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Meta-Analysis
. 2017 Nov 1;82(9):634-641.
doi: 10.1016/j.biopsych.2016.08.040. Epub 2016 Oct 18.

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

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Free PMC article
Meta-Analysis

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

Kimm J E van Hulzen et al. Biol Psychiatry. .
Free PMC article

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.

Figures

Figure 1.
Figure 1.
Manhattan plot of the primary (a) and restricted (b) cross-disorder meta-analyses. Only SNPs with p values ≤ 0.05 are shown; Horizontal lines show threshold for genome-wide significance (p<5×10−8 in red) and suggestive association (p<1×10−6 in blue).
Figure 2A.
Figure 2A.
Regional plot for genome-wide significant locus on chromosome 10 for the primary meta-analysis.
Figure 2B.
Figure 2B.
Regional plot for genome-wide significant locus on chromosome 6 for the primary meta-analysis.
Figure 2C.
Figure 2C.
Regional plot for genome-wide significant locus on chromosome 5 for the restricted meta-analysis. Results are shown as –log(p-value) for genotyped and imputed SNPs. The SNP showing strongest association is shown in the purple circle. The color of the remaining markers reflects r2 of the strongest associated SNP. The recombination rate is plotted in blue.

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