Genome-wide association study reveals genetic risk underlying Parkinson's disease
National Institutes of Health1, University of Tübingen2, University of Coimbra3, University College London4, University of Luxembourg5, University of Lübeck6, Washington University in St. Louis7, University of Bonn8, University of Florida9, University of Kiel10, Baylor College of Medicine11, Scripps Research Institute12, AARP13, Penn State Milton S. Hershey Medical Center14
TL;DR: It is demonstrated that an unequivocal role for common genetic variants in the etiology of typical PD and population-specific genetic heterogeneity in this disease is suggested, and supporting evidence that common variation around LRRK2 modulates risk for PD is provided.
Abstract: We performed a genome-wide association study (GWAS) in 1,713 individuals of European ancestry with Parkinson's disease (PD) and 3,978 controls. After replication in 3,361 cases and 4,573 controls, we observed two strong association signals, one in the gene encoding a-synuclein (SNCA; rs2736990, OR = 1.23, P = 2.24 x 10(-16)) and another at the MAPT locus (rs393152, OR = 0.77, P = 1.95 x 10(-16)). We exchanged data with colleagues performing a GWAS in Japanese PD cases. Association to PD at SNCA was replicated in the Japanese GWAS1, confirming this as a major risk locus across populations. We replicated the effect of a new locus detected in the Japanese cohort (PARK16, rs823128, OR = 0.66, P = 7.29 x 10(-8)) and provide supporting evidence that common variation around LRRK2 modulates risk for PD (rs1491923, OR = 1.14, P = 1.55 x 10(-5)). These data demonstrate an unequivocal role for common genetic variants in the etiology of typical PD and suggest population-specific genetic heterogeneity in this disease.
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TL;DR: It is found that in wild-type nontransgenic mice, a single intrastriatal inoculation of synthetic α- Syn fibrils led to the cell-to-cell transmission of pathologic α-Syn and Parkinson’s-like Lewy pathology in anatomically interconnected regions.
Abstract: Parkinson's disease is characterized by abundant α-synuclein (α-Syn) neuronal inclusions, known as Lewy bodies and Lewy neurites, and the massive loss of midbrain dopamine neurons. However, a cause-and-effect relationship between Lewy inclusion formation and neurodegeneration remains unclear. Here, we found that in wild-type nontransgenic mice, a single intrastriatal inoculation of synthetic α-Syn fibrils led to the cell-to-cell transmission of pathologic α-Syn and Parkinson's-like Lewy pathology in anatomically interconnected regions. Lewy pathology accumulation resulted in progressive loss of dopamine neurons in the substantia nigra pars compacta, but not in the adjacent ventral tegmental area, and was accompanied by reduced dopamine levels culminating in motor deficits. This recapitulation of a neurodegenerative cascade thus establishes a mechanistic link between transmission of pathologic α-Syn and the cardinal features of Parkinson's disease.
1,948 citations
Cites background from "Genome-wide association study revea..."
...The etiology of these processes remains unclear, although in familial PD, autosomal dominant α-Syn gene mutations or amplifications directly link α-Syn dysfunction to disease causation (2, 3)....
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TL;DR: An overview of current knowledge and prevailing hypotheses regarding the conformational, oligomerization and aggregation states of α-syn and their role in regulating α- synuclein function in health and disease is provided.
Abstract: Disorders characterized by α-synuclein (α-syn) accumulation, Lewy body formation and parkinsonism (and in some cases dementia) are collectively known as Lewy body diseases. The molecular mechanism (or mechanisms) through which α-syn abnormally accumulates and contributes to neurodegeneration in these disorders remains unknown. Here, we provide an overview of current knowledge and prevailing hypotheses regarding the conformational, oligomerization and aggregation states of α-syn and their role in regulating α-syn function in health and disease. Understanding the nature of the various α-syn structures, how they are formed and their relative contributions to α-syn-mediated toxicity may inform future studies aiming to develop therapeutic prevention and intervention.
1,281 citations
TL;DR: The results identify two new PD susceptibility loci, show involvement of autosomal dominant parkinsonism loci in typical PD and suggest that population differences contribute to genetic heterogeneity in PD.
