Genome-wide mapping of IBD segments in an Ashkenazi PD cohort identifies associated haplotypes.
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.
Department of Computer Science, Columbia University, New York, NY, USA.
Vladimir
V
Vacic
Department of Genetics and Genomic Sciences and Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA.
Laurie J
LJ
Ozelius
Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain.
Lorraine N
LN
Clark
Genetic Institute and.
Anat
A
Bar-Shira
Genetic Institute and.
Mali
M
Gana-Weisz
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.
Tanya
T
Gurevich
Department of Computer Science, Columbia University, New York, NY, USA.
Alexander
A
Gusev
Genetic Institute and.
Merav
M
Kedmi
Department of Computer Science, Columbia University, New York, NY, USA.
Eimear E
EE
Kenny
Department of Pathology and Cell Biology.
Xinmin
X
Liu
Gertrude H. Sergievsky Center.
Helen
H
Mejia-Santana
Department of Neurology, Movement Disorders Unit and Parkinson Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Anat
A
Mirelman
Mirken Department of Neurology, Beth Israel Medical Center, New York, NY, USA.
Deborah
D
Raymond
Mirken Department of Neurology, Beth Israel Medical Center, New York, NY, USA The Saul R. Korey Department of Neurology.
Rachel
R
Saunders-Pullman
Department of Genetics and Genomic Sciences and.
Robert J
RJ
Desnick
Department of Medicine, Department of Genetics, Institute for Aging Research.
Gil
G
Atzmon
Department of Medicine.
Edward R
ER
Burns
Department of Genetics, Department of Pathology, Department of Pediatrics.
Harry
H
Ostrer
Center for Applied Genomics, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Hakon
H
Hakonarson
Department of Systems and Computational Biology and.
Aviv
A
Bergman
Department of Medicine, Department of Genetics, Institute for Aging Research.
Nir
N
Barzilai
Department of Genetics, Institute of Life Sciences, Hebrew University of Jerusalem, Givat Ram, Jerusalem, Israel.
Ariel
A
Darvasi
Department of Genetics and Genomic Sciences and.
Inga
I
Peter
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.
Saurav
S
Guha
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.
Todd
T
Lencz
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.
Nir
N
Giladi
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.
Karen
K
Marder
Department of Computer Science, Columbia University, New York, NY, USA itsik@cs.columbia.edu.
Itsik
I
Pe'er
Mirken Department of Neurology, Beth Israel Medical Center, New York, NY, USA The Saul R. Korey Department of Neurology.
Susan B
SB
Bressman
Genetic Institute and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Avi
A
Orr-Urtreger
D000368:Aged; D002874:Chromosome Mapping; D015331:Cohort Studies; D003710:Demography; D005006:Ethnicity / Q000235:genetics*; D005260:Female; D005789:Genealogy and Heraldry; D056426:Genetic Loci / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D010300:Parkinson Disease / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015203:Reproducibility of Results