Attention-Deficit/Hyperactivity Disorder (ADHD) and obesity are frequently comorbid, genetically correlated, and share brain substrates. The biological mechanisms driving this association are unclear, but candidate systems, like dopaminergic neurotransmission and circadian rhythm, have been suggested. Our aim was to identify the biological mechanisms underpinning the genetic link between ADHD and obesity measures and investigate associations of overlapping genes with brain volumes. We tested the association of dopaminergic and circadian rhythm gene sets with ADHD, body mass index (BMI), and obesity (using GWAS data of N = 53,293, N = 681,275, and N = 98,697, respectively). We then conducted genome-wide ADHD-BMI and ADHD-obesity gene-based meta-analyses, followed by pathway enrichment analyses. Finally, we tested the association of ADHD-BMI overlapping genes with brain volumes (primary GWAS data N = 10,720-10,928; replication data N = 9428). The dopaminergic gene set was associated with both ADHD (P = 5.81 × 10-3) and BMI (P = 1.63 × 10-5); the circadian rhythm was associated with BMI (P = 1.28 × 10-3). The genome-wide approach also implicated the dopaminergic system, as the Dopamine-DARPP32 Feedback in cAMP Signaling pathway was enriched in both ADHD-BMI and ADHD-obesity results. The ADHD-BMI overlapping genes were associated with putamen volume (P = 7.7 × 10-3; replication data P = 3.9 × 10-2)-a brain region with volumetric reductions in ADHD and BMI and linked to inhibitory control. Our findings suggest that dopaminergic neurotransmission, partially through DARPP-32-dependent signaling and involving the putamen, is a key player underlying the genetic overlap between ADHD and obesity measures. Uncovering shared etiological factors underlying the frequently observed ADHD-obesity comorbidity may have important implications in terms of prevention and/or efficient treatment of these conditions.

中文翻译：

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交叉障碍遗传分析暗示多巴胺能信号传导是注意力缺陷/多动障碍和肥胖测量之间的生物学联系。

注意缺陷/多动障碍 (ADHD) 和肥胖症经常合并，遗传相关，并共享大脑基质。驱动这种关联的生物学机制尚不清楚，但已提出候选系统，如多巴胺能神经传递和昼夜节律。我们的目标是确定支持 ADHD 和肥胖测量之间遗传联系的生物学机制，并研究重叠基因与脑容量的关联。我们测试了多巴胺能和昼夜节律基因组与 ADHD、体重指数 (BMI) 和肥胖的关联（分别使用 N = 53,293、N = 681,275 和 N = 98,697 的 GWAS 数据）。然后，我们进行了全基因组 ADHD-BMI 和基于 ADHD-肥胖基因的荟萃分析，然后进行了通路富集分析。最后，我们测试了 ADHD-BMI 重叠基因与脑容量的关联（原始 GWAS 数据 N = 10,720-10,928；复制数据 N = 9428）。多巴胺能基因组与 ADHD (P = 5.81 × 10-3) 和 BMI (P = 1.63 × 10-5) 相关；昼夜节律与 BMI 相关（P = 1.28 × 10-3）。全基因组方法也涉及多巴胺能系统，因为 cAMP 信号通路中的多巴胺-DARPP32 反馈在 ADHD-BMI 和 ADHD-肥胖结果中都得到了丰富。ADHD-BMI 重叠基因与壳核体积（P = 7.7 × 10-3；复制数据 P = 3.9 × 10-2）相关 - 一个大脑区域，ADHD 和 BMI 体积减少，并与抑制控制有关。我们的研究结果表明，多巴胺能神经传递，部分通过依赖 DARPP-32 的信号传导并涉及壳核，是 ADHD 和肥胖测量之间遗传重叠的关键因素。揭示常见的 ADHD 肥胖合并症背后的共同病因可能对预防和/或有效治疗这些疾病具有重要意义。