Pub Date : 2024-01-01Epub Date: 2023-10-12DOI: 10.1016/S1474-4422(23)00406-4
Hooman Kamel
{"title":"Reassessing the implications of atrial fibrillation detected after stroke.","authors":"Hooman Kamel","doi":"10.1016/S1474-4422(23)00406-4","DOIUrl":"10.1016/S1474-4422(23)00406-4","url":null,"abstract":"","PeriodicalId":17989,"journal":{"name":"Lancet Neurology","volume":" ","pages":"9-11"},"PeriodicalIF":46.5,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41236520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01Epub Date: 2023-10-12DOI: 10.1016/S1474-4422(23)00326-5
Luciano A Sposato, Thalia S Field, Renate B Schnabel, Rolf Wachter, Jason G Andrade, Michael D Hill
Globally, up to 1·5 million individuals with ischaemic stroke or transient ischaemic attack can be newly diagnosed with atrial fibrillation per year. In the past decade, evidence has accumulated supporting the notion that atrial fibrillation first detected after a stroke or transient ischaemic attack differs from atrial fibrillation known before the occurrence of as stroke. Atrial fibrillation detected after stroke is associated with a lower prevalence of risk factors, cardiovascular comorbidities, and atrial cardiomyopathy than atrial fibrillation known before stroke occurrence. These differences might explain why it is associated with a lower risk of recurrence of ischaemic stroke than known atrial fibrillation. Patients with ischaemic stroke or transient ischaemic attack can be classified in three categories: no atrial fibrillation, known atrial fibrillation before stroke occurrence, and atrial fibrillation detected after stroke. This classification could harmonise future research in the field and help to understand the role of prolonged cardiac monitoring for secondary stroke prevention with application of a personalised risk-based approach to the selection of patients for anticoagulation.
{"title":"Towards a new classification of atrial fibrillation detected after a stroke or a transient ischaemic attack.","authors":"Luciano A Sposato, Thalia S Field, Renate B Schnabel, Rolf Wachter, Jason G Andrade, Michael D Hill","doi":"10.1016/S1474-4422(23)00326-5","DOIUrl":"10.1016/S1474-4422(23)00326-5","url":null,"abstract":"<p><p>Globally, up to 1·5 million individuals with ischaemic stroke or transient ischaemic attack can be newly diagnosed with atrial fibrillation per year. In the past decade, evidence has accumulated supporting the notion that atrial fibrillation first detected after a stroke or transient ischaemic attack differs from atrial fibrillation known before the occurrence of as stroke. Atrial fibrillation detected after stroke is associated with a lower prevalence of risk factors, cardiovascular comorbidities, and atrial cardiomyopathy than atrial fibrillation known before stroke occurrence. These differences might explain why it is associated with a lower risk of recurrence of ischaemic stroke than known atrial fibrillation. Patients with ischaemic stroke or transient ischaemic attack can be classified in three categories: no atrial fibrillation, known atrial fibrillation before stroke occurrence, and atrial fibrillation detected after stroke. This classification could harmonise future research in the field and help to understand the role of prolonged cardiac monitoring for secondary stroke prevention with application of a personalised risk-based approach to the selection of patients for anticoagulation.</p>","PeriodicalId":17989,"journal":{"name":"Lancet Neurology","volume":" ","pages":"110-122"},"PeriodicalIF":46.5,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41236585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-01Epub Date: 2023-10-12DOI: 10.1016/S1474-4422(23)00315-0
