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; Jonna Kuntsi; Benjamin M. Neale; Gerome Breen; David A. Collier; David W. Craig; Richard Day; Amanda Elkin; Anne Farmer; Radhika Kandaswamy; Peter McGuffin; Shaun Purcell; Peter R. Schofield; Erin N. Smith; John B. Vincent; Richard Williamson; Wei Xu; Allan H. Young

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, Jonna Kuntsi, Benjamin M. Neale, Gerome Breen, David A. Collier, David W. Craig, Richard Day, Amanda Elkin, Anne Farmer, Radhika Kandaswamy, Peter McGuffin, Shaun Purcell, Peter R. Schofield, Erin N. Smith, John B. Vincent, Richard Williamson, Wei Xu, Allan H. Young

^*Corresponding author for this work

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

95 Citations (Scopus)

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.

Original language	English
Pages (from-to)	634-641
Number of pages	8
Journal	Biological psychiatry
Volume	82
Issue number	9
Early online date	29 Sept 2017
DOIs	https://doi.org/10.1016/j.biopsych.2016.08.040
Publication status	Published - 1 Nov 2017

Keywords

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

UN SDGs

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

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., ... Young, A. H. (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{fb442b6a22e444869f79a5cc53c18d2e,

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

abstract = "BackgroundAttention-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.MethodsGenome-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.ResultsWe 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.ConclusionsThe 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, bipolar disorder, cross-disorder meta-analysis, genetic correlation, genetic overlap, GWAS",

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 Jonna Kuntsi and Neale, {Benjamin M.} and Gerome Breen and Collier, {David A.} and Craig, {David W.} and Richard Day and Amanda Elkin and Anne Farmer and Radhika Kandaswamy and Peter McGuffin and Shaun Purcell and Schofield, {Peter R.} and Smith, {Erin N.} and Vincent, {John B.} and Richard Williamson and Wei Xu and Young, {Allan H.}",

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",

issn = "0006-3223",

publisher = "Elsevier",

number = "9",

}

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 , Kuntsi, J , Neale, BM , Breen, G , Collier, DA , Craig, DW , Day, R , Elkin, A , Farmer, A , Kandaswamy, R , McGuffin, P , Purcell, S, Schofield, PR, Smith, EN , Vincent, JB , Williamson, R , Xu, W & Young, AH 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

AU - PGC ADHD Working Group

AU - PGC Bipolar Disorder Working Group

AU - van Hulzen, Kimm J.E.

AU - Scholz, Claus J.

AU - Franke, Barbara

AU - Ripke, Stephan

AU - Klein, Marieke

AU - McQuillin, Andrew

AU - Sonuga-Barke, Edmund J.S.

AU - Kelsoe, John R.

AU - Landén, Mikael

AU - Andreassen, Ole A.

AU - Lesch, Klaus Peter

AU - Weber, Heike

AU - Faraone, Stephen V.

AU - Arias-Vasquez, Alejandro

AU - Reif, Andreas

AU - Anney, Richard J.L.

AU - Vasquez, Alejandro Arias

AU - Arranz, Maria J.

AU - Asherson, Philip

AU - Banaschewski, Tobias J.

AU - Bayés, Mònica

AU - Biederman, Joseph

AU - Buitelaar, Jan K.

AU - Casas, Miguel

AU - Charach, Alice

AU - Cormand, Bru

AU - Crosbie, Jennifer

AU - Dalsgaard, Søren

AU - Daly, Mark J.

AU - Doyle, Alysa E.

AU - Ebstein, Richard P.

AU - Elia, Josephine

AU - Freitag, Christine

AU - Kuntsi, Jonna

AU - Neale, Benjamin M.

AU - Breen, Gerome

AU - Collier, David A.

AU - Craig, David W.

AU - Day, Richard

AU - Elkin, Amanda

AU - Farmer, Anne

AU - Kandaswamy, Radhika

AU - McGuffin, Peter

AU - Purcell, Shaun

AU - Schofield, Peter R.

AU - Smith, Erin N.

AU - Vincent, John B.

AU - Williamson, Richard

AU - Xu, Wei

AU - Young, Allan H.

PY - 2017/11/1

Y1 - 2017/11/1

N2 - BackgroundAttention-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.MethodsGenome-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.ResultsWe 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.ConclusionsThe 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 - BackgroundAttention-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.MethodsGenome-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.ResultsWe 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.ConclusionsThe 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 - bipolar disorder

KW - cross-disorder meta-analysis

KW - genetic correlation

KW - genetic overlap

KW - GWAS

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

Abstract

Keywords

UN SDGs

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