Large-scale replication and heterogeneity in Parkinson disease genetic loci

Manu Sharma; John P.A. Ioannidis; Jan O. Aasly; Grazia Annesi; Alexis Brice; Christine Van Broeckhoven; Lars Bertram; Maria Bozi; David Crosiers; Carl Clarke; Maurizio Facheris; Matthew Farrer; Gaetan Garraux; Suzana Gispert; Georg Auburger; Carles Vilariño-Güell; Georgios M. Hadjigeorgiou; Andrew A. Hicks; Nobutaka Hattori; Beom Jeon; Suzanne Lesage; Christina M. Lill; Juei Jueng Lin; Timothy Lynch; Peter Lichtner; Anthony E. Lang; Vincent Mok; Barbara Jasinska-Myga; George D. Mellick; Karen E. Morrison; Grzegorz Opala; Peter P. Pramstaller; Irene Pichler; Sung Sup Park; Aldo Quattrone; Ekaterina Rogaeva; Owen A. Ross; Leonidas Stefanis; Joanne D. Stockton; Wataru Satake; Peter A. Silburn; Jessie Theuns; Eng King Tan; Tatsushi Toda; Hiroyuki Tomiyama; Ryan J. Uitti; Karin Wirdefeldt; Zbigniew Wszolek; Georgia Xiromerisiou; Kuo Chu Yueh; Yi Zhao; Thomas Gasser; Demetrius Maraganore; Rejko Krüger

doi:10.1212/WNL.0b013e318264e353

Large-scale replication and heterogeneity in Parkinson disease genetic loci

Manu Sharma^*, John P.A. Ioannidis, Jan O. Aasly, Grazia Annesi, Alexis Brice, Christine Van Broeckhoven, Lars Bertram, Maria Bozi, David Crosiers, Carl Clarke, Maurizio Facheris, Matthew Farrer, Gaetan Garraux, Suzana Gispert, Georg Auburger, Carles Vilariño-Güell, Georgios M. Hadjigeorgiou, Andrew A. Hicks, Nobutaka Hattori, Beom JeonSuzanne Lesage, Christina M. Lill, Juei Jueng Lin, Timothy Lynch, Peter Lichtner, Anthony E. Lang, Vincent Mok, Barbara Jasinska-Myga, George D. Mellick, Karen E. Morrison, Grzegorz Opala, Peter P. Pramstaller, Irene Pichler, Sung Sup Park, Aldo Quattrone, Ekaterina Rogaeva, Owen A. Ross, Leonidas Stefanis, Joanne D. Stockton, Wataru Satake, Peter A. Silburn, Jessie Theuns, Eng King Tan, Tatsushi Toda, Hiroyuki Tomiyama, Ryan J. Uitti, Karin Wirdefeldt, Zbigniew Wszolek, Georgia Xiromerisiou, Kuo Chu Yueh, Yi Zhao, Thomas Gasser, Demetrius Maraganore, Rejko Krüger

^*Corresponding author for this work

Research output: Contribution to journal › Article › Research › peer-review

114 Citations (Scopus)

Abstract

Objective: Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown. Methods: Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry. Results: In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78-0.87 (LAMP3, BST1, and MAPT) and susceptibility per-allele odds ratios of 1.14-1.43 (STK39, GAK, SNCA, LRRK2, SYT11, and HIP1R). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes (I2 estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the BST1 (rs11724635) in Asian vs Caucasian populations and similar effects for SNCA, LRRK2, LAMP3, HIP1R, and STK39 in Asian and Caucasian populations, while MAPT rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD. Conclusion: Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity.

Original language	English
Pages (from-to)	659-667
Number of pages	9
Journal	Neurology
Volume	79
Issue number	7
DOIs	https://doi.org/10.1212/WNL.0b013e318264e353
Publication status	Published - 14 Aug 2012
Externally published	Yes

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10.1212/WNL.0b013e318264e353

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Sharma, M., Ioannidis, J. P. A., Aasly, J. O., Annesi, G., Brice, A., Van Broeckhoven, C., Bertram, L., Bozi, M., Crosiers, D., Clarke, C., Facheris, M., Farrer, M., Garraux, G., Gispert, S., Auburger, G., Vilariño-Güell, C., Hadjigeorgiou, G. M., Hicks, A. A., Hattori, N., ... Krüger, R. (2012). Large-scale replication and heterogeneity in Parkinson disease genetic loci. Neurology, 79(7), 659-667. https://doi.org/10.1212/WNL.0b013e318264e353

