Elsevier

Biological Psychiatry

Volume 82, Issue 9, 1 November 2017, Pages 634-641
Biological Psychiatry

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

https://doi.org/10.1016/j.biopsych.2016.08.040Get rights and content

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.

Section snippets

Samples

Cases, controls, and family-based samples assembled for previous genome-wide Psychiatric Genomics Consortium analyses of individual-level data were included in the current analysis (13, 14). A description of individual study data contributions and genotyping platforms is included in Supplemental Tables S1A and S1B. The ADHD sample comprised 4609 cases and 8519 controls. The full BPD sample comprised 9650 cases and 12,844 controls. For tests of the age of onset hypothesis we restricted the BPD

SNP-Based Genetic Correlation

The SNP-based rG between ADHD and BPD was substantial and significant for both the full and age-restricted samples. Interestingly, the rG was higher for the age-restricted sample as compared with the full sample (rGfull = .64, SE = .02, p = 3.13 × 10–14; rGrestricted = .71, SE = .02, p = 4.09 × 10–16; Table 1).

Discussion

In this study, we set out to identify shared genetic risk factor for ADHD and BPD through cross-disorder meta-analysis of the existing GWAS samples from the Psychiatric Genomics Consortium. We hypothesized that overlap between the disorders might be most pronounced in BPD cases with an early age of onset, and that restricting the analysis to samples with an onset ≤21 years of age would increase the power of gene finding by reducing heterogeneity (8). Our findings clearly show the substantial

Acknowledgments and Disclosures

This work was supported by core funding for the Psychiatric Genomics Consortium provided by the National Institute of Mental Health (NIMH) (Grant No. U01 MH094421). This work was also supported by grants from the NIMH (Grant Nos. MH081804, MH078151, and MH59567 to JRK).

This work was carried out on the Dutch national e-infrastructure with the support of the SURF Foundation. We especially thank Willem Vermin (SURF Foundation, Amsterdam, the Netherlands) for his valuable support in the creating

References (41)

  • S.V. Faraone et al.

    Attention-deficit/hyperactivity disorder

    Nat Rev Dis Primers

    (2015)
  • A.P. Wingo et al.

    A systematic review of rates and diagnostic validity of comorbid adult attention-deficit/hyperactivity disorder and bipolar disorder

    J Clin Psychiatry

    (2007)
  • E. Ryden et al.

    A history of childhood attention-deficit hyperactivity disorder (ADHD) impacts clinical outcome in adult bipolar patients regardless of current ADHD

    Acta Psychiatr Scand

    (2009)
  • S.H. Lee et al.

    Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs

    Nat Genet

    (2013)
  • B.G. Schimmelmann et al.

    Bipolar disorder risk alleles in children with ADHD

    J Neural Transm

    (2013)
  • E.T. Landaas et al.

    Bipolar disorder risk alleles in adult ADHD patients

    Genes Brain Behav

    (2011)
  • M. Manchia et al.

    Assessment of response to lithium maintenance treatment in bipolar disorder: A Consortium on Lithium Genetics (ConLiGen) report

    PLoS One

    (2013)
  • P. Sklar et al.

    Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4

    Nat Genet

    (2011)
  • B.K. Bulik-Sullivan et al.

    LD score regression distinguishes confounding from polygenicity in genome-wide association studies

    Nat Genet

    (2015)
  • A. Bhattacharya et al.

    PolymiRTS Database 3.0: Linking polymorphisms in microRNAs and their target sites with human diseases and biological pathways

    Nucleic Acids Res

    (2014)
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