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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

4. A pharmacogenomic assessment of psychiatric adverse drug reactions to levetiracetam

Author

Campbell, C, McCormack, M, Patel, S, Stapleton, C, Bobbili, D, Krause, R, Depondt, C, Sills, GJ, Koeleman, BP, Striano, P, Zara, F, Sander, JW, Lerche, H, Kunz, WS, Stefansson, K, Stefansson, H, Doherty, CP, Heinzen, EL, Scheffer, IE, Goldstein, DB, O'Brien, T, Cotter, D, Berkovic, SF, Sisodiya, SM, Delanty, N, Cavalleri, GL, Campbell, C, McCormack, M, Patel, S, Stapleton, C, Bobbili, D, Krause, R, Depondt, C, Sills, GJ, Koeleman, BP, Striano, P, Zara, F, Sander, JW, Lerche, H, Kunz, WS, Stefansson, K, Stefansson, H, Doherty, CP, Heinzen, EL, Scheffer, IE, Goldstein, DB, O'Brien, T, Cotter, D, Berkovic, SF, Sisodiya, SM, Delanty, N, and Cavalleri, GL

Abstract

OBJECTIVE: Levetiracetam (LEV) is an effective antiseizure medicine, but 10%-20% of people treated with LEV report psychiatric side-effects, and up to 1% may have psychotic episodes. Pharmacogenomic predictors of these adverse drug reactions (ADRs) have yet to be identified. We sought to determine the contribution of both common and rare genetic variation to psychiatric and behavioral ADRs associated with LEV. METHODS: This case-control study compared cases of LEV-associated behavioral disorder (n = 149) or psychotic reaction (n = 37) to LEV-exposed people with no history of psychiatric ADRs (n = 920). All samples were of European ancestry. We performed genome-wide association study (GWAS) analysis comparing those with LEV ADRs to controls. We estimated the polygenic risk scores (PRS) for schizophrenia and compared cases with LEV-associated psychotic reaction to controls. Rare variant burden analysis was performed using exome sequence data of cases with psychotic reactions (n = 18) and controls (n = 122). RESULTS: Univariate GWAS found no significant associations with either LEV-associated behavioural disorder or LEV-psychotic reaction. PRS analysis showed that cases of LEV-associated psychotic reaction had an increased PRS for schizophrenia relative to contr ols (p = .0097, estimate = .4886). The rare-variant analysis found no evidence of an increased burden of rare genetic variants in people who had experienced LEV-associated psychotic reaction relative to controls. SIGNIFICANCE: The polygenic burden for schizophrenia is a risk factor for LEV-associated psychotic reaction. To assess the clinical utility of PRS as a predictor, it should be tested in an independent and ideally prospective cohort. Larger sample sizes are required for the identification of significant univariate common genetic signals or rare genetic signals associated with psychiatric LEV ADRs.

Published
2022

5. Association of ultra-rare coding variants with genetic generalized epilepsy: A case–control whole exome sequencing study

