Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study

Research output: Contribution to journalArticle

Abstract

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.

Details

Authors
  • Rita Guerreiro
  • Owen A. Ross
  • Celia Kun-Rodrigues
  • Dena G. Hernandez
  • Tatiana Orme
  • John D. Eicher
  • Claire E. Shepherd
  • Laura Parkkinen
  • Lee Darwent
  • Michael G. Heckman
  • Sonja W. Scholz
  • Juan C. Troncoso
  • Olga Pletnikova
  • Olaf Ansorge
  • Jordi Clarimon
  • Alberto Lleo
  • Estrella Morenas-Rodriguez
  • Lorraine Clark
  • Lawrence S. Honig
  • Karen Marder
  • Afina Lemstra
  • Ekaterina Rogaeva
  • Peter St George-Hyslop
  • Henrik Zetterberg
  • Imelda Barber
  • Anne Braae
  • Kristelle Brown
  • Kevin Morgan
  • Claire Troakes
  • Safa Al-Sarraj
  • Tammaryn Lashley
  • Janice Holton
  • Yaroslau Compta
  • Vivianna Van Deerlin
  • Geidy E. Serrano
  • Thomas G. Beach
  • Suzanne Lesage
  • Douglas Galasko
  • Eliezer Masliah
  • Isabel Santana
  • Pau Pastor
  • Monica Diez-Fairen
  • Miquel Aguilar
  • Pentti J. Tienari
  • Liisa Myllykangas
  • Minna Oinas
  • Tamas Revesz
  • Andrew Lees
  • Brad F. Boeve
  • Ronald C. Petersen
  • Tanis J. Ferman
  • Valentina Escott-Price
  • Neill Graff-Radford
  • Nigel J. Cairns
  • John C. Morris
  • Stuart Pickering-Brown
  • David Mann
  • Glenda M. Halliday
  • John Hardy
  • John Q. Trojanowski
  • Dennis W. Dickson
  • Andrew Singleton
  • David J. Stone
  • Jose Bras
Organisations
External organisations
  • University College London
  • University of Aveiro
  • Mayo Clinic Florida
  • National Institutes of Health, United States
  • German Center for Neurodegenerative Diseases (DZNE)
  • Merck Sharp And Dohme Corp., US
  • University of New South Wales
  • University of Oxford
  • Johns Hopkins University School of Medicine
  • Autonomous University of Barcelona
  • CIBER Enfermedades Neurodegenerativas (CIBERNED)
  • Columbia University
  • VU University Medical Center
  • University of Toronto
  • University of Cambridge
  • Sahlgrenska University Hospital
  • Sahlgrenska Academy
  • University of Nottingham
  • King's College London
  • University of Barcelona
  • University of Pennsylvania
  • Banner Sun Health Research Institute
  • Pitié-Salpêtrière University Hospital
  • University of California, San Diego
  • Veterans Health Administration
  • University of Coimbra
  • Hospital Mutua de Terrassa
  • University of Helsinki
  • Helsinki University Central Hospital
  • University of Helsinki Haartman Institute
  • Mayo Clinic Minnesota
  • Cardiff University
  • Washington University in St. Louis
  • University of Manchester
  • University of Sydney
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics
Original languageEnglish
Pages (from-to)64-74
Number of pages11
JournalThe Lancet Neurology
Volume17
Issue number1
Publication statusPublished - 2018
Publication categoryResearch
Peer-reviewedYes