Integrated Program in Neurosciences, McGill University, Montreal, QC, Canada.
Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.
Sci Rep. 2024 Nov 9;14(1):27349. doi: 10.1038/s41598-024-78465-5.
Cardiometabolic and psychiatric disorders often co-exist and share common early life risk factors, such as low birth weight. However, the biological pathways linking early adversity to adult cardiometabolic/psychiatric comorbidity remain unknown. Dopamine (DA) neurotransmission in the striatum is sensitive to early adversity and influences the development of both cardiometabolic and psychiatric diseases. Here we show that a co-expression based polygenic score (ePGS) reflecting individual variations in the expression of the striatal dopamine transporter gene (SLC6A3) network significantly interacts with birth weight to predict psychiatric and cardiometabolic comorbidities in both adults (UK Biobank, N = 225,972) and adolescents (ALSPAC, N = 1188). Decreased birth weight is associated with an increased risk for psychiatric and cardiometabolic comorbidities, but the effect is dependent on a striatal SLC6A3 ePGS, that reflects individual variation in gene expression of genes coexpressed with the SLC6A3 gene in the striatum. Neuroanatomical analyses revealed that SNPs from the striatum SLC6A3 ePGS were significantly associated with prefrontal cortex gray matter density, suggesting a neuroanatomical basis for the link between early adversity and psychiatric and cardiometabolic comorbidity. Our study reveals that psychiatric and cardiometabolic diseases share common developmental pathways and underlying neurobiological mechanisms that includes dopamine signaling in the striatum.
心脏代谢和精神障碍通常并存，并具有共同的早期生活风险因素，例如低出生体重。然而，将早期逆境与成人心脏代谢/精神共病联系起来的生物学途径仍不清楚。纹状体中的多巴胺（DA）神经传递对早期逆境敏感，并影响心脏代谢和精神疾病的发展。在这里，我们表明，反映纹状体多巴胺转运蛋白基因（SLC6A3）网络表达个体差异的基于共表达的多基因评分（ePGS）与出生体重显著相互作用，可预测成人（英国生物银行，N=225972）和青少年（ALSPAC，N=1188）的精神和心脏代谢共病。较低的出生体重与精神和心脏代谢共病的风险增加有关，但这种影响取决于纹状体 SLC6A3 ePGS，它反映了与纹状体中 SLC6A3 基因共表达的基因表达的个体差异。神经解剖学分析表明，来自纹状体 SLC6A3 ePGS 的 SNPs 与前额叶皮层灰质密度显著相关，这表明早期逆境与精神和心脏代谢共病之间存在神经解剖学基础。我们的研究表明，精神和心脏代谢疾病具有共同的发育途径和潜在的神经生物学机制，包括纹状体中的多巴胺信号。
