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1. Investigation of Shared Genetic Risk Factors Between Parkinson's Disease and Cancers

Author

Sugier, P, Lucotte, E, Domenighetti, C, Law, M, Iles, M, Brown, K, Amos, C, Mckay, J, Hung, R, Karimi, M, Bacq-Daian, D, Boland-Auge, A, Olaso, R, Deleuze, J, Lesueur, F, Ostroumova, E, Kesminiene, A, de Vathaire, F, Guenel, P, Sreelatha, A, Schulte, C, Grover, S, May, P, Bobbili, D, Radivojkov-Blagojevic, M, Lichtner, P, Singleton, A, Hernandez, D, Edsall, C, Mellick, G, Zimprich, A, Pirker, W, Rogaeva, E, Lang, A, Koks, S, Taba, P, Lesage, S, Brice, A, Corvol, J, Chartier-Harlin, M, Mutez, E, Brockmann, K, Deutschlander, A, Hadjigeorgiou, G, Dardiotis, E, Stefanis, L, Simitsi, A, Valente, E, Petrucci, S, Straniero, L, Zecchinelli, A, Pezzoli, G, Brighina, L, Ferrarese, C, Annesi, G, Quattrone, A, Gagliardi, M, Matsuo, H, Nakayama, A, Hattori, N, Nishioka, K, Chung, S, Kim, Y, Kolber, P, van de Warrenburg, B, Bloem, B, Aasly, J, Toft, M, Pihlstrom, L, Guedes, L, Ferreira, J, Bardien, S, Carr, J, Tolosa, E, Ezquerra, M, Pastor, P, Diez-Fairen, M, Wirdefeldt, K, Pedersen, N, Ran, C, Belin, A, Puschmann, A, Rodstrom, E, Clarke, C, Morrison, K, Tan, M, Krainc, D, Burbulla, L, Farrer, M, Kruger, R, Gasser, T, Sharma, M, Truong, T, Elbaz, A, Sugier P. -E., Lucotte E. A., Domenighetti C., Law M. H., Iles M. M., Brown K., Amos C., McKay J. D., Hung R. J., Karimi M., Bacq-Daian D., Boland-Auge A., Olaso R., Deleuze J. -F., Lesueur F., Ostroumova E., Kesminiene A., de Vathaire F., Guenel P., Sreelatha A. A. K., Schulte C., Grover S., May P., Bobbili D. R., Radivojkov-Blagojevic M., Lichtner P., Singleton A. B., Hernandez D. G., Edsall C., Mellick G. D., Zimprich A., Pirker W., Rogaeva E., Lang A. E., Koks S., Taba P., Lesage S., Brice A., Corvol J. -C., Chartier-Harlin M. -C., Mutez E., Brockmann K., Deutschlander A. B., Hadjigeorgiou G. M., Dardiotis E., Stefanis L., Simitsi A. M., Valente E. M., Petrucci S., Straniero L., Zecchinelli A., Pezzoli G., Brighina L., Ferrarese C., Annesi G., Quattrone A., Gagliardi M., Matsuo H., Nakayama A., Hattori N., Nishioka K., Chung S. J., Kim Y. J., Kolber P., van de Warrenburg B. P. C., Bloem B. R., Aasly J., Toft M., Pihlstrom L., Guedes L. C., Ferreira J. J., Bardien S., Carr J., Tolosa E., Ezquerra M., Pastor P., Diez-Fairen M., Wirdefeldt K., Pedersen N., Ran C., Belin A. C., Puschmann A., Rodstrom E. Y., Clarke C. E., Morrison K. E., Tan M., Krainc D., Burbulla L. F., Farrer M. J., Kruger R., Gasser T., Sharma M., Truong T., Elbaz A., Sugier, P, Lucotte, E, Domenighetti, C, Law, M, Iles, M, Brown, K, Amos, C, Mckay, J, Hung, R, Karimi, M, Bacq-Daian, D, Boland-Auge, A, Olaso, R, Deleuze, J, Lesueur, F, Ostroumova, E, Kesminiene, A, de Vathaire, F, Guenel, P, Sreelatha, A, Schulte, C, Grover, S, May, P, Bobbili, D, Radivojkov-Blagojevic, M, Lichtner, P, Singleton, A, Hernandez, D, Edsall, C, Mellick, G, Zimprich, A, Pirker, W, Rogaeva, E, Lang, A, Koks, S, Taba, P, Lesage, S, Brice, A, Corvol, J, Chartier-Harlin, M, Mutez, E, Brockmann, K, Deutschlander, A, Hadjigeorgiou, G, Dardiotis, E, Stefanis, L, Simitsi, A, Valente, E, Petrucci, S, Straniero, L, Zecchinelli, A, Pezzoli, G, Brighina, L, Ferrarese, C, Annesi, G, Quattrone, A, Gagliardi, M, Matsuo, H, Nakayama, A, Hattori, N, Nishioka, K, Chung, S, Kim, Y, Kolber, P, van de Warrenburg, B, Bloem, B, Aasly, J, Toft, M, Pihlstrom, L, Guedes, L, Ferreira, J, Bardien, S, Carr, J, Tolosa, E, Ezquerra, M, Pastor, P, Diez-Fairen, M, Wirdefeldt, K, Pedersen, N, Ran, C, Belin, A, Puschmann, A, Rodstrom, E, Clarke, C, Morrison, K, Tan, M, Krainc, D, Burbulla, L, Farrer, M, Kruger, R, Gasser, T, Sharma, M, Truong, T, Elbaz, A, Sugier P. -E., Lucotte E. A., Domenighetti C., Law M. H., Iles M. M., Brown K., Amos C., McKay J. D., Hung R. J., Karimi M., Bacq-Daian D., Boland-Auge A., Olaso R., Deleuze J. -F., Lesueur F., Ostroumova E., Kesminiene A., de Vathaire F., Guenel P., Sreelatha A. A. K., Schulte C., Grover S., May P., Bobbili D. R., Radivojkov-Blagojevic M., Lichtner P., Singleton A. B., Hernandez D. G., Edsall C., Mellick G. D., Zimprich A., Pirker W., Rogaeva E., Lang A. E., Koks S., Taba P., Lesage S., Brice A., Corvol J. -C., Chartier-Harlin M. -C., Mutez E., Brockmann K., Deutschlander A. B., Hadjigeorgiou G. M., Dardiotis E., Stefanis L., Simitsi A. M., Valente E. M., Petrucci S., Straniero L., Zecchinelli A., Pezzoli G., Brighina L., Ferrarese C., Annesi G., Quattrone A., Gagliardi M., Matsuo H., Nakayama A., Hattori N., Nishioka K., Chung S. J., Kim Y. J., Kolber P., van de Warrenburg B. P. C., Bloem B. R., Aasly J., Toft M., Pihlstrom L., Guedes L. C., Ferreira J. J., Bardien S., Carr J., Tolosa E., Ezquerra M., Pastor P., Diez-Fairen M., Wirdefeldt K., Pedersen N., Ran C., Belin A. C., Puschmann A., Rodstrom E. Y., Clarke C. E., Morrison K. E., Tan M., Krainc D., Burbulla L. F., Farrer M. J., Kruger R., Gasser T., Sharma M., Truong T., and Elbaz A.

