URSINI LAB
Gianluca Ursini, MD, PhD
Investigator in Developmental Genomics, Assistant Professor of Psychiatry and Behavioral Sciences
Understanding how genes and the environment interact in early life—especially in the placenta—to influence trajectories of risk for neurodevelopmental disorders like schizophrenia.
URSINI LAB
Our research
The U.R.S.INI Lab (Unit for Research on how Schizophrenia INItiates) investigates how genes and the environment interact early in life to shape neurodevelopmental risk for schizophrenia and related disorders.
Schizophrenia is highly heritable, yet complications during pregnancy, labor/delivery and neonatal life (early life complications, ELCs) represent major environmental risk factors. Our work shows that genomic risk interacts with ELCs through the placenta, where schizophrenia-risk genes are highly expressed, especially in complicated pregnancies and male offspring (Ursini et al., Nat Med. 2018). This placental genomic risk is also linked to early brain development and one-year cognitive outcomes, particularly in male infants with a history of ELCs (Ursini, Punzi et al., PNAS 2021).
We now aim to identify placental genes and pathways mediating this risk, using genomic and computational approaches. Preliminary findings have revealed a connection between schizophrenia-risk genes in the placenta and sex-specific molecular mechanisms related to nutrient sensing and trophoblast invasiveness (Nat Commun. 2023). In parallel, we use iPSCs-derived trophoblast cultures from schizophrenia patients and neurotypical controls to test how genomic and environmental risk factors alter placenta development and function.
Our ultimate goal is to understand how placental biology influences neurodevelopment, to inform prenatal and postnatal prevention strategies for schizophrenia and other neurodevelopmental disorders, as well as personalized treatment approaches.
Placenta is our focus but we do not neglect the brain… In collaboration with Dr. Giovanna Punzi, we investigate genomic and transcriptomic signatures linked to suicide, revealing molecular patterns associated with violent methods (Mol Psychiatry 2014; Biol Psychiatry 2021; Am J Psychiatry 2022). Ongoing work with Dr. Keri Martinowich’s lab explores divergent RNAs that may fine-tune gene regulation underpinning brain development and activity (Bach, Punzi et al., medRxiv 2025).
Why it matters
Understanding how placental biology shapes the developing brain offers a new window into the origins of schizophrenia and related disorders. By uncovering how genetic and environmental factors interact before birth, our work aims to identify early biological mechanisms that increase risk, particularly in vulnerable pregnancies. These insights may guide new strategies to improve maternal and fetal health, reduce neurodevelopmental risk, and eventually tailor preventive and therapeutic approaches based on placental targets and individual genomic and environmental profiles.
Ongoing Projects
Placental Genomics and Schizophrenia
Our studies reveal that genomic risk for schizophrenia interacts with early life complications (ELCs), with the placenta playing a key mediating role. Schizophrenia risk genes are highly expressed in placentae, particularly from complicated pregnancies and in males. These discoveries support the placenta as an active regulator of early risk.
In Vitro Placenta and Brain Models
We differentiate iPSC-derived trophoblasts and placental organoids to model developmental risk, exploring effects of genetic variants and environmental exposures. Secreted factors from these models, including extracellular vesicles, can be tested for their impact on brain organoids.
Translational and Preventive Strategies
We investigate how early detection of altered trajectories can enable interventions for at-risk infants, as well as innovative approaches to preserve the health of the mother–fetus–placenta triad.
Expanding to Related Disorders
Our collaborations extend to studies on the genomic and transcriptomic signatures of completed suicide, as well as the role of noncoding RNAs in the gene regulation underpinning brain development and activity.
"Placental dysfunction or early life events don’t directly cause schizophrenia. Instead, they can nudge brain development onto a slightly different path, raising the risk down the line. The exciting part is that prevention could start even before birth and continue afterward—because brain development doesn’t simply stop at birth. That means there’s a real window of opportunity for positive change.”
The Ursini lab is pleased to acknowledge the generous support of the following major funders:
Gianluca Ursini, M.D., Ph.D., is an Investigator in Developmental Genomics at the Lieber Institute for Brain Development and Assistant Professor of Psychiatry and Behavioral Sciences at the Johns Hopkins School of Medicine. His primary interest is the dynamic interaction between genes and epigenetic factors during brain development and activity. His lab is currently investigating the role of early life (i.e., pre and peri-natal) environment in the pathophysiology of neurodevelopmental disorders. In this regard, Luca has discovered how genomic risk for schizophrenia and severe early life complications impact the risk for the disease through processes involving placental function.
