Elizabeth Gibbons, Arvid Rongve, Itziar de Rojas, Alexey Shadrin, Kaitlyn Westra, Allison Baumgartner, Levi Rosendall, Zachary Madaj, Dena G. Hernandez, Owen A. Ross, Valentina Escott-Price, Claire Shepherd, Laura Parkkinen, Sonja W. Scholz, Juan C. Troncoso, Olga Pletnikova, Ted Dawson, Liana Rosenthal, Olaf Ansorge, Jordi Clarimon, Alberto Lleo, Estrella Morenas-Rodriguez, Lorraine Clark, Lawrence S Honig, Karen Marder, Afina Lemstra, Ekaterina Rogaeva, Peter St. George-Hyslop, Elisabet Londos, Henrik Zetterberg, 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, Marta Marquie, Pablo Garcia-Gonzalez, Claudia Olive, Raquel Puerta, Amanda Cano, Oscar Sotolongo-Grau, Sergi Valero, Vanesa Veronica Pytel, Maitee Rosende-Roca, Montserrat Alegret, Lluis Tarraga, Merce Boada, Angel Carracedo, Emilio Franco-Macias, Jordi Perez-Tur, Jose Luis Royo, Jose Maria Garcia-Alberca, Luis Miguel Real, Maria Eugenia Saez, Maria Jesus Bullido, Miguel Calero, Miguel Medina, Pablo Mir, Pascual Sanchez-Juan, Victoria Alvarez, Kayenat Parveen, Kumar Parijat Tripathi, Stefanie Heilmann-Heimbach, Alfredo Ramirez, Pentti J. Tienari, Olivier Bousiges, Frederic Blanc, Chiara Fenoglio, Alessandro Padovani, Barbara Borroni, Andrea Pilotto, Flavio Nobili, Ingvild Saltvedt, Tormod Fladby, Geir Selbaek, Ingunn Bosnes, Geir Brathen, Annette Hartmann, Afina W. Lemstra, Dan Rujescu, Brit Mollenhauer, Byron Creese, Marie-Christine Chartier-Harlin, Lavinia Athanasiu, Srdjan Djurovic, Leonidas Chouliaras, John T. OBrien, Liisa Myllykangas, Minna Oinas, Tamas Revesz, Andrew Lees, Brad F Boeve, Ronald C. Petersen, Tanis J Ferman, Neill Graff-Radford, Nigel J. Cairns, John C. Morris, Glenda M. Halliday, John Hardy, Dennis W. Dickson, Andrew Singleton, David J. Stone, Ole A. Andreassen, Agustin Ruiz, Dag Aarsland, Rita Guerreiro, and Jose Bras
BackgroundGenome-wide Association Studies (GWAS) have reshaped our understanding of the genetic bases of complex diseases in general and neurodegenerative diseases in particular. Despite being a common disorder, dementia with Lewy bodies (DLB), which, together with Parkinson’s disease dementia (PDD), comprise the umbrella term Lewy body dementias (LBD), is far from being well-characterized genetically. This is primarily due to a lack of familial cases and difficulty recruiting large, deeply characterized cohorts, given the high rate of misdiagnosis. By performing the largest GWAS in DLB, we aimed to identify novel risk loci to gain a better understanding of this disease’s pathobiology.MethodsHere, we conducted the largest meta-analysis of genome-wide association studies performed in LBD, using a total of 5,119 cases and 20,988 controls, from five independent datasets, aggregating all previously published DLB genome-wide association results to date, as well as two previously undescribed cohorts. Additionally, we performed a sex stratified GWAS using the discovery datasets. We updated the heritability estimates for DLB and, to fine map these estimates, we used local heritability analysis. We calculated genetic correlation estimates between DLB and a range of other diseases and traits to identify potential pleiotropy. We also performed gene-set analysis to identify genes with excess burden of rare variability and pathway analysis. Lastly, we used the UK Biobank data to perform a PheWas using individuals at the extremes of genetic risk for DLB.FindingsBetween November 2018 and September 2022 we analyzed 8.6 million single nucleotide polymorphisms in 3293 DLB cases, 1826 LBD cases and 20,988 controls, as well as phenotypes from the UK Biobank dataset. Despite more than doubling the sample size from the previous GWAS in DLB, we did not identify significant loci in addition to those previously reported atGBA, SNCA, STX1B, andAPOE. However, the sex-stratified analysis revealed that theGBAandSNCAsignals are mainly driven by males, suggesting a sex-specific genetic architecture of disease. Using only clinical and neuropathologically diagnosed cases, we highlight four loci surpassing the significance threshold. Using the largest cohort of DLB we update our heritability estimates to 13% and fine map these results highlighting regions of the genome with high heritability but no genome-wide significant result so far.InterpretationThese data provide the most comprehensive analysis of genetic variability in DLB to date. The fact that no novel risk loci have been identified after doubling the cohort size indicates the potentially significant role of rare variants in the genetic architecture of DLB and stresses the urgent need for larger, well-characterized cohorts of this disease for genetic studies. The sex-stratified analysis shows that males and females have different signatures of genetic risk for DLB. These results have widespread implications for clinical practice and clinical trials’ design in DLB.