Genome-wide Association and Meta-analysis of Age at Onset in Parkinson Disease: Evidence From the COURAGE-PD Consortium
Considerable heterogeneity exists in the literature concerning genetic determinants of the age of onset (AAO) of Parkinson's disease (PD), which could be attributed to lack of well-powered replication cohorts. The previous largest GWAS identified nd loci on chromosome (Chr) 4 with a significant...
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| Veröffentlicht in: | Neurology 2022-08, Vol.99 (7), p.e698-e710 |
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| creator | Grover, Sandeep Kumar Sreelatha, Ashwin Ashok Pihlstrom, Lasse Domenighetti, Cloé Schulte, Claudia Sugier, Pierre-Emmanuel Radivojkov-Blagojevic, Milena Lichtner, Peter Mohamed, Océane Portugal, Berta Landoulsi, Zied May, Patrick Bobbili, Dheeraj Edsall, Connor Bartusch, Felix Hanussek, Maximilian Krüger, Jens Hernandez, Dena G. Blauwendraat, Cornelis Mellick, George D. Zimprich, Alexander Pirker, Walter Tan, Manuela Rogaeva, Ekaterina Lang, Anthony Koks, Sulev Taba, Pille Lesage, Suzanne Brice, Alexis Corvol, Jean-Christophe Chartier-Harlin, Marie-Christine Mutez, Eugenie Brockmann, Kathrin Deutschländer, Angela B. Hadjigeorgiou, Georges M. Dardiotis, Efthimos Stefanis, Leonidas Simitsi, Athina Maria Valente, Enza Maria Petrucci, Simona Straniero, Letizia Zecchinelli, Anna Pezzoli, Gianni Brighina, Laura Ferrarese, Carlo Annesi, Grazia Quattrone, Andrea Gagliardi, Monica Burbulla, Lena F. Matsuo, Hirotaka Kawamura, Yusuke Hattori, Nobutaka Nishioka, Kenya Chung, Sun Ju Kim, Yun Joong Pavelka, Lukas van de Warrenburg, Bart P.C. Bloem, Bastiaan R. Singleton, Andrew B. Aasly, Jan Toft, Mathias Guedes, Leonor Correia Ferreira, Joaquim J. Bardien, Soraya Carr, Jonathan Tolosa, Eduardo Ezquerra, Mario Pastor, Pau Diez-Fairen, Monica Wirdefeldt, Karin Pedersen, Nancy L. Ran, Caroline Belin, Andrea C. Puschmann, Andreas Hellberg, Clara Clarke, Carl E. Morrison, Karen E. Krainc, Dimitri Farrer, Matt J. Kruger, Rejko Elbaz, Alexis Gasser, Thomas Sharma, Manu |
| description | Considerable heterogeneity exists in the literature concerning genetic determinants of the age of onset (AAO) of Parkinson's disease (PD), which could be attributed to lack of well-powered replication cohorts. The previous largest GWAS identified
nd
loci on chromosome (Chr) 4 with a significant influence on AAO of PD, these have not been independently replicated. The present study aims to conduct a meta-analysis of GWAS of PD AAO and validate previously observed findings in worldwide populations.
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 up by combining our study with the largest publicly available European ancestry dataset compiled by the International Parkinson disease Genomics Consortium (IPDGC).
The COURAGE-PD included a cohort of 8,535 patients with PD (91.9%: Europeans, 9.1%: East-Asians). The average AAO in the COURAGE-PD dataset was 58.9 years (SD=11.6), with an under-representation 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 |
| doi_str_mv | 10.1212/WNL.0000000000200699 |
| format | Article |
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Kumar Sreelatha, Ashwin Ashok ; Pihlstrom, Lasse ; Domenighetti, Cloé ; Schulte, Claudia ; Sugier, Pierre-Emmanuel ; Radivojkov-Blagojevic, Milena ; Lichtner, Peter ; Mohamed, Océane ; Portugal, Berta ; Landoulsi, Zied ; May, Patrick ; Bobbili, Dheeraj ; Edsall, Connor ; Bartusch, Felix ; Hanussek, Maximilian ; Krüger, Jens ; Hernandez, Dena G. ; Blauwendraat, Cornelis ; Mellick, George D. ; Zimprich, Alexander ; Pirker, Walter ; Tan, Manuela ; Rogaeva, Ekaterina ; Lang, Anthony ; Koks, Sulev ; Taba, Pille ; Lesage, Suzanne ; Brice, Alexis ; Corvol, Jean-Christophe ; Chartier-Harlin, Marie-Christine ; Mutez, Eugenie ; Brockmann, Kathrin ; Deutschländer, Angela B. ; Hadjigeorgiou, Georges M. ; Dardiotis, Efthimos ; Stefanis, Leonidas ; Simitsi, Athina Maria ; Valente, Enza Maria ; Petrucci, Simona ; Straniero, Letizia ; Zecchinelli, Anna ; Pezzoli, Gianni ; Brighina, Laura ; Ferrarese, Carlo ; Annesi, Grazia ; Quattrone, Andrea ; Gagliardi, Monica ; Burbulla, Lena F. ; Matsuo, Hirotaka ; Kawamura, Yusuke ; Hattori, Nobutaka ; Nishioka, Kenya ; Chung, Sun Ju ; Kim, Yun Joong ; Pavelka, Lukas ; van de Warrenburg, Bart P.C. ; Bloem, Bastiaan R. ; Singleton, Andrew B. ; Aasly, Jan ; Toft, Mathias ; Guedes, Leonor Correia ; Ferreira, Joaquim J. ; Bardien, Soraya ; Carr, Jonathan ; Tolosa, Eduardo ; Ezquerra, Mario ; Pastor, Pau ; Diez-Fairen, Monica ; Wirdefeldt, Karin ; Pedersen, Nancy L. ; Ran, Caroline ; Belin, Andrea C. ; Puschmann, Andreas ; Hellberg, Clara ; Clarke, Carl E. ; Morrison, Karen E. ; Krainc, Dimitri ; Farrer, Matt J. ; Kruger, Rejko ; Elbaz, Alexis ; Gasser, Thomas ; Sharma, Manu</creator><creatorcontrib>Grover, Sandeep ; Kumar Sreelatha, Ashwin Ashok ; Pihlstrom, Lasse ; Domenighetti, Cloé ; Schulte, Claudia ; Sugier, Pierre-Emmanuel ; Radivojkov-Blagojevic, Milena ; Lichtner, Peter ; Mohamed, Océane ; Portugal, Berta ; Landoulsi, Zied ; May, Patrick ; Bobbili, Dheeraj ; Edsall, Connor ; Bartusch, Felix ; Hanussek, Maximilian ; Krüger, Jens ; Hernandez, Dena G. ; Blauwendraat, Cornelis ; Mellick, George D. ; Zimprich, Alexander ; Pirker, Walter ; Tan, Manuela ; Rogaeva, Ekaterina ; Lang, Anthony ; Koks, Sulev ; Taba, Pille ; Lesage, Suzanne ; Brice, Alexis ; Corvol, Jean-Christophe ; Chartier-Harlin, Marie-Christine ; Mutez, Eugenie ; Brockmann, Kathrin ; Deutschländer, Angela B. ; Hadjigeorgiou, Georges M. ; Dardiotis, Efthimos ; Stefanis, Leonidas ; Simitsi, Athina Maria ; Valente, Enza Maria ; Petrucci, Simona ; Straniero, Letizia ; Zecchinelli, Anna ; Pezzoli, Gianni ; Brighina, Laura ; Ferrarese, Carlo ; Annesi, Grazia ; Quattrone, Andrea ; Gagliardi, Monica ; Burbulla, Lena F. ; Matsuo, Hirotaka ; Kawamura, Yusuke ; Hattori, Nobutaka ; Nishioka, Kenya ; Chung, Sun Ju ; Kim, Yun Joong ; Pavelka, Lukas ; van de Warrenburg, Bart P.C. ; Bloem, Bastiaan R. ; Singleton, Andrew B. ; Aasly, Jan ; Toft, Mathias ; Guedes, Leonor Correia ; Ferreira, Joaquim J. ; Bardien, Soraya ; Carr, Jonathan ; Tolosa, Eduardo ; Ezquerra, Mario ; Pastor, Pau ; Diez-Fairen, Monica ; Wirdefeldt, Karin ; Pedersen, Nancy L. ; Ran, Caroline ; Belin, Andrea C. ; Puschmann, Andreas ; Hellberg, Clara ; Clarke, Carl E. ; Morrison, Karen E. ; Krainc, Dimitri ; Farrer, Matt J. ; Kruger, Rejko ; Elbaz, Alexis ; Gasser, Thomas ; Sharma, Manu ; and the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson’s Disease (COURAGE-PD) consortium ; and the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (COURAGE-PD) Consortium ; et al</creatorcontrib><description>Considerable heterogeneity exists in the literature concerning genetic determinants of the age of onset (AAO) of Parkinson's disease (PD), which could be attributed to lack of well-powered replication cohorts. The previous largest GWAS identified
nd
loci on chromosome (Chr) 4 with a significant influence on AAO of PD, these have not been independently replicated. The present study aims to conduct a meta-analysis of GWAS of PD AAO and validate previously observed findings in worldwide populations.
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 up by combining our study with the largest publicly available European ancestry dataset compiled by the International Parkinson disease Genomics Consortium (IPDGC).
The COURAGE-PD included a cohort of 8,535 patients with PD (91.9%: Europeans, 9.1%: East-Asians). The average AAO in the COURAGE-PD dataset was 58.9 years (SD=11.6), with an under-representation 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<5x10
). Nevertheless, the COURAGE-PD dataset confirmed the role of the previously published
variant as genetic determinant of AAO of PD with Bonferroni-corrected nominal levels of significance (P<0.025): (rs34311866:β(SE)
=0.477(0.203), P
=0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (N
=25,950) led to the identification of two genome-wide significant association signals on Chr 4, including the previously reported
locus (rs983361:β(SE)
=0.720(0.122), P
=3.13x10
) and a novel
locus (rs4698412:β(SE)
=-0.526(0.096), P
=4.41x10
).