Luca attended the University of Bari “A. Moro,” where he received an M.D. in 2002, a residency in Psychiatry in 2006 and a Ph.D. in “Experimental Neurobiology” in 2011. He was drawn into scientific research during his residency training in Psychiatry. Reviewing the medical history of his patients, he was intrigued by the possibility of studying how their diseases developed, which he assumed followed very diverse trajectories. Over the course of his residency and his Ph.D., Luca has been performing studies on schizophrenia using a combination of imaging and genetics techniques, triggering the investigation of the relationship between epigenetic factors, genetic variants and brain phenotypes in humans. He also received training in Constructivist Psychology and Psychotherapy. Luca has joined the Lieber Institute in the spring of 2012 as a visiting scientist first and then as a postdoctoral fellow. In 2018, he was the recipient of the Andrea Poretti award.
Jiyoung Kim, Ph.D. Staff Scientist II in the U.R.S.INI lab.
Jiyoung research interest is to identify the mechanisms through which genetic risk for schizophrenia converges with ELCs, prenatal and perinatal complications. Her research focuses mainly on the placenta. Modeling human trophoblast from patients and control groups, she is working to characterize whether patients affected with schizophrenia show phenotypic differences in differentiated trophoblast, syncytiotrophoblast, and extravillous trophoblast compared to unaffected controls. With this in vitro system, she also aims at investigating the effect of placental genomic predictors and placental genes associated with risk on placenta development and functions and the possible impact on human brain development of regulating secreted factors. Jiyoung earned her BS, MS, and Ph.D. from Konkuk University, Seoul, Korea, where she studied germline development in C. elegans animal genetic model system. Using germline defective mutants that generate no offspring, she identified the responsible gene for the sterility by forward and reverse genetics, and she found the mechanism underlying the role played by this gene in oocyte maturation. She was also a postdoctoral fellow in the National Institutes of Health, where she studied the post-transcriptional gene regulation by long noncoding RNAs in human cancer cells. Before joining the Lieber Institute, Jiyoung worked as a scientist in Elixirgen Therapeutics, participating in IND drug development for age-related diseases and an RNA-based COVID-19 vaccine.
Jisu Ha, Ph.D. Staff Data Scientist
Jisu is currently working on implementing newly developed algorithms to analyze single-cell genomic data from the brain and placenta and data from longitudinal study cohorts. His research interests include epigenomics, transcriptomics, and machine learning. He completed his Ph.D. degree in the Genetics, Genomics and Bioinformatics program at the University of California, Riverside. He carried out postdoctoral training at the National Institute of Aging of the NIH, and at the Dept. of Psychiatry and Behavioral Sciences of the Johns Hopkins School of Medicine.
- Ursini G, Bollati V, Fazio L, Porcelli A, Iacovelli L, Catalani A, Sinibaldi L, Gelao B, Romano R, Rampino A, Taurisano P, Mancini M, Di Giorgio A, Popolizio T, Baccarelli A, De Blasi A, Blasi G, Bertolino A*. Stress-related methylation of the COMT Val158 allele predicts human prefrontal cognition and activity. The Journal of Neuroscience. 2011; 31:6692-8.
This article initiated a new direction of research in brain imaging, defined as imaging epigenetics, as described in:
- Wiers CE. Methylation and the human brain: towards a new discipline of imaging epigenetics. Eur Arch Psychiatry Clin Neurosci. 2012;262:271–273;
- Nikolova YS, Hariri AR. Can we observe epigenetic effects on human brain function? Trends Cogn Sci 2015 Jul; 19(7): 366–73).
Recommended in Faculty Opinions: https://facultyopinions.com/prime/10760960
- Yoon KJ, Nguyen HN, Ursini G, Zhang F, Kim NS, Wen Z, Makri G, Nauen D, Shin JH, Park Y, Chung R, Pekle E, Zhang C, Towe M, Hussaini SM, Lee Y, Rujescu D, St Clair D, Kleinman JE, Hyde TM, Krauss G, Christian KM, Rapoport JL, Weinberger DR, Song H, Ming GL*. Modeling a Genetic Risk for Schizophrenia in iPSCs and Mice Reveals Neural Stem Cell Deficits Associated with Adherens Junctions and Polarity. Cell Stem Cell. 2014 Jul 3;15(1):79-91.