Author

Koko, M., Motelow, J. E., Stanley, K. E., Bobbili, D. R., Dhindsa, R. S., May, P., Alldredge, B. K., Allen, A. S., Altmuller, J., Amrom, D., Andermann, E., Auce, P., Avbersek, A., Baulac, S., Bautista, J. F., Becker, F., Bellows, S. T., Berghuis, B., Berkovic, S. F., Bluvstein, J., Boro, A., Bridgers, J., Burgess, R., Caglayan, H., Cascino, G. D., Cavalleri, G. L., Chung, S. -K., Cieuta-Walti, C., Cloutier, V., Consalvo, D., Cossette, P., Crumrine, P., Delanty, N., Depondt, C., Desbiens, R., Devinsky, O., Dlugos, D., Epstein, M. P., Everett, K., Fiol, M., Fountain, N. B., Francis, B., French, J., Freyer, C., Friedman, D., Gambardella, A., Geller, E. B., Girard, S., Glauser, T., Glynn, S., Goldstein, D. B., Gravel, M., Haas, K., Haut, S. R., Heinzen, E. L., Helbig, I., Hildebrand, M. S., Johnson, M. R., Jorgensen, A., Joshi, S., Kanner, A., Kirsch, H. E., Klein, K. M., Knowlton, R. C., Koeleman, B. P. C., Kossoff, E. H., Krause, R., Krenn, M., Kunz, W. S., Kuzniecky, R., Langley, S. R., Leguern, E., Lehesjoki, A. -E., Lerche, H., Leu, C., Lortie, A., Lowenstein, D. H., Marson, A. G., Mebane, C., Mefford, H. C., Meloche, C., Moreau, C., Motika, P. V., Muhle, H., Moller, R. S., Nabbout, R., Nguyen, D. K., Nikanorova, M., Novotny, E. J., Nurnberg, P., Ottman, R., O'Brien, T. J., Paolicchi, J. M., Parent, J. M., Park, K., Peter, S., Petrou, S., Petrovski, S., Pickrell, W. O., Poduri, A., Radtke, R. A., Rees, M. I., Regan, B. M., Ren, Z., Sadleir, L. G., Sander, J. W., Sander, T., Scheffer, I. E., Schubert, J., Shellhaas, R. A., Sherr, E. H., Shih, J. J., Shinnar, S., Sills, G. J., Singh, R. K., Siren, A., Sirven, J., Sisodiya, S. M., Smith, M. C., Sonsma, A. C. M., Striano, P., Sullivan, J., Thio, L. L., Thomas, R. H., Venkat, A., Vining, E. P. G., Von Allmen, G. K., Wang, Q., Weber, Y. G., Weckhuysen, S., Weisenberg, J. L., Widdess-Walsh, P., Winawer, M. R., Wolking, S., Zara, F., Zimprich, F., Canadian Epilepsy Network, Epi4K Consortium, Epilepsy Phenome/Genome Project, EpiPGX Consortium, EuroEPINOMICS-CoGIE Consortium, Department of Medical and Clinical Genetics, Medicum, Fonds National de la Recherche - FnR [sponsor], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Peter, Sarah, Petrou, Steven, Petrovski, Slavé, Pickrell, William O., Poduri, Annapurna, Radtke, Rodney A., Rees, Mark I., Regan, Brigid M., Ren, Zhong, Sadleir, Lynette G., Alldredge, Brian K., Sander, Josemir W., Sander, Thomas, Scheffer, Ingrid E., Schubert, Julian, Shellhaas, Renée A., Sherr, Elliott H., Shih, Jerry J., Shinnar, Shlomo, Sills, Graeme J., Singh, Rani K., Allen, Andrew S., Siren, Auli, Sirven, Joseph, Sisodiya, Sanjay M., Smith, Michael C., Sonsma, Anja C. M., Striano, Pasquale, Sullivan, Joseph, Thio, Liu Lin, Thomas, Rhys H., Venkat, Anu, Altmüller, Janine, Vining, Eileen P. G., Von Allmen, Gretchen K., Wang, Quanli, Weber, Yvonne G., Weckhuysen, Sarah, Weisenberg, Judith L., Widdess-Walsh, Peter, Winawer, Melodie R., Wolking, Stefan, Zara, Federico, Amrom, Dina, Zimprich, Fritz, Andermann, Eva, Auce, Pauls, Avbersek, Andreja, Baulac, Stéphanie, Bautista, Jocelyn F., Becker, Felicitas, Bellows, Susannah T., Berghuis, Bianca, Berkovic, Samuel F., Bluvstein, Judith, Boro, Alex, Bridgers, Joshua, Burgess, Rosemary, Caglayan, Hande, Cascino, Gregory D., Cavalleri, Gianpiero L., Chung, Seo-Kyung, Cieuta-Walti, Cécile, Cloutier, Véronique, Consalvo, Damian, Cossette, Patrick, Crumrine, Patricia, Delanty, Norman, Depondt, Chantal, Desbiens, Richard, Devinsky, Orrin, Dlugos, Dennis, Epstein, Michael P., Everett, Kate, Fiol, Miguel, Fountain, Nathan B., Francis, Ben, French, Jacqueline, Freyer, Catharine, Friedman, Daniel, Gambardella, Antonio, Geller, Eric B., Girard, Simon, Glauser, Tracy, Glynn, Simon, Goldstein, David B., Gravel, Micheline, Haas, Kevin, Haut, Sheryl R., Heinzen, Erin L., Helbig, Ingo, Hildebrand, Michael S., Johnson, Michael R., Jorgensen, Andrea, Joshi, Sucheta, Kanner, Andres, Kirsch, Heidi E., Klein, Karl M., Knowlton, Robert C., Koeleman, Bobby P. C., Kossoff, Eric H., Krause, Roland, Krenn, Martin, Kunz, Wolfram S., Kuzniecky, Ruben, Langley, Sarah R., LeGuern, Eric, Lehesjoki, Anna-Elina, Lerche, Holger, Leu, Costin, Lortie, Anne, Lowenstein, Daniel H., Marson, Anthony G., Mebane, Caroline, Mefford, Heather C., Meloche, Caroline, Moreau, Claudia, Motika, Paul V., Muhle, Hiltrud, Møller, Rikke S., Nabbout, Rima, Nguyen, Dang K., Nikanorova, Marina, Novotny, Edward J., Nürnberg, Peter, Ottman, Ruth, O'Brien, Terence J., Paolicchi, Juliann M., Parent, Jack M., and Park, Kristen

Subjects
GABA receptors, Neurology [D14] [Human health sciences], Clinical Sciences, GABA(A) receptors, GABRG2, familial epilepsy, Article, Clinical Research, Receptors, Exome Sequencing, Genetics, 2.1 Biological and endogenous factors, Humans, GGE, Genetic Predisposition to Disease, sporadic epilepsy, EpiPGX Consortium, Aetiology, gamma-Aminobutyric Acid, GABAA receptors, Epi4K Consortium, Epilepsy, Neurology & Neurosurgery, Neurologie [D14] [Sciences de la santé humaine], Generalized, GABA-A, Prevention, Human Genome, Neurosciences, 1184 Genetics, developmental biology, physiology, 3112 Neurosciences, Receptors, GABA-A, EuroEPINOMICS-CoGIE Consortium, Neurology, Case-Control Studies, Epilepsy, Generalized, Canadian Epilepsy Network, Neurology (clinical), Genetics & genetic processes [F10] [Life sciences], 3111 Biomedicine, Human medicine, Génétique & processus génétiques [F10] [Sciences du vivant], Epilepsy Phenome/Genome Project
Abstract

ObjectiveWe aimed to identify genes associated with genetic generalized epilepsy (GGE) by combining large cohorts enriched with individuals with a positive family history. Secondarily, we set out to compare the association of genes independently with familial and sporadic GGE.MethodsWe performed a case-control whole exome sequencing study in unrelated individuals of European descent diagnosed with GGE (previously recruited and sequenced through multiple international collaborations) and ancestry-matched controls. The association of ultra-rare variants (URVs; in 18834 protein-coding genes) with epilepsy was examined in 1928 individuals with GGE (vs. 8578 controls), then separately in 945 individuals with familial GGE (vs. 8626 controls), and finally in 1005 individuals with sporadic GGE (vs. 8621 controls). We additionally examined the association of URVs with familial and sporadic GGE in two gene sets important for inhibitory signaling (19genes encoding γ-aminobutyric acid type A [GABAA ] receptors, 113genes representing the GABAergic pathway).ResultsGABRG2 was associated with GGE (p=1.8×10-5 ), approaching study-wide significance in familial GGE (p=3.0×10-6 ), whereas no gene approached a significant association with sporadic GGE. Deleterious URVs in the most intolerant subgenic regions in genes encoding GABAA receptors were associated with familial GGE (odds ratio [OR]=3.9, 95% confidence interval [CI]=1.9-7.8, false discovery rate [FDR]-adjusted p=.0024), whereas their association with sporadic GGE had marginally lower odds (OR=3.1, 95% CI=1.3-6.7, FDR-adjusted p=.022). URVs in GABAergic pathway genes were associated with familial GGE (OR=1.8, 95% CI=1.3-2.5, FDR-adjusted p=.0024) but not with sporadic GGE (OR=1.3, 95% CI=.9-1.9, FDR-adjusted p=.19).SignificanceURVs in GABRG2 are likely an important risk factor for familial GGE. The association of gene sets of GABAergic signaling with familial GGE is more prominent than with sporadic GGE.

