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

Vladimir Vacic, Laurie J. Ozelius, Lorraine N. Clark, Anat Bar-Shira, Mali Gana-Weisz, Tanya Gurevich, Alexander Gusev, Merav Kedmi, Eimear E. Kenny, Xinmin Liu, Helen Mejia-Santana, Anat Mirelman, Deborah Raymond, Rachel Saunders-Pullman, Robert J. Desnick, Gil Atzmon, Edward R. Burns, Harry Ostrer, Hakon Hakonarson, Aviv BergmanNir Barzilai, Ariel Darvasi, Inga Peter, Saurav Guha, Todd Lencz, Nir Giladi, Karen Marder, Itsik Pe'er, Susan B. Bressman, Avi Orr-Urtreger

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

The recent series of large genome-wide association studies in European and Japanese cohorts established that Parkinson disease (PD) has a substantial geneticcomponent.Tofurther investigate the genetic landscape of PD, weperformed agenome-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-bydescent (IBD) haplotype sharing in this founder population, we conducted a haplotype association study based on mapping of shared IBD segments.Weobserved significant haplotype association signals at three previously implicated Parkinson loci: LRRK2 (OR 5 12.05, P 5 1.23 3 10-56), MAPT(OR 5 0.62, P 5 1.78 3 10-11) and GBA (multiple distinct haplotypes, OR > 8.28, P 5 1.13 3 10-11 and OR 5 2.50, P 5 1.22 3 10-9). In addition, we identified a novel association signal on chr2q14.3 coming from a rare haplotype (OR 5 22.58, P 5 1.21 3 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.

Original languageEnglish (US)
Article numberddu158
Pages (from-to)4693-4702
Number of pages10
JournalHuman molecular genetics
Volume23
Issue number17
DOIs
StatePublished - Sep 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Vacic, V., Ozelius, L. J., Clark, L. N., Bar-Shira, A., Gana-Weisz, M., Gurevich, T., Gusev, A., Kedmi, M., Kenny, E. E., Liu, X., Mejia-Santana, H., Mirelman, A., Raymond, D., Saunders-Pullman, R., Desnick, R. J., Atzmon, G., Burns, E. R., Ostrer, H., Hakonarson, H., ... Orr-Urtreger, A. (2014). Genome-wide mapping of IBD segments in an Ashkenazi PD cohort identifies associated haplotypes. Human molecular genetics, 23(17), 4693-4702. [ddu158]. https://doi.org/10.1093/hmg/ddu158