Abstract

Background: Epidemiological studies that examined the association between Parkinson's disease (PD) and cancers led to inconsistent results, but they face a number of methodological difficulties. Objective: We used results from genome-wide association studies (GWASs) to study the genetic correlation between PD and different cancers to identify common genetic risk factors. Methods: We used individual data for participants of European ancestry from the Courage-PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease; PD, N = 16,519) and EPITHYR (differentiated thyroid cancer, N = 3527) consortia and summary statistics of GWASs from iPDGC (International Parkinson Disease Genomics Consortium; PD, N = 482,730), Melanoma Meta-Analysis Consortium (MMAC), Breast Cancer Association Consortium (breast cancer), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (prostate cancer), International Lung Cancer Consortium (lung cancer), and Ovarian Cancer Association Consortium (ovarian cancer) (N comprised between 36,017 and 228,951 for cancer GWASs). We estimated the genetic correlation between PD and cancers using linkage disequilibrium score regression. We studied the association between PD and polymorphisms associated with cancers, and vice versa, using cross-phenotypes polygenic risk score (PRS) analyses. Results: We confirmed a previously reported positive genetic correlation of PD with melanoma (Gcorr = 0.16 [0.04; 0.28]) and reported an additional significant positive correlation of PD with prostate cancer (Gcorr = 0.11 [0.03; 0.19]). There was a significant inverse association between the PRS for ovarian cancer and PD (odds ratio [OR] = 0.89 [0.84; 0.94]). Conversely, the PRS of PD was positively associated with breast cancer (OR = 1.08 [1.06; 1.10]) and inversely associated with ovarian cancer (OR = 0.95 [0.91; 0.99]). The association between PD and ovarian cancer was mostly driven b

Published
2023

2. Mendelian Randomisation Study of Smoking, Alcohol, and Coffee Drinking in Relation to Parkinson's Disease

Author

Domenighetti, C, Sugier, P, Sreelatha, A, Schulte, C, Grover, S, Mohamed, O, Portugal, B, May, P, Bobbili, D, Radivojkov-Blagojevic, M, Lichtner, P, Singleton, A, Hernandez, D, Edsall, C, Mellick, G, Zimprich, A, Pirker, W, Rogaeva, E, Lang, A, Koks, S, Taba, P, Lesage, S, Brice, A, Corvol, J, Chartier-Harlin, M, Mutez, E, Brockmann, K, Deutschlander, A, Hadjigeorgiou, G, Dardiotis, E, Stefanis, L, Simitsi, A, Valente, E, Petrucci, S, Duga, S, Straniero, L, Zecchinelli, A, Pezzoli, G, Brighina, L, Ferrarese, C, Annesi, G, Quattrone, A, Gagliardi, M, Matsuo, H, Kawamura, Y, Hattori, N, Nishioka, K, Chung, S, Kim, Y, Kolber, P, Van De Warrenburg, B, Bloem, B, Aasly, J, Toft, M, Pihlstrom, L, Guedes, L, Ferreira, J, Bardien, S, Carr, J, Tolosa, E, Ezquerra, M, Pastor, P, Diez-Fairen, M, Wirdefeldt, K, Pedersen, N, Ran, C, Belin, A, Puschmann, A, Hellberg, C, Clarke, C, Morrison, K, Tan, M, Krainc, D, Burbulla, L, Farrer, M, Kruger, R, Gasser, T, Sharma, M, Elbaz, A, Domenighetti C., Sugier P. -E., Sreelatha A. A. K., Schulte C., Grover S., Mohamed O., Portugal B., May P., Bobbili D. R., Radivojkov-Blagojevic M., Lichtner P., Singleton A. B., Hernandez D. G., Edsall C., Mellick G. D., Zimprich A., Pirker W., Rogaeva E., Lang A. E., Koks S., Taba P., Lesage S., Brice A., Corvol J. -C., Chartier-Harlin M. -C., Mutez E., Brockmann K., Deutschlander A. B., Hadjigeorgiou G. M., Dardiotis E., Stefanis L., Simitsi A. M., Valente E. M., Petrucci S., Duga S., Straniero L., Zecchinelli A., Pezzoli G., Brighina L., Ferrarese C., Annesi G., Quattrone A., Gagliardi M., Matsuo H., Kawamura Y., Hattori N., Nishioka K., Chung S. J., Kim Y. J., Kolber P., Van De Warrenburg B. P. C., Bloem B. R., Aasly J., Toft M., Pihlstrom L., Guedes L. C., Ferreira J. J., Bardien S., Carr J., Tolosa E., Ezquerra M., Pastor P., Diez-Fairen M., Wirdefeldt K., Pedersen N. L., Ran C., Belin A. C., Puschmann A., Hellberg C., Clarke C. E., Morrison K. E., Tan M., Krainc D., Burbulla L. F., Farrer M. J., Kruger R., Gasser T., Sharma M., Elbaz A., Domenighetti, C, Sugier, P, Sreelatha, A, Schulte, C, Grover, S, Mohamed, O, Portugal, B, May, P, Bobbili, D, Radivojkov-Blagojevic, M, Lichtner, P, Singleton, A, Hernandez, D, Edsall, C, Mellick, G, Zimprich, A, Pirker, W, Rogaeva, E, Lang, A, Koks, S, Taba, P, Lesage, S, Brice, A, Corvol, J, Chartier-Harlin, M, Mutez, E, Brockmann, K, Deutschlander, A, Hadjigeorgiou, G, Dardiotis, E, Stefanis, L, Simitsi, A, Valente, E, Petrucci, S, Duga, S, Straniero, L, Zecchinelli, A, Pezzoli, G, Brighina, L, Ferrarese, C, Annesi, G, Quattrone, A, Gagliardi, M, Matsuo, H, Kawamura, Y, Hattori, N, Nishioka, K, Chung, S, Kim, Y, Kolber, P, Van De Warrenburg, B, Bloem, B, Aasly, J, Toft, M, Pihlstrom, L, Guedes, L, Ferreira, J, Bardien, S, Carr, J, Tolosa, E, Ezquerra, M, Pastor, P, Diez-Fairen, M, Wirdefeldt, K, Pedersen, N, Ran, C, Belin, A, Puschmann, A, Hellberg, C, Clarke, C, Morrison, K, Tan, M, Krainc, D, Burbulla, L, Farrer, M, Kruger, R, Gasser, T, Sharma, M, Elbaz, A, Domenighetti C., Sugier P. -E., Sreelatha A. A. K., Schulte C., Grover S., Mohamed O., Portugal B., May P., Bobbili D. R., Radivojkov-Blagojevic M., Lichtner P., Singleton A. B., Hernandez D. G., Edsall C., Mellick G. D., Zimprich A., Pirker W., Rogaeva E., Lang A. E., Koks S., Taba P., Lesage S., Brice A., Corvol J. -C., Chartier-Harlin M. -C., Mutez E., Brockmann K., Deutschlander A. B., Hadjigeorgiou G. M., Dardiotis E., Stefanis L., Simitsi A. M., Valente E. M., Petrucci S., Duga S., Straniero L., Zecchinelli A., Pezzoli G., Brighina L., Ferrarese C., Annesi G., Quattrone A., Gagliardi M., Matsuo H., Kawamura Y., Hattori N., Nishioka K., Chung S. J., Kim Y. J., Kolber P., Van De Warrenburg B. P. C., Bloem B. R., Aasly J., Toft M., Pihlstrom L., Guedes L. C., Ferreira J. J., Bardien S., Carr J., Tolosa E., Ezquerra M., Pastor P., Diez-Fairen M., Wirdefeldt K., Pedersen N. L., Ran C., Belin A. C., Puschmann A., Hellberg C., Clarke C. E., Morrison K. E., Tan M., Krainc D., Burbulla L. F., Farrer M. J., Kruger R., Gasser T., Sharma M., and Elbaz A.

Abstract

Background: Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson's disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. Objective: To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. Methods: We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017). Results: We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60-0.93, p = 0.009) without significant directional pleiotropy. Associations in participants =67 years old and cases with disease duration =7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. Conclusion: Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power.