Published
2022

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

Author

Athina Simitsi, Grazia Annesi, Hirotaka Matsuo, Leonor Correia Guedes, Mario Ezquerra, Kenya Nishioka, Ashwin Ashok Kumar Sreelatha, Simona Petrucci, Dimitri Krainc, Angela Deutschländer, Ekaterina Rogaeva, Lasse Pihlstrøm, Manu Sharma, Thomas Gasser, Mathias Toft, Jan O. Aasly, Cloé Domenighetti, Monica Diez-Fairen, Milena Radivojkov-Blagojevic, Sandeep Grover, Andrew B. Singleton, Bart P.C. van de Warrenburg, Yun Joong Kim, Andrea Quattrone, Sun Ju Chung, Gianni Pezzoli, Pierre-Emmanuel Sugier, Sulev Kõks, Lena F. Burbulla, Jonathan Carr, Walter Pirker, Efthimos Dardiotis, Karin Wirdefeldt, George D. Mellick, Jean-Christophe Corvol, Dheeraj Reddy Bobbili, Anthony E. Lang, Eugénie Mutez, Georges M. Hadjigeorgiou, Anna Zecchinelli, Laura Brighina, Connor Edsall, Océane Mohamed, Berta Portugal, Andreas Puschmann, Nancy L. Pedersen, Alexander Zimprich, Patrick May, Matthew J. Farrer, Leonidas Stefanis, Yusuke Kawamura, Eduardo Tolosa, Claudia Schulte, Alexis Brice, Caroline Ran, Manuela Tan, Pille Taba, Peter Lichtner, Alexis Elbaz, Dena G. Hernandez, Monica Gagliardi, Andrea Carmine Belin, Joaquim J. Ferreira, Suzanne Lesage, Pierre Kolber, Kathrin Brockmann, Marie-Christine Chartier-Harlin, Carl E Clarke, Karen E. Morrison, Nobutaka Hattori, Stefano Duga, Letizia Straniero, Rejko Krüger, Carlo Ferrarese, Pau Pastor, Soraya Bardien, Clara Hellberg, Bastiaan R. Bloem, Enza Maria Valente, 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, and Elbaz, A

Subjects
Inverse Association, Parkinson's disease, parkinson’s disease, Alcohol Drinking, coffee, Alcohol, Disease, epidemiology [Alcohol Drinking], Coffee, Article, Cellular and Molecular Neuroscience, symbols.namesake, chemistry.chemical_compound, genetics [Parkinson Disease], Risk Factors, epidemiology [Smoking], Humans, Medicine, ddc:610, Coffee drinking, Aged, alcohol, business.industry, Smoking, Confounding, Parkinson Disease, Odds ratio, Mendelian Randomization Analysis, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], medicine.disease, mendelian randomisation, chemistry, genetics [Alcohol Drinking], Parkinson’s disease, smoking, aged, alcohol drinking, genome-wide association study, humans, mendelian randomization analysis, risk factors, parkinson disease, Mendelian inheritance, symbols, etiology [Parkinson Disease], Neurology (clinical), business, Genome-Wide Association Study, Demography
Abstract

Contains fulltext : 248871.pdf (Publisher’s version ) (Open Access) 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. Rare coding variants in genes encoding GABAA receptors in genetic generalised epilepsies: an exome-based case-control study

