Dr. John Hagan is a tenured Associate Professor in the Department of Neurosurgery at The University of Texas Health Science Center at Houston. His research has two primary focuses: the genetics of intracranial aneurysms and epigenetics in cancers. To date, his research efforts has been supported by five external grants, including awards from National Institute of Neurological Disorders and Stroke, GlaxoSmithKline, and National Cancer Institute. His recent research identified rare, deleterious variants in THSD1 that cause intracranial aneurysms and subarachnoid hemorrhages in both familial and sporadic cases. From 2004, he has co-authored >50 peer-reviewed publications that have been cited >12,000 times (Google Scholar). These research studies have often been published in prestigious journals such as Cell (2), Nature, PNAS (3), JAMA, JCO, Stroke, Blood, Nature Structural & Molecular Biology, and Nature Communications (2). Ongoing research seeks to identify and characterize additional genes that cause intracranial aneurysms and subarachnoid hemorrhages.

Please tell us your background, where you are from, schooling, etc.

My father was a neurosurgeon and from my youth, I understood the devastating consequences of brain injury and disease and the nobility of improving human health through compassionate care and innovation. Throughout my academic career, I have undertaken research to understand disease mechanisms with an eye towards translating research discoveries to the clinic. I earned dual B.S. degrees in Physics and Biology from Virginia Tech. After completing a Ph.D. at the University of Pittsburgh under the mentorship of Dr. Paula Grabowski, I received postdoctoral training at the National Institutes of Health, Ohio State University, and Harvard Medical School, honing expertise across multidisciplinary biomedical research. Currently, I am a tenured Associate Professor in the Department of Neurosurgery at The University of Texas Health Science Center at Houston (UTHSC-H). My research focuses on understanding the pathobiology of intracranial aneurysms (IA), using clinical genetics and mouse disease models.

What led you to become involved with brain aneurysm research?

Based upon my expertise in genetics, bioinformatics, and human disease in mouse models, I was recruited to the Department of Neurosurgery at UTHSC-H.  I quickly gained the confidence of the Departmental Chair, Dr. Dong Kim, who asked me to co-direct the Departmental research on intracranial aneurysms. In this collaborative research, we discovered that deleterious THSD1 rare variants cause IA in non-syndromic familial and sporadic cases, with supporting evidence from two vertebrate models. This research was the first study to combine whole exome sequencing in an IA/SAH family, case-control studies, and animal models to identify a causative IA gene.  To date, our IA research has led to an NINDS/NIH R01, several research publications, and an awarded patent. Our ongoing research seeks to understand the genetic basis of intracranial aneurysms to identify those individuals at high risk that they can be monitored and treated prior to intracranial aneurysms rupture.

In the simplest terms, what is the purpose of your project?

Our proposed research seeks to identify specific candidate genes that cause human intracranial aneurysms (IA) and subarachnoid hemorrhage (SAH), using familial genetic analyses and case-control studies. The discovery of IA-causing genes is requisite preclinical step in the development of genetic biomarkers for early detection of IA and may suggests novel targets for therapeutic intervention. 

In the simplest terms, what do you hope will change through your research findings?

Our research holds promise to yield clinically relevant biomarkers for early detection of high-risk patients and to identify potential molecular targets for therapies. As whole genome sequencing becomes increasingly prevalent in health care, we envision that this research will lead to the early identification of individuals predisposed to an intracranial aneurysm, leading to vigilant screening and if necessary, treatment prior to IA rupture, thereby reducing the morbidity and mortality associated with subarachnoid hemorrhage.

Why is the funding you are receiving through the Brain Aneurysm Foundation so important?

Funding from the Brain Aneurysm Foundation is critical to us in numerous ways. First, our prior intracranial aneurysm research used whole exome sequencing in IA/SAH affected families. Our proposed work demonstrates technical feasibility and provides critical proof-of-principle that whole genome sequencing is an alternative and superior technique as it comprehensively interrogates the entire human genome, rather than the 5% investigated by whole exome sequencing.  Next, it provides preliminary data to define which candidate IA/SAH genes are most likely bona fide that warrant further interrogation and functional validation using mouse models. Lastly, it may yield clinically relevant biomarkers and novel molecular targets for therapeutic intervention, leading to early detection and intervention, reducing SAH morbidity and mortality.