{"doi":"10.1038/nn.4402","title":"Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia","abstract":"By analyzing the exomes of 12,332 unrelated Swedish individuals, including 4,877 individuals affected with schizophrenia, in ways informed by exome sequences from 45,376 other individuals, we identified 244,246 coding-sequence and splice-site ultra-rare variants (URVs) that were unique to individual Swedes. We found that gene-disruptive and putatively protein-damaging URVs (but not synonymous URVs) were more abundant among individuals with schizophrenia than among controls (P = 1.3 × 10<sup>-10</sup>). This elevation of protein-compromising URVs was several times larger than an analogously elevated rate for de novo mutations, suggesting that most rare-variant effects on schizophrenia risk are inherited. Among individuals with schizophrenia, the elevated frequency of protein-compromising URVs was concentrated in brain-expressed genes, particularly in neuronally expressed genes; most of this elevation arose from large sets of genes whose RNAs have been found to interact with synaptically localized proteins. Our results suggest that synaptic dysfunction may mediate a large fraction of strong, individually rare genetic influences on schizophrenia risk.","journal":"Nature Neuroscience","year":2016,"id":417,"datarank":0.9309863890087393,"base_score":6.206575926724928,"endowment":6.206575926724928,"self_citation_contribution":0.9309863890087393,"citation_network_contribution":0.0,"self_endowment_contribution":0.9309863890087393,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":495,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.0615,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2016-10-03","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":3814,"name":"Menachem Fromer","orcid":"0000-0003-3749-4342","position":1,"is_corresponding":false},{"id":3815,"name":"Eli A. Stahl","orcid":"0000-0002-1192-0561","position":2,"is_corresponding":false},{"id":3816,"name":"Douglas M. Ruderfer","orcid":"0000-0002-2365-386X","position":3,"is_corresponding":false},{"id":28798,"name":"Kimberly D. Chambert","orcid":null,"position":4,"is_corresponding":false},{"id":3818,"name":"Mikael Landén","orcid":"0000-0002-4496-6451","position":5,"is_corresponding":false},{"id":3819,"name":"Jennifer L. Moran","orcid":"0000-0002-5664-4716","position":6,"is_corresponding":false},{"id":98251,"name":"Jacob Lawrence","orcid":"0000-0002-3548-1583","position":7,"is_corresponding":false},{"id":1162,"name":"Jeremiah M. Scharf","orcid":"0000-0002-4742-5896","position":8,"is_corresponding":false},{"id":213,"name":"Patrick F. Sullivan","orcid":"0000-0002-6619-873X","position":9,"is_corresponding":false},{"id":1068,"name":"Christina M. Hultman","orcid":"0000-0002-0327-2410","position":10,"is_corresponding":false},{"id":1158,"name":"Steven A. McCarroll","orcid":"0000-0002-6954-8184","position":11,"is_corresponding":false},{"id":3821,"name":"Shaun Purcell","orcid":"0000-0002-7402-5812","position":12,"is_corresponding":false},{"id":3813,"name":"Giulio Genovese","orcid":"0000-0003-3066-5575","position":0,"is_corresponding":true}],"reference_count":109,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-03-01T18:20:47.508186Z","pmid":null,"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":[]}