Author

Patrick May, Simon Girard, Merle Harrer, Dheeraj R Bobbili, Julian Schubert, Stefan Wolking, Felicitas Becker, Pamela Lachance-Touchette, Caroline Meloche, Micheline Gravel, Cristina E Niturad, Julia Knaus, Carolien De Kovel, Mohamad Toliat, Anne Polvi, Michele Iacomino, Rosa Guerrero-López, Stéphanie Baulac, Carla Marini, Holger Thiele, Janine Altmüller, Kamel Jabbari, Ann-Kathrin Ruppert, Wiktor Jurkowski, Dennis Lal, Raffaella Rusconi, Sandrine Cestèle, Benedetta Terragni, Ian D Coombs, Christopher A Reid, Pasquale Striano, Hande Caglayan, Auli Siren, Kate Everett, Rikke S Møller, Helle Hjalgrim, Hiltrud Muhle, Ingo Helbig, Wolfram S Kunz, Yvonne G Weber, Sarah Weckhuysen, Peter De Jonghe, Sanjay M Sisodiya, Rima Nabbout, Silvana Franceschetti, Antonietta Coppola, Maria S Vari, Dorothée Kasteleijn-Nolst Trenité, Betul Baykan, Ugur Ozbek, Nerses Bebek, Karl M Klein, Felix Rosenow, Dang K Nguyen, François Dubeau, Lionel Carmant, Anne Lortie, Richard Desbiens, Jean-François Clément, Cécile Cieuta-Walti, Graeme J Sills, Pauls Auce, Ben Francis, Michael R Johnson, Anthony G Marson, Bianca Berghuis, Josemir W Sander, Andreja Avbersek, Mark McCormack, Gianpiero L Cavalleri, Norman Delanty, Chantal Depondt, Martin Krenn, Fritz Zimprich, Sarah Peter, Marina Nikanorova, Robert Kraaij, Jeroen van Rooij, Rudi Balling, M Arfan Ikram, André G Uitterlinden, Giuliano Avanzini, Stephanie Schorge, Steven Petrou, Massimo Mantegazza, Thomas Sander, Eric LeGuern, Jose M Serratosa, Bobby P C Koeleman, Aarno Palotie, Anna-Elina Lehesjoki, Michael Nothnagel, Peter Nürnberg, Snezana Maljevic, Federico Zara, Patrick Cossette, Roland Krause, Holger Lerche, Edoardo Ferlazzo, Carlo di Bonaventura, Angela La Neve, Paolo Tinuper, Francesca Bisulli, Aglaia Vignoli, Giuseppe Capovilla, Giovanni Crichiutti, Antonio Gambardella, Vincenzo Belcastro, Amedeo Bianchi, Destina Yalçın, Gulsen Dizdarer, Kezban Arslan, Zuhal Yapıcı, Demet Kuşcu, Costin Leu, Kristin Heggeli, Joseph Willis, Sarah R Langley, Andrea Jorgensen, Prashant Srivastava, Sarah Rau, Christian Hengsbach, Anja C.M. Sonsma, Université Côte d'Azur, CNRS, UMR 7275, Institut de Pharmacologie Moléculaire et Cellulaire, Sophia Antipolis, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Laboratory of Molecular Genetics of Stem Cells [University of Montreal], University of Montreal-Institut de Recherche en Immunologie et en Cancérologie [UdeM-Montréal] (IRIC), Université de Montréal (UdeM)-Université de Montréal (UdeM), University of Tübingen, University Medical Center [Utrecht], Universita degli studi di Genova, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), A.Meyer Children's Hospital, Max Planck Institute for Plant Breeding Research (MPIPZ), Génomique métabolique (UMR 8030), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), University of Cologne, The Genome Analysis Centre (TGAC), Cologne Center for Genomics, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Ingénierie des protéines (IP), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Department of Neurophysiopathology, Besta Neurological Institute, University of Southern Denmark (SDU), Medical Genetics Laboratory, Children’s Hospital of Philadelphia (CHOP ), Universitätsklinikum Bonn (UKB), Antwerp University Hospital [Edegem] (UZA), University of Antwerp (UA), Department of Clinical and Experimental Epilepsy, University College of London [London] (UCL), Département de Neuropédiatrie, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Instituco Neurologico C. Besta, Instituto Neurologico C. Besta, Medical Genetics and Pediatric Cardiology, IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Département de mathématiques [Sherbrooke] (UdeS), Faculté des sciences [Sherbrooke] (UdeS), Université de Sherbrooke (UdeS)-Université de Sherbrooke (UdeS), University of Liverpool, Institute of Neurology [London], Royal College of Surgeons in Ireland (RCSI), Neurology Division, Beaumont Hospital, Dublin 9, Ireland, Beaumont Hospital, Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Medizinische Universität Wien = Medical University of Vienna, Department of Epilepsy Clinic and Experimental Neurophysiology, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Department of Medical and Clinical Genetics [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Institute of Medical Informatics and Statistics, Pediatric Neurology and Neuromuscular Diseases Unit, Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Hertie Institute for Clinical Brain Research [Tubingen], Regional Epilepsy Center, Reggio Calabria, Agronomes et Vétérinaires Sans Frontières (AVSF), AVSF, NIHR Biomedical Research Centre [London], Guy's and St Thomas' NHS Foundation Trust-King‘s College London, Wellcome Trust, Commission of the European Communities, Imperial College Healthcare NHS Trust- BRC Funding, Internal Medicine, Epidemiology, Luxembourg Centre For Systems Biomedicine (LCSB), University of Luxembourg [Luxembourg], Università degli studi di Genova = University of Genoa (UniGe), Heart Center Leipzig, University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, Acibadem University Dspace, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université d'Évry-Val-d'Essonne (UEVE), Université Nice Sophia Antipolis (... - 2019) (UNS), University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Medicum, Research Programme for Molecular Neurology, Research Programs Unit, Neuroscience Center, University of Helsinki, Genomics of Neurological and Neuropsychiatric Disorders, Epicure Consortium, EuroEPINOMICS COGIE Consortium, EpiPGX Consortium, May, Gabriella, Girard, S., Harrer, M., Bobbili, D. R., Schubert, J., Wolking, S., Becker, F., Lachance-Touchette, P., Meloche, C., Gravel, M., Niturad, C. E., Knaus, J., De Kovel, C., Toliat, M., Polvi, A., Iacomino, M., Guerrero-López, R., Baulac, S., Marini, C., Thiele, H., Altmüller, J., Jabbari, K., Ruppert, A. -K., Jurkowski, W., Lal, D., Rusconi, R., Cestèle, S., Terragni, B., Coombs, I. D., Reid, C. A., Striano, P., Caglayan, H., Siren, A., Everett, K., Møller, R. S., Hjalgrim, H., Muhle, H., Helbig, I., Kunz, W. S., Weber, Y. G., Weckhuysen, S., Jonghe, P. D., Sisodiya, S. M., Nabbout, R., Franceschetti, S., Coppola, A., Vari, M. S., Kasteleijn-Nolst Trenité, D., Baykan, B., Ozbek, U., Bebek, N., Klein, K. M., Rosenow, F., Nguyen, D. K., Dubeau, F., Carmant, L., Lortie, A., Desbiens, R., Clément, J. -F., Cieuta-Walti, C., Sills, G. J., Auce, P., Francis, B., Johnson, M. R., Marson, A. G., Berghuis, B., Sander, J. W., Avbersek, A., Mccormack, M., Cavalleri, G. L., Delanty, N., Depondt, C., Krenn, M., Zimprich, F., Peter, S., Nikanorova, M., Kraaij, R., van Rooij, J., Balling, R., Ikram, M. A., Uitterlinden, A. G., Avanzini, Giulio, Schorge, S., Petrou, S., Mantegazza, M., Sander, T., Leguern, E., Serratosa, J. M., Koeleman, B. P. C., Palotie, A., Lehesjoki, A. -E., Nothnagel, M., Nürnberg, P., Maljevic, S., Zara, F., Cossette, P., Krause, R., Lerche, H., De Jonghe, P., Arfan Ikram, M., Ferlazzo, E., di Bonaventura, C., La Neve, A., Tinuper, P., Bisulli, F., Vignoli, Massimo, Capovilla, G., Crichiutti, G., Gambardella, A., Belcastro, V., Bianchi, A., Yalçın, D., Dizdarer, G., Arslan, K., Yapıcı, Z., Kuşcu, D., Leu, C., Heggeli, K., Willis, J., Langley, S. R., Jorgensen, A., Srivastava, P., Rau, S., Hengsbach, C., Sonsma, A. C. M., University of Montreal-Institute for Research in Immunology and Cancer (IRIC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université d'Évry-Val-d'Essonne (UEVE), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Département de Mathématiques, Université de Sherbrooke, Université de Sherbrooke [Sherbrooke], Hôpital Erasme (Bruxelles), May, Patrick, Girard, Simon, Harrer, Merle, Bobbili, Dheeraj R, Schubert, Julian, Wolking, Stefan, Becker, Felicita, Lachance-Touchette, Pamela, Meloche, Caroline, Gravel, Micheline, Niturad, Cristina E, Knaus, Julia, De Kovel, Carolien, Toliat, Mohamad, Polvi, Anne, Iacomino, Michele, Guerrero-López, Rosa, Baulac, Stéphanie, Marini, Carla, Thiele, Holger, Altmüller, Janine, Jabbari, Kamel, Ruppert, Ann-Kathrin, Jurkowski, Wiktor, Lal, Denni, Rusconi, Raffaella, Cestèle, Sandrine, Terragni, Benedetta, Coombs, Ian D, Reid, Christopher A, Striano, Pasquale, Caglayan, Hande, Siren, Auli, Everett, Kate, Møller, Rikke S, Hjalgrim, Helle, Muhle, Hiltrud, Helbig, Ingo, Kunz, Wolfram S, Weber, Yvonne G, Weckhuysen, Sarah, Jonghe, Peter De, Sisodiya, Sanjay M, Nabbout, Rima, Franceschetti, Silvana, Coppola, Antonietta, Vari, Maria S, Kasteleijn-Nolst Trenité, Dorothée, Baykan, Betul, Ozbek, Ugur, Bebek, Nerse, Klein, Karl M, Rosenow, Felix, Nguyen, Dang K, Dubeau, Françoi, Carmant, Lionel, Lortie, Anne, Desbiens, Richard, Clément, Jean-Françoi, Cieuta-Walti, Cécile, Sills, Graeme J, Auce, Paul, Francis, Ben, Johnson, Michael R, Marson, Anthony G, Berghuis, Bianca, Sander, Josemir W, Avbersek, Andreja, McCormack, Mark, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Krenn, Martin, Zimprich, Fritz, Peter, Sarah, Nikanorova, Marina, Kraaij, Robert, van Rooij, Jeroen, Balling, Rudi, Ikram, M Arfan, Uitterlinden, André G, Avanzini, Giuliano, Schorge, Stephanie, Petrou, Steven, Mantegazza, Massimo, Sander, Thoma, LeGuern, Eric, Serratosa, Jose M, Koeleman, Bobby P C, Palotie, Aarno, Lehesjoki, Anna-Elina, Nothnagel, Michael, Nürnberg, Peter, Maljevic, Snezana, Zara, Federico, Cossette, Patrick, Krause, Roland, Lerche, Holger, De Jonghe, Peter, Ferlazzo, Edoardo, di Bonaventura, Carlo, La Neve, Angela, Tinuper, Paolo, Bisulli, Francesca, Vignoli, Aglaia, Capovilla, Giuseppe, Crichiutti, Giovanni, Gambardella, Antonio, Belcastro, Vincenzo, Bianchi, Amedeo, Yalçın, Destina, Dizdarer, Gulsen, Arslan, Kezban, Yapıcı, Zuhal, Kuşcu, Demet, Leu, Costin, Heggeli, Kristin, Willis, Joseph, Langley, Sarah R, Jorgensen, Andrea, Srivastava, Prashant, Rau, Sarah, Hengsbach, Christian, and Sonsma, Anja C.M.

