Education, Research, Patient Care qd

Chronic Complex Genetic Disorders

The evolution of genomic technologies has had a profound effect on the tractability of the genetic basis of complex traits. Most notably, high-density genotyping and now genome sequencing have mapped thousands of risk loci for complex traits. However, the transition from association to causality has remained challenging, largely bereft of experimentally tractable solutions. Our Center, in addition to participating in large consortia association studies, has placed heavy emphasis on the development of conceptual and technical tools to identify penetrant coding variants and biological mechanisms for several complex traits.

Autism is a multifactorial neurodevelopmental disorder characterized by deficits in communication and social interaction, and repetitive behaviors. The prevalence for this condition is ~1% worldwide with a 4:1 male to female ratio. Several co-morbidities have been associated with autism spectrum disorders (ASD) including intellectual disability, craniofacial malformations, gastrointestinal problems, and heart malformations. Our researchers are currently investigating the candidacy of select genetic determinants and specific pathways in the development of the disorder [25807484 and 23332918]. We are also identifying major chromosomal lesions (deletions and duplications) for both neuroanatomical phenotypes and associated comorbidities [22596160 and 24998929]. Ultimately, we hope to contribute to the rational stratification of this highly heterogeneous group of disorders; to define common pathway that might predict manageable co-morbidities; and to help design rational therapeutic paradigms for some AS/ASD patients.

Complex Ocular Disorders
Our faculty have had a long-standing interest in understanding the genetic causes of eye disorders. Transitioning from the rare to the common, we have used a combination of genetics, genomics, and model organisms to identify genes and alleles associated with a number of phenotypes. These include age-related macular degeneration (AMD), Fuch’s corneal dystrophy (FCD) and primary open angle glaucoma (POAG), three of the most common hereditary forms of blindness in adults and CHDM investigators have contributed to the identification of genetic risk factors for both of these ocular diseases. Read more on AMD [26691988 and 23455636], FCD [26200491 and 24094747] and POAG [26752265 and 24875647]. We continue to invest effort into the development of new conceptual and practical tools for the dissection of pathomechanisms across ocular disorders.

Genetic Modifiers of Sickle Cell Disease (SCD)
SCD is a hematologic disorder, with a wide range of associated symptoms such as pain, stroke, infections, heart and kidney disease. Although SCD is classified as a Mendelian disorder, the symptom presentation and severity in individuals with SCD varies considerably. With this in mind, scientists in our Center have been involved in identification of genes that modify the presentation of SCD. Read more [21910715, 18248572, and 18187665]. Most recently, our team has utilized zebrafish as an in vivo model to understand pathomechanism in sickle cell nephropathy [26147622]. Looking forward, our aspirational goals include the transcriptomic analyses of stable SCD animal models as a means of identifying relevant pathomechanisms and the execution of rational small molecule screens for candidate therapeutics.

Schizophrenia (SZ)
With a prevalence of ~1% worldwide, schizophrenia is a neurological condition that is characterized broadly by reduced motivation and social engagement, and a higher incidence of hallucinations. Both genetic and environmental factors contribute to the etiology of the disorder. Using mouse and zebrafish animal models and cell-based assays, the CHDM is establishing how specific genetic lesions can lead to neuroanatomical and behavioral alterations that may be relevant to the disorder [26605881 and 18762586]. Through these studies, we hope to understand the genetic architecture of SZ; to predict (and enable the management of) systemic co-morbidities; and to identify subsets of SZ patients who might benefit from innovative drug discovery paradigms.