Abstract: To identify susceptibility variants for Parkinson's disease (PD), we performed a genome-wide association study (GWAS) and two replication studies in a total of 2,011 cases and 18,381 controls from Japan. We identified a new susceptibility locus on 1q32 (P = 1.52 x 10(-12)) and designated this as PARK16, and we also identified BST1 on 4p15 as a second new risk locus (P = 3.94 x 10(-9)). We also detected strong associations at SNCA on 4q22 (P = 7.35 x 10(-17)) and LRRK2 on 12q12 (P = 2.72 x 10(-8)), both of which are implicated in autosomal dominant forms of parkinsonism. By comparing results of a GWAS performed on individuals of European ancestry, we identified PARK16, SNCA and LRRK2 as shared risk loci for PD and BST1 and MAPT as loci showing population differences. Our results identify two new PD susceptibility loci, show involvement of autosomal dominant parkinsonism loci in typical PD and suggest that population differences contribute to genetic heterogeneity in PD.
1,206 citations
TL;DR: The relevance of Lewy's discovery 100 years ago for the current understanding of PD and related disorders is reviewed.
Abstract: In 1817, James Parkinson described the symptoms of the shaking palsy, a disease that was subsequently defined in greater detail, and named after Parkinson, by Jean-Martin Charcot. Parkinson expected that the publication of his monograph would lead to a rapid elucidation of the anatomical substrate of the shaking palsy; in the event, this process took almost a century. In 1912, Fritz Heinrich Lewy identified the protein aggregates that define Parkinson disease (PD) in some brain regions outside the substantia nigra. In 1919, Konstantin Nikolaevich Tretiakoff found similar aggregates in the substantia nigra and named them after Lewy. In the 1990s, α-synuclein was identified as the main constituent of the Lewy pathology, and its aggregation was shown to be central to PD, dementia with Lewy bodies, and multiple system atrophy. In 2003, a staging scheme for idiopathic PD was introduced, according to which α-synuclein pathology originates in the dorsal motor nucleus of the vagal nerve and progresses from there to other brain regions, including the substantia nigra. In this article, we review the relevance of Lewy's discovery 100 years ago for the current understanding of PD and related disorders.
925 citations
TL;DR: These data provide an insight into the genetics of Parkinson's disease and the molecular cause of the disease and could provide future targets for therapies.
895 citations
References
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TL;DR: This work introduces PLINK, an open-source C/C++ WGAS tool set, and describes the five main domains of function: data management, summary statistics, population stratification, association analysis, and identity-by-descent estimation, which focuses on the estimation and use of identity- by-state and identity/descent information in the context of population-based whole-genome studies.
Abstract: Whole-genome association studies (WGAS) bring new computational, as well as analytic, challenges to researchers. Many existing genetic-analysis tools are not designed to handle such large data sets in a convenient manner and do not necessarily exploit the new opportunities that whole-genome data bring. To address these issues, we developed PLINK, an open-source C/C++ WGAS tool set. With PLINK, large data sets comprising hundreds of thousands of markers genotyped for thousands of individuals can be rapidly manipulated and analyzed in their entirety. As well as providing tools to make the basic analytic steps computationally efficient, PLINK also supports some novel approaches to whole-genome data that take advantage of whole-genome coverage. We introduce PLINK and describe the five main domains of function: data management, summary statistics, population stratification, association analysis, and identity-by-descent estimation. In particular, we focus on the estimation and use of identity-by-state and identity-by-descent information in the context of population-based whole-genome studies. This information can be used to detect and correct for population stratification and to identify extended chromosomal segments that are shared identical by descent between very distantly related individuals. Analysis of the patterns of segmental sharing has the potential to map disease loci that contain multiple rare variants in a population-based linkage analysis.
26,280 citations
"Genome-wide association study revea..." refers methods in this paper
...For association analyses, all estimates and tests were performed with the PLINK toolse...
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TL;DR: Haploview is a software package that provides computation of linkage disequilibrium statistics and population haplotype patterns from primary genotype data in a visually appealing and interactive interface.
Abstract: Summary: Research over the last few years has revealed significant haplotype structure in the human genome. The characterization of these patterns, particularly in the context of medical genetic association studies, is becoming a routine research activity. Haploview is a software package that provides computation of linkage disequilibrium statistics and population haplotype patterns from primary genotype data in a visually appealing and interactive interface.
