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

Research output: Contribution to journalArticle

19 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 languageEnglish (US)
Pages (from-to)634-641
Number of pages8
JournalBiological Psychiatry
Volume82
Issue number9
DOIs
StatePublished - Nov 1 2017

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Genome-Wide Association Study
Attention Deficit Disorder with Hyperactivity
Bipolar Disorder
Meta-Analysis
Nucleotides
Genome
Chromosomes, Human, Pair 10
Chromosomes, Human, Pair 5
Chromosomes, Human, Pair 6
Quantitative Trait Loci
Age of Onset
Genes
Comorbidity
Mental Health
Alleles

Keywords

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

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

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.

In: Biological Psychiatry, Vol. 82, No. 9, 01.11.2017, p. 634-641.

Research output: Contribution to journalArticle

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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, 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.} 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 Faraone, {Stephen V.} and Barbara Franke 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 Lesch, {Klaus Peter} and Loo, {Sandra K.} and Joanna Martin and McGough, {James J.} and Howard Edenberg and Tatiana Foroud and John Nurnberger",
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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.

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 - Faraone, Stephen V.

AU - Franke, Barbara

AU - Freitag, Christine

AU - Gill, Michael

AU - Hakonarson, Hakon

AU - Hervas, Amaia

AU - Holmans, Peter

AU - Kent, Lindsey

AU - Kuntsi, Jonna

AU - Lambregts-Rommelse, Nanda

AU - Langley, Kate

AU - Lesch, Klaus Peter

AU - Loo, Sandra K.

AU - Martin, Joanna

AU - McGough, James J.

AU - Edenberg, Howard

AU - Foroud, Tatiana

AU - Nurnberger, John

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 - bipolar disorder

KW - cross-disorder meta-analysis

KW - genetic correlation

KW - genetic overlap

KW - GWAS

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