Rustam Al-Shahi Salman, Jacqueline Stephen, Jayne F Tierney, Steff C Lewis, David E Newby, Adrian R Parry-Jones, Philip M White, Stuart J Connolly, Oscar R Benavente, Dar Dowlatshahi, Charlotte Cordonnier, Catherine M Viscoli, Kevin N Sheth, Hooman Kamel, Roland Veltkamp, Kristin T Larsen, Jeannette Hofmeijer, Henk Kerkhoff, Floris H B M Schreuder, Ashkan Shoamanesh, Catharina J M Klijn, H Bart van der Worp
<p><strong>Background: </strong>The safety and efficacy of oral anticoagulation for prevention of major adverse cardiovascular events in people with atrial fibrillation and spontaneous intracranial haemorrhage are uncertain. We planned to estimate the effects of starting versus avoiding oral anticoagulation in people with spontaneous intracranial haemorrhage and atrial fibrillation.</p><p><strong>Methods: </strong>In this prospective meta-analysis, we searched bibliographic databases and trial registries using the strategies of a Cochrane systematic review (CD012144) on June 23, 2023. We included clinical trials if they were registered, randomised, and included participants with spontaneous intracranial haemorrhage and atrial fibrillation who were assigned to either start long-term use of any oral anticoagulant agent or avoid oral anticoagulation (ie, placebo, open control, another antithrombotic agent, or another intervention for the prevention of major adverse cardiovascular events). We assessed eligible trials using the Cochrane Risk of Bias tool. We sought data for individual participants who had not opted out of data sharing from chief investigators of completed trials, pending completion of ongoing trials in 2028. The primary outcome was any stroke or cardiovascular death. We used individual participant data to construct a Cox regression model of the time to the first occurrence of outcome events during follow-up in the intention-to-treat dataset supplied by each trial, followed by meta-analysis using a fixed-effect inverse-variance model to generate a pooled estimate of the hazard ratio (HR) with 95% CI. This study is registered with PROSPERO, CRD42021246133.</p><p><strong>Findings: </strong>We identified four eligible trials; three were restricted to participants with atrial fibrillation and intracranial haemorrhage (SoSTART [NCT03153150], with 203 participants) or intracerebral haemorrhage (APACHE-AF [NCT02565693], with 101 participants, and NASPAF-ICH [NCT02998905], with 30 participants), and one included a subgroup of participants with previous intracranial haemorrhage (ELDERCARE-AF [NCT02801669], with 80 participants). After excluding two participants who opted out of data sharing, we included 412 participants (310 [75%] aged 75 years or older, 249 [60%] with CHA<sub>2</sub>DS<sub>2</sub>-VASc score ≤4, and 163 [40%] with CHA<sub>2</sub>DS<sub>2</sub>-VASc score >4). The intervention was a direct oral anticoagulant in 209 (99%) of 212 participants who were assigned to start oral anticoagulation, and the comparator was antiplatelet monotherapy in 67 (33%) of 200 participants assigned to avoid oral anticoagulation. The primary outcome of any stroke or cardiovascular death occurred in 29 (14%) of 212 participants who started oral anticoagulation versus 43 (22%) of 200 who avoided oral anticoagulation (pooled HR 0·68 [95% CI 0·42-1·10]; I<sup>2</sup>=0%). Oral anticoagulation reduced the risk of ischaemic major adverse cardiovascular even
{"title":"Effects of oral anticoagulation in people with atrial fibrillation after spontaneous intracranial haemorrhage (COCROACH): prospective, individual participant data meta-analysis of randomised trials.","authors":"Rustam Al-Shahi Salman, Jacqueline Stephen, Jayne F Tierney, Steff C Lewis, David E Newby, Adrian R Parry-Jones, Philip M White, Stuart J Connolly, Oscar R Benavente, Dar Dowlatshahi, Charlotte Cordonnier, Catherine M Viscoli, Kevin N Sheth, Hooman Kamel, Roland Veltkamp, Kristin T Larsen, Jeannette Hofmeijer, Henk Kerkhoff, Floris H B M Schreuder, Ashkan Shoamanesh, Catharina J M Klijn, H Bart van der Worp","doi":"10.1016/S1474-4422(23)00315-0","DOIUrl":"10.1016/S1474-4422(23)00315-0","url":null,"abstract":"<p><strong>Background: </strong>The safety and efficacy of oral anticoagulation for prevention of major adverse cardiovascular events in people with atrial fibrillation and spontaneous intracranial haemorrhage are uncertain. We planned to estimate the effects of starting versus avoiding oral anticoagulation in people with spontaneous intracranial haemorrhage and atrial fibrillation.