Identification of a sex-specific genetic signature in dementia with Lewy bodies: a meta-analysis of genome-wide association studies
Authors: Gibbons Elizabeth , Rongve Arvid , de Rojas Itziar , Shadrin Alexey , Westra Kaitlyn , Baumgartner Allison , Rosendall Levi , Madaj Zachary , Hernandez Dena G. , Ross Owen A. , Escott-Price Valentina , Shepherd Claire , Parkkinen Laura , Scholz Sonja W. , Troncoso Juan C. , Pletnikova Olga , Dawson Ted , Rosenthal Liana , Ansorge Olaf , Clarimon Jordi , Lleo Alberto , Morenas-Rodriguez Estrella , Clark Lorraine , Honig Lawrence S , Marder Karen , Lemstra Afina , Rogaeva Ekaterina , George-Hyslop Peter St. , Londos Elisabet , Zetterberg Henrik , Morgan Kevin , Troakes Claire , Al-Sarraj Safa , Lashley Tammaryn , Holton Janice , Compta Yaroslau , Van Deerlin Vivianna , Serrano Geidy E , Beach Thomas G , Lesage Suzanne , Galasko Douglas , Masliah Eliezer , Santana Isabel , Pastor Pau , Diez-Fairen Monica , Aguilar Miquel , Marquie Marta , Garcia-Gonzalez Pablo , Olive Claudia , Puerta Raquel , Cano Amanda , Sotolongo-Grau Oscar , Valero Sergi , Pytel Vanesa Veronica , Rosende-Roca Maitee , Alegret Montserrat , Tarraga Lluis , Boada Merce , Carracedo Angel , Franco-Macias Emilio , Perez-Tur Jordi , Royo Jose Luis , Garcia-Alberca Jose Maria , Real Luis Miguel , Saez Maria Eugenia , Bullido Maria Jesus , Calero Miguel , Medina Miguel , Mir Pablo , Sanchez-Juan Pascual , Alvarez Victoria , Parveen Kayenat , Tripathi Kumar Parijat , Heilmann-Heimbach Stefanie , Ramirez Alfredo , Tienari Pentti J. , Bousiges Olivier , Blanc Frederic , Fenoglio Chiara , Padovani Alessandro , Borroni Barbara , Pilotto Andrea , Nobili Flavio , Saltvedt Ingvild , Fladby Tormod , Selbaek Geir , Bosnes Ingunn , Brathen Geir , Hartmann Annette , Lemstra Afina W. , Rujescu Dan , Mollenhauer Brit , Creese Byron , Chartier-Harlin Marie-Christine , Athanasiu Lavinia , Djurovic Srdjan , Chouliaras Leonidas , OBrien John T. , Myllykangas Liisa , Oinas Minna , Revesz Tamas , Lees Andrew , Boeve Brad F , Petersen Ronald C. , Ferman Tanis J , Graff-Radford Neill , Cairns Nigel J. , Morris John C. , Halliday Glenda M. , Hardy John , Dickson Dennis W. , Singleton Andrew , Stone David J. , Andreassen Ole A. , Ruiz Agustin , Aarsland Dag , Guerreiro Rita , Bras Jose 
Published: November 2022

Background

Genome-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.

Methods

Here, 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.

Findings

Between 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.

Interpretation

These 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.