Published
2022

3. Dairy Intake and Parkinson's Disease: A Mendelian Randomization Study

Author

Domenighetti, C, Sugier, P, Ashok Kumar Sreelatha, A, Schulte, C, Grover, S, Mohamed, O, Portugal, B, May, P, Bobbili, D, Radivojkov-Blagojevic, M, Lichtner, P, Singleton, A, Hernandez, D, Edsall, C, Mellick, G, Zimprich, A, Pirker, W, Rogaeva, E, Lang, A, Koks, S, Taba, P, Lesage, S, Brice, A, Corvol, J, Chartier-Harlin, M, Mutez, E, Brockmann, K, Deutschlander, A, Hadjigeorgiou, G, Dardiotis, E, Stefanis, L, Simitsi, A, Valente, E, Petrucci, S, Duga, S, Straniero, L, Zecchinelli, A, Pezzoli, G, Brighina, L, Ferrarese, C, Annesi, G, Quattrone, A, Gagliardi, M, Matsuo, H, Kawamura, Y, Hattori, N, Nishioka, K, Chung, S, Kim, Y, Kolber, P, van de Warrenburg, B, Bloem, B, Aasly, J, Toft, M, Pihlstrom, L, Correia Guedes, L, Ferreira, J, Bardien, S, Carr, J, Tolosa, E, Ezquerra, M, Pastor, P, Diez-Fairen, M, Wirdefeldt, K, Pedersen, N, Ran, C, Belin, A, Puschmann, A, Hellberg, C, Clarke, C, Morrison, K, Tan, M, Krainc, D, Burbulla, L, Farrer, M, Kruger, R, Gasser, T, Sharma, M, Elbaz, A, Domenighetti C., Sugier P. -E., Ashok Kumar Sreelatha A., Schulte C., Grover S., Mohamed O., Portugal B., May P., Bobbili D. R., Radivojkov-Blagojevic M., Lichtner P., Singleton A. B., Hernandez D. G., Edsall C., Mellick G. D., Zimprich A., Pirker W., Rogaeva E., Lang A. E., Koks S., Taba P., Lesage S., Brice A., Corvol J. -C., Chartier-Harlin M. -C., Mutez E., Brockmann K., Deutschlander A. B., Hadjigeorgiou G. M., Dardiotis E., Stefanis L., Simitsi A. M., Valente E. M., Petrucci S., Duga S., Straniero L., Zecchinelli A., Pezzoli G., Brighina L., Ferrarese C., Annesi G., Quattrone A., Gagliardi M., Matsuo H., Kawamura Y., Hattori N., Nishioka K., Chung S. J., Kim Y. J., Kolber P., van de Warrenburg B. P. C., Bloem B. R., Aasly J., Toft M., Pihlstrom L., Correia Guedes L., Ferreira J. J., Bardien S., Carr J., Tolosa E., Ezquerra M., Pastor P., Diez-Fairen M., Wirdefeldt K., Pedersen N. L., Ran C., Belin A. C., Puschmann A., Hellberg C., Clarke C. E., Morrison K. E., Tan M., Krainc D., Burbulla L. F., Farrer M. J., Kruger R., Gasser T., Sharma M., Elbaz A., Domenighetti, C, Sugier, P, Ashok Kumar Sreelatha, A, Schulte, C, Grover, S, Mohamed, O, Portugal, B, May, P, Bobbili, D, Radivojkov-Blagojevic, M, Lichtner, P, Singleton, A, Hernandez, D, Edsall, C, Mellick, G, Zimprich, A, Pirker, W, Rogaeva, E, Lang, A, Koks, S, Taba, P, Lesage, S, Brice, A, Corvol, J, Chartier-Harlin, M, Mutez, E, Brockmann, K, Deutschlander, A, Hadjigeorgiou, G, Dardiotis, E, Stefanis, L, Simitsi, A, Valente, E, Petrucci, S, Duga, S, Straniero, L, Zecchinelli, A, Pezzoli, G, Brighina, L, Ferrarese, C, Annesi, G, Quattrone, A, Gagliardi, M, Matsuo, H, Kawamura, Y, Hattori, N, Nishioka, K, Chung, S, Kim, Y, Kolber, P, van de Warrenburg, B, Bloem, B, Aasly, J, Toft, M, Pihlstrom, L, Correia Guedes, L, Ferreira, J, Bardien, S, Carr, J, Tolosa, E, Ezquerra, M, Pastor, P, Diez-Fairen, M, Wirdefeldt, K, Pedersen, N, Ran, C, Belin, A, Puschmann, A, Hellberg, C, Clarke, C, Morrison, K, Tan, M, Krainc, D, Burbulla, L, Farrer, M, Kruger, R, Gasser, T, Sharma, M, Elbaz, A, Domenighetti C., Sugier P. -E., Ashok Kumar Sreelatha A., Schulte C., Grover S., Mohamed O., Portugal B., May P., Bobbili D. R., Radivojkov-Blagojevic M., Lichtner P., Singleton A. B., Hernandez D. G., Edsall C., Mellick G. D., Zimprich A., Pirker W., Rogaeva E., Lang A. E., Koks S., Taba P., Lesage S., Brice A., Corvol J. -C., Chartier-Harlin M. -C., Mutez E., Brockmann K., Deutschlander A. B., Hadjigeorgiou G. M., Dardiotis E., Stefanis L., Simitsi A. M., Valente E. M., Petrucci S., Duga S., Straniero L., Zecchinelli A., Pezzoli G., Brighina L., Ferrarese C., Annesi G., Quattrone A., Gagliardi M., Matsuo H., Kawamura Y., Hattori N., Nishioka K., Chung S. J., Kim Y. J., Kolber P., van de Warrenburg B. P. C., Bloem B. R., Aasly J., Toft M., Pihlstrom L., Correia Guedes L., Ferreira J. J., Bardien S., Carr J., Tolosa E., Ezquerra M., Pastor P., Diez-Fairen M., Wirdefeldt K., Pedersen N. L., Ran C., Belin A. C., Puschmann A., Hellberg C., Clarke C. E., Morrison K. E., Tan M., Krainc D., Burbulla L. F., Farrer M. J., Kruger R., Gasser T., Sharma M., and Elbaz A.

Abstract

Background: Previous prospective studies highlighted dairy intake as a risk factor for Parkinson's disease (PD), particularly in men. It is unclear whether this association is causal or explained by reverse causation or confounding. Objective: The aim is to examine the association between genetically predicted dairy intake and PD using two-sample Mendelian randomization (MR). Methods: We genotyped a well-established instrumental variable for dairy intake located in the lactase gene (rs4988235) within the Courage-PD consortium (23 studies; 9823 patients and 8376 controls of European ancestry). Results: Based on a dominant model, there was an association between genetic predisposition toward higher dairy intake and PD (odds ratio [OR] per one serving per day = 1.70, 95% confidence interval = 1.12–2.60, P = 0.013) that was restricted to men (OR = 2.50 [1.37–4.56], P = 0.003; P-difference with women = 0.029). Conclusions: Using MR, our findings provide further support for a causal relationship between dairy intake and higher PD risk, not biased by confounding or reverse causation. Further studies are needed to elucidate the underlying mechanisms. © 2022 International Parkinson and Movement Disorder Society.

Published
2022

5. Dairy Intake and Parkinson's Disease: A Mendelian Randomization Study

Author

Domenighetti, C., Sugier, P‐E, Ashok Kumar Sreelatha, A., Schulte, C., Grover, S., Mohamed, O., Portugal, B., May, P., Bobbili, D.R., Radivojkov‐Blagojevic, M., Lichtner, P., Singleton, A.B., Hernandez, D.G., Edsall, C., Mellick, G.D., Zimprich, A., Pirker, W., Rogaeva, E., Lang, A.E., Kõks, S., Taba, P., Lesage, S., Brice, A., Corvol, J‐C, Chartier‐Harlin, M‐C, Mutez, E., Brockmann, K., Deutschländer, A.B., Hadjigeorgiou, G.M., Dardiotis, E., Stefanis, L., Simitsi, A.M., Valente, E.M., Petrucci, S., Duga, S., Straniero, L., Zecchinelli, A., Pezzoli, G., Brighina, L., Ferrarese, C., Annesi, G., Quattrone, A., Gagliardi, M., Matsuo, H., Kawamura, Y., Hattori, N., Nishioka, K., Chung, S.J., Kim, Y.J., Kolber, P., Warrenburg, B.P.C., Bloem, B.R., Aasly, J., Toft, M., Pihlstrøm, L., Correia Guedes, L., Ferreira, J.J., Bardien, S., Carr, J., Tolosa, E., Ezquerra, M., Pastor, P., Diez‐Fairen, M., Wirdefeldt, K., Pedersen, N.L., Ran, C., Belin, A.C., Puschmann, A., Hellberg, C., Clarke, C.E., Morrison, K.E., Tan, M., Krainc, D., Burbulla, L.F., Farrer, M.J., Krüger, R., Gasser, T., Sharma, M., Elbaz, A., Domenighetti, C., Sugier, P‐E, Ashok Kumar Sreelatha, A., Schulte, C., Grover, S., Mohamed, O., Portugal, B., May, P., Bobbili, D.R., Radivojkov‐Blagojevic, M., Lichtner, P., Singleton, A.B., Hernandez, D.G., Edsall, C., Mellick, G.D., Zimprich, A., Pirker, W., Rogaeva, E., Lang, A.E., Kõks, S., Taba, P., Lesage, S., Brice, A., Corvol, J‐C, Chartier‐Harlin, M‐C, Mutez, E., Brockmann, K., Deutschländer, A.B., Hadjigeorgiou, G.M., Dardiotis, E., Stefanis, L., Simitsi, A.M., Valente, E.M., Petrucci, S., Duga, S., Straniero, L., Zecchinelli, A., Pezzoli, G., Brighina, L., Ferrarese, C., Annesi, G., Quattrone, A., Gagliardi, M., Matsuo, H., Kawamura, Y., Hattori, N., Nishioka, K., Chung, S.J., Kim, Y.J., Kolber, P., Warrenburg, B.P.C., Bloem, B.R., Aasly, J., Toft, M., Pihlstrøm, L., Correia Guedes, L., Ferreira, J.J., Bardien, S., Carr, J., Tolosa, E., Ezquerra, M., Pastor, P., Diez‐Fairen, M., Wirdefeldt, K., Pedersen, N.L., Ran, C., Belin, A.C., Puschmann, A., Hellberg, C., Clarke, C.E., Morrison, K.E., Tan, M., Krainc, D., Burbulla, L.F., Farrer, M.J., Krüger, R., Gasser, T., Sharma, M., and Elbaz, A.