Subjects
0301 basic medicine, GAMMA-2-SUBUNIT, [SDV]Life Sciences [q-bio], GABRA5, Clinical Neurology, 15Q13.3 MICRODELETIONS, ABSENCE EPILEPSY, SEQUENCE DATA, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 3124 Neurology and psychiatry, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Genetic variation, medicine, EPILEPTIC ENCEPHALOPATHIES, Exome, Exome sequencing, ComputingMilieux_MISCELLANEOUS, Genetic association, Genetics, RISK, Science & Technology, FEBRILE SEIZURES, Neurology & Neurosurgery, biology, 3112 Neurosciences, 1103 Clinical Sciences, MOUSE MODEL, medicine.disease, ASSOCIATION ANALYSIS, 030104 developmental biology, DE-NOVO MUTATIONS, Cohort, biology.protein, Neurology (clinical), Human medicine, Neurosciences & Neurology, 1109 Neurosciences, Life Sciences & Biomedicine, 030217 neurology & neurosurgery, Cohort study
Abstract

BACKGROUND: Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy.METHODS: For this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABAA receptors and was compared to the respective GABAA receptor variants of a third independent control cohort. Functional investigations were done with automated two-microelectrode voltage clamping in Xenopus laevis oocytes.FINDINGS: Statistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABAA receptors in cases (odds ratio [OR] 2·40 [95% CI 1·41-4·10]; pNonsyn=0·0014, adjusted pNonsyn=0·019). Enrichment for these genes was validated in a whole-exome sequencing cohort of 357 sporadic and familial genetic generalised epilepsy cases and 1485 independent controls (OR 1·46 [95% CI 1·05-2·03]; pNonsyn=0·0081, adjusted pNonsyn=0·016). Comparison of genes encoding GABAA receptors in the independent replication cohort of 583 familial and sporadic genetic generalised epilepsy index cases, based on candidate-gene panel sequencing, with a third independent control cohort of 635 controls confirmed the overall enrichment of rare missense variants for 15 GABAA receptor genes in cases compared with controls (OR 1·46 [95% CI 1·02-2·08]; pNonsyn=0·013, adjusted pNonsyn=0·027). Functional studies for two selected genes (GABRB2 and GABRA5) showed significant loss-of-function effects with reduced current amplitudes in four of seven tested variants compared with wild-type receptors.INTERPRETATION: Functionally relevant variants in genes encoding GABAA receptor subunits constitute a significant risk factor for genetic generalised epilepsy. Examination of the role of specific gene groups and pathways can disentangle the complex genetic architecture of genetic generalised epilepsy.FUNDING: EuroEPINOMICS (European Science Foundation through national funding organisations), Epicure and EpiPGX (Sixth Framework Programme and Seventh Framework Programme of the European Commission), Research Unit FOR2715 (German Research Foundation and Luxembourg National Research Fund).

