Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study
<h4>Background</h4> <p>Dementia with Lewy Bodies (DLB) is the second most common form of dementia in the elderly but has been overshadowed in the research field, in part due to similarities between DLB, Parkinson's (PD) and Alzheimer’s diseases (AD). So far, no large-scale ge...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Elsevier
2017
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| _version_ | 1826275958128115712 |
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| author | Guerreiro, R Ross, OA Kun-Rodrigues, C Hernandez, DG Orme, T Eicher, JD Shepherd, CE Parkkinen, L Darwent, L Heckman, MG Scholz, SW Troncoso, JC Pletnikova, O Ansorge, O Clarimon, J Lleo, A Morenas-Rodriguez, E Clark, L Honig, LS Marder, K Lemstra, A Rogaeva, E St George-Hyslop, P Londos, E Zetterberg, H Barber, I Braae, A Brown, K Morgan, K Troakes, C Al-Sarraj, S Lashley, T Holton, J Compta, Y Van Deerlin, V Serrano, GE Beach, TG Lesage, S Galasko, D Masliah, E Santana, I Pastor, P Diez-Fairen, M Aguilar, M Tienari, PJ Myllykangas, L Oinas, M Revesz, T Lees, A Boeve, BF Petersen, RC Ferman, TJ Escott-Price, V Graff-Radford, N Cairns, NJ Morris, JC Pickering-Brown, S Mann, D Halliday, GM Hardy, J Trojanowski, JQ Dickson, DW Singleton, A Stone, DJ Bras, J |
| author_facet | Guerreiro, R Ross, OA Kun-Rodrigues, C Hernandez, DG Orme, T Eicher, JD Shepherd, CE Parkkinen, L Darwent, L Heckman, MG Scholz, SW Troncoso, JC Pletnikova, O Ansorge, O Clarimon, J Lleo, A Morenas-Rodriguez, E Clark, L Honig, LS Marder, K Lemstra, A Rogaeva, E St George-Hyslop, P Londos, E Zetterberg, H Barber, I Braae, A Brown, K Morgan, K Troakes, C Al-Sarraj, S Lashley, T Holton, J Compta, Y Van Deerlin, V Serrano, GE Beach, TG Lesage, S Galasko, D Masliah, E Santana, I Pastor, P Diez-Fairen, M Aguilar, M Tienari, PJ Myllykangas, L Oinas, M Revesz, T Lees, A Boeve, BF Petersen, RC Ferman, TJ Escott-Price, V Graff-Radford, N Cairns, NJ Morris, JC Pickering-Brown, S Mann, D Halliday, GM Hardy, J Trojanowski, JQ Dickson, DW Singleton, A Stone, DJ Bras, J |
| author_sort | Guerreiro, R |
| collection | OXFORD |
| description | <h4>Background</h4> <p>Dementia with Lewy Bodies (DLB) is the second most common form of dementia in the elderly but has been overshadowed in the research field, in part due to similarities between DLB, Parkinson's (PD) and Alzheimer’s diseases (AD). So far, no large-scale genetic study of DLB has been performed. To better understand the genetic basis of DLB, we have performed a genome-wide association study, with the aim of identifying genetic risk factors for this disorder</p> <h4>Methods</h4> <p>Here we have performed the first genome-wide association study of DLB in a combined cohort of 1,743 DLB patients and 4,454 controls. To reduce genetic heterogeneity, all samples were of European ancestry. All cases were diagnosed according to established criteria for clinical or pathological DLB. In the discovery stage (comprising 1,216 cases and 3,791 controls, the latter were part of two publicly available dbGaP studies (phs000404.v1.p1 and phs000982.v1.p1)) we performed genotyping and exploited the recently established Haplotype Reference Consortium panel as the basis for imputation. Association analysis was performed in all cases as well as in only those with pathological diagnosis (974 cases). In the replication stage (comprising 527 DLB cases and 663 controls) we performed genotyping of significant and suggestive results. Lastly, we conducted a meta-analysis of both stages. Genotyping was undertaken at three locations: UCL, NIH and the Mayo Clinic.</p> <h4>Findings</h4> <p>Results confirm previously reported associations: APOE (rs429358; OR=2.4 [95%CI 2.14-2.70]; p=1.05x10-48), SNCA (rs7681440; OR=0.73 [0.66- 0.81]; p=6.39x10-10) and GBA (rs35749011; OR=2.55 [1.88-3.46]; p=1.78x10-09). They also provide novel candidate loci, namely CNTN1 (rs7314908; OR=1.53 [1.29-1.81]; p=1.02x10-06); further replication of findings at these two loci will be important. Additionally, we estimate the heritable component of DLB to be approximately 36%.</p> <h4>Interpretation</h4> <p>Despite the relatively modest sample size for a GWAS, and acknowledging the potential biases from ascertaining samples from multiple locations, we present the most comprehensive and well-powered genetic study in DLB to date. These data unequivocally show that common genetic variability plays a role in this disease.</p> |
| first_indexed | 2024-03-06T23:06:44Z |
| format | Journal article |
| id | oxford-uuid:64125b0e-cad4-4418-892a-fef17f4af038 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:06:44Z |