- Ursini G, Cavalleri T, Fazio T, Angrisano T, Iacovelli L, Porcelli A, Maddalena G, Punzi G, Mancini M, Gelao B, Romano R, Masellis R, Calabrese F, Rampino A, Taurisano P, Di Giorgio A, Keller S, Tarantini L, Sinibaldi L, Quarto T, Popolizio T, Caforio G, Blasi G, Riva MA, De Blasi A, Chiariotti L, Bollati V, Bertolino A*. BDNF rs6265 methylation and genotype interact on risk for schizophrenia. Epigenetics. 2016 Jan 2;11(1):11-23.
- Chen Q^, Ursini G^, Romer AL, Knodt AR, Mezeivtch K, Xiao E, Pergola G, Blasi G, Straub RE, Callicott JH, Berman KF, Hariri AR, Bertolino A, Mattay VS, Weinberger DR*. Schizophrenia polygenic risk score predicts mnemonic hippocampal activity. Brain. 2018 Apr 1;141(4):1218-1228. [^: co-first authors]
Video abstract per Brain, A Journal of Neurology: https://www.youtube.com/watch?v=2L8u7USlAUs&t=36s
Press release: https://scholars.duke.edu/display/pub1314147
- Ursini G, Punzi G, Chen Q, Marenco S, Robinson JF, Porcelli A, Hamilton EG, Mitjans M, Maddalena G, Begemann M, Seidel J, Yanamori H, Jaffe AE, Berman KF, Egan MF, Straub RE, Colantuoni CC, Blasi G, Hashimoto R, Rujescu D, Ehrenreich H, Bertolino A, Weinberger DR*. Convergence of placenta biology and genetic risk for schizophrenia. Nature Medicine. 2018 Jun;24(6):792-801.
Press release:
https://www.libd.org/new-study-finds-placenta-health-affects-risk-of-schizophrenia/
Mentioned on:
Commented in:
- McCarthy M, Intersection of schizophrenia genetics and placental complications. Nature Medicine. 2018 24: 707–8.
- Wood H. Placental gene expression linked to schizophrenia risk. Nature Reviews Neurology. 2018 Jul;14(7):381.
- Ursini G^, Punzi G^, Langworthy BW, Chen Q, Xia K, Cornea EA, Goldman BD, Styner MA, Knickmeyer RC, Gilmore JH*, Weinberger DR*. Placental genomic risk scores and early neurodevelopmental outcomes. Proceedings of the National Academy of Sciences (PNAS). February 16, 2021 118 (7) e2019789118; https://doi.org/10.1073/pnas.2019789118 [^: co-first authors]
Press release:
Mentioned on journals, magazines, and media:
https://bobkolker.medium.com/the-seed-of-mental-illness-might-be-planted-before-birth-9cecbe1df440 https://pnas.altmetric.com/details/99761729/news
- Punzi G*, Ursini G, Chen Q, Radulescu E, Tao R, Huuki LA, Di Carlo P, Collado-Torres L, Shin JH, Catanesi R, Jaffe AE, Hyde TM, Kleinman JE, Mackay TFC, Weinberger DR*. Genetics and brain transcriptomics of completed suicide. The American Journal of Psychiatry. 2022 Mar;179(3):226-241.
Commented in:
- Almeida D, Turecki G. Is Violent Suicide Molecularly Distinct? Am J Psychiatry. 2022 Mar;179(3):180-181.
- Ursini G*, Di Carlo P, Mukherjee S, Chen Q, Han S, Kim J, Deyssenroth M, Marsit CJ, Chen J, Hao K, Punzi G, Weinberger DR*. Prioritization of Placental Schizophrenia Risk Genes. Nature Communications, 2023 May 15;14(1):2613. doi: 10.1038/s41467-023-38140-1.
Press release:
Mentioned on:
https://nature.altmetric.com/details/148346116/news
- Wortinger L, Shadrin A, Szabo A, Nerland S, Smelror R, Jørgensen K, Barth C, Andreou D, Thoresen M, Andreassen O, Djurovic S, Ursini G, Agartz I. The impact of placental genetic risk for schizophrenia and birth asphyxia on brain development. Translational Psychiatry 2023 Nov 8;13(1):343. doi: 10.1038/s41398-023-02639-4
- Bach SV^, Punzi G^, Smith NE, Mukherjee S, Shin JH, Chen Q, Pertea G, Collado-Torres L, Maynard KR, Page SC, Kleinman JE, Hyde TM, Weinberger DR, Martinowich K*, Ursini G*. BDNF-DT and BDNF-AS-DT: Novel Genes in the BDNF locus. medRciv [Preprint]. 2025 Jul 14:2025.07.10.25331311. doi: 10.1101/2025.07.10.25331311. [*: corresponding authors]
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