TY - JOUR
T1 - Investigating the genetic architecture of dementia with Lewy bodies
T2 - a two-stage genome-wide association study
AU - Guerreiro, Rita
AU - Ross, Owen A.
AU - Kun-Rodrigues, Celia
AU - Hernandez, Dena G.
AU - Orme, Tatiana
AU - Eicher, John D.
AU - Shepherd, Claire E.
AU - Parkkinen, Laura
AU - Darwent, Lee
AU - Heckman, Michael G.
AU - Scholz, Sonja W.
AU - Troncoso, Juan C.
AU - Pletnikova, Olga
AU - Ansorge, Olaf
AU - Clarimon, Jordi
AU - Lleo, Alberto
AU - Morenas-Rodriguez, Estrella
AU - Clark, Lorraine
AU - Honig, Lawrence S.
AU - Marder, Karen
AU - Lemstra, Afina
AU - Rogaeva, Ekaterina
AU - St George-Hyslop, Peter
AU - Londos, Elisabet
AU - Zetterberg, Henrik
AU - Barber, Imelda
AU - Braae, Anne
AU - Brown, Kristelle
AU - Morgan, Kevin
AU - Troakes, Claire
AU - Al-Sarraj, Safa
AU - Lashley, Tammaryn
AU - Holton, Janice
AU - Compta, Yaroslau
AU - Van Deerlin, Vivianna
AU - Serrano, Geidy E.
AU - Beach, Thomas G.
AU - Lesage, Suzanne
AU - Galasko, Douglas
AU - Masliah, Eliezer
AU - Santana, Isabel
AU - Pastor, Pau
AU - Diez-Fairen, Monica
AU - Aguilar, Miquel
AU - Tienari, Pentti J.
AU - Myllykangas, Liisa
AU - Oinas, Minna
AU - Revesz, Tamas
AU - Lees, Andrew
AU - Boeve, Brad F.
AU - Petersen, Ronald C.
AU - Ferman, Tanis J.
AU - Escott-Price, Valentina
AU - Graff-Radford, Neill
AU - Cairns, Nigel J.
AU - Morris, John C.
AU - Pickering-Brown, Stuart
AU - Mann, David
AU - Halliday, Glenda M.
AU - Hardy, John
AU - Trojanowski, John Q.
AU - Dickson, Dennis W.
AU - Singleton, Andrew
AU - Stone, David J.
AU - Bras, Jose
N1 - Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2018/1
Y1 - 2018/1
N2 - Background Dementia with Lewy bodies is the second most common form of dementia in elderly people but has been overshadowed in the research field, partly because of similarities between dementia with Lewy bodies, Parkinson's disease, and Alzheimer's disease. So far, to our knowledge, no large-scale genetic study of dementia with Lewy bodies has been done. To better understand the genetic basis of dementia with Lewy bodies, we have done a genome-wide association study with the aim of identifying genetic risk factors for this disorder. Methods In this two-stage genome-wide association study, we collected samples from white participants of European ancestry who had been diagnosed with dementia with Lewy bodies according to established clinical or pathological criteria. In the discovery stage (with the case cohort recruited from 22 centres in ten countries and the controls derived from two publicly available database of Genotypes and Phenotypes studies [phs000404.v1.p1 and phs000982.v1.p1] in the USA), we performed genotyping and exploited the recently established Haplotype Reference Consortium panel as the basis for imputation. Pathological samples were ascertained following autopsy in each individual brain bank, whereas clinical samples were collected after participant examination. There was no specific timeframe for collection of samples. We did association analyses in all participants with dementia with Lewy bodies, and also only in participants with pathological diagnosis. In the replication stage, we performed genotyping of significant and suggestive results from the discovery stage. Lastly, we did a meta-analysis of both stages under a fixed-effects model and used logistic regression to test for association in each stage. Findings This study included 1743 patients with dementia with Lewy bodies (1324 with pathological diagnosis) and 4454 controls (1216 patients with dementia with Lewy bodies vs 3791 controls in the discovery stage; 527 vs 663 in the replication stage). Results confirm previously reported associations: APOE (rs429358; odds ratio [OR] 2·40, 95% CI 2·14–2·70; p=1·05 × 10−48), SNCA (rs7681440; OR 0·73, 0·66–0·81; p=6·39 × 10−10), an GBA (rs35749011; OR 2·55, 1·88–3·46; p=1·78 × 10−9). They also provide some evidence for a novel candidate locus, namely CNTN1 (rs7314908; OR 1·51, 1·27–1·79; p=2·32 × 10−6); further replication will be important. Additionally, we estimate the heritable component of dementia with Lewy bodies to be about 36%. Interpretation Despite the small sample size for a genome-wide association study, and acknowledging the potential biases from ascertaining samples from multiple locations, we present the most comprehensive and well powered genetic study in dementia with Lewy bodies so far. These data show that common genetic variability has a role in the disease. Funding The Alzheimer's Society and the Lewy Body Society.
