Abstract
Uncovering the genetic risk and protective factors for complex diseases is of fundamental importance for advancing therapeutic and biomarker discoveries. This endeavor is particularly challenging for neuropsychiatric diseases where diagnoses predominantly rely on the clinical presentation, which may be heterogeneous, possibly due to the heterogeneity of the underlying genetic susceptibility factors and environmental exposures. Although genome-wide association studies of various neuropsychiatric diseases have recently identified susceptibility loci, there likely remain additional genetic risk factors that underlie the liability to these conditions. Furthermore, identification and characterization of the causal risk variant(s) in each of these novel susceptibility loci constitute a formidable task, particularly in the absence of any prior knowledge about their function or mechanism of action. Biologically relevant, quantitative phenotypes, i.e., endophenotypes, provide a powerful alternative to the more traditional, binary disease phenotypes in the discovery and characterization of susceptibility genes for neuropsychiatric conditions. In this review, we focus on Alzheimer's disease (AD) as a model neuropsychiatric disease and provide a synopsis of the recent literature on the use of endophenotypes in AD genetics. We highlight gene expression, neuropathology and cognitive endophenotypes in AD, with examples demonstrating the utility of these alternative approaches in the discovery of novel susceptibility genes and pathways. In addition, we discuss how these avenues generate testable hypothesis about the pathophysiology of genetic factors that have far-reaching implications for therapies.