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@ARTICLE{Guerreiro:139693,
author = {Guerreiro, Rita and Ross, Owen A and Kun-Rodrigues, Celia
and Hernandez, Dena G and Orme, Tatiana and Eicher, John D
and Shepherd, Claire E and Parkkinen, Laura and Darwent, Lee
and Heckman, Michael G and Scholz, Sonja W and Troncoso,
Juan C and Pletnikova, Olga and Ansorge, Olaf and Clarimon,
Jordi and Lleo, Alberto and Morenas-Rodriguez, Estrella and
Clark, Lorraine and Honig, Lawrence S and Marder, Karen and
Lemstra, Afina and Rogaeva, Ekaterina and St George-Hyslop,
Peter and Londos, Elisabet and Zetterberg, Henrik and
Barber, Imelda and Braae, Anne and Brown, Kristelle and
Morgan, Kevin and Troakes, Claire and Al-Sarraj, Safa and
Lashley, Tammaryn and Holton, Janice and Compta, Yaroslau
and Van Deerlin, Vivianna and Serrano, Geidy E and Beach,
Thomas G and Lesage, Suzanne and Galasko, Douglas and
Masliah, Eliezer and Santana, Isabel and Pastor, Pau and
Diez-Fairen, Monica and Aguilar, Miquel and Tienari, Pentti
J and Myllykangas, Liisa and Oinas, Minna and Revesz, Tamas
and Lees, Andrew and Boeve, Brad F and Petersen, Ronald C
and Ferman, Tanis J and Escott-Price, Valentina and
Graff-Radford, Neill and Cairns, Nigel J and Morris, John C
and Pickering-Brown, Stuart and Mann, David and Halliday,
Glenda M and Hardy, John and Trojanowski, John Q and
Dickson, Dennis W and Singleton, Andrew and Stone, David J
and Bras, Jose},
title = {{I}nvestigating the genetic architecture of dementia with
{L}ewy bodies: a two-stage genome-wide association study.},
journal = {The lancet / Neurology},
volume = {17},
number = {1},
issn = {1474-4422},
address = {London},
publisher = {Lancet Publ. Group},
reportid = {DZNE-2020-06015},
pages = {64-74},
year = {2018},
abstract = {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.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.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 $36\%.Despite$ 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.The Alzheimer's Society and the Lewy Body
Society.},
keywords = {Cohort Studies / Genome-Wide Association Study: methods /
Humans / Lewy Body Disease: genetics},
cin = {AG Heutink},
ddc = {610},
cid = {I:(DE-2719)1210002},
pnm = {345 - Population Studies and Genetics (POF3-345)},
pid = {G:(DE-HGF)POF3-345},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:29263008},
pmc = {pmc:PMC5805394},
doi = {10.1016/S1474-4422(17)30400-3},
url = {https://pub.dzne.de/record/139693},
}