Abstract

Background Previous prospective studies highlighted dairy intake as a risk factor for Parkinson's disease (PD), particularly in men. It is unclear whether this association is causal or explained by reverse causation or confounding. Objective The aim is to examine the association between genetically predicted dairy intake and PD using two-sample Mendelian randomization (MR). Methods We genotyped a well-established instrumental variable for dairy intake located in the lactase gene (rs4988235) within the Courage-PD consortium (23 studies; 9823 patients and 8376 controls of European ancestry). Results Based on a dominant model, there was an association between genetic predisposition toward higher dairy intake and PD (odds ratio [OR] per one serving per day = 1.70, 95% confidence interval = 1.12–2.60, P = 0.013) that was restricted to men (OR = 2.50 [1.37–4.56], P = 0.003; P-difference with women = 0.029). Conclusions Using MR, our findings provide further support for a causal relationship between dairy intake and higher PD risk, not biased by confounding or reverse causation. Further studies are needed to elucidate the underlying mechanisms. © 2022 International Parkinson and Movement Disorder Society

Published
2022

6. Mendelian randomisation study of smoking, alcohol, and coffee drinking in relation to Parkinson’s Disease

Author

Domenighetti, C., Sugier, P-E, Sreelatha, A.A.K., Schulte, C., Grover, S., Mohamed, O., Portugal, B., May, P., Bobbili, D.R., Radivojkov-Blagojevic, M., Lichtner, P., Singleton, A.B., Hernandez, D.G., Edsall, C., Mellick, G.D., Zimprich, A., Pirker, W., Rogaeva, E., Lang, A.E., Kõks, S., Taba, P., Lesage, S., Brice, A., Corvol, J-C, Chartier-Harlin, M-C, Mutez, E., Brockmann, K., Deutschländer, A.B., Hadjigeorgiou, G.M., Dardiotis, E., Stefanis, L., Simitsi, A.M., Valente, E.M., Petrucci, S., Duga, S., Straniero, L., Zecchinelli, A., Pezzoli, G., Brighina, L., Ferrarese, C., Annesi, G., Quattrone, A., Gagliardi, M., Matsuo, H., Kawamura, Y., Hattori, N., Nishioka, K., Chung, S.J., Kim, Y.J., Kolber, P., van de Warrenburg, B.P.C., Bloem, B.R., Aasly, J., Toft, M., Pihlstrøm, L., Guedes, L.C., Ferreira, J.J., Bardien, S., Carr, J., Tolosa, E., Ezquerra, M., Pastor, P., Diez-Fairen, M., Wirdefeldt, K., Pedersen, N.L., Ran, C., Belin, A.C., Puschmann, A., Hellberg, C., Clarke, C.E., Morrison, K.E., Tan, M., Krainc, D., Burbulla, L.F., Farrer, M.J., Krüger, R., Gasser, T., Sharma, M., Elbaz, A., Domenighetti, C., Sugier, P-E, Sreelatha, A.A.K., Schulte, C., Grover, S., Mohamed, O., Portugal, B., May, P., Bobbili, D.R., Radivojkov-Blagojevic, M., Lichtner, P., Singleton, A.B., Hernandez, D.G., Edsall, C., Mellick, G.D., Zimprich, A., Pirker, W., Rogaeva, E., Lang, A.E., Kõks, S., Taba, P., Lesage, S., Brice, A., Corvol, J-C, Chartier-Harlin, M-C, Mutez, E., Brockmann, K., Deutschländer, A.B., Hadjigeorgiou, G.M., Dardiotis, E., Stefanis, L., Simitsi, A.M., Valente, E.M., Petrucci, S., Duga, S., Straniero, L., Zecchinelli, A., Pezzoli, G., Brighina, L., Ferrarese, C., Annesi, G., Quattrone, A., Gagliardi, M., Matsuo, H., Kawamura, Y., Hattori, N., Nishioka, K., Chung, S.J., Kim, Y.J., Kolber, P., van de Warrenburg, B.P.C., Bloem, B.R., Aasly, J., Toft, M., Pihlstrøm, L., Guedes, L.C., Ferreira, J.J., Bardien, S., Carr, J., Tolosa, E., Ezquerra, M., Pastor, P., Diez-Fairen, M., Wirdefeldt, K., Pedersen, N.L., Ran, C., Belin, A.C., Puschmann, A., Hellberg, C., Clarke, C.E., Morrison, K.E., Tan, M., Krainc, D., Burbulla, L.F., Farrer, M.J., Krüger, R., Gasser, T., Sharma, M., and Elbaz, A.

Abstract

Background:Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson’s disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. Objective:To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. Methods:We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017). Results:We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60–0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. Conclusion:Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power.

Published
2022

7. Mendelian Randomisation Study of Smoking, Alcohol, and Coffee Drinking in Relation to Parkinson's Disease

Author

Domenighetti, C. Sugier, P.-E. Sreelatha, A.A.K. Schulte, C. Grover, S. Mohamed, O. Portugal, B. May, P. Bobbili, D.R. Radivojkov-Blagojevic, M. Lichtner, P. Singleton, A.B. Hernandez, D.G. Edsall, C. Mellick, G.D. Zimprich, A. Pirker, W. Rogaeva, E. Lang, A.E. Koks, S. Taba, P. Lesage, S. Brice, A. Corvol, J.-C. Chartier-Harlin, M.-C. Mutez, E. Brockmann, K. Deutschländer, A.B. Hadjigeorgiou, G.M. Dardiotis, E. Stefanis, L. Simitsi, A.M. Valente, E.M. Petrucci, S. Duga, S. Straniero, L. Zecchinelli, A. Pezzoli, G. Brighina, L. Ferrarese, C. Annesi, G. Quattrone, A. Gagliardi, M. Matsuo, H. Kawamura, Y. Hattori, N. Nishioka, K. Chung, S.J. Kim, Y.J. Kolber, P. Van De Warrenburg, B.P.C. Bloem, B.R. Aasly, J. Toft, M. Pihlstrøm, L. Guedes, L.C. Ferreira, J.J. Bardien, S. Carr, J. Tolosa, E. Ezquerra, M. Pastor, P. Diez-Fairen, M. Wirdefeldt, K. Pedersen, N.L. Ran, C. Belin, A.C. Puschmann, A. Hellberg, C. Clarke, C.E. Morrison, K.E. Tan, M. Krainc, D. Burbulla, L.F. Farrer, M.J. Krüger, R. Gasser, T. Sharma, M. Elbaz, A.

Abstract

Background: Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson's disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. Objective: To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. Methods: We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017). Results: We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60-0.93, p = 0.009) without significant directional pleiotropy. Associations in participants =67 years old and cases with disease duration =7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. Conclusion: Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power. © 2022 - IOS Press. All rights reserved.

Published
2022

8. Genetic Variability and Alzheimer’s Disease

Author

Hardy, J., Mullan, M., Crawford, F., Duff, K., Crook, R., Diaz, P., Bennett, C., Houlden, H., Fidani, L., Goate, A., Parfitt, M., Roques, P., Rossor, M., Chartier-Harlin, M.-C., Christen, Yves, editor, Masters, C. L., editor, Beyreuther, K., editor, Trillet, M., editor, and Christen, Y., editor

Published
1994
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10. Association study of Notch 4 polymorphisms with Alzheimer's disease

Author

Lambert, J.-C., Mann, D., Harris, J., Araria-Goumidi, L., Chartier-Harlin, M.-C., Cottel, D., Iwatsubo, T., Amouyel, P., and Lendon, C.

