Program Results

Introduction to the event

Over the past year, my research has focused on uncovering how genetic factors shape psychiatric illness, with an emphasis on treatment-resistant depression and schizophrenia, illustrated in two separate studies:

Polygenic Dissection of Treatment-Resistant Depression

Treatment-resistant depression (TRD) affects nearly one-third of patients with major depressive disorder (MDD), leaving many individuals struggling despite multiple therapeutic attempts. Using electronic health records from 230,000 participants in the UK Biobank, we identified proxy phenotypes of TRD and characterized their clinical and genetic profiles. Compared to non-TRD MDD, individuals classified as TRD often had an earlier onset of depression, lower employment and education levels, and more frequent hospitalizations. TRD showed a substantially stronger inherited polygenic component (20–30% of risk) than MDD overall (~8%). Higher polygenic risk scores (PRS) for MDD, ADHD, and bipolar disorder were linked to medication switching and mood stabilizer use, while schizophrenia PRS specifically predicted antipsychotic use. Higher bipolar PRS also increased the likelihood of using electroconvulsive therapy (ECT), lithium, or valproate by 1.27–1.80 fold. These findings demonstrate that TRD has a clear polygenic basis, highlighting the utility of PRS to uncover pharmacogenomic effects that may aid treatment options for TRD (Figure 1).

Delayed Fatherhood, De Novo Mutations, and Schizophrenia Onset

In collaboration with Dr. Shi-Heng Wang at NHRI, we addressed the long-observed link between delayed fatherhood and schizophrenia risk, whose underlying mechanism remains unclear. Using trio analysis of schizophrenia sib-pairs from five Taiwanese multiplex families, we identified de novo mutations (DNMs) as a likely mediator. DNMs were associated both with advanced paternal age (+1.50 DNMs/year) and with earlier schizophrenia onset in probands (0.16-year earlier). Causal mediation analysis indicated that ~28% (95% CI: 19-38%) of the observed effect of paternal age on schizophrenia onset age could be significantly explained by DNMs. This work provides a potential causal genetic mechanism that connects paternal age-related mutations with increased psychiatric vulnerability in offspring, deepening our understanding of intergenerational risk factors (Figure 2).

Together, these studies demonstrate how genetic analyses—from polygenic risk profiling to rare mutation discovery—can shed light on the complexity of treatment response and psychiatric onset, providing insights toward more personalized approaches to mental health care.

References:
1. Wang, L.-H., Shih, M.-Y., Lin, Y.-F., Kuo, P.-H., & Feng, Y. A. (2025). Polygenic dissection of treatment-resistant depression with proxy phenotypes in the UK Biobank. Journal of Affective Disorders, 381, 350–359.
2. Feng, Y. A., Chen, W. J., Lin, M. C., Hsu, J. S., Cheng, C. F., Liu, C. H., Hwu, H. G., Huang, Y. T., Lu, T. P., & Wang, S. H. (2025) Paternal age, de novo mutation, and age at onset among co-affected schizophrenia sib-pairs: whole-genome sequencing in multiplex families. Molecular Psychiatry, 1–8.