Availability: http://www.broad.mit.edu/mpg/haploview/
Contact: jcbarret@broad.mit.edu
13,862 citations
TL;DR: The pathological findings in 100 patients diagnosed prospectively by a group of consultant neurologists as having idiopathic Parkinson's disease are reported, and these observations call into question current concepts of Parkinson's Disease as a single distinct morbid entity.
Abstract: Few detailed clinico-pathological correlations of Parkinson's disease have been published. The pathological findings in 100 patients diagnosed prospectively by a group of consultant neurologists as having idiopathic Parkinson's disease are reported. Seventy six had nigral Lewy bodies, and in all of these Lewy bodies were also found in the cerebral cortex. In 24 cases without Lewy bodies, diagnoses included progressive supranuclear palsy, multiple system atrophy, Alzheimer's disease, Alzheimer-type pathology, and basal ganglia vascular disease. The retrospective application of recommended diagnostic criteria improved the diagnostic accuracy to 82%. These observations call into question current concepts of Parkinson's disease as a single distinct morbid entity.
9,411 citations
"Genome-wide association study revea..." refers background in this paper
...All patients were diagnosed according to the UK Brain Bank criteri...
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TL;DR: A mutation was identified in the α-synuclein gene, which codes for a presynaptic protein thought to be involved in neuronal plasticity, in the Italian kindred and in three unrelated families of Greek origin with autosomal dominant inheritance for the PD phenotype.
Abstract: Parkinson's disease (PD) is a common neurodegenerative disorder with a lifetime incidence of approximately 2 percent. A pattern of familial aggregation has been documented for the disorder, and it was recently reported that a PD susceptibility gene in a large Italian kindred is located on the long arm of human chromosome 4. A mutation was identified in the α-synuclein gene, which codes for a presynaptic protein thought to be involved in neuronal plasticity, in the Italian kindred and in three unrelated families of Greek origin with autosomal dominant inheritance for the PD phenotype. This finding of a specific molecular alteration associated with PD will facilitate the detailed understanding of the pathophysiology of the disorder.
7,387 citations
Baylor College of Medicine1, Chinese Academy of Sciences2, Chinese National Human Genome Center3, University of Hong Kong4, The Chinese University of Hong Kong5, Hong Kong University of Science and Technology6, Illumina7, McGill University8, Washington University in St. Louis9, University of California, San Francisco10, Wellcome Trust Sanger Institute11, Beijing Normal University12, Health Sciences University of Hokkaido13, Shinshu University14, University of Tsukuba15, Howard University16, University of Ibadan17, Case Western Reserve University18, University of Utah19, Cold Spring Harbor Laboratory20, Johns Hopkins University21, University of Oxford22, North Carolina State University23, National Institutes of Health24, Massachusetts Institute of Technology25, Chinese Academy of Social Sciences26, Kyoto University27, Nagasaki University28, Wellcome Trust29, Genome Canada30, Foundation for the National Institutes of Health31, University of Maryland, Baltimore32, Vanderbilt University33, Stanford University34, University of California, Berkeley35, New York University36, University of Oklahoma37, University of New Mexico38, Université de Montréal39, University of California, Los Angeles40, University of Michigan41, University of Wisconsin-Madison42, London School of Economics and Political Science43, Genetic Alliance44, GlaxoSmithKline45, University of Washington46, Harvard University47, University of Chicago48, Fred Hutchinson Cancer Research Center49, University of Tokyo50
TL;DR: The HapMap will allow the discovery of sequence variants that affect common disease, will facilitate development of diagnostic tools, and will enhance the ability to choose targets for therapeutic intervention.
Abstract: The goal of the International HapMap Project is to determine the common patterns of DNA sequence variation in the human genome and to make this information freely available in the public domain. An international consortium is developing a map of these patterns across the genome by determining the genotypes of one million or more sequence variants, their frequencies and the degree of association between them, in DNA samples from populations with ancestry from parts of Africa, Asia and Europe. The HapMap will allow the discovery of sequence variants that affect common disease, will facilitate development of diagnostic tools, and will enhance our ability to choose targets for therapeutic intervention.
5,926 citations