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Hum Mol Genet. 2014 Sep 1;23(17):4693-702. doi: 10.1093/hmg/ddu158. Epub 2014 May 19.

Genome-wide mapping of IBD segments in an Ashkenazi PD cohort identifies associated haplotypes.

Author information

1
Department of Computer Science, Columbia University, New York, NY, USA.
2
Department of Genetics and Genomic Sciences and Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA.
3
Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain.
4
Genetic Institute and.
5
Department of Neurology, Movement Disorders Unit and Parkinson Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
6
Department of Pathology and Cell Biology.
7
Gertrude H. Sergievsky Center.
8
Department of Neurology, Movement Disorders Unit and Parkinson Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
9
Mirken Department of Neurology, Beth Israel Medical Center, New York, NY, USA.
10
Mirken Department of Neurology, Beth Israel Medical Center, New York, NY, USA The Saul R. Korey Department of Neurology.
11
Department of Genetics and Genomic Sciences and.
12
Department of Medicine, Department of Genetics, Institute for Aging Research.
13
Department of Medicine.
14
Department of Genetics, Department of Pathology, Department of Pediatrics.
15
Center for Applied Genomics, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
16
Department of Systems and Computational Biology and.
17
Department of Genetics, Institute of Life Sciences, Hebrew University of Jerusalem, Givat Ram, Jerusalem, Israel.
18
Department of Genetics and Genomic Sciences and Department of Psychiatry, Division of Research, The Zucker Hillside Hospital Division of the North Shore-Long Island Jewish Health System, Glen Oaks, NY, USA.
19
Department of Psychiatry, Division of Research, The Zucker Hillside Hospital Division of the North Shore-Long Island Jewish Health System, Glen Oaks, NY, USA Center for Psychiatric Neuroscience, The Feinstein Institute for Medical Research, Manhasset, NY, USA Department of Psychiatry and Behavioral Science, Albert Einstein College of Medicine, Bronx, NY, USA Department of Psychiatry and Department of Molecular Medicine, Hofstra University School of Medicine, Hempstead, NY, USA.
20
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Gertrude H. Sergievsky Center, Department of Neurology and Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
21
Department of Computer Science, Columbia University, New York, NY, USA itsik@cs.columbia.edu.
22
Genetic Institute and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Abstract

The recent series of large genome-wide association studies in European and Japanese cohorts established that Parkinson disease (PD) has a substantial genetic component. To further investigate the genetic landscape of PD, we performed a genome-wide scan in the largest to date Ashkenazi Jewish cohort of 1130 Parkinson patients and 2611 pooled controls. Motivated by the reduced disease allele heterogeneity and a high degree of identical-by-descent (IBD) haplotype sharing in this founder population, we conducted a haplotype association study based on mapping of shared IBD segments. We observed significant haplotype association signals at three previously implicated Parkinson loci: LRRK2 (OR = 12.05, P = 1.23 × 10(-56)), MAPT (OR = 0.62, P = 1.78 × 10(-11)) and GBA (multiple distinct haplotypes, OR > 8.28, P = 1.13 × 10(-11) and OR = 2.50, P = 1.22 × 10(-9)). In addition, we identified a novel association signal on chr2q14.3 coming from a rare haplotype (OR = 22.58, P = 1.21 × 10(-10)) and replicated it in a secondary cohort of 306 Ashkenazi PD cases and 2583 controls. Our results highlight the power of our haplotype association method, particularly useful in studies of founder populations, and reaffirm the benefits of studying complex diseases in Ashkenazi Jewish cohorts.

PMID:
24842889
PMCID:
PMC4119402
DOI:
10.1093/hmg/ddu158
[Indexed for MEDLINE]
Free PMC Article

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