Major depression (MD) and obesity are complex genetic disorders that are frequently comorbid. However, the study of both diseases concurrently remains poorly addressed and therefore the underlying genetic mechanisms involved in this comorbidity remain largely unknown. Here we examine the contribution of common and rare variants to this comorbidity through a next-generation sequencing (NGS) approach. Specific genomic regions of interest in MD and obesity were sequenced in a group of 654 individuals from the PISMA-ep epidemiological study. We obtained variants across the entire frequency spectrum and assessed their association with comorbid MD and obesity, both at variant and gene levels. We identified 55 independent common variants and a burden of rare variants in 4 genes (PARK2, FGF21, HIST1H3D and RSRC1) associated with the comorbid phenotype. Follow-up analyses revealed significantly enriched gene-sets associated with biological processes and pathways involved in metabolic dysregulation, hormone signaling and cell cycle regulation. Our results suggest that, while risk variants specific to the comorbid phenotype have been identified, the genes functionally impacted by the risk variants share cell biological processes and signaling pathways with MD and obesity phenotypes separately. To the best of our knowledge, this is the first study involving a targeted sequencing approach toward the study of the comorbid MD and obesity. The framework presented here allowed a deep characterization of the genetics of the co-occurring MD and obesity, revealing insights into the mutational and functional profile that underlies this comorbidity and contributing to a better understanding of the relationship between these two disabling disorders.

重度抑郁症 (MD) 和肥胖症是复杂的遗传性疾病，经常同时出现。然而，对这两种疾病的研究仍然没有得到很好的解决，因此与这种共病相关的潜在遗传机制仍然很大程度上未知。在这里，我们通过下一代测序（NGS）方法检查常见和罕见变异对这种合并症的影响。对 PISMA-ep 流行病学研究的 654 名个体中与 MD 和肥胖相关的特定基因组区域进行了测序。我们获得了整个频谱的变异，并在变异和基因水平上评估了它们与共病MD和肥胖的关联。我们在与共病表型相关的 4 个基因（ PARK2 、 FGF21 、 HIST1H3D和RSRC1 ）中确定了 55 个独立的常见变异和大量罕见变异。后续分析显示，与代谢失调、激素信号传导和细胞周期调节相关的生物过程和途径相关的基因组显着丰富。我们的结果表明，虽然已经确定了共病表型特有的风险变异，但受风险变异功能影响的基因分别与MD和肥胖表型共享细胞生物学过程和信号通路。据我们所知，这是第一项涉及针对共病MD和肥胖症的靶向测序方法的研究。 这里提出的框架可以深入描述同时发生的MD和肥胖的遗传学特征，揭示这种合并症背后的突变和功能特征，并有助于更好地理解这两种致残性疾病之间的关系。