Until recently, our understanding of the genetic causes for human diseases were largely limited to the study of extreme phenotypes produced by Mendelian disorders. Advances in genomic technologies and statistical methods have converged to allow the discovery of susceptibility loci for complex genetic traits, and the field now confronts the enormous challenge to confirm the responsible genes and define their functions in the biology of health and disease. In addition to the potential for fundamental biological insights, functional dissection of susceptibility genes will be essential to realize the full promise of human genetics for clinical applications. In the coming years, with the completion of the largest possible genetic meta-analyses along with the advent of whole-genome sequencing, our knowledge of common and rare susceptibility variants will rapidly expand, implicating vast genetic networks including hundreds of loci in neurologic diseases. Innovative strategies are therefore urgently needed to accelerate functional studies.
Background and Significance: The power of disease endophenotypes
Gene discovery in Alzheimer's disease (AD) and Parkinson's disease (PD) has largely relied on the case-control design based on clinical diagnoses; however, this approach is potentially limited by etiologic heterogeneity amongst patients and the presence of substantial but sub-clinical pathology in controls. A complementary approach directly leverages the underlying disease pathology as an intermediate trait, or endophenotype. The clinical manifestation of neurodegenerative disease is the culmination of a multi-tiered pathogenic cascade that evolves over decades—understanding how genetic variants impact this causal chain is essential. Substantial evidence supports a model in which many genetic variants promote the development of neuropathology, subsequently leading to the clinical manifestations of disease.
We continue to leverage endophenotypes for gene discovery and functional genomic dissection in neurodegenerative diseases, collaborating closely with Dr. David Bennett (Rush University Medical Center) and Dr. Philip De Jager (Brigham and Women's Hospital, Harvard Medical School, and the Broad Institute). Our goal is to perform joint meta-analyses in a combined cohort of more than 2,000 prospectively acquired brain autopsies. These efforts will substantially enhance the power of our genetic analyses of AD pathology traits. In addition, we are applying the endophenotype strategy to the functional investigation and discovery of PD susceptibility genes. First, we are investigating the large number of emerging PD loci for associations with endophenotypes, including alpha-synuclein Lewy bodies, substantia nigra neuronal loss, and the development of parkinsonian motor signs. Second, we are performing a genome-wide scan in our collaborative autopsy cohort to identify susceptibility loci for Lewy body pathology. Discovered variants will be interrogated for their impact along the causal chain of disease, evaluating associations for nigral degeneration and parkinsonism, and we will also determine if these loci impact clinical PD.
We are also developing cohorts of well-characterized patients and families with PD and related movement disorders, including longitudinal data on disease progression, co-morbidities, and medication response. This work is performed in collaboration with clinician-investigators in the Baylor Parkinson's Disease Center and Movement Disorders Clinic and the University of Maryland Parkinson's Disease Center. Our investigation of these valuable study populations are complementary to the projects described above, allowing further exploration of the contribution of common and rare genomic variation to disease susceptibility and progression.