Genetic Evidence Linking Prefrontal Surface Area to ADHD, Major Depression, and Smoking Initiation
Abstract
Background: Attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), and smoking behaviour exhibit substantial comorbidity and evidence of sequential occurrence. However, the shared upstream neurodevelopmental structural basis underlying this psychiatric–addiction cascade remains poorly understood. Methods: This study applied a high-dimensional imaging-genetics framework. First, an exploratory Mendelian randomization (MR) screening was conducted across 3,935 UK Biobank imaging-derived phenotypes (IDPs) to prioritize candidate brain structural targets. Subsequently, univariable MR, multivariable MR (MVMR), and serial mediation analyses were used to characterize the potential temporal and causal cascade, with MRlap applied to account for potential sample overlap and weak instrument bias. Finally, Bayesian colocalization with expression quantitative trait loci (eQTLs) and functional network annotation were integrated to explore potential molecular mechanisms. Results: High-dimensional screening prioritized left rostral middle frontal gyrus (rMFG) surface area as a core upstream structural phenotype. Genetically predicted larger left rMFG surface area showed consistent directional evidence of association with lower risks of ADHD, MDD, and smoking initiation. MVMR analyses showed that the conditional direct association between left rMFG surface area and smoking initiation was substantially attenuated and was no longer statistically detectable after adjustment for psychopathological liability, although limited conditional instrument strength warranted cautious interpretation. Exploratory MRlap-adjusted pathway analysis suggested a substantial relative contribution of the prespecified sequential pathway, with the product of path coefficients corresponding to an exploratory estimate of approximately 65.51% of the estimated total effect. Bayesian colocalization (PP.H4 = 0.911) and functional mapping further suggested BDNF-AS and neurodevelopment-related modules as potential molecular mechanisms. Conclusions: Structural developmental vulnerability of the prefrontal cortex does not appear to relate to smoking initiation through an independent direct pathway. The association between genetically predicted left rMFG surface area and smoking initiation may be partly consistent with a pathway involving ADHD and MDD; however, this interpretation remains exploratory because of limited conditional instrument strength and the pairwise nature of the pathway analysis. These findings provide a neuroimaging-genetics perspective on cross-diagnostic comorbidity and suggest a potential role for shared neurotrophic regulatory mechanisms.
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BibTeX
@misc{wang2026genetic,
title = {{Genetic Evidence Linking Prefrontal Surface Area to ADHD, Major Depression, and Smoking Initiation}},
author = {rui wang and Yifan Du and Yunkai Yang},
howpublished = {PsyArXiv},
year = {2026},
month = sep,
doi = {10.31234/osf.io/u72y4_v1},
url = {https://osf.io/preprints/psyarxiv/u72y4_v1/},
note = {CC BY 4.0},
}
RIS
TY - UNPB
TI - Genetic Evidence Linking Prefrontal Surface Area to ADHD, Major Depression, and Smoking Initiation
AU - rui wang
AU - Yifan Du
AU - Yunkai Yang
PY - 2026
DA - 2026/09/20
PB - PsyArXiv
DO - 10.31234/osf.io/u72y4_v1
UR - https://osf.io/preprints/psyarxiv/u72y4_v1/
AB - Background: Attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), and smoking behaviour exhibit substantial comorbidity and evidence of sequential occurrence. However, the shared upstream neurodevelopmental structural basis underlying this psychiatric–addiction cascade remains poorly understood. Methods: This study applied a high-dimensional imaging-genetics framework. First, an exploratory Mendelian randomization (MR) screening was conducted across 3,935 UK Biobank imaging-derived phenotypes (IDPs) to prioritize candidate brain structural targets. Subsequently, univariable MR, multivariable MR (MVMR), and serial mediation analyses were used to characterize the potential temporal and causal cascade, with MRlap applied to account for potential sample overlap and weak instrument bias. Finally, Bayesian colocalization with expression quantitative trait loci (eQTLs) and functional network annotation were integrated to explore potential molecular mechanisms. Results: High-dimensional screening prioritized left rostral middle frontal gyrus (rMFG) surface area as a core upstream structural phenotype. Genetically predicted larger left rMFG surface area showed consistent directional evidence of association with lower risks of ADHD, MDD, and smoking initiation. MVMR analyses showed that the conditional direct association between left rMFG surface area and smoking initiation was substantially attenuated and was no longer statistically detectable after adjustment for psychopathological liability, although limited conditional instrument strength warranted cautious interpretation. Exploratory MRlap-adjusted pathway analysis suggested a substantial relative contribution of the prespecified sequential pathway, with the product of path coefficients corresponding to an exploratory estimate of approximately 65.51% of the estimated total effect. Bayesian colocalization (PP.H4 = 0.911) and functional mapping further suggested BDNF-AS and neurodevelopment-related modules as potential molecular mechanisms. Conclusions: Structural developmental vulnerability of the prefrontal cortex does not appear to relate to smoking initiation through an independent direct pathway. The association between genetically predicted left rMFG surface area and smoking initiation may be partly consistent with a pathway involving ADHD and MDD; however, this interpretation remains exploratory because of limited conditional instrument strength and the pairwise nature of the pathway analysis. These findings provide a neuroimaging-genetics perspective on cross-diagnostic comorbidity and suggest a potential role for shared neurotrophic regulatory mechanisms.
ER -