Towards Unveiling the Genetics of Neurodegenerative Diseases Christina M. Lill, M.D., 1,2 and Lars Bertram, M.D. 1 ABSTRACT In addition to sharing several clinical, pathologic, and molecular characteristics, many neurodegenerative disorders show extensive familial histories suggesting a substantial contribution of genetic factors to disease causation and progression. In this review, the authors provide overviews of the status of current genetics research in Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, and amyotrophic lateral sclerosis. Across these four disorders alone, nearly 60 different loci can now be considered as established to be involved in pathogenesis for both Mendelian and non-Mendelian disease forms. In addition to reviewing the most compelling of these loci based on current data from genome-wide association studies and next-generation sequencing projects, genes that have been linked to more than one disease entity are emphasized. Such overlapping findings could point to one or several common genetic and mechanistic denominators for neuronal death in neurodegeneration. Unveiling the identity of these and other genetic factors will not only improve our understanding of the underlying pathophysiology, but may also lead to new avenues for preventing and treating these devastating diseases. KEYWORDS: Neurodegeneration, neurodegenerative disease, genetics, mutation, polymorphism, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, AlzGene, PDGene, ALSGene, genome-wide association study, GWAS, meta-analysis GENETIC ASPECTS OF COMMON NEURODEGENERATIVE DISEASES Many neurodegenerative diseases share several clinical, pathologic, and molecular characteristics. 1 Clinically, these disorders are often represented by an insidious onset during adulthood, after which they progress at varying rates, ultimately leading to severe physical dis- ability or death. Clinical symptoms are often common to more than one disease: dementia is not only a character- istic of Alzheimer’s disease (AD) or frontotemporal dementia (FTD), but can also accompany Parkinson’s disease (PD) or amyotrophic lateral sclerosis (ALS). Pathologically, neurodegeneration is initially limited to specific types of cells or tissues in the central nervous system (CNS), for example, dopaminergic neurons in the substantia nigra in PD or hippocampal neurons in AD. In later stages, it often extends to other regions of the CNS, frequently leading to substantial macroscopic atrophy. In addition to these alterations, neuronal cell death is often accompanied by widespread inflammation and immune activation. Histopathologically, many neu- rodegenerative diseases are characterized by deposits of 1 Departments of Vertebrate Genomics, Neuropsychiatric Genetics Group, Max Planck Institute for Molecular Genetics, Berlin; 2 Neurol- ogy, University Medical Center of the Johannes Gutenberg University, Mainz, Germany. Address for correspondence and reprint requests: Lars Bertram, M.D., Head, Neuropsychiatric Genetics Group, Department of Vertebrate Genomics, Max-Planck Institute for Molecular Genetics, Ihnestrasse 63, Room 204.1, 14195 Berlin, Germany (e-mail: bertram@molgen.mpg.de). Neurogenetics; Guest Editor, Christine Klein, M.D. Semin Neurol 2011;31:531–541. Copyright # 2011 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. DOI: http://dx.doi.org/10.1055/s-0031-1299791. ISSN 0271-8235. 531 Downloaded by: Stanford University. Copyrighted material.