Dr. Hauser’s laboratory uses molecular genomics techniques to identify genetic variants that are involved in a variety of Mendelian and complex diseases. These studies range from family-based linkage studies to large case/control association analyses, and are supplemented by gene expression and DNA methylation studies from a variety of tissues.
Dr. Hauser and his collaborator Dr. R Rand Allingham have collected DNA samples and detailed phenotypic data from more than 7500 glaucoma cases, controls, and family members. They have performed the largest family-based linkage study in glaucoma to date (1), and identified the early adult onset GLC1I locus on chromosome 15 (2). Dr. Hauser was co-PI of the NEIGHBOR consortium, a group of investigators who assembled more than 4000 Caucasian primary open angle glaucoma cases and controls (3). The NEGIBHOR/GLAUGEN genome wide association study using this dataset identified a number of genetic variants associated with central corneal thickness (4, 5), as well as three different loci associated with glaucoma, including the SIX6 gene (6). In collaboration with Dr. Edwin Oh and the Center for Human Disease Modelling, Dr. Hauser’s group has shown that hypomorphic non-synonymous coding variants in SIX6 lead to reduced optic nerve volume during zebrafish embryonic development. Human patients with these risk factors show a similar reduction the number of retinal ganglion cells, the neuron that carries the visual impulse to the brain. Dr. Hauser’s lab has a strong interest in the study of glaucoma in African Americans and other populations of African ancestry (7,8).
The LOXL1 gene was associated with exfoliation glaucoma in an Icelandic population, but the mechanism of disease has been elusive. Based on findings in a South African population (9), Dr. Hauser's lab is currently exploring the role of a long non-coding RNA in the regulation of LOXL1. Finally, Dr. Hauser’s lab is using whole exome sequencing to identify mutations that give rise to the Mendelian disease primary congenital glaucoma (PCG). PCG patients and their parents are being recruited to this study by Dr. Sharon Freedman, Chief of the Duke Pediatrics and Strabismus service.
Post traumatic stress disorder (PTSD):
Dr. Hauser is working with collaborators in the MIRECC study at the Durham Veteran's Administration who have extensively phenotyped PTSD cases and controls from the Iraq and Afghanistan conflicts. Studies of this dataset have revealed much about the attitudes of veterans to genetic studies (10), the ways in which PTSD disrupts brain function (11), and genetic variants associated with the disorder (12). Dr. Hauser and colleagues Jean Beckham and Allison Ashley-Koch have performed a GWAS of 2000 individuals from this dataset. DNA methylation is likely to play a role in PTSD and methylation studies are ongoing. A collaboration with Dr. Christine Marx focuses on the metabolic signatures of PTSD.
Amyotrophic lateral sclerosis (ALS):
Dr. Hauser and colleagues Liu and Ashley-Koch have performed a GWAS on ALS cases included in the VA CSP#500A ALS Registry (13). A new study approved for funding in March 2014 will use whole genome sequencing of more than 600 ALS cases and 1200 controls. This work focuses on identifying variants that are associated with risk and the rate of progression of disease.
Limb Girdle muscular dystrophy:
Dr. Hauser identified mutations in the myotilin gene as the cause of limb girdle muscular dystrophy 1A (LGMD1A) (14,15), and constructed mouse models that recapitulate many of the pathological features of this disease (16,17). This model system is being used to develop and test possible therapeutic strategies involving virally mediated delivery of hsRNA constructs to muscle, to knock down total MYOT expression. Dr. Hauser has shown that muscular dystrophy is also caused by mutations in GFPT1 (18), MATR3 (19), STAC3 (20), and DNAJB6 (21) Whole exome sequencing has been applied to muscular dystrophy families, identifying multiple disease-causing mutations (22).