Published
2018

8. Association of Body Mass Index and Parkinson Disease: A Bidirectional Mendelian Randomization Study.

Author

Domenighetti C, Sugier PE, Ashok Kumar Sreelatha A, Schulte C, Grover S, Portugal B, Lee PC, May P, Bobbili D, Radivojkov Blagojevic M, Lichtner P, Singleton AB, Hernandez D, Edsall C, Mellick GD, Zimprich AA, Pirker W, Rogaeva EA, Lang AE, Koks S, Taba P, Lesage S, Brice A, Corvol JC, Chartier-Harlin MC, Mutez E, Brockmann K, Deutschlander AB, Hadjigeorgiou GM, Dardiotis E, Stefanis L, Simitsi AM, Valente EM, Petrucci S, Straniero L, Zecchinelli AL, Pezzoli G, Brighina L, Ferrarese C, Annesi G, Quattrone A, Gagliardi M, Matsuo H, Nakayama A, Hattori N, Nishioka K, Chung SJ, Kim YJ, Kolber P, Van De Warrenburg BPC, Bloem BR, Toft M, Pihlstrøm L, Correia Guedes L, Ferreira JJ, Bardien S, Carr J, Tolosa E, Ezquerra M, Pastor P, Diez-Fairen M, Wirdefeldt K, Pedersen NL, Ran C, Belin AC, Puschmann A, Hellberg C, Clarke CE, Morrison KE, Tan MM, Krainc D, Burbulla LF, Farrer M, Kruger R, Gasser T, Sharma M, and Elbaz A

Subjects
Humans, Female, Male, Middle Aged, Aged, Risk Factors, Mendelian Randomization Analysis, Parkinson Disease genetics, Parkinson Disease epidemiology, Body Mass Index, Polymorphism, Single Nucleotide genetics, Genome-Wide Association Study
Abstract

Background and Objectives: The role of body mass index (BMI) in Parkinson disease (PD) is unclear. Based on the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in PD (Courage-PD) consortium, we used 2-sample Mendelian randomization (MR) to replicate a previously reported inverse association of genetically predicted BMI with PD and investigated whether findings were robust in analyses addressing the potential for survival and incidence-prevalence biases. We also examined whether the BMI-PD relation is bidirectional by performing a reverse MR., Methods: We used summary statistics from a genome-wide association study (GWAS) to extract the association of 501 single-nucleotide polymorphisms (SNPs) with BMI and from the Courage-PD and international Parkinson Disease Genomics Consortium (iPDGC) to estimate their association with PD. Analyses are based on participants of European ancestry. We used the inverse-weighted method to compute odds ratios (OR IVW per 4.8 kg/m 2 [95% CI]) of PD and additional pleiotropy robust methods. We performed analyses stratified by age, disease duration, and sex. For reverse MR, we used SNPs associated with PD from 2 iPDGC GWAS to assess the effect of genetic liability toward PD on BMI., Results: Summary statistics for BMI are based on 806,834 participants (54% women). Summary statistics for PD are based on 8,919 (40% women) cases and 7,600 (55% women) controls from Courage-PD, and 19,438 (38% women) cases and 24,388 (51% women) controls from iPDGC. In Courage-PD, we found an inverse association between genetically predicted BMI and PD (OR IVW 0.82 [0.70-0.97], p = 0.012) without evidence for pleiotropy. This association tended to be stronger in younger participants (≤67 years, OR IVW 0.71 [0.55-0.92]) and cases with shorter disease duration (≤7 years, OR IVW 0.75 [0.62-0.91]). In pooled Courage-PD + iPDGC analyses, the association was stronger in women (OR IVW 0.85 [0.74-0.99], p = 0.032) than men (OR IVW 0.92 [0.80-1.04], p = 0.18), but the interaction was not statistically significant ( p -interaction = 0.48). In reverse MR, there was evidence for pleiotropy, but pleiotropy robust methods showed a significant inverse association., Discussion: Using an independent data set (Courage-PD), we replicate an inverse association of genetically predicted BMI with PD, not explained by survival or incidence-prevalence biases. Moreover, reverse MR analyses support an inverse association between genetic liability toward PD and BMI, in favor of a bidirectional relation.

Published
2024
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9. Dissecting genetics of spectrum of epilepsies with eyelid myoclonia by exome sequencing.

Author

Coppola A, Krithika S, Iacomino M, Bobbili D, Balestrini S, Bagnasco I, Bilo L, Buti D, Casellato S, Cuccurullo C, Ferlazzo E, Leu C, Giordano L, Gobbi G, Hernandez-Hernandez L, Lench N, Martins H, Meletti S, Messana T, Nigro V, Pinelli M, Pippucci T, Bellampalli R, Salis B, Sofia V, Striano P, Striano S, Tassi L, Vignoli A, Vaudano AE, Viri M, Scheffer IE, May P, Zara F, and Sisodiya SM

Subjects
Humans, Exome Sequencing, Interferon-Induced Helicase, IFIH1 genetics, Electroencephalography, Eyelids, Carrier Proteins genetics, Nerve Tissue Proteins genetics, Myoclonus, Epilepsy, Reflex genetics, Epilepsy, Generalized
Abstract

