Identification of a sex-specific genetic signature in dementia with Lewy bodies: a meta-analysis of genome-wide association studies

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 at GBA, SNCA, STX1B , and APOE . However, the sex-stratified analysis revealed that the GBA and SNCA signals 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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement JB is supported by the National Institutes on Aging (R56 #AG070857) and the National Institutes of Neurological Diseases and Stroke (RF1 #NS124848). RG is supported by the National Institutes on Aging (R01 #AG067426). ER is supported by the Canadian Consortium on Neurodegeneration in Aging. We are grateful to the Banner Sun Health Research Institute Brain and Body Donation Program of Sun City Arizona for the provision of human biological materials. The Brain and Body Donation Program has been supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinsons Disease and Related Disorders) the National Institute on Aging (P30 AG19610 Arizona Alzheimers Disease Core Center) the Arizona Department of Health Services (contract 211002 Arizona Alzheimers Research Center) the Arizona Biomedical Research Commission (contracts 4001 0011 05-901 and 1001 to the Arizona Parkinsons Disease Consortium) and the Michael J. Fox Foundation for Parkinsons Research. This research has been conducted using data from UK Biobank a major biomedical database ([www.ukbiobank.ac.uk][1]) under application number 11036. The authors acknowledge the contribution of data from the studies National Cancer Institute (NCI) Head and Neck Cancer Study Cutaneous Melanoma GWAS Combining Multiple Populations and Risk Phenotypes and DEMENTIA-SEQ: Genome sequencing in Lewy Body Dementia Frontotemporal Dementia and neurologically healthy controls accessed through the database of Genotypes and Phenotypes (phs001173.v1.p1 phs001868.v1.p1 and phs001963.v1.p1 respectively). GR@ACE cohort: We would like to thank patients and controls who participated in this project. The Genome Research @ Ace Alzheimer Center Barcelona project (GR@ACE) is supported by Grifols SA Fundacion bancaria La Caixa Ace Alzheimer Center Barcelona and CIBERNED. We are indebted to Trinitat Port-Carbo legacy and her family for their support of Ace Alzheimer Center Barcelona research programs. Ace Alzheimer Center Barcelona is one of the participating centers of the Dementia Genetics Spanish Consortium (DEGESCO). A.R. and M.B. receive support from the European Union/EFPIA Innovative Medicines Initiative Joint undertaking ADAPTED and MOPEAD projects (grant numbers 115975 and 115985 respectively). M.B. and A.R. are also supported by national grants PI13/02434 PI16/01861 PI17/01474 PI19/01240 and PI19/01301. Accion Estrategica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)- Subdireccion General de Evaluacion and the Fondo Europeo de Desarrollo Regional (FEDER- Una manera de hacer Europa). I.dR. is supported by national grant from the Instituto de Salud Carlos III FI20/00215. Some control samples and data from patients included in this study were provided in part by the National DNA Bank Carlos III ([www.bancoadn.org][2] University of Salamanca Spain) and Hospital Universitario Virgen de Valme (Sevilla Spain); they were processed following standard operating procedures with the appropriate approval of the Ethical and Scientific Committee. OAR is supported by NIH (RF1 NS085070; U54-NS100693; U01 NS100620; R01 AG056366; U19 AG071754) DOD (W81XWH-17-1-0249) The Michael J. Fox Foundation The Little Family Foundation the Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy Body Dementia Program at Mayo Clinic Ted Turner and family with the Functional Genomics of LBD Program and the Mayo Clinic LBD Center without Walls (U54-NS110435). Mayo Clinic is an American Parkinson Disease Association (APDA) Mayo Clinic Information and Referral Center an APDA Center for Advanced Research and a Lewy Body Dementia Association (LBDA) Research Center of Excellence. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: IRB of Van Andel Institute gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Summary statistics will be deposited in the GWAS catalog [1]: http://www.ukbiobank.ac.uk [2]: http://www.bancoadn.org