New paper published in Journal of Affective Disorders: Polygenic dissection of treatment-resistant depression with proxy phenotypes in the UK Biobank

For about one in three people with major depressive disorder (MDD), standard antidepressant treatments don’t work. This form, called treatment resistant depression (TRD), leaves patients struggling despite trying at least two different medications.

Our team asked: could genetics help explain who develops TRD—and even guide more personalized treatments?

Using primary-care electronic health records from 230,000 people in the UK Biobank, we identified those likely to have TRD based on their prescription history. Compared to others with depression, these individuals often had an earlier onset of depression, lower employment and education levels, and more frequent hospitalizations.

The genetic findings were clear: TRD showed a much stronger inherited component (20–30% of risk) than depression overall (~8%). People with higher polygenic risk scores (PRS) for MDD, ADHD, and bipolar disorder were more likely to switch medications or use mood stabilizers, while those with a higher genetic risk for schizophrenia specifically predicted the use of antipsychotics. Higher bipolar PRS also increased the likelihood of using electroconvulsive therapy (ECT), lithium, or valproate by 1.27–1.80 fold.

These results support that TRD has a non-trivial genetic basis and highlight the potential of PRS to uncover pharmacogenomic effects that may aid treatment options for managing TRD.

Reference:
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.

Shih-Hsiang (Shaun) Luo received the highest honor at NTU for his bachelor thesis, titled “A multifactorial risk assessment of depression integrating genomic, epigenomic, and psychosocial factors in the Taiwanese population” – Congratulations!

New paper published in Molecular Psychiatry: Whole-genome sequencing in multiplex families of schizophrenia revealed a mediating role of de novo mutations between paternal age and disease risk

Delayed fatherhood has long been linked to an increased risk of schizophrenia in offspring, but the underlying mechanism remains unclear. In collaboration with Dr. Shi-Heng Wang from the NHRI, we performed trio analysis on schizophrenia sib-pairs to identify de novo mutations (DNMs). We discovered that DNMs were associated with both advanced paternal age and an earlier schizophrenia onset in probands. Further, causal mediation analysis showed that DNMs significantly mediated the effect of paternal age on the age of schizophrenia onset. Our study offers a potential causal explanation linking paternal age-related mutations to increased psychiatric risk in offspring.

Reference:
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, 30(8), 3560–3567.

ASHG, WCPG, and IASC-ARS

Kudos to all the first-time attendees from the lab for presenting their work at the World Congress of Psychiatric Genetics (WCPG), American Society of Human Genetics (ASHG), and the Asian Regional Section of the International Association for Statistical Computing (IASC-ARS) conference.

Yi-Ru Lin received the institutional Oral Presentation award for her research on deciphering the genetics of epilepsy in East and Southeast Asian populations.