Objective: Epilepsy with eyelid myoclonia (EEM) spectrum is a generalized form of epilepsy characterized by eyelid myoclonia with or without absences, eye closure-induced seizures with electroencephalographic paroxysms, and photosensitivity. Based on the specific clinical features, age at onset, and familial occurrence, a genetic cause has been postulated. Pathogenic variants in CHD2, SYNGAP1, NEXMIF, RORB, and GABRA1 have been reported in individuals with photosensitivity and eyelid myoclonia, but whether other genes are also involved, or a single gene is uniquely linked with EEM, or its subtypes, is not yet known. We aimed to dissect the genetic etiology of EEM., Methods: We studied a cohort of 105 individuals by using whole exome sequencing. Individuals were divided into two groups: EEM- (isolated EEM) and EEM+ (EEM accompanied by intellectual disability [ID] or any other neurodevelopmental/psychiatric disorder)., Results: We identified nine variants classified as pathogenic/likely pathogenic in the entire cohort (8.57%); among these, eight (five in CHD2, one in NEXMIF, one in SYNGAP1, and one in TRIM8) were found in the EEM+ subcohort (28.57%). Only one variant (IFIH1) was found in the EEM- subcohort (1.29%); however, because the phenotype of the proband did not fit with published data, additional evidence is needed before considering IFIH1 variants and EEM- an established association. Burden analysis did not identify any single burdened gene or gene set., Significance: Our results suggest that for EEM, as for many other epilepsies, the identification of a genetic cause is more likely with comorbid ID and/or other neurodevelopmental disorders. Pathogenic variants were mostly found in CHD2, and the association of CHD2 with EEM+ can now be considered a reasonable gene-disease association. We provide further evidence to strengthen the association of EEM+ with NEXMIF and SYNGAP1. Possible new associations between EEM+ and TRIM8, and EEM- and IFIH1, are also reported. Although we provide robust evidence for gene variants associated with EEM+, the core genetic etiology of EEM- remains to be elucidated., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Published
2024
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11. Trans-ancestry polygenic models for the prediction of LDL blood levels: an analysis of the United Kingdom Biobank and Taiwan Biobank.

Author

Hassanin E, Lee KH, Hsieh TC, Aldisi R, Lee YL, Bobbili D, Krawitz P, May P, Chen CY, and Maj C

Abstract

Polygenic risk score (PRS) predictions often show bias toward the population of available genome-wide association studies (GWASs), which is typically of European ancestry. This study aimed to assess the performance differences of ancestry-specific PRS and test the implementation of multi-ancestry PRS to enhance the generalizability of low-density lipoprotein (LDL) cholesterol predictions in the East Asian (EAS) population. In this study, we computed ancestry-specific and multi-ancestry PRSs for LDL using data obtained from the Global Lipid Genetics Consortium, while accounting for population-specific linkage disequilibrium patterns using the PRS-CSx method in the United Kingdom Biobank dataset (UKB, n = 423,596) and Taiwan Biobank dataset (TWB, n = 68,978). Population-specific PRSs were able to predict LDL levels better within the target population, whereas multi-ancestry PRSs were more generalizable. In the TWB dataset, covariate-adjusted R 2 values were 9.3% for ancestry-specific PRS, 6.7% for multi-ancestry PRS, and 4.5% for European-specific PRS. Similar trends (8.6%, 7.8%, and 6.2%) were observed in the smaller EAS population of the UKB (n = 1,480). Consistent with R 2 values, PRS stratification in EAS regions (TWB) effectively captured a heterogenous variability in LDL blood cholesterol levels across PRS strata. The mean difference in LDL levels between the lowest and highest EAS-specific PRS (EAS_PRS) deciles was 0.82, compared to 0.59 for European-specific PRS (EUR_PRS) and 0.76 for multi-ancestry PRS. Notably, the mean LDL values in the top decile of multi-ancestry PRS were comparable to those of EAS_PRS (3.543 vs. 3.541, p = 0.86). Our analysis of the PRS prediction model for LDL cholesterol further supports the issue of PRS generalizability across populations. Our targeted analysis of the EAS population revealed that integrating non-European genotyping data with a powerful European-based GWAS can enhance the generalizability of LDL PRS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hassanin, Lee, Hsieh, Aldisi, Lee, Bobbili, Krawitz, May, Chen and Maj.)

Published
2023
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12. Accurate long-read sequencing identified GBA1 as major risk factor in the Luxembourgish Parkinson's study.

Author

Pachchek S, Landoulsi Z, Pavelka L, Schulte C, Buena-Atienza E, Gross C, Hauser AK, Reddy Bobbili D, Casadei N, May P, and Krüger R

Abstract

Heterozygous variants in the glucocerebrosidase GBA1 gene are an increasingly recognized risk factor for Parkinson's disease (PD). Due to the GBAP1 pseudogene, which shares 96% sequence homology with the GBA1 coding region, accurate variant calling by array-based or short-read sequencing methods remains a major challenge in understanding the genetic landscape of GBA1-associated PD. We analyzed 660 patients with PD, 100 patients with Parkinsonism and 808 healthy controls from the Luxembourg Parkinson's study, sequenced using amplicon-based long-read DNA sequencing technology. We found that 12.1% (77/637) of PD patients carried GBA1 variants, with 10.5% (67/637) of them carrying known pathogenic variants (including severe, mild, risk variants). In comparison, 5% (34/675) of the healthy controls carried GBA1 variants, and among them, 4.3% (29/675) were identified as pathogenic variant carriers. We found four GBA1 variants in patients with atypical parkinsonism. Pathogenic GBA1 variants were 2.6-fold more frequently observed in PD patients compared to controls (OR = 2.6; CI = [1.6,4.1]). Three novel variants of unknown significance (VUS) were identified. Using a structure-based approach, we defined a potential risk prediction method for VUS. This study describes the full landscape of GBA1-related parkinsonism in Luxembourg, showing a high prevalence of GBA1 variants as the major genetic risk for PD. Although the long-read DNA sequencing technique used in our study may be limited in its effectiveness to detect potential structural variants, our approach provides an important advancement for highly accurate GBA1 variant calling, which is essential for providing access to emerging causative therapies for GBA1 carriers., (© 2023. The Author(s).)

Published
2023
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13. Genome-wide Association and Meta-analysis of Age at Onset in Parkinson Disease: Evidence From the COURAGE-PD Consortium.