@article{e6ffe6637c79422b88aab6c543fb9104,

title = "Large-scale replication and heterogeneity in Parkinson disease genetic loci",

abstract = "Objective: Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown. Methods: Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry. Results: In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78-0.87 (LAMP3, BST1, and MAPT) and susceptibility per-allele odds ratios of 1.14-1.43 (STK39, GAK, SNCA, LRRK2, SYT11, and HIP1R). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes (I2 estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the BST1 (rs11724635) in Asian vs Caucasian populations and similar effects for SNCA, LRRK2, LAMP3, HIP1R, and STK39 in Asian and Caucasian populations, while MAPT rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD. Conclusion: Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity.",

author = "Manu Sharma and Ioannidis, {John P.A.} and Aasly, {Jan O.} and Grazia Annesi and Alexis Brice and {Van Broeckhoven}, Christine and Lars Bertram and Maria Bozi and David Crosiers and Carl Clarke and Maurizio Facheris and Matthew Farrer and Gaetan Garraux and Suzana Gispert and Georg Auburger and Carles Vilari{\~n}o-G{\"u}ell and Hadjigeorgiou, {Georgios M.} and Hicks, {Andrew A.} and Nobutaka Hattori and Beom Jeon and Suzanne Lesage and Lill, {Christina M.} and Lin, {Juei Jueng} and Timothy Lynch and Peter Lichtner and Lang, {Anthony E.} and Vincent Mok and Barbara Jasinska-Myga and Mellick, {George D.} and Morrison, {Karen E.} and Grzegorz Opala and Pramstaller, {Peter P.} and Irene Pichler and Park, {Sung Sup} and Aldo Quattrone and Ekaterina Rogaeva and Ross, {Owen A.} and Leonidas Stefanis and Stockton, {Joanne D.} and Wataru Satake and Silburn, {Peter A.} and Jessie Theuns and Tan, {Eng King} and Tatsushi Toda and Hiroyuki Tomiyama and Uitti, {Ryan J.} and Karin Wirdefeldt and Zbigniew Wszolek and Georgia Xiromerisiou and Yueh, {Kuo Chu} and Yi Zhao and Thomas Gasser and Demetrius Maraganore and Rejko Kr{\"u}ger",