| publishDate | 2017 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:64125b0e-cad4-4418-892a-fef17f4af0382022-03-26T18:17:00ZInvestigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association studyJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:64125b0e-cad4-4418-892a-fef17f4af038EnglishSymplectic Elements at OxfordElsevier2017Guerreiro, RRoss, OAKun-Rodrigues, CHernandez, DGOrme, TEicher, JDShepherd, CEParkkinen, LDarwent, LHeckman, MGScholz, SWTroncoso, JCPletnikova, OAnsorge, OClarimon, JLleo, AMorenas-Rodriguez, EClark, LHonig, LSMarder, KLemstra, ARogaeva, ESt George-Hyslop, PLondos, EZetterberg, HBarber, IBraae, ABrown, KMorgan, KTroakes, CAl-Sarraj, SLashley, THolton, JCompta, YVan Deerlin, VSerrano, GEBeach, TGLesage, SGalasko, DMasliah, ESantana, IPastor, PDiez-Fairen, MAguilar, MTienari, PJMyllykangas, LOinas, MRevesz, TLees, ABoeve, BFPetersen, RCFerman, TJEscott-Price, VGraff-Radford, NCairns, NJMorris, JCPickering-Brown, SMann, DHalliday, GMHardy, JTrojanowski, JQDickson, DWSingleton, AStone, DJBras, J <h4>Background</h4> <p>Dementia with Lewy Bodies (DLB) is the second most common form of dementia in the elderly but has been overshadowed in the research field, in part due to similarities between DLB, Parkinson's (PD) and Alzheimer’s diseases (AD). So far, no large-scale genetic study of DLB has been performed. To better understand the genetic basis of DLB, we have performed a genome-wide association study, with the aim of identifying genetic risk factors for this disorder</p> <h4>Methods</h4> <p>Here we have performed the first genome-wide association study of DLB in a combined cohort of 1,743 DLB patients and 4,454 controls. To reduce genetic heterogeneity, all samples were of European ancestry. All cases were diagnosed according to established criteria for clinical or pathological DLB. In the discovery stage (comprising 1,216 cases and 3,791 controls, the latter were part of two publicly available dbGaP studies (phs000404.v1.p1 and phs000982.v1.p1)) we performed genotyping and exploited the recently established Haplotype Reference Consortium panel as the basis for imputation. Association analysis was performed in all cases as well as in only those with pathological diagnosis (974 cases). In the replication stage (comprising 527 DLB cases and 663 controls) we performed genotyping of significant and suggestive results. Lastly, we conducted a meta-analysis of both stages. Genotyping was undertaken at three locations: UCL, NIH and the Mayo Clinic.</p> <h4>Findings</h4> <p>Results confirm previously reported associations: APOE (rs429358; OR=2.4 [95%CI 2.14-2.70]; p=1.05x10-48), SNCA (rs7681440; OR=0.73 [0.66- 0.81]; p=6.39x10-10) and GBA (rs35749011; OR=2.55 [1.88-3.46]; p=1.78x10-09). They also provide novel candidate loci, namely CNTN1 (rs7314908; OR=1.53 [1.29-1.81]; p=1.02x10-06); further replication of findings at these two loci will be important. Additionally, we estimate the heritable component of DLB to be approximately 36%.</p> <h4>Interpretation</h4> <p>Despite the relatively modest sample size for a GWAS, and acknowledging the potential biases from ascertaining samples from multiple locations, we present the most comprehensive and well-powered genetic study in DLB to date. These data unequivocally show that common genetic variability plays a role in this disease.</p> |
| spellingShingle | Guerreiro, R Ross, OA Kun-Rodrigues, C Hernandez, DG Orme, T Eicher, JD Shepherd, CE Parkkinen, L Darwent, L Heckman, MG Scholz, SW Troncoso, JC Pletnikova, O Ansorge, O Clarimon, J Lleo, A Morenas-Rodriguez, E Clark, L Honig, LS Marder, K Lemstra, A Rogaeva, E St George-Hyslop, P Londos, E Zetterberg, H Barber, I Braae, A Brown, K Morgan, K Troakes, C Al-Sarraj, S Lashley, T Holton, J Compta, Y Van Deerlin, V Serrano, GE Beach, TG Lesage, S Galasko, D Masliah, E Santana, I Pastor, P Diez-Fairen, M Aguilar, M Tienari, PJ Myllykangas, L Oinas, M Revesz, T Lees, A Boeve, BF Petersen, RC Ferman, TJ Escott-Price, V Graff-Radford, N Cairns, NJ Morris, JC Pickering-Brown, S Mann, D Halliday, GM Hardy, J Trojanowski, JQ Dickson, DW Singleton, A Stone, DJ Bras, J Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study |
| title | Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study |
| title_full | Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study |
| title_fullStr | Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study |
| title_full_unstemmed | Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study |
| title_short | Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study |
| title_sort | investigating the genetic architecture of dementia with lewy bodies a two stage genome wide association study |
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