Our study further refines the genetic architecture of Chr 4 underlying the AAO of the PD phenotype through the identification of
as a novel AAO PD locus. These findings open a new direction for the development of treatments to delay the onset of PD.</description><identifier>ISSN: 0028-3878</identifier><identifier>EISSN: 1526-632X</identifier><identifier>DOI: 10.1212/WNL.0000000000200699</identifier><identifier>PMID: 35618440</identifier><language>eng</language><publisher>United States: Lippincott Williams & Wilkins</publisher><subject>Age of Onset ; Basic Medicine ; Clinical Medicine ; courage ; female ; genetic predisposition ; Genetic Predisposition to Disease ; genetics ; genome-wide association study ; human ; Humans ; Klinisk medicin ; Life Sciences ; Medical and Health Sciences ; Medical Genetics ; Medicin och hälsovetenskap ; Medicinsk genetik ; Medicinska och farmaceutiska grundvetenskaper ; meta analysis ; Neurologi ; Neurology ; onset age ; Parkinson disease ; Polymorphism, Single Nucleotide ; single nucleotide polymorphism</subject><ispartof>Neurology, 2022-08, Vol.99 (7), p.e698-e710</ispartof><rights>Lippincott Williams & Wilkins</rights><rights>Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4081-f3e18377f7984f4cc16d054fba4aca2cf793d8ddf10520356a60961304f9c5b23</citedby><cites>FETCH-LOGICAL-c4081-f3e18377f7984f4cc16d054fba4aca2cf793d8ddf10520356a60961304f9c5b23</cites><orcidid>0000-0001-6087-6643 ; 0000-0002-2598-4398 ; 0000-0003-1159-5321 ; 0000-0002-1733-7561 ; 0000-0002-0600-6820 ; 0000-0003-2615-4916 ; 0000-0002-3508-3438 ; 0000-0003-4258-6241 ; 0000-0001-6408-0351 ; 0000-0001-9724-5490 ; 0000-0002-4716-1886 ; 0000-0001-6876-1496 ; 0000-0002-6723-6865 ; 0000-0002-2956-1552 ; 0000-0001-8698-3770 ; 0000-0003-0711-5196 ; 0000-0002-2636-3163 ; 0000-0003-4665-6710 ; 0000-0002-7635-8645 ; 0000-0002-7493-8777 ; 0000-0002-0941-3990 ; 0000-0003-1882-0309 ; 0000-0002-7677-426X ; 0000-0003-2478-3436 ; 0000-0002-7092-7034 ; 0000-0003-2071-2083 ; 0000-0003-1229-3667 ; 0000-0001-7325-0199 ; 0000-0002-3201-8198 ; 0000-0002-5947-0432 ; 0000-0003-3246-6641</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,551,777,781,882,27905,27906</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35618440$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-03775820$$DView record in HAL$$Hfree_for_read</backlink><backlink>$$Uhttps://lup.lub.lu.se/record/6e85247c-3ace-46d9-a3e7-41b40c54c468$$DView record from Swedish Publication Index$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:150436955$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Grover, Sandeep</creatorcontrib><creatorcontrib>Kumar Sreelatha, Ashwin Ashok</creatorcontrib><creatorcontrib>Pihlstrom, Lasse</creatorcontrib><creatorcontrib>Domenighetti, Cloé</creatorcontrib><creatorcontrib>Schulte, Claudia</creatorcontrib><creatorcontrib>Sugier, Pierre-Emmanuel</creatorcontrib><creatorcontrib>Radivojkov-Blagojevic, Milena</creatorcontrib><creatorcontrib>Lichtner, Peter</creatorcontrib><creatorcontrib>Mohamed, Océane</creatorcontrib><creatorcontrib>Portugal, Berta</creatorcontrib><creatorcontrib>Landoulsi, Zied</creatorcontrib><creatorcontrib>May, Patrick</creatorcontrib><creatorcontrib>Bobbili, Dheeraj</creatorcontrib><creatorcontrib>Edsall, Connor</creatorcontrib><creatorcontrib>Bartusch, Felix</creatorcontrib><creatorcontrib>Hanussek, Maximilian</creatorcontrib><creatorcontrib>Krüger, Jens</creatorcontrib><creatorcontrib>Hernandez, Dena G.</creatorcontrib><creatorcontrib>Blauwendraat, Cornelis</creatorcontrib><creatorcontrib>Mellick, George D.</creatorcontrib><creatorcontrib>Zimprich, Alexander</creatorcontrib><creatorcontrib>Pirker, Walter</creatorcontrib><creatorcontrib>Tan, Manuela</creatorcontrib><creatorcontrib>Rogaeva, Ekaterina</creatorcontrib><creatorcontrib>Lang, Anthony</creatorcontrib><creatorcontrib>Koks, Sulev</creatorcontrib><creatorcontrib>Taba, Pille</creatorcontrib><creatorcontrib>Lesage, Suzanne</creatorcontrib><creatorcontrib>Brice, Alexis</creatorcontrib><creatorcontrib>Corvol, Jean-Christophe</creatorcontrib><creatorcontrib>Chartier-Harlin, Marie-Christine</creatorcontrib><creatorcontrib>Mutez, Eugenie</creatorcontrib><creatorcontrib>Brockmann, Kathrin</creatorcontrib><creatorcontrib>Deutschländer, Angela B.</creatorcontrib><creatorcontrib>Hadjigeorgiou, Georges M.