Edward Ginns completed his PhD in Physical Chemistry at Rensselaer Polytechnic Institute in NY, and went on to receive his MD from Johns Hopkins School of Medicine. Following a Medical Internship at Baltimore City Hospital, he trained in Neurology at Albert Einstein College of Medicine, NY. In 1980 he joined the Developmental and Metabolic Neurology Branch, NINDS at the National Institutes of Health in Bethesda, Maryland where he became a tenured Senior Investigator Neurologist in the Molecular and Medical Genetics Section. In 1986 Dr. Ginns transferred to NIMH as Chief, Section on Molecular Neurogenetics, NIMH. In 2000 he was recruited to the University of Massachusetts Medical School as founding Director of the Brudnick Neuropsychiatric Research Institute from the Intramural Research Program of NIMH where he was Chief, Clinical Neuroscience Branch and Supervising Scientist of the NIMH Transgenic and Targeted Gene Modified Mouse Resource. At the University of Massachusetts Medical School Dr. Ginns was founding Director of the Molecular Diagnostics Laboratory, and he is currently Director of the Program in Medical Genetics and the Lysosomal Disorders Treatment and Research Program. He is Professor of Neurology, Pediatrics, Psychiatry, Clinical Pathology and the Program in Neuroscience. Dr. Ginns is board certified in Neurology with a special interest in developmental and neurogenetic disorders. He is an elected member of the American College of Neuropsychopharmacology.
Our research is directed toward identifying and understanding the consequences of gene mutations on protein and cell function in inherited human disease. Cell biological and molecular genetic approaches are used in conjunction with clinical studies to obtain a better understanding of gene expression and the molecular pathophysiology underlying selected Mendelian and complex trait diseases. To accomplish this objective, we study gene variation and function in unique human genetic isolates, inbred animal models and families with inherited developmental disorders. Research projects reflect a “bench to bedside” approach, combining efforts from interdisciplinary investigations on humans and animal models. Project areas include Gaucher disease associated Parkinsons, Ellis-van Creveld syndrome, and selected psychiatric disorders, including bipolar affective disorder, obsessive compulsive disorder and autism spectrum disorders. These disorders globally affect more than four hundred million individuals and comprise major causes of disability. Patient symptoms are generally only partially responsive to treatment. These illnesses are associated with other comorbid chronic conditions, shorter life span and situations having devastating effects on the quality of life of the individuals and their families.
Despite compelling clinical-epidemiological evidence supporting a genetic susceptibility to develop major behavioral and mental disorders, the identification of the genetic variants and the associated underlying molecular mechanisms or pathophysiology for these disorders have remained elusive. To circumvent this long standing problem, our approach utilizes an innovative strategy, based on leveraging the properties through which protective alleles exert their dominant effects on causative pathways, to uncover the root causes and molecular pathways responsible for the growing health care burden of mental illness. Using bipolar affective disorder as a prototype, we have obtained convincing clinical, genetic and statistical data supporting the successful application of this protective allele based strategy. Our studies identified the sonic hedgehog (Shh) signaling pathway as a key genetic pathway underlying bipolar disorder, a breakthrough that could lead to improved diagnosis and better drugs for treating bipolar affective disorder.
Bipolar Affective Disorder:
Despite compelling evidence from many studies supporting a significant genetic susceptibility, elucidation of an underlying molecular mechanism causing bipolar affective disorder (BPAD) has remained elusive. Twin, family, and adoption studies have provided strong evidence for an important genetic component in the susceptibility to develop BPAD. However, unlike for other common medical illnesses, genetic linkage studies have had to mainly rely on categorical diagnoses. Genetic heterogeneity, phenocopies, genotyping errors, and the complexities of performing and interpreting statistical analyses probably contribute to some of the inconsistences observed in genetic studies. Technologies to identify genetic factors associated with complex human disease have dramatically improved, but a major limitation to most current approaches has been the limiting theoretical framework derived from Mendelian genetics, and an incomplete understanding of complex disease physiology. To date, most genetic studies of affective disorders have been limited to identifying genetic variants that increase the risk of disease. By contrast, I developed the novel hypothesis that there are protective genes, in addition to susceptibility alleles, for psychiatric disorders, and in particular for BPAD.
Decades of longitudinal research in collaboration with Dr. Janice Egeland and colleagues in Old Order Amish families of Pennsylvania revealed co-segregation of high numbers of a rare genetic dwarfism, Ellis-van Creveld (EvC), and bipolar disorder (BPAD) in a few special Old Order Amish families in the Amish Study descending from the same pioneer. Despite more than forty years of research documenting the high prevalence of both EvC and BPAD in these families, no EvC individual has ever been reported with BPI. Our analyses confirmed the association between absence of BPI and the presence of EvC (P=.029, Fisher’s exact test, two-sided, confirmed by a permutation test), supported our hypothesis that EvC confers protection (i.e mental health wellness) from BPI, as well as suggesting a more general protection against the spectrum of affective disorders in these families. This finding suggested that the genetic cause of this rare dwarfism had a molecular change that is protective of bipolar affective disorder. Understanding how the Amish mutations causing EvC disrupted sonic hedgehog (Shh) signaling was key to uncovering the molecular mechanism underlying bipolar disorder
We previously reported strong evidence for a BPAD locus with protective minor alleles(s) on chromosome 4p at D4S2949 and suggestive evidence for a locus on chromosome 4q at D4S397. The EVC and hedgehog interacting protein (Hhip) genes, were subsequently cloned and located within 5 million bases of our chromosome 4p16 and 4q putative loci for BPAD, respectively. The proximity of the EvC gene to our previously reported chromosome 4p16 BPAD locus, coupled with detailed clinical observations and statistical confirmation that EvC and BPI do not occur in the same Amish individuals, led us to postulate that the molecular mechanism underlying EvC is protective against BPI. Since homozygous Amish EVC mutations causing EvC dwarfism do so by disrupting sonic hedgehog (Shh) signaling, our data implicate Shh signaling in the underlying pathophysiology of BPAD.
