Striatal dopamine gene network moderates the effect of early adversity on the risk for adult psychiatric and cardiometabolic comorbidity.
In plain language
Dopamine-related biology and the risk of mental and metabolic illness together
Poor growth before birth is associated with later mental health problems and with conditions such as diabetes and cardiovascular disease. The strength of those associations varies between people. This study investigated whether part of that variation relates to dopamine signaling in the striatum, a brain region involved in motivation and reward.
Studying a network of genes. Dopamine is a chemical messenger used by brain cells. The dopamine transporter, encoded by the SLC6A3 gene, helps control dopamine signaling by removing it from the space between cells. Rather than examine this gene alone, the researchers created a genetic score based on a network of genes whose activity tends to vary together with SLC6A3 in the striatum. The score used DNA differences to represent predicted differences in this network’s gene expression. It was not a direct measurement of dopamine in participants’ brains.
Connecting early growth with later health. In 225,972 UK Biobank adults, the researchers tested whether the relationship between birth weight and having both psychiatric and cardiometabolic conditions depended on this score. They also examined 1,188 adolescents in the ALSPAC cohort. The adult analysis concerned diagnosed conditions; the adolescent analysis concerned indicators of psychiatric and cardiometabolic risk.
In both groups, the relationship with lower birth weight varied according to the dopamine-related genetic score. This suggests that biology associated with this striatal network may help shape vulnerability or resilience following poor fetal growth. A further analysis linked variants within the score to gray matter density in the prefrontal cortex, a brain region involved in regulating behavior. That finding provides an additional anatomical association, rather than proof of a causal chain.
The study offers a specific biological direction for understanding why mental and metabolic health problems cluster in some people with an adverse early history. It brings birth weight, a dopamine-related gene network and later health into the same analysis. The next question is how this network affects developing brain circuits and whether those changes actually contribute to the combined health outcomes.
Original abstract
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.
Reproduced from the original publication under CC BY 4.0. Wording unchanged; layout and typography normalized.
Barth B, Arcego DM, de Mendonça Filho EJ, de Lima RMS, Parent C, Dalmaz C, Portella AK, Pokhvisneva I, Meaney MJ, Silveira PP. Striatal dopamine gene network moderates the effect of early adversity on the risk for adult psychiatric and cardiometabolic comorbidity. Sci Rep. 2024 Nov 9;14(1):27349. doi: 10.1038/s41598-024-78465-5. PMID: 39521843; PMCID: PMC11550826.
Read the original publication and abstract