</p><p><strong>Methods: </strong>In this prospective meta-analysis, we searched bibliographic databases and trial registries using the strategies of a Cochrane systematic review (CD012144) on June 23, 2023. We included clinical trials if they were registered, randomised, and included participants with spontaneous intracranial haemorrhage and atrial fibrillation who were assigned to either start long-term use of any oral anticoagulant agent or avoid oral anticoagulation (ie, placebo, open control, another antithrombotic agent, or another intervention for the prevention of major adverse cardiovascular events). We assessed eligible trials using the Cochrane Risk of Bias tool. We sought data for individual participants who had not opted out of data sharing from chief investigators of completed trials, pending completion of ongoing trials in 2028. The primary outcome was any stroke or cardiovascular death. We used individual participant data to construct a Cox regression model of the time to the first occurrence of outcome events during follow-up in the intention-to-treat dataset supplied by each trial, followed by meta-analysis using a fixed-effect inverse-variance model to generate a pooled estimate of the hazard ratio (HR) with 95% CI. This study is registered with PROSPERO, CRD42021246133.</p><p><strong>Findings: </strong>We identified four eligible trials; three were restricted to participants with atrial fibrillation and intracranial haemorrhage (SoSTART [NCT03153150], with 203 participants) or intracerebral haemorrhage (APACHE-AF [NCT02565693], with 101 participants, and NASPAF-ICH [NCT02998905], with 30 participants), and one included a subgroup of participants with previous intracranial haemorrhage (ELDERCARE-AF [NCT02801669], with 80 participants). After excluding two participants who opted out of data sharing, we included 412 participants (310 [75%] aged 75 years or older, 249 [60%] with CHA<sub>2</sub>DS<sub>2</sub>-VASc score ≤4, and 163 [40%] with CHA<sub>2</sub>DS<sub>2</sub>-VASc score >4). The intervention was a direct oral anticoagulant in 209 (99%) of 212 participants who were assigned to start oral anticoagulation, and the comparator was antiplatelet monotherapy in 67 (33%) of 200 participants assigned to avoid oral anticoagulation. The primary outcome of any stroke or cardiovascular death occurred in 29 (14%) of 212 participants who started oral anticoagulation versus 43 (22%) of 200 who avoided oral anticoagulation (pooled HR 0·68 [95% CI 0·42-1·10]; I<sup>2</sup>=0%). Oral anticoagulation reduced the risk of ischaemic major adverse cardiovascular even","PeriodicalId":17989,"journal":{"name":"Lancet Neurology","volume":" ","pages":"1140-1149"},"PeriodicalIF":48.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41236517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-01Epub Date: 2023-10-09DOI: 10.1016/S1474-4422(23)00387-3
David A Watkins
{"title":"Policy priorities for preventing stroke-related mortality and disability worldwide.","authors":"David A Watkins","doi":"10.1016/S1474-4422(23)00387-3","DOIUrl":"10.1016/S1474-4422(23)00387-3","url":null,"abstract":"","PeriodicalId":17989,"journal":{"name":"Lancet Neurology","volume":" ","pages":"1096-1098"},"PeriodicalIF":48.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41204409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-01Epub Date: 2023-10-09DOI: 10.1016/S1474-4422(23)00277-6