</creatorcontrib><creatorcontrib>Dardiotis, Efthimos</creatorcontrib><creatorcontrib>Stefanis, Leonidas</creatorcontrib><creatorcontrib>Simitsi, Athina Maria</creatorcontrib><creatorcontrib>Valente, Enza Maria</creatorcontrib><creatorcontrib>Petrucci, Simona</creatorcontrib><creatorcontrib>Straniero, Letizia</creatorcontrib><creatorcontrib>Zecchinelli, Anna</creatorcontrib><creatorcontrib>Pezzoli, Gianni</creatorcontrib><creatorcontrib>Brighina, Laura</creatorcontrib><creatorcontrib>Ferrarese, Carlo</creatorcontrib><creatorcontrib>Annesi, Grazia</creatorcontrib><creatorcontrib>Quattrone, Andrea</creatorcontrib><creatorcontrib>Gagliardi, Monica</creatorcontrib><creatorcontrib>Burbulla, Lena F.</creatorcontrib><creatorcontrib>Matsuo, Hirotaka</creatorcontrib><creatorcontrib>Kawamura, Yusuke</creatorcontrib><creatorcontrib>Hattori, Nobutaka</creatorcontrib><creatorcontrib>Nishioka, Kenya</creatorcontrib><creatorcontrib>Chung, Sun Ju</creatorcontrib><creatorcontrib>Kim, Yun Joong</creatorcontrib><creatorcontrib>Pavelka, Lukas</creatorcontrib><creatorcontrib>van de Warrenburg, Bart P.C.</creatorcontrib><creatorcontrib>Bloem, Bastiaan R.</creatorcontrib><creatorcontrib>Singleton, Andrew B.</creatorcontrib><creatorcontrib>Aasly, Jan</creatorcontrib><creatorcontrib>Toft, Mathias</creatorcontrib><creatorcontrib>Guedes, Leonor Correia</creatorcontrib><creatorcontrib>Ferreira, Joaquim J.</creatorcontrib><creatorcontrib>Bardien, Soraya</creatorcontrib><creatorcontrib>Carr, Jonathan</creatorcontrib><creatorcontrib>Tolosa, Eduardo</creatorcontrib><creatorcontrib>Ezquerra, Mario</creatorcontrib><creatorcontrib>Pastor, Pau</creatorcontrib><creatorcontrib>Diez-Fairen, Monica</creatorcontrib><creatorcontrib>Wirdefeldt, Karin</creatorcontrib><creatorcontrib>Pedersen, Nancy L.</creatorcontrib><creatorcontrib>Ran, Caroline</creatorcontrib><creatorcontrib>Belin, Andrea C.</creatorcontrib><creatorcontrib>Puschmann, Andreas</creatorcontrib><creatorcontrib>Hellberg, Clara</creatorcontrib><creatorcontrib>Clarke, Carl E.</creatorcontrib><creatorcontrib>Morrison, Karen E.</creatorcontrib><creatorcontrib>Krainc, Dimitri</creatorcontrib><creatorcontrib>Farrer, Matt J.</creatorcontrib><creatorcontrib>Kruger, Rejko</creatorcontrib><creatorcontrib>Elbaz, Alexis</creatorcontrib><creatorcontrib>Gasser, Thomas</creatorcontrib><creatorcontrib>Sharma, Manu</creatorcontrib><creatorcontrib>and the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson’s Disease (COURAGE-PD) consortium</creatorcontrib><creatorcontrib>and the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (COURAGE-PD) Consortium</creatorcontrib><creatorcontrib>et al</creatorcontrib><title>Genome-wide Association and Meta-analysis of Age at Onset in Parkinson Disease: Evidence From the COURAGE-PD Consortium</title><title>Neurology</title><addtitle>Neurology</addtitle><description>Considerable heterogeneity exists in the literature concerning genetic determinants of the age of onset (AAO) of Parkinson's disease (PD), which could be attributed to lack of well-powered replication cohorts. The previous largest GWAS identified
nd
loci on chromosome (Chr) 4 with a significant influence on AAO of PD, these have not been independently replicated. The present study aims to conduct a meta-analysis of GWAS of PD AAO and validate previously observed findings in worldwide populations.
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 up by combining our study with the largest publicly available European ancestry dataset compiled by the International Parkinson disease Genomics Consortium (IPDGC).
The COURAGE-PD included a cohort of 8,535 patients with PD (91.9%: Europeans, 9.1%: East-Asians). The average AAO in the COURAGE-PD dataset was 58.9 years (SD=11.6), with an under-representation 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<5x10
). Nevertheless, the COURAGE-PD dataset confirmed the role of the previously published
variant as genetic determinant of AAO of PD with Bonferroni-corrected nominal levels of significance (P<0.025): (rs34311866:β(SE)
=0.477(0.203), P
=0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (N
=25,950) led to the identification of two genome-wide significant association signals on Chr 4, including the previously reported
locus (rs983361:β(SE)
=0.720(0.122), P
=3.13x10
) and a novel
locus (rs4698412:β(SE)
=-0.526(0.096), P
=4.41x10
).