Subjects
Alzheimer's disease -- Research -- Genetic aspects, Health, Psychology and mental health, Genetic aspects, Research
Abstract

J Neurol Neurosurg Psychiatry 2004;75:377-381. doi: 10.1136/jnnp.2003.017368 Background: The NOTCH4 gene is located at 6p21.3, a site shown in several studies to have significant linkage with Alzheimer's disease. Objective: To [...]

Published
2004

22. Population-specific frequencies for LRRK2 susceptibility variants in the Genetic Epidemiology of Parkinson's Disease (GEO-PD) Consortium

Author

Heckman, M. G., Soto Ortolaza, A. I., Aasly, J. O., Abahuni, N., Annesi, G., Bacon, J. A., Bardien, S., Bozi, M., Brice, A., Brighina, L., Carr, J., Chartier Harlin, M., Dardiotis, E., Dickson, D. W., Diehl, N. N., Elbaz, A., Ferrarese, C., Fiske, B., Gibson, J. M., Gibson, R., Hadjigeorgiou, G. M., Hattori, N., J. P. A., Boczarska Jedynak, M., Jasinska Myga, B., Jeon, B. S., Kim, Y. J., Klein, C., Kruger, R., Kyratzi, E., Lesage, S., Lin, C., Lynch, T., Maraganore, D. M., Mellick, G. D., Mutez, E., Nilsson, C., Opala, G., Park, S. S., Petrucci, S., Puschmann, A., Quattrone, A., Sharma, M., Silburn, P. A., Sohn, Y. H., Stefanis, L., Tadic, V., Theuns, J., Tomiyama, H., Uitti, R. J., Valente, Enza Maria, Broeckhoven, C. V., S. v., De, Vassilatis, D. K., Vilariño Güell, C., White, L. R., Wirdefeldt, K., Wszolek, Z. K., Wu, R., Hentati, F., Farrer, M. J., Ross, O. A., G. E., Of, Heckman, M, Soto Ortolaza, A, Aasly, J, Abahuni, N, Annesi, G, Bacon, J, Bardien, S, Bozi, M, Brice, A, Brighina, L, Carr, J, Chartier Harlin, M, Dardiotis, E, Dickson, D, Diehl, N, Elbaz, A, Ferrarese, C, Fiske, B, Gibson, J, Gibson, R, Hadjigeorgiou, G, Hattori, N, Ioannidis, J, Boczarska Jedynak, M, Jasinska Myga, B, Jeon, B, Kim, Y, Klein, C, Kruger, R, Kyratzi, E, Lesage, S, Lin, C, Lynch, T, Maraganore, D, Mellick, G, Mutez, E, Nilsson, C, Opala, G, Park, S, Petrucci, S, Puschmann, A, Quattrone, A, Sharma, M, Silburn, P, Sohn, Y, Stefanis, L, Tadic, V, Theuns, J, Tomiyama, H, Uitti, R, Valente, E, Van Broeckhoven, C, van de Loo, S, Vassilatis, D, Vilariño Güell, C, White, L, Wirdefeldt, K, Wszolek, Z, Wu, R, Hentati, F, Farrer, M, and Ross, O

Subjects
Molecular Epidemiology, Genotype, Parkinson's disease, LRRK2, Parkinson Disease, Protein Serine-Threonine Kinases, association study, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Protein-Serine-Threonine Kinases, Polymorphism, Single Nucleotide, genetics [Protein-Serine-Threonine Kinases], Article, Genetics, Population, Gene Frequency, Haplotypes, genetics [Parkinson Disease], Humans, genetics, lrrk2, parkinson's disease, genetic association studies, population, genotype, haplotypes, hHumans, leucine-rich repeat serine-threonine protein kinase-2, molecular epidemiology, parkinson disease, polymorphism, single nucleotide, protein-serine-threonine kinases, gene frequency, genetic predisposition to disease, Genetic Predisposition to Disease, ddc:610, epidemiology [Parkinson Disease], LRRK2 protein, human, genetic, Genetic Association Studies
Abstract

Variants within the leucine-rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson's disease. Leucine-rich repeat kinase 2 variation related to disease susceptibility displays many features that reflect the nature of complex, late-onset sporadic disorders like Parkinson's disease.The Genetic Epidemiology of Parkinson's Disease Consortium recently performed the largest genetic association study for variants in the leucine-rich repeat kinase 2 gene across 23 different sites in 15 countries.Herein, we detail the allele frequencies for the novel risk factors (p.A419V and p.M1646T) and the protective haplotype (p.N551K-R1398H-K1423K) nominated in the original publication. Simple population allele frequencies not only can provide insight into the clinical relevance of specific variants but also can help genetically define patient groups.Establishing individual patient-based genomic susceptibility profiles that incorporate both risk factors and protective factors will determine future diagnostic and treatment strategies.

Published
2013

24. Independent and joint effects of the MAPT and SNCA genes in Parkinson disease

Author

Elbaz, A. Ross, O.A. Ioannidis, J.P.A. Soto-Ortolaza, A.I. Moisan, F. Aasly, J. Annesi, G. Bozi, M. Brighina, L. Chartier-Harlin, M.-C. Destée, A. Ferrarese, C. Ferraris, A. Gibson, J.M. Gispert, S. Hadjigeorgiou, G.M. Jasinska-Myga, B. Klein, C. Krüger, R. Lambert, J.-C. Lohmann, K. Van De Loo, S. Loriot, M.-A. Lynch, T. Mellick, G.D. Mutez, E. Nilsson, C. Opala, G. Puschmann, A. Quattrone, A. Sharma, M. Silburn, P.A. Stefanis, L. Uitti, R.J. Valente, E.M. Vilariño-Güell, C. Wirdefeldt, K. Wszolek, Z.K. Xiromerisiou, G. Maraganore, D.M. Farrer, M.J.

Abstract

Objective: We studied the independent and joint effects of the genes encoding alpha-synuclein (SNCA) and microtubule-associated protein tau (MAPT) in Parkinson disease (PD) as part of a large meta-analysis of individual data from case-control studies participating in the Genetic Epidemiology of Parkinson's Disease (GEO-PD) consortium. Methods: Participants of Caucasian ancestry were genotyped for a total of 4 SNCA (rs2583988, rs181489, rs356219, rs11931074) and 2 MAPT (rs1052553, rs242557) single nucleotide polymorphism (SNPs). Individual and joint effects of SNCA and MAPT SNPs were investigated using fixed- and random-effects logistic regression models. Interactions were studied on both a multiplicative and an additive scale, and using a case-control and case-only approach. Results: Fifteen GEO-PD sites contributed a total of 5,302 cases and 4,161 controls. All 4 SNCA SNPs and the MAPT H1-haplotype-defining SNP (rs1052553) displayed a highly significant marginal association with PD at the significance level adjusted for multiple comparisons. For SNCA, the strongest associations were observed for SNPs located at the 3′ end of the gene. There was no evidence of statistical interaction between any of the 4 SNCA SNPs and rs1052553 or rs242557, neither on the multiplicative nor on the additive scale. Interpretation: This study confirms the association between PD and both SNCA SNPs and the H1 MAPT haplotype. It shows, based on a variety of approaches, that the joint action of variants in these 2 loci is consistent with independent effects of the genes without additional interacting effects. © 2011 American Neurological Association.

Published
2011

25. [Parkinson disease: genetics and neuronal death]

Author

Destee, A., Eugenie Mutez, Kreisler, A., Vanbesien-Maillot, C., and Chartier-Harlin, M. C.