Valery L Feigin, Mayowa O Owolabi
{"title":"Pragmatic solutions to reduce the global burden of stroke: a World Stroke Organization-Lancet Neurology Commission.","authors":"Valery L Feigin, Mayowa O Owolabi","doi":"10.1016/S1474-4422(23)00277-6","DOIUrl":"10.1016/S1474-4422(23)00277-6","url":null,"abstract":"","PeriodicalId":17989,"journal":{"name":"Lancet Neurology","volume":" ","pages":"1160-1206"},"PeriodicalIF":46.5,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10715732/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41204410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-01Epub Date: 2023-10-09DOI: 10.1016/S1474-4422(23)00386-1
Samuel B Brusca, Michelle A Albert
{"title":"Balancing the scales of adversity: a socioecological approach to reducing the global burden of stroke and cardiovascular disease.","authors":"Samuel B Brusca, Michelle A Albert","doi":"10.1016/S1474-4422(23)00386-1","DOIUrl":"10.1016/S1474-4422(23)00386-1","url":null,"abstract":"","PeriodicalId":17989,"journal":{"name":"Lancet Neurology","volume":" ","pages":"1094-1096"},"PeriodicalIF":48.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41204408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-01Epub Date: 2023-10-12DOI: 10.1016/S1474-4422(23)00331-9
Shinichiro Uchiyama
{"title":"Anticoagulation in people with atrial fibrillation after intracranial haemorrhage.","authors":"Shinichiro Uchiyama","doi":"10.1016/S1474-4422(23)00331-9","DOIUrl":"10.1016/S1474-4422(23)00331-9","url":null,"abstract":"","PeriodicalId":17989,"journal":{"name":"Lancet Neurology","volume":" ","pages":"1091-1092"},"PeriodicalIF":48.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41236516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-01Epub Date: 2023-08-23DOI: 10.1016/S1474-4422(23)00283-1
Mie Rizig, Sara Bandres-Ciga, Mary B Makarious, Oluwadamilola Omolara Ojo, Peter Wild Crea, Oladunni Victoria Abiodun, Kristin S Levine, Sani Atta Abubakar, Charles Obiora Achoru, Dan Vitale, Olaleye Akinmola Adeniji, Osigwe Paul Agabi, Mathew J Koretsky, Uchechi Agulanna, Deborah A Hall, Rufus Olusola Akinyemi, Tao Xie, Mohammed Wulgo Ali, Ejaz A Shamim, Ifeyinwa Ani-Osheku, Mahesh Padmanaban, Ohwotemu Michael Arigbodi, David G Standaert, Abiodun Hamzat Bello, Marissa N Dean, Cyril Oshomah Erameh, Inas Elsayed, Temitope Hannah Farombi, Olaitan Okunoye, Michael Bimbola Fawale, Kimberley J Billingsley, Frank Aiwansoba Imarhiagbe, Pilar Alvarez Jerez, Emmanuel Uzodinma Iwuozo, Breeana Baker, Morenikeji Adeyoyin Komolafe, Laksh Malik, Paul Osemeke Nwani, Kensuke Daida, Ernest Okwundu Nwazor, Abigail Miano-Burkhardt, Yakub Wilberforce Nyandaiti, Zih-Hua Fang, Yahaya Olugbo Obiabo, Jillian H Kluss, Olanike Adedoyin Odeniyi, Dena G Hernandez, Francis Ehidiamen Odiase, Nahid Tayebi, Francis Ibe Ojini, Ellen Sidranksy, Gerald Awele Onwuegbuzie, Andrea M D'Souza, Godwin Osawaru Osaigbovo, Bahafta Berhe, Nosakhare Osemwegie, Xylena Reed, Olajumoke Olufemi Oshinaike, Hampton L Leonard, Folajimi Morenikeji Otubogun, Chelsea X Alvarado, Shyngle Imiewan Oyakhire, Simon Izuchukwu Ozomma, Sarah Chabiri Samuel, Funmilola Tolulope Taiwo, Kolawole Wasiu Wahab, Yusuf Agboola Zubair, Hirotaka Iwaki, Jonggeol Jeffrey Kim, Huw R Morris, John Hardy, Mike A Nalls, Karl Heilbron, Lucy Norcliffe-Kaufmann, Cornelis Blauwendraat, Henry Houlden, Andrew Singleton, Njideka Ulunma Okubadejo
