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JAMA Neurol. 2013 Jun;70(6):719-26. doi: 10.1001/jamaneurol.2013.275.

An inflection point in gene discovery efforts for neurodegenerative diseases: from syndromic diagnoses toward endophenotypes and the epigenome.

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Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women’s Hospital, Boston, Massachusetts, USA.


We are at an inflection point in our study of the human genome as it relates to neurodegenerative disease. The sequencing of the human genome, and its associated cataloging of human genetic variation and technological as well as methodological development, introduced a period of rapid gene discovery over the past decade. These efforts have yielded many new insights and will continue to uncover the genetic architecture of syndromically defined neurodegenerative diseases in the coming decades. More recently, these successful study designs have been applied to the investigation of intermediate traits that relate to and inform our understanding of clinical syndromes and to exploration of the epigenome, the higher-order structure of DNA that dictates the expression of a given genetic risk factor. While still nascent, given the challenges of accumulating large numbers of subjects with detailed phenotypes and technological hurdles in characterizing the state of chromatin, these efforts represent key investments that will enable the study of the functional consequences of a genetic risk factor and, eventually, its contribution to the clinical manifestations of a given disease. As a community of investigators, we are therefore at an exciting inflection point at which gene discovery efforts are transitioning toward the functional characterization of implicated genetic variation; this transition is crucial for understanding the molecular, cellular, and systemic events that lead to a syndromic diagnosis for a neurodegenerative disease.

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