Subjects
Neurons, Ubiquitin-Protein Ligases, alpha-Synuclein, Humans, Parkinson Disease, Protein Serine-Threonine Kinases, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Ubiquitin Thiolesterase
Published
2009

27. Population-specific frequencies for LRRK2 susceptibility variants in the genetic epidemiology of Parkinson's disease (GEO-PD) consortium

Author

Heckman, M, Soto Ortolaza, A, Aasly, J, Abahuni, N, Annesi, G, Bacon, J, Bardien, S, Bozi, M, Brice, A, Brighina, L, Carr, J, Chartier Harlin, M, Dardiotis, E, Dickson, D, Diehl, N, Elbaz, A, Ferrarese, C, Fiske, B, Gibson, J, Gibson, R, Hadjigeorgiou, G, Hattori, N, Ioannidis, J, Boczarska Jedynak, M, Jasinska Myga, B, Jeon, B, Kim, Y, Klein, C, Kruger, R, Kyratzi, E, Lesage, S, Lin, C, Lynch, T, Maraganore, D, Mellick, G, Mutez, E, Nilsson, C, Opala, G, Park, S, Petrucci, S, Puschmann, A, Quattrone, A, Sharma, M, Silburn, P, Sohn, Y, Stefanis, L, Tadic, V, Theuns, J, Tomiyama, H, Uitti, R, Valente, E, Van Broeckhoven, C, van de Loo, S, Vassilatis, D, Vilariño Güell, C, White, L, Wirdefeldt, K, Wszolek, Z, Wu, R, Hentati, F, Farrer, M, Ross, O, Heckman, MG, Soto Ortolaza, AI, Aasly, JO, Bacon, JA, Dickson, DW, Diehl, NN, Gibson, JM, Hadjigeorgiou, GM, Ioannidis, JPA, Jeon, BS, Kim, YJ, Maraganore, DM, Mellick, GD, Park, SS, Silburn, PA, Sohn, YH, Uitti, RJ, Valente, EM, Vassilatis, DK, White, LR, Wszolek, ZK, Farrer, MJ, Ross, OA, FERRARESE, CARLO, Heckman, M, Soto Ortolaza, A, Aasly, J, Abahuni, N, Annesi, G, Bacon, J, Bardien, S, Bozi, M, Brice, A, Brighina, L, Carr, J, Chartier Harlin, M, Dardiotis, E, Dickson, D, Diehl, N, Elbaz, A, Ferrarese, C, Fiske, B, Gibson, J, Gibson, R, Hadjigeorgiou, G, Hattori, N, Ioannidis, J, Boczarska Jedynak, M, Jasinska Myga, B, Jeon, B, Kim, Y, Klein, C, Kruger, R, Kyratzi, E, Lesage, S, Lin, C, Lynch, T, Maraganore, D, Mellick, G, Mutez, E, Nilsson, C, Opala, G, Park, S, Petrucci, S, Puschmann, A, Quattrone, A, Sharma, M, Silburn, P, Sohn, Y, Stefanis, L, Tadic, V, Theuns, J, Tomiyama, H, Uitti, R, Valente, E, Van Broeckhoven, C, van de Loo, S, Vassilatis, D, Vilariño Güell, C, White, L, Wirdefeldt, K, Wszolek, Z, Wu, R, Hentati, F, Farrer, M, Ross, O, Heckman, MG, Soto Ortolaza, AI, Aasly, JO, Bacon, JA, Dickson, DW, Diehl, NN, Gibson, JM, Hadjigeorgiou, GM, Ioannidis, JPA, Jeon, BS, Kim, YJ, Maraganore, DM, Mellick, GD, Park, SS, Silburn, PA, Sohn, YH, Uitti, RJ, Valente, EM, Vassilatis, DK, White, LR, Wszolek, ZK, Farrer, MJ, Ross, OA, and FERRARESE, CARLO

Abstract

Variants within the leucine-rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson's disease. Leucine-rich repeat kinase 2 variation related to disease susceptibility displays many features that reflect the nature of complex, late-onset sporadic disorders like Parkinson's disease.

Published
2013

28. Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: a case-control study

Author

Ross, O, Soto Ortolaza, A, Heckman, M, Aasly, J, Abahuni, N, Annesi, G, Bacon, J, Bardien, S, Bozi, M, Brice, A, Brighina, L, Van Broeckhoven, C, Carr, J, Chartier Harlin, M, Dardiotis, E, Dickson, D, Diehl, N, Elbaz, A, Ferrarese, C, Ferraris, A, Fiske, B, Gibson, J, Gibson, R, Hadjigeorgiou, G, Hattori, N, Ioannidis, J, Jasinska Myga, B, Jeon, B, Kim, Y, Klein, C, Kruger, R, Kyratzi, E, Lesage, S, Lin, C, Lynch, T, Maraganore, D, Mellick, G, Mutez, E, Nilsson, C, Opala, G, Park, S, Puschmann, A, Quattrone, A, Sharma, M, Silburn, P, Sohn, Y, Stefanis, L, Tadic, V, Theuns, J, Tomiyama, H, Uitti, R, Valente, E, van de Loo, S, Vassilatis, D, Vilariño Güell, C, White, L, Wirdefeldt, K, Wszolek, Z, Wu, R, Farrer, M, FERRARESE, CARLO, Farrer, M., Ross, O, Soto Ortolaza, A, Heckman, M, Aasly, J, Abahuni, N, Annesi, G, Bacon, J, Bardien, S, Bozi, M, Brice, A, Brighina, L, Van Broeckhoven, C, Carr, J, Chartier Harlin, M, Dardiotis, E, Dickson, D, Diehl, N, Elbaz, A, Ferrarese, C, Ferraris, A, Fiske, B, Gibson, J, Gibson, R, Hadjigeorgiou, G, Hattori, N, Ioannidis, J, Jasinska Myga, B, Jeon, B, Kim, Y, Klein, C, Kruger, R, Kyratzi, E, Lesage, S, Lin, C, Lynch, T, Maraganore, D, Mellick, G, Mutez, E, Nilsson, C, Opala, G, Park, S, Puschmann, A, Quattrone, A, Sharma, M, Silburn, P, Sohn, Y, Stefanis, L, Tadic, V, Theuns, J, Tomiyama, H, Uitti, R, Valente, E, van de Loo, S, Vassilatis, D, Vilariño Güell, C, White, L, Wirdefeldt, K, Wszolek, Z, Wu, R, Farrer, M, FERRARESE, CARLO, and Farrer, M.

Abstract

Background The leucine-rich repeat kinase 2 gene (LRRK2) harbours highly penetrant mutations that are linked to familial parkinsonism. However, the extent of its polymorphic variability in relation to risk of Parkinson's disease (PD) has not been assessed systematically. We therefore assessed the frequency of LRRK2 exonic variants in individuals with and without PD, to investigate the role of the variants in PD susceptibility. Methods LRRK2 was genotyped in patients with PD and controls from three series (white, Asian, and Arab-Berber) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Genotyping was done for exonic variants of LRRK2 that were identified through searches of literature and the personal communications of consortium members. Associations with PD were assessed by use of logistic regression models. For variants that had a minor allele frequency of 0.5% or greater, single variant associations were assessed, whereas for rarer variants information was collapsed across variants. Findings 121 exonic LRRK2 variants were assessed in 15 540 individuals: 6995 white patients with PD and 5595 controls, 1376 Asian patients and 962 controls, and 240 Arab-Berber patients and 372 controls. After exclusion of carriers of known pathogenic mutations, new independent risk associations were identified for polymorphic variants in white individuals (M1646T, odds ratio 1.43, 95% CI 1.15-1.78; p=0.0012) and Asian individuals (A419V, 2.27, 1.35-3.83; p=0.0011). A protective haplotype (N551K-R1398H-K1423K) was noted at a frequency greater than 5% in the white and Asian series, with a similar finding in the Arab-Berber series (combined odds ratio 0.82, 0.72-0.94; p=0.0043). Of the two previously reported Asian risk variants, G2385R was associated with disease (1.73, 1.20-2.49; p=0.0026), but no association was noted for R1628P (0.62, 0.36-1.07; p=0.087). In the Arab-Berber series, Y2189C showed potential evidence of risk association with PD (4.