<p><strong>Background: </strong>An understanding of the genetic mechanisms underlying diseases in ancestrally diverse populations is an important step towards development of targeted treatments. Research in African and African admixed populations can enable mapping of complex traits, because of their genetic diversity, extensive population substructure, and distinct linkage disequilibrium patterns. We aimed to do a comprehensive genome-wide assessment in African and African admixed individuals to better understand the genetic architecture of Parkinson's disease in these underserved populations.</p><p><strong>Methods: </strong>We performed a genome-wide association study (GWAS) in people of African and African admixed ancestry with and without Parkinson's disease. Individuals were included from several cohorts that were available as a part of the Global Parkinson's Genetics Program, the International Parkinson's Disease Genomics Consortium Africa, and 23andMe. A diagnosis of Parkinson's disease was confirmed clinically by a movement disorder specialist for every individual in each cohort, except for 23andMe, in which it was self-reported based on clinical diagnosis. We characterised ancestry-specific risk, differential haplotype structure and admixture, coding and structural genetic variation, and enzymatic activity.</p><p><strong>Findings: </strong>We included 197 918 individuals (1488 cases and 196 430 controls) in our genome-wide analysis. We identified a novel common risk factor for Parkinson's disease (overall meta-analysis odds ratio for risk of Parkinson's disease 1·58 [95% CI 1·37-1·80], p=2·397 × 10<sup>-14</sup>) and age at onset at the GBA1 locus, rs3115534-G (age at onset β=-2·00 [SE=0·57], p=0·0005, for African ancestry; and β=-4·15 [0·58], p=0·015, for African admixed ancestry), which was rare in non-African or non-African admixed populations. Downstream short-read and long-read whole-genome sequencing analyses did not reveal any coding or structural variant underlying the GWAS signal. The identified signal seems to be associated with decreased glucocerebrosidase activity.</p><p><strong>Interpretation: </strong>Our study identified a novel genetic risk factor in GBA1 in people of African ancestry, which has not been seen in European populations, and it could be a major mechanistic basis of Parkinson's disease in African populations. This population-specific variant exerts substantial risk on Parkinson's disease as compared with common variation identified through GWAS and it was found to be present in 39% of the cases assessed in this study. This finding highlights the importance of understanding ancestry-specific genetic risk in complex diseases, a particularly crucial point as the Parkinson's disease field moves towards targeted treatments in clinical trials. The distinctive genetics of African populations highlights the need for equitable inclusion of ancestrally diverse groups in future trials, which will be a valuable step towar
{"title":"Identification of genetic risk loci and causal insights associated with Parkinson's disease in African and African admixed populations: a genome-wide association study.","authors":"Mie Rizig, Sara Bandres-Ciga, Mary B Makarious, Oluwadamilola Omolara Ojo, Peter Wild Crea, Oladunni Victoria Abiodun, Kristin S Levine, Sani Atta Abubakar, Charles Obiora Achoru, Dan Vitale, Olaleye Akinmola Adeniji, Osigwe Paul Agabi, Mathew J Koretsky, Uchechi Agulanna, Deborah A Hall, Rufus Olusola Akinyemi, Tao Xie, Mohammed Wulgo Ali, Ejaz A Shamim, Ifeyinwa Ani-Osheku, Mahesh Padmanaban, Ohwotemu Michael Arigbodi, David G Standaert, Abiodun Hamzat Bello, Marissa N Dean, Cyril Oshomah Erameh, Inas Elsayed, Temitope Hannah Farombi, Olaitan Okunoye, Michael Bimbola Fawale, Kimberley J Billingsley, Frank Aiwansoba Imarhiagbe, Pilar Alvarez Jerez, Emmanuel Uzodinma Iwuozo, Breeana Baker, Morenikeji Adeyoyin Komolafe, Laksh Malik, Paul Osemeke Nwani, Kensuke Daida, Ernest Okwundu Nwazor, Abigail Miano-Burkhardt, Yakub Wilberforce Nyandaiti, Zih-Hua Fang, Yahaya Olugbo Obiabo, Jillian H Kluss, Olanike Adedoyin Odeniyi, Dena G Hernandez, Francis Ehidiamen Odiase, Nahid Tayebi, Francis Ibe Ojini, Ellen Sidranksy, Gerald Awele Onwuegbuzie, Andrea M D'Souza, Godwin Osawaru Osaigbovo, Bahafta Berhe, Nosakhare Osemwegie, Xylena