Author

Grover S, Kumar Sreelatha AA, Pihlstrom L, Domenighetti C, Schulte C, Sugier PE, Radivojkov-Blagojevic M, Lichtner P, Mohamed O, Portugal B, Landoulsi Z, May P, Bobbili D, Edsall C, Bartusch F, Hanussek M, Krüger J, Hernandez DG, Blauwendraat C, Mellick GD, Zimprich A, Pirker W, Tan M, Rogaeva E, Lang A, Koks S, Taba P, Lesage S, Brice A, Corvol JC, Chartier-Harlin MC, Mutez E, Brockmann K, Deutschländer AB, Hadjigeorgiou GM, Dardiotis E, Stefanis L, Simitsi AM, Valente EM, Petrucci S, Straniero L, Zecchinelli A, Pezzoli G, Brighina L, Ferrarese C, Annesi G, Quattrone A, Gagliardi M, Burbulla LF, Matsuo H, Kawamura Y, Hattori N, Nishioka K, Chung SJ, Kim YJ, Pavelka L, van de Warrenburg BPC, Bloem BR, Singleton AB, Aasly J, Toft M, Guedes LC, Ferreira JJ, Bardien S, Carr J, Tolosa E, Ezquerra M, Pastor P, Diez-Fairen M, Wirdefeldt K, Pedersen NL, Ran C, Belin AC, Puschmann A, Hellberg C, Clarke CE, Morrison KE, Krainc D, Farrer MJ, Kruger R, Elbaz A, Gasser T, and Sharma M

Subjects
Age of Onset, Female, Genetic Predisposition to Disease genetics, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Courage, Parkinson Disease epidemiology, Parkinson Disease genetics
Abstract

Background and Objectives: Considerable heterogeneity exists in the literature concerning genetic determinants of the age at onset (AAO) of Parkinson disease (PD), which could be attributed to a lack of well-powered replication cohorts. The previous largest genome-wide association studies (GWAS) identified SNCA and TMEM175 loci on chromosome (Chr) 4 with a significant influence on the AAO of PD; these have not been independently replicated. This study aims to conduct a meta-analysis of GWAS of PD AAO and validate previously observed findings in worldwide populations., Methods: A meta-analysis was performed on PD AAO GWAS of 30 populations of predominantly European ancestry from the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (COURAGE-PD) Consortium. This was followed by combining our study with the largest publicly available European ancestry dataset compiled by the International Parkinson Disease Genomics Consortium (IPDGC)., Results: The COURAGE-PD Consortium included a cohort of 8,535 patients with PD (91.9%: Europeans and 9.1%: East Asians). The average AAO in the COURAGE-PD dataset was 58.9 years (SD = 11.6), with an underrepresentation of females (40.2%). The heritability estimate for AAO in COURAGE-PD was 0.083 (SE = 0.057). None of the loci reached genome-wide significance ( p < 5 × 10 -8 ). Nevertheless, the COURAGE-PD dataset confirmed the role of the previously published TMEM175 variant as a genetic determinant of the AAO of PD with Bonferroni-corrected nominal levels of significance ( p < 0.025): (rs34311866: β(SE) COURAGE = 0.477(0.203), p COURAGE = 0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (N total = 25,950) led to the identification of 2 genome-wide significant association signals on Chr 4, including the previously reported SNCA locus (rs983361: β(SE) COURAGE+IPDGC = 0.720(0.122), p COURAGE+IPDGC = 3.13 × 10 -9 ) and a novel BST1 locus (rs4698412: β(SE) COURAGE+IPDGC = -0.526(0.096), p COURAGE+IPDGC = 4.41 × 10 -8 )., Discussion: Our study further refines the genetic architecture of Chr 4 underlying the AAO of the PD phenotype through the identification of BST1 as a novel AAO PD locus. These findings open a new direction for the development of treatments to delay the onset of PD., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Published
2022
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14. A pharmacogenomic assessment of psychiatric adverse drug reactions to levetiracetam.

Author

Campbell C, McCormack M, Patel S, Stapleton C, Bobbili D, Krause R, Depondt C, Sills GJ, Koeleman BP, Striano P, Zara F, Sander JW, Lerche H, Kunz WS, Stefansson K, Stefansson H, Doherty CP, Heinzen EL, Scheffer IE, Goldstein DB, O'Brien T, Cotter D, Berkovic SF, Sisodiya SM, Delanty N, and Cavalleri GL

Subjects
Anticonvulsants adverse effects, Case-Control Studies, Genetic Predisposition to Disease genetics, Humans, Levetiracetam adverse effects, Pharmacogenetics, Prospective Studies, Drug-Related Side Effects and Adverse Reactions, Genome-Wide Association Study
Abstract

Objective: Levetiracetam (LEV) is an effective antiseizure medicine, but 10%-20% of people treated with LEV report psychiatric side-effects, and up to 1% may have psychotic episodes. Pharmacogenomic predictors of these adverse drug reactions (ADRs) have yet to be identified. We sought to determine the contribution of both common and rare genetic variation to psychiatric and behavioral ADRs associated with LEV., Methods: This case-control study compared cases of LEV-associated behavioral disorder (n = 149) or psychotic reaction (n = 37) to LEV-exposed people with no history of psychiatric ADRs (n = 920). All samples were of European ancestry. We performed genome-wide association study (GWAS) analysis comparing those with LEV ADRs to controls. We estimated the polygenic risk scores (PRS) for schizophrenia and compared cases with LEV-associated psychotic reaction to controls. Rare variant burden analysis was performed using exome sequence data of cases with psychotic reactions (n = 18) and controls (n = 122)., Results: Univariate GWAS found no significant associations with either LEV-associated behavioural disorder or LEV-psychotic reaction. PRS analysis showed that cases of LEV-associated psychotic reaction had an increased PRS for schizophrenia relative to contr ols (p = .0097, estimate = .4886). The rare-variant analysis found no evidence of an increased burden of rare genetic variants in people who had experienced LEV-associated psychotic reaction relative to controls., Significance: The polygenic burden for schizophrenia is a risk factor for LEV-associated psychotic reaction. To assess the clinical utility of PRS as a predictor, it should be tested in an independent and ideally prospective cohort. Larger sample sizes are required for the identification of significant univariate common genetic signals or rare genetic signals associated with psychiatric LEV ADRs., (© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Published
2022
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