Browsing by Author "Trinh, Joanne"

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    Genome-wide case-only analysis of gene-gene interactions with known Parkinson's disease risk variants reveals link between LRRK2 and SYT10
    (Springer Nature, 2023-06-29) Aleknonytė-Resch, Milda; Trinh, Joanne; Leonard, Hampton; Delcambre, Sylvie; Leitão, Elsa; Lai, Dongbing; Smajić, Semra; Orr-Urtreger, Avi; Thaler, Avner; Blauwendraat, Cornelis; Sharma, Arunabh; Makarious, Mary B.; Kim, Jonggeol Jeff; Lake, Julie; Rahmati, Pegah; Freitag-Wolf, Sandra; Seibler, Philip; Foroud, Tatiana; Singleton, Andrew B.; The International Parkinson Disease Genomics Consortium; Grünewald, Anne; Kaiser, Frank; Klein, Christine; Krawczak, Michael; Dempfle, Astrid; Medical and Molecular Genetics, School of Medicine
    The effects of one genetic factor upon Parkinson’s disease (PD) risk may be modified by other genetic factors. Such gene-gene interaction (G×G) could explain some of the ‘missing heritability’ of PD and the reduced penetrance of known PD risk variants. Using the largest single nucleotide polymorphism (SNP) genotype data set currently available for PD (18,688 patients), provided by the International Parkinson’s Disease Genomics Consortium, we studied G×G with a case-only (CO) design. To this end, we paired each of 90 SNPs previously reported to be associated with PD with one of 7.8 million quality-controlled SNPs from a genome-wide panel. Support of any putative G×G interactions found was sought by the analysis of independent genotype-phenotype and experimental data. A total of 116 significant pairwise SNP genotype associations were identified in PD cases, pointing towards G×G. The most prominent associations involved a region on chromosome 12q containing SNP rs76904798, which is a non-coding variant of the LRRK2 gene. It yielded the lowest interaction p-value overall with SNP rs1007709 in the promoter region of the SYT10 gene (interaction OR = 1.80, 95% CI: 1.65–1.95, p = 2.7 × 10−43). SNPs around SYT10 were also associated with the age-at-onset of PD in an independent cohort of carriers of LRRK2 mutation p.G2019S. Moreover, SYT10 gene expression during neuronal development was found to differ between cells from affected and non-affected p.G2019S carriers. G×G interaction on PD risk, involving the LRRK2 and SYT10 gene regions, is biologically plausible owing to the known link between PD and LRRK2, its involvement in neural plasticity, and the contribution of SYT10 to the exocytosis of secretory vesicles in neurons.
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    Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease
    (Wiley, 2021-07) Lai, Dongbing; Alipanahi, Babak; Fontanillas, Pierre; Schwantes, Tae-Hwi; Aasly, Jan; Alcalay, Roy N.; Beecham, Gary W.; Berg, Daniela; Bressman, Susan; Brice, Alexis; Brockman, Kathrin; Clark, Lorraine; Cookson, Mark; Das, Sayantan; Van Deerlin, Vivianna; Follett, Jordan; Farrer, Matthew J.; Trinh, Joanne; Gasser, Thomas; Goldwurm, Stefano; Gustavsson, Emil; Klein, Christine; Lang, Anthony E.; Langston, J. William; Latourelle, Jeanne; Lynch, Timothy; Marder, Karen; Marras, Connie; Martin, Eden R.; McLean, Cory Y.; Mejia-Santana, Helen; Molho, Eric; Myers, Richard H.; Nuytemans, Karen; Ozelius, Laurie; Payami, Haydeh; Raymond, Deborah; Rogaeva, Ekaterina; Rogers, Michael P.; Ross, Owen A.; Samii, Ali; Saunders-Pullman, Rachel; Schüle, Birgitt; Schulte, Claudia; Scott, William K.; Tanner, Caroline; Tolosa, Eduardo; Tomkins, James E.; Vilas, Dolores; Trojanowski, John Q.; Uitti, Ryan; Vance, Jeffery M.; Visanji, Naomi P.; Wszolek, Zbigniew K.; Zabetian, Cyrus P.; Mirelman, Anat; Giladi, Nir; Urtreger, Avi Orr; Cannon, Paul; Fiske, Brian; Foroud, Tatiana; Medical and Molecular Genetics, School of Medicine
    Objective: The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease. Methods: We performed the first genomewide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genomewide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers. Results: A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; p value = 2.5E-08, beta = 1.27, SE = 0.23, risk allele: C) met genomewide significance for the penetrance model. Co-immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these 2 proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: p value = 1.1E-07; age-at-onset top variant: p value = 9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset. Interpretation: This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations. ANN NEUROL 2021;90:82-94.