AB - Background Dementia with Lewy bodies is the second most common form of dementia in elderly people but has been overshadowed in the research field, partly because of similarities between dementia with Lewy bodies, Parkinson's disease, and Alzheimer's disease. So far, to our knowledge, no large-scale genetic study of dementia with Lewy bodies has been done. To better understand the genetic basis of dementia with Lewy bodies, we have done a genome-wide association study with the aim of identifying genetic risk factors for this disorder. Methods In this two-stage genome-wide association study, we collected samples from white participants of European ancestry who had been diagnosed with dementia with Lewy bodies according to established clinical or pathological criteria. In the discovery stage (with the case cohort recruited from 22 centres in ten countries and the controls derived from two publicly available database of Genotypes and Phenotypes studies [phs000404.v1.p1 and phs000982.v1.p1] in the USA), we performed genotyping and exploited the recently established Haplotype Reference Consortium panel as the basis for imputation. Pathological samples were ascertained following autopsy in each individual brain bank, whereas clinical samples were collected after participant examination. There was no specific timeframe for collection of samples. We did association analyses in all participants with dementia with Lewy bodies, and also only in participants with pathological diagnosis. In the replication stage, we performed genotyping of significant and suggestive results from the discovery stage. Lastly, we did a meta-analysis of both stages under a fixed-effects model and used logistic regression to test for association in each stage. Findings This study included 1743 patients with dementia with Lewy bodies (1324 with pathological diagnosis) and 4454 controls (1216 patients with dementia with Lewy bodies vs 3791 controls in the discovery stage; 527 vs 663 in the replication stage). Results confirm previously reported associations: APOE (rs429358; odds ratio [OR] 2·40, 95% CI 2·14–2·70; p=1·05 × 10−48), SNCA (rs7681440; OR 0·73, 0·66–0·81; p=6·39 × 10−10), an GBA (rs35749011; OR 2·55, 1·88–3·46; p=1·78 × 10−9). They also provide some evidence for a novel candidate locus, namely CNTN1 (rs7314908; OR 1·51, 1·27–1·79; p=2·32 × 10−6); further replication will be important. Additionally, we estimate the heritable component of dementia with Lewy bodies to be about 36%. Interpretation Despite the small sample size for a genome-wide association study, and acknowledging the potential biases from ascertaining samples from multiple locations, we present the most comprehensive and well powered genetic study in dementia with Lewy bodies so far. These data show that common genetic variability has a role in the disease. Funding The Alzheimer's Society and the Lewy Body Society.
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U2 - 10.1016/S1474-4422(17)30400-3
DO - 10.1016/S1474-4422(17)30400-3
M3 - Article
C2 - 29263008
AN - SCOPUS:85039561634
SN - 1474-4422
VL - 17
SP - 64
EP - 74
JO - The Lancet Neurology
JF - The Lancet Neurology
IS - 1
ER -