MDGA1 – Schizophrenia

MDGA1 (HGNC:19267) has been implicated in the susceptibility to schizophrenia (MONDO_0005090) based on multiple independent case‑control studies. Several analyses have examined populations with diverse ancestries, including a Scandinavian cohort of 839 cases (PMID:18384059) and a Chinese Han cohort of 1135 patients (PMID:21146959), where nominally significant associations were identified using tagSNP approaches.

The genetic evidence highlights that while there are no clear rare, high‑penetrance variants with robust segregation data, the cumulative association signals from common variants provide a statistically significant relationship. These studies did not document familial segregation, and as such, the segregation count of affected relatives is currently unreported.

Experimental investigations further illuminate MDGA1’s role in neuronal biology. Functional assessments have shown that MDGA1 participates in neuronal migration and synaptic adhesion, with in vivo studies demonstrating that it is a substrate for the Alzheimer protease BACE1 (PMID:31908000). Additionally, structural and cell‑based assays have delineated its critical role in modulating interactions with neuroligins (PMID:28641111, PMID:36889589).

In complementary models, MDGA1’s perturbation in the lateral habenula was shown to alter inhibitory synapse density and confer resistance to stress‑induced depressive behaviors, suggesting that its regulatory impact on synaptic transmission is of functional and clinical relevance (PMID:39897557).

Integrating the genetic and functional findings, the evidence converges on a moderate overall association between MDGA1 and schizophrenia. Although rare, high‑penetrance variants remain unreported, the statistically significant tagSNP associations and supportive experimental models provide a coherent narrative linking MDGA1 dysfunction to aberrant neuronal migration and synapse formation.

It is noteworthy that additional evidence exists in the literature and beyond current scoring thresholds. However, the present synthesis is sufficient to inform diagnostic decision‑making and support further research as well as commercial utility.

Key Take‑home: MDGA1 represents a promising susceptibility factor for schizophrenia, with convergent genetic and functional evidence indicating its critical role in neuronal migration and synaptic regulation.

References

• American journal of medical genetics. Part B, Neuropsychiatric genetics • 2008 • Association analysis of schizophrenia on 18 genes involved in neuronal migration: MDGA1 as a new susceptibility gene PMID:18384059
• Schizophrenia research • 2011 • The MDGA1 gene confers risk to schizophrenia and bipolar disorder PMID:21146959
• FASEB journal • 2020 • Mouse brain proteomics establishes MDGA1 and CACHD1 as in vivo substrates of the Alzheimer protease BACE1 PMID:31908000
• Neuron • 2017 • Structural Insights into Modulation of Neurexin-Neuroligin Trans-synaptic Adhesion by MDGA1/Neuroligin-2 Complex PMID:28641111
• The Journal of biological chemistry • 2023 • Designer molecules of the synaptic organizer MDGA1 reveal 3D conformational control of biological function PMID:36889589
• Theranostics • 2025 • Chronic stress induces depression through MDGA1-Neuroligin2 mediated suppression of inhibitory synapses in the lateral habenula PMID:39897557

Evidence Based Scoring (AI generated)