Reed, Olajumoke Olufemi Oshinaike, Hampton L Leonard, Folajimi Morenikeji Otubogun, Chelsea X Alvarado, Shyngle Imiewan Oyakhire, Simon Izuchukwu Ozomma, Sarah Chabiri Samuel, Funmilola Tolulope Taiwo, Kolawole Wasiu Wahab, Yusuf Agboola Zubair, Hirotaka Iwaki, Jonggeol Jeffrey Kim, Huw R Morris, John Hardy, Mike A Nalls, Karl Heilbron, Lucy Norcliffe-Kaufmann, Cornelis Blauwendraat, Henry Houlden, Andrew Singleton, Njideka Ulunma Okubadejo","doi":"10.1016/S1474-4422(23)00283-1","DOIUrl":"10.1016/S1474-4422(23)00283-1","url":null,"abstract":"<p><strong>Background: </strong>An understanding of the genetic mechanisms underlying diseases in ancestrally diverse populations is an important step towards development of targeted treatments. Research in African and African admixed populations can enable mapping of complex traits, because of their genetic diversity, extensive population substructure, and distinct linkage disequilibrium patterns. We aimed to do a comprehensive genome-wide assessment in African and African admixed individuals to better understand the genetic architecture of Parkinson's disease in these underserved populations.</p><p><strong>Methods: </strong>We performed a genome-wide association study (GWAS) in people of African and African admixed ancestry with and without Parkinson's disease. Individuals were included from several cohorts that were available as a part of the Global Parkinson's Genetics Program, the International Parkinson's Disease Genomics Consortium Africa, and 23andMe. A diagnosis of Parkinson's disease was confirmed clinically by a movement disorder specialist for every individual in each cohort, except for 23andMe, in which it was self-reported based on clinical diagnosis. We characterised ancestry-specific risk, differential haplotype structure and admixture, coding and structural genetic variation, and enzymatic activity.</p><p><strong>Findings: </strong>We included 197 918 individuals (1488 cases and 196 430 controls) in our genome-wide analysis. We identified a novel common risk factor for Parkinson's disease (overall meta-analysis odds ratio for risk of Parkinson's disease 1·58 [95% CI 1·37-1·80], p=2·397 × 10<sup>-14</sup>) and age at onset at the GBA1 locus, rs3115534-G (age at onset β=-2·00 [SE=0·57], p=0·0005, for African ancestry; and β=-4·15 [0·58], p=0·015, for African admixed ancestry), which was rare in non-African or non-African admixed populations. Downstream short-read and long-read whole-genome sequencing analyses did not reveal any coding or structural variant underlying the GWAS signal. The identified signal seems to be associated with decreased glucocerebrosidase activity.</p><p><strong>Interpretation: </strong>Our study identified a novel genetic risk factor in GBA1 in people of African ancestry, which has not been seen in European populations, and it could be a major mechanistic basis of Parkinson's disease in African populations. This population-specific variant exerts substantial risk on Parkinson's disease as compared with common variation identified through GWAS and it was found to be present in 39% of the cases assessed in this study. This finding highlights the importance of understanding ancestry-specific genetic risk in complex diseases, a particularly crucial point as the Parkinson's disease field moves towards targeted treatments in clinical trials. The distinctive genetics of African populations highlights the need for equitable inclusion of ancestrally diverse groups in future trials, which will be a valuable step towar","PeriodicalId":17989,"journal":{"name":"Lancet Neurology","volume":" ","pages":"1015-1025"},"PeriodicalIF":46.5,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10593199/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10147325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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