Published
2011

29. Independent and joint effects of the MAPT and SNCA genes in Parkinson disease

Author

Elbaz, A, Ross, O, Ioannidis, J, Soto Ortolaza, A, Moisan, F, Aasly, J, Annesi, G, Bozi, M, Brighina, L, Chartier Harlin, M, Destée, A, Ferrarese, C, Ferraris, A, Gibson, J, Gispert, S, Hadjigeorgiou, G, Jasinska Myga, B, Klein, C, Krüger, R, Lambert, J, Lohmann, K, van de Loo, S, Loriot, M, Lynch, T, Mellick, G, Mutez, E, Nilsson, C, Opala, G, Puschmann, A, Quattrone, A, Sharma, M, Silburn, P, Stefanis, L, Uitti, R, Valente, E, Vilariño Güell, C, Wirdefeldt, K, Wszolek, Z, Xiromerisiou, G, Maraganore, D, Farrer, M, Farrer, M., FERRARESE, CARLO, Elbaz, A, Ross, O, Ioannidis, J, Soto Ortolaza, A, Moisan, F, Aasly, J, Annesi, G, Bozi, M, Brighina, L, Chartier Harlin, M, Destée, A, Ferrarese, C, Ferraris, A, Gibson, J, Gispert, S, Hadjigeorgiou, G, Jasinska Myga, B, Klein, C, Krüger, R, Lambert, J, Lohmann, K, van de Loo, S, Loriot, M, Lynch, T, Mellick, G, Mutez, E, Nilsson, C, Opala, G, Puschmann, A, Quattrone, A, Sharma, M, Silburn, P, Stefanis, L, Uitti, R, Valente, E, Vilariño Güell, C, Wirdefeldt, K, Wszolek, Z, Xiromerisiou, G, Maraganore, D, Farrer, M, Farrer, M., and FERRARESE, CARLO

Abstract

We studied the independent and joint effects of the genes encoding alpha-synuclein (SNCA) and microtubule-associated protein tau (MAPT) in Parkinson disease (PD) as part of a large meta-analysis of individual data from case-control studies participating in the Genetic Epidemiology of Parkinson's Disease (GEO-PD) consortium.

Published
2011

30. Role of sepiapterin reductase gene at the PARK3 locus in Parkinson's disease

Author

Sharma, M, Maraganore, D, Ioannidis, J, Riess, O, Aasly, J, Annesi, G, Abahuni, N, Bentivoglio, A, Brice, A, Van Broeckhoven, C, Chartier Harlin, M, Destée, A, Djarmati, A, Elbaz, A, Farrer, M, Ferrarese, C, Gibson, J, Gispert, S, Hattori, N, Jasinska Myga, B, Klein, C, Lesage, S, Lynch, T, Lichtner, P, Lambert, J, Lang, A, Mellick, G, De Nigris, F, Opala, G, Quattrone, A, Riva, C, Rogaeva, E, Ross, O, Satake, W, Silburn, P, Theuns, J, Toda, T, Tomiyama, H, Uitti, R, Wirdefeldt, K, Wszolek, Z, Gasser, T, Krüger, R, FERRARESE, CARLO, RIVA, CHIARA, Krüger, R., Sharma, M, Maraganore, D, Ioannidis, J, Riess, O, Aasly, J, Annesi, G, Abahuni, N, Bentivoglio, A, Brice, A, Van Broeckhoven, C, Chartier Harlin, M, Destée, A, Djarmati, A, Elbaz, A, Farrer, M, Ferrarese, C, Gibson, J, Gispert, S, Hattori, N, Jasinska Myga, B, Klein, C, Lesage, S, Lynch, T, Lichtner, P, Lambert, J, Lang, A, Mellick, G, De Nigris, F, Opala, G, Quattrone, A, Riva, C, Rogaeva, E, Ross, O, Satake, W, Silburn, P, Theuns, J, Toda, T, Tomiyama, H, Uitti, R, Wirdefeldt, K, Wszolek, Z, Gasser, T, Krüger, R, FERRARESE, CARLO, RIVA, CHIARA, and Krüger, R.

Abstract

Sepiapterin reductase (SPR) gene is an enzyme which catalyses the final step of tetrahydrobiopterin synthesis (BH4) and was implicated in Parkinson's disease (PD) pathogenesis as a candidate gene for PARK3 locus. A number of studies yielded association of the PARK3 locus with PD, and SPR knockout mice were shown to display parkinsonian features. To evaluate the role of SPR gene polymorphisms in diverse populations in PD, we performed collaborative analyses in the Genetic Epidemiology of Parkinson Disease (GEO-PD) Consortium. A total of 5 single nucleotide polymorphisms (3 in the promoter region and 2 in the 3′ untranslated region [UTR]) were genotyped. Fixed as well as random effect models were used to provide summary risk estimates of SPR variants. A total of 19 sites provided data for 6547 cases and 9321 controls. Overall odds ratio estimates varied from 0.92 to 1.01. No overall association with the SPR gene using either fixed effect or random effect model was observed in the studied population. I2 Metric varied from 0% to 36.2%. There was some evidence for an association for participants of North European/Scandinavian descent with the strongest signal for rs1876487 (odds ratio = 0.82; p value = 0.003). Interestingly, families which were used to map the PARK3 locus, have Scandinavian ancestry suggesting a founder effect. In conclusion, this large association study for the SPR gene revealed no association for PD worldwide. However, taking the initial mapping of the PARK3 into account, the role of a population-specific effect warrants consideration in future studies. © 2011 Elsevier Inc.

Published
2011

31. Translation initiator EIF4G1 mutations in familial Parkinson disease

Author

Chartier Harlin, M, Dachsel, Jc, Vilariño Güell, C, Lincoln, Sj, Leprêtre, F, Hulihan, Mm, Kachergus, J, Milnerwood, Aj, Tapia, L, Song, M, Le Rhun, E, Mutez, E, Larvor, L, Duflot, A, Vanbesien Mailliot, C, Kreisler, A, Ross, Oa, Nishioka, K, Soto Ortolaza, Ai, Cobb, Sa, Melrose, Hl, Behrouz, B, Keeling, Bh, Bacon, Ja, Hentati, E, Williams, L, Yanagiya, A, Sonenberg, N, Lockhart, Pj, Zubair, Ac, Uitti, Rj, Aasly, Jo, Krygowska Wajs, A, Opala, G, Wszolek, Zk, Frigerio, R, Maraganore, Dm, Gosal, D, Lynch, T, Hutchinson, M, Bentivoglio, Anna Rita, Valente, Enza Maria, Nichols, Wc, Pankratz, N, Foroud, T, Gibson, Ra, Hentati, F, Dickson, Dw, Destée, A, Farrer, Mj, Bentivoglio, Anna Rita (ORCID:0000-0002-9663-095X), Chartier Harlin, M, Dachsel, Jc, Vilariño Güell, C, Lincoln, Sj, Leprêtre, F, Hulihan, Mm, Kachergus, J, Milnerwood, Aj, Tapia, L, Song, M, Le Rhun, E, Mutez, E, Larvor, L, Duflot, A, Vanbesien Mailliot, C, Kreisler, A, Ross, Oa, Nishioka, K, Soto Ortolaza, Ai, Cobb, Sa, Melrose, Hl, Behrouz, B, Keeling, Bh, Bacon, Ja, Hentati, E, Williams, L, Yanagiya, A, Sonenberg, N, Lockhart, Pj, Zubair, Ac, Uitti, Rj, Aasly, Jo, Krygowska Wajs, A, Opala, G, Wszolek, Zk, Frigerio, R, Maraganore, Dm, Gosal, D, Lynch, T, Hutchinson, M, Bentivoglio, Anna Rita, Valente, Enza Maria, Nichols, Wc, Pankratz, N, Foroud, T, Gibson, Ra, Hentati, F, Dickson, Dw, Destée, A, Farrer, Mj, and Bentivoglio, Anna Rita (ORCID:0000-0002-9663-095X)

Abstract

Genome-wide analysis of a multi-incident family with autosomal-dominant parkinsonism has implicated a locus on chromosomal region 3q26-q28. Linkage and disease segregation is explained by a missense mutation c.3614G>A (p.Arg1205His) in eukaryotic translation initiation factor 4-gamma (EIF4G1). Subsequent sequence and genotype analysis identified EIF4G1 c.1505C>T (p.Ala502Val), c.2056G>T (p.Gly686Cys), c.3490A>C (p.Ser1164Arg), c.3589C>T (p.Arg1197Trp) and c.3614G>A (p.Arg1205His) substitutions in affected subjects with familial parkinsonism and idiopathic Lewy body disease but not in control subjects. Despite different countries of origin, persons with EIF4G1 c.1505C>T (p.Ala502Val) or c.3614G>A (p.Arg1205His) mutations appear to share haplotypes consistent with ancestral founders. eIF4G1 p.Ala502Val and p.Arg1205His disrupt eIF4E or eIF3e binding, although the wild-type protein does not, and render mutant cells more vulnerable to reactive oxidative species. EIF4G1 mutations implicate mRNA translation initiation in familial parkinsonism and highlight a convergent pathway for monogenic, toxin and perhaps virally-induced Parkinson disease.

