# RACF: A Multimodal Deep Learning Framework for Parkinson's Disease Diagnosis Using SNP and MRI Data
## 4 Discussion
### Biological Validation from Genetic and Imaging Perspectives  
#### 4.2.1 Genetic Analysis  
In this study, among the top 20 SNP loci selected through SHAP value analysis, in addition to the 11 risk loci previously reported, 9 potential risk loci predicted by the RACF model were identified (rs78251200, rs4538475, rs356182, rs11724635, rs6595513, rs4698412, rs1013496, rs11711441, rs4771268). The gene functions associated with these loci are highly correlated with the pathological mechanisms of PD, particularly in key pathways such as neuroinflammation, energy metabolism disruption, and synaptic plasticity, suggesting their potential pathogenic roles. Among the previously reported risk loci, rs11230569 and rs823156, located in SLC41A1, encode magnesium ion transport proteins that regulate intracellular magnesium ion concentration. Chronic magnesium deficiency may lead to the loss of dopaminergic neurons in the substantia nigra, exacerbating synaptic pathology [26]. The loci rs356220, rs356219, and rs2736990 are situated in the core regulatory region of SNCA, which encodes \(\alpha\)-synuclein. Variants in these loci may disrupt synaptic vesicle transport in dopaminergic neurons, leading to neurodegenerative changes [27]. Furthermore, rs242557, rs17649553, and rs12185268 are located in MAPT, which encodes tau protein. Abnormal phosphorylation of tau is a hallmark of neurofibrillary tangles in Lewy bodies and is significantly associated with the loss of dopaminergic neurons in the substantia nigra [28,29]. Rs947211 in PARK16 regulates the RAB7L1 protein, which influences synaptic vesicle transport efficiency. Dysfunction in this process may result in impaired synaptic transmission, thereby accelerating the progression of PD [30]. Additionally, rs1564282 and rs11248051 in GAK may influence the development of PD by modulating \(\alpha\)-synuclein degradation and other cellular functions [31]. Although the potential loci predicted by the RACF model have not been explicitly reported in existing literature, their annotated gene functions may also be closely related to PD pathogenesis. For instance, rs78251200 in SAAL1 is thought to be involved in the regulation of the secretion of the inflammatory cytokine IL-6, which is elevated in the substantia nigra of PD patients. Increased IL-6 levels may activate the JAK-STAT signaling pathway, promoting \(\alpha\)-synuclein aggregation and ultimately leading to dopaminergic neuron death [32]. This suggests that SAAL1 may contribute to the early pathological processes of PD by modulating the neuroinflammatory microenvironment. Additionally, rs4538475, rs11724635, and rs4698412 are located in BST1, which encodes CD38, a key regulator of NAD\({}^{+}\) metabolism. Dysfunction of BST1 may influence PD progression [33]. Notably, rs4538475 is located in the promoter region of BST1, suggesting that it may regulate gene expression levels through epigenetic modifications, thereby amplifying its pathological effects. Moreover, rs11711441 is located in the MCCC1/LAMP3 locus. MCCC1 may regulate leucine metabolism and mitochondrial function, whereas LAMP3 may modulate autophagic flux through lysosome-associated membrane proteins [34]. These two genes may act synergistically to exacerbate neuronal energy metabolism disorders, further accelerating PD progression. Lastly, rs4771268 in MBNL2 may influence the expression of proteins related to synaptic plasticity by regulating mRNA alternative splicing [35]. Dysfunction in this process may significantly reduce dopamine transmission efficiency, thereby impairing synaptic maturation, which may promote PD progression. The biological functions of these newly predicted loci are highly consistent with the core pathological mechanisms of PD, such as neuroinflammation, mitochondrial dysfunction, and protein homeostasis imbalance.