note = "Funding Information: M. Sharma received funding support from Michael J Fox Foundation USA and travel grant from Movement Disorders Society. J.P.A. Ioannidis reports no disclosures. J.O. Aasly is supported by Norwegian Research Council and Reberg's Legacy. G. Annesi reports no disclosures. A. Brice receives grant support from Eranet Neuron (Co-PI), ANR Maladies Neurologiques et Psychiatriques 2008 (Co-PI), and PHRC National 2006 and 2008. C. Van Broeckhoven received funding from Research Foundation Flanders (FWO), research grant G.0085.08, co-PI; Research Foundation Flanders (FWO), Belgium, postdoctoral fellowship, PI; Agency for Innovation by Science and Technology-Flanders (IWT), research grant 080020, co-PI; Flemish Government, Belgium, Methusalem excellence grant, key personnel; Belgian Science Policy Office, Interuniversity Attraction Poles program (IUAP) P6/43, key personnel; University of Antwerp, Belgium, Special Research Fund, key personnel; Foundation for Alzheimer Research (SAO-FRMA), Belgium; research grant 09007, PI; Alzheimer's Association, USA, New Investigator Research Grant, NIRG-09-132000, PI; Belgian Parkinson Foundation, Belgium, research grant, PI. L. Bertram, M. Bozi, D. Crosiers, C. Clarke, and M. Facheris report no disclosures. M. Farrer and Mayo Foundation received royalties from H. Lundbeck A/S and Isis Pharmaceuticals. In addition, Dr. Farrer has received an honorarium for a seminar at Genzyme. G. Garraux, S. Gispert, G. Auburger, C. Vilari{\~n}o-G{\"u}ell, G.M. Hadjigeorgiou, and A. Hicks report no disclosures. N. Hattori has been serving as an advisory board member for Boehringer Ingelheim; as a result of attending advisory board meetings he received personal compensation. Nobutaka Hattori also has been serving as an advisory board member for FP Pharmaceutical Company by attending these advisory meetings he received personal compensation. He has been consulting with Ohtsuska Pharmaceutical Company, Kyowa Hakko Kirin Pharmaceutical Company, GlaxoSmithKline, Novartis, and Schering-Plough, and when he attended these advisory board meetings, he received personal compensation. B. Jeon has received funding for travel from GlaxoSmithKline Korea and Novartis Korea and has received research support as PI from Novartis, Boehringer Ingelheim, Ipsen Korea, the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (#A030001), ABRC (Advanced Biometric Research Center), KOSEF (Korea Science and Engineering Foundation), Seoul National University Hospital, the Mr. Chung Suk-Gyoo and Sinyang Cultural Foundation, and the Song Foundation. S. Lesage, C.M. Lill, and J.-J. Lin report no disclosures. T. Lynch has served on an advisory board for Biogen and Novartis and has received honoraria from Lundbeck, Biogen, and Boehringer-Ingelheim. P. Lichtner reports no disclosures. A.E. Lang has served as an advisor for Abbott, Allon Therapeutics, Astra Zeneca, Biovail, Boerhinger-Ingelheim, Cephalon, Ceregene, Eisai, Medtronic, Lundbeck A/S, Novartis, Merck Serono, Solvay, and Teva and received grants from Canadian Institutes of Health Research, Dystonia Medical Research Foundation, Michael J. Fox Foundation, National Parkinson Foundation, and Ontario Problem Gambling Research Centre and has served as an expert witness in cases related to the welding industry. V. Mok reports no disclosures. B. Jasinska-Myga was partially supported by the Robert and Clarice Smith Fellowship Program and the Pacific Alzheimer Research Foundation (PARF) C06-01 grant. G.D. Mellick reports no disclosures. K. E. Morrison has received grant support from Parkinson's UK, The Medical Research Council UK, the Wellcome Trust, and the Midlands Neurological Teaching and Research Fund. G. Opala was partially supported by the Robert and Clarice Smith Fellowship Program and the Pacific Alzheimer Research Foundation (PARF) C06-01 grant. P.P. Pramstaller, I. Pichler, S.S. Park, A. Quattrone, and E. Rogaeva report no disclosures. O.A. Ross is funded by NIH/NINDS awards P50 NS072187 and R01 NS078086, and the Michael J Fox Foundation. L. Stefanis has received a grant for genetic studies of PD from the Hellenic Secretariat of Research and Technology (PENED 2003), in which Novartis Hellas acted as a co-sponsor. J.D. Stockton reports no disclosures. W. Satake receives research support from Japan Intractable Disease Research Foundation. P.A. Silburn and J. Theuns report no disclosures. E.-K. Tan is funded by National Medical Research Council, Duke-NUS Graduate Medical School, and Singapore Millennium Foundation. He has received honoraria from Novartis, Boehringer Ingelheim, and GSK. T. Toda receives research support from Ministry of Health, Labour and Welfare of Japan. H. Tomiyama reports no disclosures. R.J. Uitti has received research funding from the NIH, PARRF, PSG, Noscira, Inc. and Advanced Neuromodulation Systems, Inc. Dr. Uitti has served as a Continuing Medical Educator for the AAN. His institution has received annual royalties from the licensing of the technology related to PARK8/LRRK2 greater than the federal threshold for significant financial interest. Dr. Uitti has not received any royalties. Dr. Uitti receives an honorarium as Associate Editor of Neurology{\textregistered}. K. Wirdefeldt reports no disclosures. Z. Wszolek holds and has contractual rights for receipt of future royalty payments from patents re: A novel polynucleotide involved in heritable Parkinson's disease, receives educational research support from Allergan, Inc., the NIH/NINDS 1RC2NS070276, NS057567, P50NS072187, Mayo Clinic Florida (MCF) Research Committee CR programs (MCF #90052018 and MCF #90052030), and the gift from Carl Edward Bolch, Jr. and Susan Bass Bolch (MCF #90052031/PAU #90052). G. Xiromerisiou, K.-C. Yueh, and Y. Zhao report no disclosures. T. Gasser is funded by Novartis Pharma, the Federal Ministry of Education and Research (BMBF) (NGFN-Plus and ERA-Net NEURON), the Helmholtz Association (HelMA, Helmholtz Alliance for Health in an Ageing Society), and the European Union (MeFoPa, Mendelian Forms of Parkinsonism). He received speaker honoraria from Novartis, Merck-Serono, Schwarz Pharma, Boehringer Ingelheim, and Valeant Pharma and royalties for his consulting activities from Cefalon Pharma and Merck-Serono. Dr. Gasser holds a patent concerning the LRRK2 gene and neurodegenerative disorders. D.M. Maraganore received funding support from the National Institutes of Health grant ES10751 (“Molecular Epidemiology of Parkinson's Disease”). He also received funding support from Alnylam Pharmaceuticals and Medtronic, Inc. to conduct an observational study of Parkinson's disease outcomes. Dr. Maraganore had a patent filed for a method to treat Parkinson disease. It has been licensed to Alnylam Pharmaceuticals. R. Kr{\"u}ger has received research grants of the German Research Council (DFG; KR2119/3-2), the Michael J Fox Foundation, and the Federal Ministry for Education and Research (BMBF, NGFNplus; 01GS08134), as well as speaker honoraria and/or travel grants from UCB Pharma, Cephalon, Abbott Pharmaceuticals, Takeda Pharmaceuticals, and Medtronic. Go to Neurology.org for full disclosures.",