Our study further refines the genetic architecture of Chr 4 underlying the AAO of the PD phenotype through the identification of
as a novel AAO PD locus. These findings open a new direction for the development of treatments to delay the onset of PD.</description><subject>Age of Onset</subject><subject>Basic Medicine</subject><subject>Clinical Medicine</subject><subject>courage</subject><subject>female</subject><subject>genetic predisposition</subject><subject>Genetic Predisposition to Disease</subject><subject>genetics</subject><subject>genome-wide association study</subject><subject>human</subject><subject>Humans</subject><subject>Klinisk medicin</subject><subject>Life Sciences</subject><subject>Medical and Health Sciences</subject><subject>Medical Genetics</subject><subject>Medicin och hälsovetenskap</subject><subject>Medicinsk genetik</subject><subject>Medicinska och farmaceutiska grundvetenskaper</subject><subject>meta analysis</subject><subject>Neurologi</subject><subject>Neurology</subject><subject>onset age</subject><subject>Parkinson disease</subject><subject>Polymorphism, Single Nucleotide</subject><subject>single nucleotide 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Lasse</creator><creator>Domenighetti, Cloé</creator><creator>Schulte, Claudia</creator><creator>Sugier, Pierre-Emmanuel</creator><creator>Radivojkov-Blagojevic, Milena</creator><creator>Lichtner, Peter</creator><creator>Mohamed, Océane</creator><creator>Portugal, Berta</creator><creator>Landoulsi, Zied</creator><creator>May, Patrick</creator><creator>Bobbili, Dheeraj</creator><creator>Edsall, Connor</creator><creator>Bartusch, Felix</creator><creator>Hanussek, Maximilian</creator><creator>Krüger, Jens</creator><creator>Hernandez, Dena G.</creator><creator>Blauwendraat, Cornelis</creator><creator>Mellick, George D.</creator><creator>Zimprich, Alexander</creator><creator>Pirker, Walter</creator><creator>Tan, Manuela</creator><creator>Rogaeva, Ekaterina</creator><creator>Lang, Anthony</creator><creator>Koks, Sulev</creator><creator>Taba, Pille</creator><creator>Lesage, Suzanne</creator><creator>Brice, Alexis</creator><creator>Corvol, Jean-Christophe</creator><creator>Chartier-Harlin, 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Association and Meta-analysis of Age at Onset in Parkinson Disease: Evidence From the COURAGE-PD Consortium</title><author>Grover, Sandeep ; Kumar Sreelatha, Ashwin Ashok ; Pihlstrom, Lasse ; Domenighetti, Cloé ; Schulte, Claudia ; Sugier, Pierre-Emmanuel ; Radivojkov-Blagojevic, Milena ; Lichtner, Peter ; Mohamed, Océane ; Portugal, Berta ; Landoulsi, Zied ; May, Patrick ; Bobbili, Dheeraj ; Edsall, Connor ; Bartusch, Felix ; Hanussek, Maximilian ; Krüger, Jens ; Hernandez, Dena G. ; Blauwendraat, Cornelis ; Mellick, George D. ; Zimprich, Alexander ; Pirker, Walter ; Tan, Manuela ; Rogaeva, Ekaterina ; Lang, Anthony ; Koks, Sulev ; Taba, Pille ; Lesage, Suzanne ; Brice, Alexis ; Corvol, Jean-Christophe ; Chartier-Harlin, Marie-Christine ; Mutez, Eugenie ; Brockmann, Kathrin ; Deutschländer, Angela B. ; Hadjigeorgiou, Georges M. ; Dardiotis, Efthimos ; Stefanis, Leonidas ; Simitsi, Athina Maria ; Valente, Enza Maria ; Petrucci, Simona ; Straniero, Letizia ; Zecchinelli, Anna ; Pezzoli, Gianni ; Brighina, Laura ; Ferrarese, Carlo ; Annesi, Grazia ; Quattrone, Andrea ; Gagliardi, Monica ; Burbulla, Lena F. ; Matsuo, Hirotaka ; Kawamura, Yusuke ; Hattori, Nobutaka ; Nishioka, Kenya ; Chung, Sun Ju ; Kim, Yun Joong ; Pavelka, Lukas ; van de Warrenburg, Bart P.C. ; Bloem, Bastiaan R. ; Singleton, Andrew B. ; Aasly, Jan ; Toft, Mathias ; Guedes, Leonor Correia ; Ferreira, Joaquim J. ; Bardien, Soraya ; Carr, Jonathan ; Tolosa, Eduardo ; Ezquerra, Mario ; Pastor, Pau ; Diez-Fairen, Monica ; Wirdefeldt, Karin ; Pedersen, Nancy L. ; Ran, Caroline ; Belin, Andrea C. ; Puschmann, Andreas ; Hellberg, Clara ; Clarke, Carl E. ; Morrison, Karen E. ; Krainc, Dimitri ; Farrer, Matt J. ; Kruger, Rejko ; Elbaz, Alexis ; Gasser, Thomas ; Sharma, Manu</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4081-f3e18377f7984f4cc16d054fba4aca2cf793d8ddf10520356a60961304f9c5b23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Age of Onset</topic><topic>Basic Medicine</topic><topic>Clinical Medicine</topic><topic>courage</topic><topic>female</topic><topic>genetic predisposition</topic><topic>Genetic Predisposition to Disease</topic><topic>genetics</topic><topic>genome-wide