Vacic Vladimir, Ozelius Laurie J, Clark Lorraine N, Bar-Shira Anat, Gana-Weisz Mali, Gurevich Tanya, Gusev Alexander, Kedmi Merav, Kenny Eimear E, Liu Xinmin, Mejia-Santana Helen, Mirelman Anat, Raymond Deborah, Saunders-Pullman Rachel, Desnick Robert J, Atzmon Gil, Burns Edward R, Ostrer Harry, Hakonarson Hakon, Bergman Aviv, Barzilai Nir, Darvasi Ariel, Peter Inga, Guha Saurav, Lencz Todd, Giladi Nir, Marder Karen, Pe'er Itsik, Bressman Susan B, Orr-Urtreger Avi
Department of Computer Science, Columbia University, New York, NY, USA.
Department of Genetics and Genomic Sciences and Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA.
Hum Mol Genet. 2014 Sep 1;23(17):4693-702. doi: 10.1093/hmg/ddu158. Epub 2014 May 19.
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.
近期在欧洲和日本人群中开展的一系列大规模全基因组关联研究证实，帕金森病（PD）具有显著的遗传成分。为进一步探究PD的遗传图谱，我们在迄今最大的1130例帕金森病患者和2611例汇总对照的阿什肯纳兹犹太人群体中进行了全基因组扫描。鉴于该奠基者群体中疾病等位基因异质性降低以及高度的同源染色体片段共享，我们基于共享的同源染色体片段图谱开展了单倍型关联研究。我们在三个先前已涉及的帕金森病位点观察到显著的单倍型关联信号：LRRK2（比值比[OR]=12.05，P=1.23×10⁻⁵⁶）、MAPT（OR=0.62，P=1.78×10⁻¹¹）和GBA（多个不同单倍型，OR>8.28，P=1.13×10⁻¹¹以及OR=2.50，P=1.22×10⁻⁹）。此外，我们在2号染色体q14.3区域鉴定出一个来自罕见单倍型的新型关联信号（OR=22.58，P=1.21×10⁻¹⁰），并在306例阿什肯纳兹帕金森病病例和2583例对照的第二个队列中进行了验证。我们的结果凸显了我们单倍型关联方法的效能，该方法在奠基者群体研究中尤为有用，并重申了在阿什肯纳兹犹太人群体中研究复杂疾病的益处。
