Revealing new genetic variants associated with Lewy body dementia

2021

Challenge

Age-related neurodegenerative conditions place a growing and substantial socioeconomic burden on U.S. society. To develop treatments for them, it will be necessary to increase our understanding of the genetic determinants underlying these complex syndromes and identify potential targets for therapeutic interventions. Lewy body dementia (LBD), for example, is a common form of dementia in the aging population, but its causes are poorly understood. Current treatments address only the symptoms, rather than the ailment’s root cause, and they have limited effectiveness.

Advance

To extend modern gene discovery efforts to LBD and to generate a resource for the research community, IRP researchers led by Sonya W. Scholz, M.D., Ph.D., performed whole-genome sequencing in a large group of patients with LBD as well as neurologically healthy individuals for comparison. They identified novel locations in the genome associated with the development of this devastating disease and showed similarities between the genetic underpinnings of LBD and those of Parkinson’s disease and Alzheimer’s disease.

Impact

The high-quality sequencing data generated in this study constitute the largest sequencing effort in LBD to date and are designed to accelerate the pace of discovery in dementia research. To that end, the data that the study produced have been made into a resource accessible to the broader research community. The molecular insights from this effort provide an important foundation for addressing a common form of dementia within the U.S. population and pave the way for developing precision medicine approaches to treating it.

Publications

Chia R, Sabir MS, Bandres-Ciga S, Saez-Atienzar S, Reynolds RH, Gustavsson E, Walton RL, Ahmed S, Viollet C, Ding J, Makarious MB, Diez-Fairen M, Portley MK, Shah Z, Abramzon Y, Hernandez DG, Blauwendraat C, Stone DJ, Eicher J, Parkkinen L, Ansorge O, Clark L, Honig LS, Marder K, Lemstra A, St George-Hyslop P, Londos E, Morgan K, Lashley T, Warner TT, Jaunmuktane Z, Galasko D, Santana I, Tienari PJ, Myllykangas L, Oinas M, Cairns NJ, Morris JC, Halliday GM, Van Deerlin VM, Trojanowski JQ, Grassano M, Calvo A, Mora G, Canosa A, Floris G, Bohannan RC, Brett F, Gan-Or Z, Geiger JT, Moore A, May P, Krüger R, Goldstein DS, Lopez G, Tayebi N, Sidransky E; American Genome Center, Norcliffe-Kaufmann L, Palma JA, Kaufmann H, Shakkottai VG, Perkins M, Newell KL, Gasser T, Schulte C, Landi F, Salvi E, Cusi D, Masliah E, Kim RC, Caraway CA, Monuki ES, Brunetti M, Dawson TM, Rosenthal LS, Albert MS, Pletnikova O, Troncoso JC, Flanagan ME, Mao Q, Bigio EH, Rodríguez-Rodríguez E, Infante J, Lage C, González-Aramburu I, Sanchez-Juan P, Ghetti B, Keith J, Black SE, Masellis M, Rogaeva E, Duyckaerts C, Brice A, Lesage S, Xiromerisiou G, Barrett MJ, Tilley BS, Gentleman S, Logroscino G, Serrano GE, Beach TG, McKeith IG, Thomas AJ, Attems J, Morris CM, Palmer L, Love S, Troakes C, Al-Sarraj S, Hodges AK, Aarsland D, Klein G, Kaiser SM, Woltjer R, Pastor P, Bekris LM, Leverenz JB, Besser LM, Kuzma A, Renton AE, Goate A, Bennett DA, Scherzer CR, Morris HR, Ferrari R, Albani D, Pickering-Brown S, Faber K, Kukull WA, Morenas-Rodriguez E, Lleó A, Fortea J, Alcolea D, Clarimon J, Nalls MA, Ferrucci L, Resnick SM, Tanaka T, Foroud TM, Graff-Radford NR, Wszolek ZK, Ferman T, Boeve BF, Hardy JA, Topol EJ, Torkamani A, Singleton AB, Ryten M, Dickson DW, Chiò A, Ross OA, Gibbs JR, Dalgard CL, Traynor BJ, Scholz SW. (2021). Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture. Nat Genet. Mar;53(3):294-303. doi: 10.1038/s41588-021-00785-3.