association study</topic><topic>human</topic><topic>Humans</topic><topic>Klinisk medicin</topic><topic>Life Sciences</topic><topic>Medical and Health Sciences</topic><topic>Medical Genetics</topic><topic>Medicin och hälsovetenskap</topic><topic>Medicinsk genetik</topic><topic>Medicinska och farmaceutiska grundvetenskaper</topic><topic>meta analysis</topic><topic>Neurologi</topic><topic>Neurology</topic><topic>onset age</topic><topic>Parkinson disease</topic><topic>Polymorphism, Single Nucleotide</topic><topic>single nucleotide polymorphism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Grover, Sandeep</creatorcontrib><creatorcontrib>Kumar Sreelatha, Ashwin Ashok</creatorcontrib><creatorcontrib>Pihlstrom, Lasse</creatorcontrib><creatorcontrib>Domenighetti, Cloé</creatorcontrib><creatorcontrib>Schulte, Claudia</creatorcontrib><creatorcontrib>Sugier, Pierre-Emmanuel</creatorcontrib><creatorcontrib>Radivojkov-Blagojevic, Milena</creatorcontrib><creatorcontrib>Lichtner, Peter</creatorcontrib><creatorcontrib>Mohamed, Océane</creatorcontrib><creatorcontrib>Portugal, Berta</creatorcontrib><creatorcontrib>Landoulsi, Zied</creatorcontrib><creatorcontrib>May, Patrick</creatorcontrib><creatorcontrib>Bobbili, Dheeraj</creatorcontrib><creatorcontrib>Edsall, Connor</creatorcontrib><creatorcontrib>Bartusch, Felix</creatorcontrib><creatorcontrib>Hanussek, Maximilian</creatorcontrib><creatorcontrib>Krüger, Jens</creatorcontrib><creatorcontrib>Hernandez, Dena G.</creatorcontrib><creatorcontrib>Blauwendraat, Cornelis</creatorcontrib><creatorcontrib>Mellick, George D.</creatorcontrib><creatorcontrib>Zimprich, Alexander</creatorcontrib><creatorcontrib>Pirker, Walter</creatorcontrib><creatorcontrib>Tan, Manuela</creatorcontrib><creatorcontrib>Rogaeva, Ekaterina</creatorcontrib><creatorcontrib>Lang, Anthony</creatorcontrib><creatorcontrib>Koks, Sulev</creatorcontrib><creatorcontrib>Taba, Pille</creatorcontrib><creatorcontrib>Lesage, Suzanne</creatorcontrib><creatorcontrib>Brice, Alexis</creatorcontrib><creatorcontrib>Corvol, Jean-Christophe</creatorcontrib><creatorcontrib>Chartier-Harlin, Marie-Christine</creatorcontrib><creatorcontrib>Mutez, Eugenie</creatorcontrib><creatorcontrib>Brockmann, Kathrin</creatorcontrib><creatorcontrib>Deutschländer, Angela B.</creatorcontrib><creatorcontrib>Hadjigeorgiou, Georges M.</creatorcontrib><creatorcontrib>Dardiotis, Efthimos</creatorcontrib><creatorcontrib>Stefanis, Leonidas</creatorcontrib><creatorcontrib>Simitsi, Athina Maria</creatorcontrib><creatorcontrib>Valente, Enza Maria</creatorcontrib><creatorcontrib>Petrucci, Simona</creatorcontrib><creatorcontrib>Straniero, Letizia</creatorcontrib><creatorcontrib>Zecchinelli, Anna</creatorcontrib><creatorcontrib>Pezzoli, Gianni</creatorcontrib><creatorcontrib>Brighina, Laura</creatorcontrib><creatorcontrib>Ferrarese, Carlo</creatorcontrib><creatorcontrib>Annesi, Grazia</creatorcontrib><creatorcontrib>Quattrone, Andrea</creatorcontrib><creatorcontrib>Gagliardi, Monica</creatorcontrib><creatorcontrib>Burbulla, Lena F.</creatorcontrib><creatorcontrib>Matsuo, Hirotaka</creatorcontrib><creatorcontrib>Kawamura, Yusuke</creatorcontrib><creatorcontrib>Hattori, Nobutaka</creatorcontrib><creatorcontrib>Nishioka, Kenya</creatorcontrib><creatorcontrib>Chung, Sun Ju</creatorcontrib><creatorcontrib>Kim, Yun Joong</creatorcontrib><creatorcontrib>Pavelka, Lukas</creatorcontrib><creatorcontrib>van de Warrenburg, Bart P.C.</creatorcontrib><creatorcontrib>Bloem, Bastiaan R.</creatorcontrib><creatorcontrib>Singleton, Andrew B.</creatorcontrib><creatorcontrib>Aasly, Jan</creatorcontrib><creatorcontrib>Toft, Mathias</creatorcontrib><creatorcontrib>Guedes, Leonor Correia</creatorcontrib><creatorcontrib>Ferreira, Joaquim J.</creatorcontrib><creatorcontrib>Bardien, Soraya</creatorcontrib><creatorcontrib>Carr, Jonathan</creatorcontrib><creatorcontrib>Tolosa, Eduardo</creatorcontrib><creatorcontrib>Ezquerra, Mario</creatorcontrib><creatorcontrib>Pastor, Pau</creatorcontrib><creatorcontrib>Diez-Fairen, Monica</creatorcontrib><creatorcontrib>Wirdefeldt, Karin</creatorcontrib><creatorcontrib>Pedersen, Nancy L.</creatorcontrib><creatorcontrib>Ran, Caroline</creatorcontrib><creatorcontrib>Belin, Andrea C.</creatorcontrib><creatorcontrib>Puschmann, Andreas</creatorcontrib><creatorcontrib>Hellberg, Clara</creatorcontrib><creatorcontrib>Clarke, Carl E.</creatorcontrib><creatorcontrib>Morrison, Karen E.