year = "2012",

month = aug,

day = "14",

doi = "10.1212/WNL.0b013e318264e353",

language = "English",

volume = "79",

pages = "659--667",

journal = "Neurology",

issn = "0028-3878",

publisher = "Lippincott Williams and Wilkins Ltd.",

number = "7",

}

Sharma, M, Ioannidis, JPA, Aasly, JO, Annesi, G, Brice, A, Van Broeckhoven, C, Bertram, L, Bozi, M, Crosiers, D, Clarke, C, Facheris, M, Farrer, M, Garraux, G, Gispert, S, Auburger, G, Vilariño-Güell, C, Hadjigeorgiou, GM, Hicks, AA, Hattori, N, Jeon, B, Lesage, S, Lill, CM, Lin, JJ, Lynch, T, Lichtner, P, Lang, AE, Mok, V, Jasinska-Myga, B, Mellick, GD, Morrison, KE, Opala, G, Pramstaller, PP, Pichler, I, Park, SS, Quattrone, A, Rogaeva, E, Ross, OA, Stefanis, L, Stockton, JD, Satake, W, Silburn, PA, Theuns, J, Tan, EK, Toda, T, Tomiyama, H, Uitti, RJ, Wirdefeldt, K, Wszolek, Z, Xiromerisiou, G, Yueh, KC, Zhao, Y, Gasser, T, Maraganore, D & Krüger, R 2012, 'Large-scale replication and heterogeneity in Parkinson disease genetic loci', Neurology, vol. 79, no. 7, pp. 659-667. https://doi.org/10.1212/WNL.0b013e318264e353

TY - JOUR

T1 - Large-scale replication and heterogeneity in Parkinson disease genetic loci

AU - Sharma, Manu

AU - Ioannidis, John P.A.

AU - Aasly, Jan O.

AU - Annesi, Grazia

AU - Brice, Alexis

AU - Van Broeckhoven, Christine

AU - Bertram, Lars

AU - Bozi, Maria

AU - Crosiers, David

AU - Clarke, Carl

AU - Facheris, Maurizio

AU - Farrer, Matthew

AU - Garraux, Gaetan

AU - Gispert, Suzana

AU - Auburger, Georg

AU - Vilariño-Güell, Carles

AU - Hadjigeorgiou, Georgios M.

AU - Hicks, Andrew A.

AU - Hattori, Nobutaka

AU - Jeon, Beom

AU - Lesage, Suzanne

AU - Lill, Christina M.

AU - Lin, Juei Jueng

AU - Lynch, Timothy

AU - Lichtner, Peter

AU - Lang, Anthony E.

AU - Mok, Vincent

AU - Jasinska-Myga, Barbara

AU - Mellick, George D.

AU - Morrison, Karen E.

AU - Opala, Grzegorz

AU - Pramstaller, Peter P.

AU - Pichler, Irene

AU - Park, Sung Sup

AU - Quattrone, Aldo

AU - Rogaeva, Ekaterina

AU - Ross, Owen A.

AU - Stefanis, Leonidas

AU - Stockton, Joanne D.

AU - Satake, Wataru

AU - Silburn, Peter A.

AU - Theuns, Jessie

AU - Tan, Eng King

AU - Toda, Tatsushi

AU - Tomiyama, Hiroyuki

AU - Uitti, Ryan J.

