{"doi":"10.1002/alz.12319","title":"Whole‐genome sequencing reveals new Alzheimer's disease–associated rare variants in loci related to synaptic function and neuronal development","abstract":"INTRODUCTION: Genome-wide association studies have led to numerous genetic loci associated with Alzheimer's disease (AD). Whole-genome sequencing (WGS) now permits genome-wide analyses to identify rare variants contributing to AD risk. METHODS: We performed single-variant and spatial clustering-based testing on rare variants (minor allele frequency [MAF] ≤1%) in a family-based WGS-based association study of 2247 subjects from 605 multiplex AD families, followed by replication in 1669 unrelated individuals. RESULTS: We identified 13 new AD candidate loci that yielded consistent rare-variant signals in discovery and replication cohorts (4 from single-variant, 9 from spatial-clustering), implicating these genes: FNBP1L, SEL1L, LINC00298, PRKCH, C15ORF41, C2CD3, KIF2A, APC, LHX9, NALCN, CTNNA2, SYTL3, and CLSTN2. DISCUSSION: Downstream analyses of these novel loci highlight synaptic function, in contrast to common AD-associated variants, which implicate innate immunity and amyloid processing. These loci have not been associated previously with AD, emphasizing the ability of WGS to identify AD-associated rare variants, particularly outside of the exome.","journal":"Alzheimer s & Dementia","year":2021,"id":149520,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":105,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.8399,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":39870,"name":"Sarah Morgan","orcid":"0000-0002-1734-4710","position":1,"is_corresponding":false},{"id":637344,"name":"Kristina Mullin","orcid":null,"position":2,"is_corresponding":false},{"id":356982,"name":"Oliver Hofmann","orcid":"0000-0002-7738-1513","position":3,"is_corresponding":false},{"id":45247,"name":"Brad Chapman","orcid":"0000-0002-3026-1856","position":4,"is_corresponding":false},{"id":356981,"name":"Rory Kirchner","orcid":"0000-0003-4814-5885","position":5,"is_corresponding":false},{"id":637345,"name":"Alzheimer's Disease Neuroimaging Initiative (ADNI)","orcid":null,"position":6,"is_corresponding":false},{"id":232927,"name":"Sandeep Amberkar","orcid":"0000-0001-5544-6059","position":7,"is_corresponding":false},{"id":7723,"name":"Inken Wohlers","orcid":"0000-0003-4004-0464","position":8,"is_corresponding":false},{"id":24794,"name":"Christoph Lange","orcid":"0000-0003-2620-1030","position":9,"is_corresponding":false},{"id":356983,"name":"Winston Hide","orcid":"0000-0002-8621-3271","position":10,"is_corresponding":false},{"id":242548,"name":"Lars Bertram","orcid":"0000-0002-0108-124X","position":11,"is_corresponding":false},{"id":226532,"name":"Rudolph E. Tanzi","orcid":"0000-0002-7032-1454","position":12,"is_corresponding":false},{"id":24853,"name":"Dmitry Prokopenko","orcid":"0000-0002-1844-5652","position":0,"is_corresponding":true}],"reference_count":103,"raw_metadata":null,"created_at":"2026-07-18T23:42:56.251607Z","pmid":"33797837","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}