Published
2011

32. Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease

Author

Maraganore, D, de Andrade, M, Elbaz, A, Farrer, M, Ioannidis, J, Kruger, R, Rocca, W, Schneider, N, Lesnick, T, Lincoln, S, Hulihan, M, Aasly, J, Ashizawa, T, Chartier Harlin, M, Checkoway, H, Ferrarese, C, Hadjigeorgiou, G, Hattori, N, Kawakami, H, Lambert, J, Lynch, T, Mellick, G, Papapetropoulos, S, Parsian, A, Quattrone, A, Riess, O, Tan, E, Van Broeckhoven, C, Maraganore, DM, Farrer, MJ, Ioannidis, JP, Rocca, WA, Schneider, NK, Lesnick, TG, Lincoln, SJ, Hulihan, MM, Aasly, JO, Chartier Harlin, MC, Lambert, JC, Mellick, GD, Tan, EK, Van Broeckhoven, C., FERRARESE, CARLO, Maraganore, D, de Andrade, M, Elbaz, A, Farrer, M, Ioannidis, J, Kruger, R, Rocca, W, Schneider, N, Lesnick, T, Lincoln, S, Hulihan, M, Aasly, J, Ashizawa, T, Chartier Harlin, M, Checkoway, H, Ferrarese, C, Hadjigeorgiou, G, Hattori, N, Kawakami, H, Lambert, J, Lynch, T, Mellick, G, Papapetropoulos, S, Parsian, A, Quattrone, A, Riess, O, Tan, E, Van Broeckhoven, C, Maraganore, DM, Farrer, MJ, Ioannidis, JP, Rocca, WA, Schneider, NK, Lesnick, TG, Lincoln, SJ, Hulihan, MM, Aasly, JO, Chartier Harlin, MC, Lambert, JC, Mellick, GD, Tan, EK, Van Broeckhoven, C., and FERRARESE, CARLO

Abstract

Context Identification and replication of susceptibility genes for Parkinson disease at the population level have been hampered by small studies with potential biases. alpha-Synuclein (SNCA) has been one of the most promising susceptibility genes, but largescale studies have been lacking. Objective To determine whether allele-length variability in the dinucleotide repeat sequence (REP1) of the SNCA gene promoter is associated with Parkinson disease susceptibility, whether SNCA promoter haplotypes are associated with Parkinson disease, and whether REP1 variability modifies age at onset. Design, Setting, and Participants We performed a collaborative analysis of individual-level data on SNCA REP1 and flanking markers in patients with Parkinson disease and controls. Study site recruitment, data collection, and analyses were performed between April 5, 2004, and December 31, 2005. Eighteen participating sites of a global genetics consortium provided clinical data. Genotyping was performed for SNCA REP1, -770, and -116 markers at individual sites; however, each site also provided 20 DNA samples for regenotyping centrally. Main Outcome Measures Measures included estimations of Hardy-Weinberg equilibrium in controls; a test of heterogeneity; analyses for association of single variants or haplotypes; and survival analyses for age at onset. Results Of the 18 sites, 11 met stringent criteria for concordance with Hardy-Weinberg equilibrium and low genotyping error rate. These 11 sites provided complete data for 2692 cases and 2652 controls. There was no heterogeneity across studies (P > .60). The SNCA REP1 alleles differed in frequency for cases and controls (P < .001). Genotypes defined by the 263 base-pair allele were associated with Parkinson disease (odds ratio, 1.43; 95% confidence interval, 1.22-1.69; P < .001 for trend). Multilocus haplotypes differed in frequency for cases and controls (global score statistic, P < .001). Two- loci haplotypes were associated with Parkinso

Published
2006

33. Mutations du gène EIF4G 1 (Eukaryotic translation initiation factor 4-gamma) et maladie de Parkinson

Author

Destée, A., primary, Mutez, E., additional, Le Rhun, E., additional, Leprêtre, F., additional, Semaille, P., additional, Duflot, A., additional, Vanbesien-Maillot, C., additional, Kreisler, A., additional, Simonin, C., additional, Comptdaer, T., additional, de Broucker, A., additional, Dachsel, J., additional, Farrer, M.-J., additional, and Chartier-Harlin, M.-C., additional

Published
2012
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36. 3.074 TRANSCRIPTOME PROFILING OF BLOOD MONONUCLEAR CELLS FROM SCA2 PATIENTS ACCORDING TO CEREBELLAR OR PARKINSONIAN PHENOTYPES

Author

Simonin, C., primary, Mutez, E., additional, Sablonnière, B., additional, Duflot, A., additional, Figeac, M., additional, Lepretre, F., additional, Defebvre, L., additional, Kreisler, A., additional, Vanbesien-Mailliot, C., additional, Devos, D., additional, Frigard, B., additional, Destée, A., additional, and Chartier-Harlin, M.-C., additional

Published
2012
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37. P2.206 EIF4G1 mutations in familial parkinsonism

Author

Chartier-Harlin, M.-C., primary, Dachsel, J., additional, Hulihan, M., additional, Kachergus, J., additional, Lepretre, F., additional, Le Rhun, E., additional, Mutez, E., additional, Lincoln, S., additional, Ross, O., additional, Vilariño-Güell, C., additional, Yanagiya, A., additional, Sonenberg, N., additional, Lockhart, P., additional, Wszolek, Z., additional, Aasly, J., additional, Frigerio, R., additional, Maraganore, D., additional, Lynch, T., additional, Ferraris, A., additional, Valente, E.-M., additional, Destée, A., additional, and Farrer, M., additional

Published
2009
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39. Characterization of DCTN1 genetic variability in neurodegeneration

Author

Vilarino-Guell, C., primary, Wider, C., additional, Soto-Ortolaza, A. I., additional, Cobb, S. A., additional, Kachergus, J. M., additional, Keeling, B. H., additional, Dachsel, J. C., additional, Hulihan, M. M., additional, Dickson, D. W., additional, Wszolek, Z. K., additional, Uitti, R. J., additional, Graff-Radford, N. R., additional, Boeve, B. F., additional, Josephs, K. A., additional, Miller, B., additional, Boylan, K. B., additional, Gwinn, K., additional, Adler, C. H., additional, Aasly, J. O., additional, Hentati, F., additional, Destee, A., additional, Krygowska-Wajs, A., additional, Chartier-Harlin, M. -C., additional, Ross, O. A., additional, Rademakers, R., additional, and Farrer, M. J., additional

Published
2009
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46. Contribution of APOE promoter polymorphisms to Alzheimer’s disease risk

Author

Lambert, J. C., primary, Araria-Goumidi, L., additional, Myllykangas, L., additional, Ellis, C., additional, Wang, J. C., additional, Bullido, M. J., additional, Harris, J. M., additional, Artiga, M. J., additional, Hernandez, D., additional, Kwon, J. M., additional, Frigard, B., additional, Petersen, R. C., additional, Cumming, A. M., additional, Pasquier, F., additional, Sastre, I., additional, Tienari, P. J., additional, Frank, A., additional, Sulkava, R., additional, Morris, J. C., additional, St. Clair, D., additional, Mann, D. M., additional, Wavrant-DeVrièze, F., additional, Ezquerra-Trabalon, M., additional, Amouyel, P., additional, Hardy, J., additional, Haltia, M., additional, Valdivieso, F., additional, Goate, A. M., additional, Pérez-Tur, J., additional, Lendon, C. L., additional, and Chartier-Harlin, M. C., additional

Published
2002
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48. A polymorphism within intron 11 of the tau gene is not increased in frequency in patients with sporadic Alzheimer's disease, nor does it influence the extent of tau pathology in the brain

Author

Green, E.K, primary, Thaker, U, additional, McDonagh, A.M, additional, Iwatsubo, T, additional, Lambert, J.-C, additional, Chartier-Harlin, M.-C, additional, Harris, J.M, additional, Pickering-Brown, S.M, additional, Lendon, C.L, additional, and Mann, D.M.A, additional

Published
2002
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49. The transcriptional factor LBP-1c/CP2/LSF gene on chromosome 12 is a genetic determinant of Alzheimer's disease

Author

Lambert, J.-C., primary, Goumidi, L., additional, Vrieze, F. W.-D., additional, Frigard, B., additional, Harris, J. M., additional, Cummings, A., additional, Coates, J., additional, Pasquier, F., additional, Cottel, D., additional, Gaillac, M., additional, St Clair, D., additional, Mann, D. M.A., additional, Hardy, J., additional, Lendon, C. L., additional, Amouyel, P., additional, and Chartier-Harlin, M.-C., additional

Published
2000
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