AU - Wirdefeldt, Karin

AU - Wszolek, Zbigniew

AU - Xiromerisiou, Georgia

AU - Yueh, Kuo Chu

AU - Zhao, Yi

AU - Gasser, Thomas

AU - Maraganore, Demetrius

AU - Krüger, Rejko

N1 - Funding Information: M. Sharma received funding support from Michael J Fox Foundation USA and travel grant from Movement Disorders Society. J.P.A. Ioannidis reports no disclosures. J.O. Aasly is supported by Norwegian Research Council and Reberg's Legacy. G. Annesi reports no disclosures. A. Brice receives grant support from Eranet Neuron (Co-PI), ANR Maladies Neurologiques et Psychiatriques 2008 (Co-PI), and PHRC National 2006 and 2008. C. Van Broeckhoven received funding from Research Foundation Flanders (FWO), research grant G.0085.08, co-PI; Research Foundation Flanders (FWO), Belgium, postdoctoral fellowship, PI; Agency for Innovation by Science and Technology-Flanders (IWT), research grant 080020, co-PI; Flemish Government, Belgium, Methusalem excellence grant, key personnel; Belgian Science Policy Office, Interuniversity Attraction Poles program (IUAP) P6/43, key personnel; University of Antwerp, Belgium, Special Research Fund, key personnel; Foundation for Alzheimer Research (SAO-FRMA), Belgium; research grant 09007, PI; Alzheimer's Association, USA, New Investigator Research Grant, NIRG-09-132000, PI; Belgian Parkinson Foundation, Belgium, research grant, PI. L. Bertram, M. Bozi, D. Crosiers, C. Clarke, and M. Facheris report no disclosures. M. Farrer and Mayo Foundation received royalties from H. Lundbeck A/S and Isis Pharmaceuticals. In addition, Dr. Farrer has received an honorarium for a seminar at Genzyme. G. Garraux, S. Gispert, G. Auburger, C. Vilariño-Güell, G.M. Hadjigeorgiou, and A. Hicks report no disclosures. N. Hattori has been serving as an advisory board member for Boehringer Ingelheim; as a result of attending advisory board meetings he received personal compensation. Nobutaka Hattori also has been serving as an advisory board member for FP Pharmaceutical Company by attending these advisory meetings he received personal compensation. He has been consulting with Ohtsuska Pharmaceutical Company, Kyowa Hakko Kirin Pharmaceutical Company, GlaxoSmithKline, Novartis, and Schering-Plough, and when he attended these advisory board meetings, he received personal compensation. B. Jeon has received funding for travel from GlaxoSmithKline Korea and Novartis Korea and has received research support as PI from Novartis, Boehringer Ingelheim, Ipsen Korea, the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (#A030001), ABRC (Advanced Biometric Research Center), KOSEF (Korea Science and Engineering Foundation), Seoul National University Hospital, the Mr. Chung Suk-Gyoo and Sinyang Cultural Foundation, and the Song Foundation. S. Lesage, C.M. Lill, and J.-J. Lin report no disclosures. T. Lynch has served on an advisory board for Biogen and Novartis and has received honoraria from Lundbeck, Biogen, and Boehringer-Ingelheim. P. Lichtner reports no disclosures. A.E. Lang has served as an advisor for Abbott, Allon Therapeutics, Astra Zeneca, Biovail, Boerhinger-Ingelheim, Cephalon, Ceregene, Eisai, Medtronic, Lundbeck A/S, Novartis, Merck Serono, Solvay, and Teva and received grants from Canadian Institutes of Health Research, Dystonia Medical Research Foundation, Michael J. Fox Foundation, National Parkinson Foundation, and Ontario Problem Gambling Research Centre and has served as an expert witness in cases related to the welding industry. V. Mok reports no disclosures. B. Jasinska-Myga was partially supported by the Robert and Clarice Smith Fellowship Program and the Pacific Alzheimer Research Foundation (PARF) C06-01 grant. G.D. Mellick reports no disclosures. K. E. Morrison has received grant support from Parkinson's UK, The Medical Research Council UK, the Wellcome Trust, and the Midlands Neurological Teaching and Research Fund. G. Opala was partially supported by the Robert and Clarice Smith Fellowship Program and the Pacific Alzheimer Research Foundation (PARF) C06-01 grant. P.P. Pramstaller, I. Pichler, S.S. Park, A. Quattrone, and E. Rogaeva report no disclosures. O.A. Ross is funded by NIH/NINDS awards P50 NS072187 and R01 NS078086, and the Michael J Fox Foundation. L. Stefanis has received a grant for genetic studies of PD from the Hellenic Secretariat of Research and Technology (PENED 2003), in which Novartis Hellas acted as a co-sponsor. J.D. Stockton reports no disclosures. W. Satake receives research support from Japan Intractable Disease Research Foundation. P.A. Silburn and J. Theuns report no disclosures. E.-K. Tan is funded by National Medical Research Council, Duke-NUS Graduate Medical School, and Singapore Millennium Foundation. He has received honoraria from Novartis, Boehringer Ingelheim, and GSK. T. Toda receives research support from Ministry of Health, Labour and Welfare of Japan. H. Tomiyama reports no disclosures. R.J. Uitti has received research funding from the NIH, PARRF, PSG, Noscira, Inc. and Advanced Neuromodulation Systems, Inc. Dr. Uitti has served as a Continuing Medical Educator for the AAN. His institution has received annual royalties from the licensing of the technology related to PARK8/LRRK2 greater than the federal threshold for significant financial interest. Dr. Uitti has not received any royalties. Dr. Uitti receives an honorarium as Associate Editor of Neurology®. K. Wirdefeldt reports no disclosures. Z. Wszolek holds and has contractual rights for receipt of future royalty payments from patents re: A novel polynucleotide involved in heritable Parkinson's disease, receives educational research support from Allergan, Inc., the NIH/NINDS 1RC2NS070276, NS057567, P50NS072187, Mayo Clinic Florida (MCF) Research Committee CR programs (MCF #90052018 and MCF #90052030), and the gift from Carl Edward Bolch, Jr. and Susan Bass Bolch (MCF #90052031/PAU #90052). G. Xiromerisiou, K.-C. Yueh, and Y. Zhao report no disclosures. T. Gasser is funded by Novartis Pharma, the Federal Ministry of Education and Research (BMBF) (NGFN-Plus and ERA-Net NEURON), the Helmholtz Association (HelMA, Helmholtz Alliance for Health in an Ageing Society), and the European Union (MeFoPa, Mendelian Forms of Parkinsonism). He received speaker honoraria from Novartis, Merck-Serono, Schwarz Pharma, Boehringer Ingelheim, and Valeant Pharma and royalties for his consulting activities from Cefalon Pharma and Merck-Serono. Dr. Gasser holds a patent concerning the LRRK2 gene and neurodegenerative disorders. D.M. Maraganore received funding support from the National Institutes of Health grant ES10751 (“Molecular Epidemiology of Parkinson's Disease”). He also received funding support from Alnylam Pharmaceuticals and Medtronic, Inc. to conduct an observational study of Parkinson's disease outcomes. Dr. Maraganore had a patent filed for a method to treat Parkinson disease. It has been licensed to Alnylam Pharmaceuticals. R. Krüger has received research grants of the German Research Council (DFG; KR2119/3-2), the Michael J Fox Foundation, and the Federal Ministry for Education and Research (BMBF, NGFNplus; 01GS08134), as well as speaker honoraria and/or travel grants from UCB Pharma, Cephalon, Abbott Pharmaceuticals, Takeda Pharmaceuticals, and Medtronic. Go to Neurology.org for full disclosures.