Molecules in the sonic hedgehog signaling pathway transmit information required for regulation of where neurons are located during development and how the neurons function in the adult brain. At a time when many pharmaceutical companies have all but abandoned the search for new treatments, connecting Shh signaling to bipolar disorder provides a mechanism with new targets for drugs that could dramatically change the way we treat this condition. Our discovery suggests that sonic hedgehog signaling can be modulated to help manage bipolar symptoms in adults by repurposing drugs used for other medical conditions. Shh signaling and reactivation occurring in a wide range of cancers, has led to identification of Shh signaling antagonists that are already in human clinical studies. Research collaborations are underway to unravel more details of the puzzle and to identify changes and biomarkers in the sonic hedgehog signaling and related pathways that correlate with disease symptoms. Linking abnormal Shh signaling to affective disorders provides a concrete molecular and medical basis for patients’ symptoms.
Autism Spectrum Disorders:
A goal of our research is to determine the extent and mechanisms by which sonic hedgehog (Shh) signaling is involved in the pathogenesis of ASD.
Autism spectrum disorder (ASD) is a common developmental disorder affecting more than three million individuals in the US, with a 4:1 male to female occurrence. Major clinical manifestations include impairments in verbal and nonverbal communication and social interaction that are often accompanied by repetitive, stereotyped behaviors and attention disturbances. Some individuals with ASD excel in visual skills, music, math and art. Most cases of autism appear to be caused by a combination of autism risk genes and environmental stress factors during early brain development. Several rare gene changes have been associated with autism, but the etiology of most cases remains unknown.
Sonic hedgehog signaling has key roles in nervous system developmental regulation of neuron generation and localization, regeneration and neuronal electrophysiological activity. Elevated serum levels of Shh protein have been reported in children with ASD. Our studies should lead to a better understanding of ASD pathophysiology, identification of biomarkers and potentially translate into improved diagnosis and treatments.
Obsessive Compulsive Disorder:
We are using highly-accessible, inbred animal models for identifying causal factors that could provide a better understanding of the neurophysiologic pathways in canine compulsive disorder (CCD) and human compulsive disorder (OCD). Similarities in presentations in these devastating canine and human diseases and pharmacological responsiveness suggested common neurobiological etiologies.
Compulsive disorders are severe behaviors with onset in childhood that affect approximately 2% of the world population and cause great personal and societal burden. They often disrupt academic, social and occupational functioning. Current treatments are usually only partially effective in reducing symptoms, and often involve adverse side effects. There remains a major unmet public health need for better interventions and diagnostics.
In addition to our finding that cadherin-2 (CDH2) confers risk for canine compulsive disorder (CCD) in Doberman pinschers, we have identified another locus that implicates serotonergic function. We are now pursuing molecular and genomic signature studies to identify dogs at risk for CCD and identify and validate endophenotypes of genetic risk while continuing to identify additional risk variants. Endophenotype studies are being integrated with genetics to identify modifying loci that exacerbate or attenuate compulsive disorder risk or severity. Using canine compulsive disorder as a prototype, we are bridging our canine findings to human compulsive disorders. Our goal is to provide insights into mechanisms responsible for OCD, overcoming a critical barrier to developing more effective treatments and perhaps even prevention that would dramatically improve the quality of life of individuals both at-risk and currently suffering from this disorder.
Gaucher Disease Associated Parkinsons:
We are using mouse models of Gaucher disesase to (i) identify novel molecular abnormalities impacting pathophysiology of Gaucher related PD and sporadic PD, (ii) carry out longitudinal studies of PD progression and biomarker discovery, and (iii) enable testing of novel strategies for treatment, intervention, and potentially even prevention of Gaucher disease and Parkinsons.
Recent clinical, epidemiological and experimental studies have confirmed a strong connection between Parkinson’s disease (PD) and individuals carrying a glucocerebrosidase gene (GBA) Gaucher mutation. We are building upon our published in-vivo findings of altered nigrostriatal pathway dopaminergic neurotransmission in the conduritol-beta-epoxide (CBE) pharmacological Gaucher mouse model of reduced GBA enzyme activity. This is the first description in an animal model to recapitulate the synaptic dysfunction reported in human striatal imaging studies of Gaucher mutation carriers asymptomatic for Parkinsonism. CBE administration produced markedly reduced evoked dopamine release and post-synaptic density size. These synaptic abnormalities were accompanied by robust elevation of neuroinflammatory markers and alpha-synuclein (a-syn) in nigrostriatal tissue. To further address the unmet need for better understanding and treatment of bone and brain involvement in Gaucher disease, and more specifically as models for the study of Gaucher-related Parkinsonism and sporadic Parkinson’s disease, we are using two long-lived transgenic mouse models of Gaucher disease bearing the L444P or the R463C point mutations frequently found in Gaucher patients. These aged homozygous Gaucher transgenic mutant mice have a lifespan of from 1-2 years and show abnormal a-syn accumulation and astroglial activation in the striatum.