt, Caroline M.

AU - Nikolov, Ivan

AU - Nimgaonkar, Vishwajit

AU - Nöthen, Markus M.

AU - Nurnberger, John I.

AU - Nwulia, Evaristus A.

AU - O'Dushlaine, Colm

AU - Osby, Urban

AU - Óskarsson, Högni

AU - Perlis, Roy

AU - Petursson, Hannes

AU - Pickard, Benjamin S.

AU - Potash, James B.

AU - Propping, Peter

AU - Purcell, Shaun

AU - Quinn, Emma

AU - Raychaudhuri, Soumya

AU - Rice, John

AU - Rietschel, Marcella

PY - 2017/11/1

Y1 - 2017/11/1

N2 - Background Attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder (BPD) are frequently co-occurring and highly heritable mental health conditions. We hypothesized that BPD cases with an early age of onset (≤21 years old) would be particularly likely to show genetic covariation with ADHD. Methods Genome-wide association study data were available for 4609 individuals with ADHD, 9650 individuals with BPD (5167 thereof with early-onset BPD), and 21,363 typically developing controls. We conducted a cross-disorder genome-wide association study meta-analysis to identify whether the observed comorbidity between ADHD and BPD could be due to shared genetic risks. Results We found a significant single nucleotide polymorphism–based genetic correlation between ADHD and BPD in the full and age-restricted samples (rGfull =.64, p = 3.13 × 10–14; rGrestricted =.71, p = 4.09 × 10–16). The meta-analysis between the full BPD sample identified two genome-wide significant (prs7089973 = 2.47 × 10–8; prs11756438 = 4.36 × 10–8) regions located on chromosomes 6 (CEP85L) and 10 (TAF9BP2). Restricting the analyses to BPD cases with an early onset yielded one genome-wide significant association (prs58502974 = 2.11 × 10–8) on chromosome 5 in the ADCY2 gene. Additional nominally significant regions identified contained known expression quantitative trait loci with putative functional consequences for NT5DC1, NT5DC2, and CACNB3 expression, whereas functional predictions implicated ABLIM1 as an allele-specific expressed gene in neuronal tissue. Conclusions The single nucleotide polymorphism–based genetic correlation between ADHD and BPD is substantial, significant, and consistent with the existence of genetic overlap between ADHD and BPD, with potential differential genetic mechanisms involved in early and later BPD onset.

AB - Background Attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder (BPD) are frequently co-occurring and highly heritable mental health conditions. We hypothesized that BPD cases with an early age of onset (≤21 years old) would be particularly likely to show genetic covariation with ADHD. Methods Genome-wide association study data were available for 4609 individuals with ADHD, 9650 individuals with BPD (5167 thereof with early-onset BPD), and 21,363 typically developing controls. We conducted a cross-disorder genome-wide association study meta-analysis to identify whether the observed comorbidity between ADHD and BPD could be due to shared genetic risks. Results We found a significant single nucleotide polymorphism–based genetic correlation between ADHD and BPD in the full and age-restricted samples (rGfull =.64, p = 3.13 × 10–14; rGrestricted =.71, p = 4.09 × 10–16). The meta-analysis between the full BPD sample identified two genome-wide significant (prs7089973 = 2.47 × 10–8; prs11756438 = 4.36 × 10–8) regions located on chromosomes 6 (CEP85L) and 10 (TAF9BP2). Restricting the analyses to BPD cases with an early onset yielded one genome-wide significant association (prs58502974 = 2.11 × 10–8) on chromosome 5 in the ADCY2 gene. Additional nominally significant regions identified contained known expression quantitative trait loci with putative functional consequences for NT5DC1, NT5DC2, and CACNB3 expression, whereas functional predictions implicated ABLIM1 as an allele-specific expressed gene in neuronal tissue. Conclusions The single nucleotide polymorphism–based genetic correlation between ADHD and BPD is substantial, significant, and consistent with the existence of genetic overlap between ADHD and BPD, with potential differential genetic mechanisms involved in early and later BPD onset.

KW - Attention-deficit/hyperactivity disorder

KW - GWAS

KW - bipolar disorder

KW - cross-disorder meta-analysis

KW - genetic correlation

KW - genetic overlap

UR - http://www.scopus.com/inward/record.url?scp=85007193533&partnerID=8YFLogxK

U2 - 10.1016/j.biopsych.2016.08.040

DO - 10.1016/j.biopsych.2016.08.040

M3 - Article

C2 - 27890468

AN - SCOPUS:85007193533

SN - 0006-3223

VL - 82

SP - 634

EP - 641

JO - Biological Psychiatry

JF - Biological Psychiatry

IS - 9

ER -

Genetic Overlap Between Attention-Deficit/Hyperactivity Disorder and Bipolar Disorder: Evidence From Genome-wide Association Study Meta-analysis

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