PY - 2012/8/14

Y1 - 2012/8/14

N2 - Objective: Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown. Methods: Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry. Results: In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78-0.87 (LAMP3, BST1, and MAPT) and susceptibility per-allele odds ratios of 1.14-1.43 (STK39, GAK, SNCA, LRRK2, SYT11, and HIP1R). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes (I2 estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the BST1 (rs11724635) in Asian vs Caucasian populations and similar effects for SNCA, LRRK2, LAMP3, HIP1R, and STK39 in Asian and Caucasian populations, while MAPT rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD. Conclusion: Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity.

AB - Objective: Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown. Methods: Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry. Results: In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78-0.87 (LAMP3, BST1, and MAPT) and susceptibility per-allele odds ratios of 1.14-1.43 (STK39, GAK, SNCA, LRRK2, SYT11, and HIP1R). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes (I2 estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the BST1 (rs11724635) in Asian vs Caucasian populations and similar effects for SNCA, LRRK2, LAMP3, HIP1R, and STK39 in Asian and Caucasian populations, while MAPT rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD. Conclusion: Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity.

UR - http://www.scopus.com/inward/record.url?scp=84865196862&partnerID=8YFLogxK

U2 - 10.1212/WNL.0b013e318264e353

DO - 10.1212/WNL.0b013e318264e353

M3 - Article

AN - SCOPUS:84865196862

SN - 0028-3878

VL - 79

SP - 659

EP - 667

JO - Neurology

JF - Neurology

IS - 7

ER -

Large-scale replication and heterogeneity in Parkinson disease genetic loci

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