Dataset Information

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture.

ABSTRACT: The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.

SUBMITTER: Chia R

PROVIDER: S-EPMC7946812 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture.

Chia Ruth R Sabir Marya S MS Bandres-Ciga Sara S Saez-Atienzar Sara S Reynolds Regina H RH Gustavsson Emil E Walton Ronald L RL Ahmed Sarah S Viollet Coralie C Ding Jinhui J Makarious Mary B MB Diez-Fairen Monica M Portley Makayla K MK Shah Zalak Z Abramzon Yevgeniya Y Hernandez Dena G DG Blauwendraat Cornelis C Stone David J DJ Eicher John J Parkkinen Laura L Ansorge Olaf O Clark Lorraine L Honig Lawrence S LS Marder Karen K Lemstra Afina A St George-Hyslop Peter P Londos Elisabet E Morgan Kevin K Lashley Tammaryn T Warner Thomas T TT Jaunmuktane Zane Z Galasko Douglas D Santana Isabel I Tienari Pentti J PJ Myllykangas Liisa L Oinas Minna M Cairns Nigel J NJ Morris John C JC Halliday Glenda M GM Van Deerlin Vivianna M VM Trojanowski John Q JQ Grassano Maurizio M Calvo Andrea A Mora Gabriele G Canosa Antonio A Floris Gianluca G Bohannan Ryan C RC Brett Francesca F Gan-Or Ziv Z Geiger Joshua T JT Moore Anni A May Patrick P Krüger Rejko R Goldstein David S DS Lopez Grisel G Tayebi Nahid N Sidransky Ellen E Norcliffe-Kaufmann Lucy L Palma Jose-Alberto JA Kaufmann Horacio H Shakkottai Vikram G VG Perkins Matthew M Newell Kathy L KL Gasser Thomas T Schulte Claudia C Landi Francesco F Salvi Erika E Cusi Daniele D Masliah Eliezer E Kim Ronald C RC Caraway Chad A CA Monuki Edwin S ES Brunetti Maura M Dawson Ted M TM Rosenthal Liana S LS Albert Marilyn S MS Pletnikova Olga O Troncoso Juan C JC Flanagan Margaret E ME Mao Qinwen Q Bigio Eileen H EH Rodríguez-Rodríguez Eloy E Infante Jon J Lage Carmen C González-Aramburu Isabel I Sanchez-Juan Pascual P Ghetti Bernardino B Keith Julia J Black Sandra E SE Masellis Mario M Rogaeva Ekaterina E Duyckaerts Charles C Brice Alexis A Lesage Suzanne S Xiromerisiou Georgia G Barrett Matthew J MJ Tilley Bension S BS Gentleman Steve S Logroscino Giancarlo G Serrano Geidy E GE Beach Thomas G TG McKeith Ian G IG Thomas Alan J AJ Attems Johannes J Morris Christopher M CM Palmer Laura L Love Seth S Troakes Claire C Al-Sarraj Safa S Hodges Angela K AK Aarsland Dag D Klein Gregory G Kaiser Scott M SM Woltjer Randy R Pastor Pau P Bekris Lynn M LM Leverenz James B JB Besser Lilah M LM Kuzma Amanda A Renton Alan E AE Goate Alison A Bennett David A DA Scherzer Clemens R CR Morris Huw R HR Ferrari Raffaele R Albani Diego D Pickering-Brown Stuart S Faber Kelley K Kukull Walter A WA Morenas-Rodriguez Estrella E Lleó Alberto A Fortea Juan J Alcolea Daniel D Clarimon Jordi J Nalls Mike A MA Ferrucci Luigi L Resnick Susan M SM Tanaka Toshiko T Foroud Tatiana M TM Graff-Radford Neill R NR Wszolek Zbigniew K ZK Ferman Tanis T Boeve Bradley F BF Hardy John A JA Topol Eric J EJ Torkamani Ali A Singleton Andrew B AB Ryten Mina M Dickson Dennis W DW Chiò Adriano A Ross Owen A OA Gibbs J Raphael JR Dalgard Clifton L CL Traynor Bryan J BJ Scholz Sonja W SW

Nature genetics 20210215 3

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that L ...[more]

PMID: 33589841

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Project description:BackgroundDue to a significant decline in the costs associated with next-generation sequencing, it has become possible to decipher the genetic architecture of a population by sequencing a large number of individuals to a deep coverage. The Korean Personal Genomes Project (KPGP) recently sequenced 35 Korean genomes at high coverage using the Illumina Hiseq platform and made the deep sequencing data publicly available, providing the scientific community opportunities to decipher the genetic architecture of the Korean population.MethodsIn this study, we used two single nucleotide variant (SNV) calling pipelines: mapping the raw reads obtained from whole genome sequencing of 35 Korean individuals in KPGP using BWA and SOAP2 followed by SNV calling using SAMtools and SOAPsnp, respectively. The consensus SNVs obtained from the two SNV pipelines were used to represent the SNVs of the Korean population. We compared these SNVs to those from 17 other populations provided by the HapMap consortium and the 1000 Genomes Project (1KGP) and identified SNVs that were only present in the Korean population. We studied the mutation spectrum and analyzed the genes of non-synonymous SNVs only detected in the Korean population.ResultsWe detected a total of 8,555,726 SNVs in the 35 Korean individuals and identified 1,213,613 SNVs detected in at least one Korean individual (SNV-1) and 12,640 in all of 35 Korean individuals (SNV-35) but not in 17 other populations. In contrast with the SNVs common to other populations in HapMap and 1KGP, the Korean only SNVs had high percentages of non-silent variants, emphasizing the unique roles of these Korean only SNVs in the Korean population. Specifically, we identified 8,361 non-synonymous Korean only SNVs, of which 58 SNVs existed in all 35 Korean individuals. The 5,754 genes of non-synonymous Korean only SNVs were highly enriched in some metabolic pathways. We found adhesion is the top disease term associated with SNV-1 and Nelson syndrome is the only disease term associated with SNV-35. We found that a significant number of Korean only SNVs are in genes that are associated with the drug term of adenosine.ConclusionWe identified the SNVs that were found in the Korean population but not seen in other populations, and explored the corresponding genes and pathways as well as the associated disease terms and drug terms. The results expand our knowledge of the genetic architecture of the Korean population, which will benefit the implementation of personalized medicine for the Korean population.

Dataset Information

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture.

Publications

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture.

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