</creatorcontrib><creatorcontrib>Krainc, Dimitri</creatorcontrib><creatorcontrib>Farrer, Matt J.</creatorcontrib><creatorcontrib>Kruger, Rejko</creatorcontrib><creatorcontrib>Elbaz, Alexis</creatorcontrib><creatorcontrib>Gasser, Thomas</creatorcontrib><creatorcontrib>Sharma, Manu</creatorcontrib><creatorcontrib>and the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson’s Disease (COURAGE-PD) consortium</creatorcontrib><creatorcontrib>and the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (COURAGE-PD) Consortium</creatorcontrib><creatorcontrib>et al</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>SwePub</collection><collection>SWEPUB Lunds universitet full text</collection><collection>SwePub Articles</collection><collection>SWEPUB Freely available online</collection><collection>SWEPUB Lunds universitet</collection><collection>SwePub Articles full text</collection><jtitle>Neurology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Grover, Sandeep</au><au>Kumar Sreelatha, Ashwin Ashok</au><au>Pihlstrom, Lasse</au><au>Domenighetti, Cloé</au><au>Schulte, Claudia</au><au>Sugier, Pierre-Emmanuel</au><au>Radivojkov-Blagojevic, Milena</au><au>Lichtner, Peter</au><au>Mohamed, Océane</au><au>Portugal, Berta</au><au>Landoulsi, Zied</au><au>May, Patrick</au><au>Bobbili, Dheeraj</au><au>Edsall, Connor</au><au>Bartusch, Felix</au><au>Hanussek, Maximilian</au><au>Krüger, Jens</au><au>Hernandez, Dena G.</au><au>Blauwendraat, Cornelis</au><au>Mellick, George D.</au><au>Zimprich, Alexander</au><au>Pirker, Walter</au><au>Tan, Manuela</au><au>Rogaeva, Ekaterina</au><au>Lang, Anthony</au><au>Koks, Sulev</au><au>Taba, Pille</au><au>Lesage, Suzanne</au><au>Brice, Alexis</au><au>Corvol, Jean-Christophe</au><au>Chartier-Harlin, Marie-Christine</au><au>Mutez, Eugenie</au><au>Brockmann, Kathrin</au><au>Deutschländer, Angela B.</au><au>Hadjigeorgiou, Georges M.</au><au>Dardiotis, Efthimos</au><au>Stefanis, Leonidas</au><au>Simitsi, Athina Maria</au><au>Valente, Enza Maria</au><au>Petrucci, Simona</au><au>Straniero, Letizia</au><au>Zecchinelli, Anna</au><au>Pezzoli, Gianni</au><au>Brighina, Laura</au><au>Ferrarese, Carlo</au><au>Annesi, Grazia</au><au>Quattrone, Andrea</au><au>Gagliardi, Monica</au><au>Burbulla, Lena F.</au><au>Matsuo, Hirotaka</au><au>Kawamura, Yusuke</au><au>Hattori, Nobutaka</au><au>Nishioka, Kenya</au><au>Chung, Sun Ju</au><au>Kim, Yun Joong</au><au>Pavelka, Lukas</au><au>van de Warrenburg, Bart P.C.</au><au>Bloem, Bastiaan R.</au><au>Singleton, Andrew B.</au><au>Aasly, Jan</au><au>Toft, Mathias</au><au>Guedes, Leonor Correia</au><au>Ferreira, Joaquim J.</au><au>Bardien, Soraya</au><au>Carr, Jonathan</au><au>Tolosa, Eduardo</au><au>Ezquerra, Mario</au><au>Pastor, Pau</au><au>Diez-Fairen, Monica</au><au>Wirdefeldt, Karin</au><au>Pedersen, Nancy L.</au><au>Ran, Caroline</au><au>Belin, Andrea C.</au><au>Puschmann, Andreas</au><au>Hellberg, Clara</au><au>Clarke, Carl E.</au><au>Morrison, Karen E.</au><au>Krainc, Dimitri</au><au>Farrer, Matt J.</au><au>Kruger, Rejko</au><au>Elbaz, Alexis</au><au>Gasser, Thomas</au><au>Sharma, Manu</au><aucorp>and the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson’s Disease (COURAGE-PD) consortium</aucorp><aucorp>and the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (COURAGE-PD) Consortium</aucorp><aucorp>et al</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Genome-wide Association and Meta-analysis of Age at Onset in Parkinson Disease: Evidence From the COURAGE-PD Consortium</atitle><jtitle>Neurology</jtitle><addtitle>Neurology</addtitle><date>2022-08-16</date><risdate>2022</risdate><volume>99</volume><issue>7</issue><spage>e698</spage><epage>e710</epage><pages>e698-e710</pages><issn>0028-3878</issn><eissn>1526-632X</eissn><abstract>Considerable heterogeneity exists in the literature concerning genetic determinants of the age of onset (AAO) of Parkinson's disease (PD), which could be attributed to lack of well-powered replication cohorts. The previous largest GWAS identified
nd
loci on chromosome (Chr) 4 with a significant influence on AAO of PD, these have not been independently replicated. The present study aims to conduct a meta-analysis of GWAS of PD AAO and validate previously observed findings in worldwide populations.
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 up by combining our study with the largest publicly available European ancestry dataset compiled by the International Parkinson disease Genomics Consortium (IPDGC).
The COURAGE-PD included a cohort of 8,535 patients with PD (91.9%: Europeans, 9.1%: East-Asians). The average AAO in the COURAGE-PD dataset was 58.9 years (SD=11.6), with an under-representation 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<5x10
). Nevertheless, the COURAGE-PD dataset confirmed the role of the previously published
variant as genetic determinant of AAO of PD with Bonferroni-corrected nominal levels of significance (P<0.025): (rs34311866:β(SE)
=0.477(0.203), P
=0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (N
=25,950) led to the identification of two genome-wide significant association signals on Chr 4, including the previously reported
locus (rs983361:β(SE)
=0.720(0.122), P
=3.13x10
) and a novel
locus (rs4698412:β(SE)
=-0.526(0.096), P
=4.41x10
).
Our study further refines the genetic architecture of Chr 4 underlying the AAO of the PD phenotype through the identification of
as a novel AAO PD locus. These findings open a new direction for the development of treatments to delay the onset of PD.</abstract><cop>United States</cop><pub>Lippincott Williams & Wilkins</pub><pmid>35618440</pmid><doi>10.1212/WNL.0000000000200699</doi><orcidid>https://orcid.org/0000-0001-6087-6643</orcidid><orcidid>https://orcid.org/0000-0002-2598-4398</orcidid><orcidid>https://orcid.org/0000-0003-1159-5321</orcidid><orcidid>https://orcid.org/0000-0002-1733-7561</orcidid><orcidid>https://orcid.org/0000-0002-0600-6820</orcidid><orcidid>https://orcid.org/0000-0003-2615-4916</orcidid><orcidid>https://orcid.org/0000-0002-3508-3438</orcidid><orcidid>https://orcid.org/0000-0003-4258-6241</orcidid><orcidid>https://orcid.org/0000-0001-6408-0351</orcidid><orcidid>https://orcid.org/0000-0001-9724-5490</orcidid><orcidid>https://orcid.org/0000-0002-4716-1886</orcidid><orcidid>https://orcid.org/0000-0001-6876-1496</orcidid><orcidid>https://orcid.org/0000-0002-6723-6865</orcidid><orcidid>https://orcid.org/0000-0002-2956-1552</orcidid><orcidid>https://orcid.org/0000-0001-8698-3770</orcidid><orcidid>https://orcid.org/0000-0003-0711-5196</orcidid><orcidid>https://orcid.org/0000-0002-2636-3163</orcidid><orcidid>https://orcid.org/0000-0003-4665-6710</orcidid><orcidid>https://orcid.org/0000-0002-7635-8645</orcidid><orcidid>https://orcid.org/0000-0002-7493-8777</orcidid><orcidid>https://orcid.org/0000-0002-0941-3990</orcidid><orcidid>https://orcid.org/0000-0003-1882-0309</orcidid><orcidid>https://orcid.org/0000-0002-7677-426X</orcidid><orcidid>https://orcid.org/0000-0003-2478-3436</orcidid><orcidid>https://orcid.org/0000-0002-7092-7034</orcidid><orcidid>https://orcid.org/0000-0003-2071-2083</orcidid><orcidid>https://orcid.org/0000-0003-1229-3667</orcidid><orcidid>https://orcid.org/0000-0001-7325-0199</orcidid><orcidid>https://orcid.org/0000-0002-3201-8198</orcidid><orcidid>https://orcid.org/0000-0002-5947-0432</orcidid><orcidid>https://orcid.org/0000-0003-3246-6641</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0028-3878 |
| ispartof | Neurology, 2022-08, Vol.99 (7), p.e698-e710 |
| issn | 0028-3878 1526-632X |
| language | eng |
| recordid | cdi_swepub_primary_oai_swepub_ki_se_451500 |
| source | SWEPUB Freely available online; Journals@Ovid Complete; Alma/SFX Local Collection |
| subjects | Age of Onset Basic Medicine Clinical Medicine courage female genetic predisposition Genetic Predisposition to Disease genetics genome-wide association study human Humans Klinisk medicin Life Sciences Medical and Health Sciences Medical Genetics Medicin och hälsovetenskap Medicinsk genetik Medicinska och farmaceutiska grundvetenskaper meta analysis Neurologi Neurology onset age Parkinson disease Polymorphism, Single Nucleotide single nucleotide polymorphism |
| title | Genome-wide Association and Meta-analysis of Age at Onset in Parkinson Disease: Evidence From the COURAGE-PD Consortium |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-19T11%3A26%3A55IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_swepu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Genome-wide%20Association%20and%20Meta-analysis%20of%20Age%20at%20Onset%20in%20Parkinson%20Disease:%20Evidence%20From%20the%20COURAGE-PD%20Consortium&rft.jtitle=Neurology&rft.au=Grover,%20Sandeep&rft.aucorp=and%20the%20Comprehensive%20Unbiased%20Risk%20Factor%20Assessment%20for%20Genetics%20and%20Environment%20in%20Parkinson%E2%80%99s%20Disease%20(COURAGE-PD)%20consortium&rft.date=2022-08-16&rft.volume=99&rft.issue=7&rft.spage=e698&rft.epage=e710&rft.pages=e698-e710&rft.issn=0028-3878&rft.eissn=1526-632X&rft_id=info:doi/10.1212/WNL.0000000000200699&rft_dat=%3Cproquest_swepu%3E2702975708%3C/proquest_swepu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2702975708&rft_id=info:pmid/35618440&rfr_iscdi=true |