{"doi":"10.1101/2022.03.12.22272299","title":"Integrative genomics analysis implicates decreased <i>FGD6</i> expression underlying risk of intracranial aneurysm rupture","abstract":"Abstract Background The genetic determinants and mechanisms underlying intracranial aneurysm rupture (rIA) are largely unknown. Given the ∼50% mortality rate of rIA, approaches to identify patients at high-risk will inform screening, diagnostic, and preventative measures. Objective Our goal was to identify and characterize the genetic basis of rIA. Methods We perform a genome-wide association study (GWAS) use functional genomics approaches to identify and characterize rIA-associated loci and genes. We perform a meta-analysis across 24 published GWAS of rIA. Single nucleotide polymorphisms (SNP), gene-burden analysis, and functional genomics identify and characterize genetic risk factors for rIA. Results Our cohort contains 84,353 individuals (7,843 rIA cases and 76,510 controls). We identify 5 independent genetic loci reaching genome-wide significance (p&lt;5.0×10 −8 ) for rIA including rs12310399 ( FGD6 , OR=1.16), which to our knowledge, has not been implicated in prior GWAS of rIA. We then quantified gene-level mutation-burden across ∼20,000 genes, and only FGD6 (containing 21 rIA-associated SNPs) reached transcriptome-wide significance. Expression quantitative trait loci (eQTL) mapping indicates that rs12310399 causes decreased FGD6 gene expression in arterial tissue. Next, we utilized publicly available single-cell RNA sequencing of normal human cerebrovascular cells obtained during resection surgery and identify high expression of FGD6 in 1 of 3 arterial lineages but absent in perivascular cells. These data suggest how alterations in FGD6 may confer risk to rIA. Conclusion We identify and characterize a previously unknown risk loci for rIA containing FGD6 . Elucidation of high-risk genetic loci may instruct population-genetic screening and clinical-genetic testing strategies to identify patients predisposed to rIA. Funding No funding sources were used for the material presented herein.","journal":"medRxiv","year":2022,"id":306500,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.942,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":926962,"name":"Jing He","orcid":"0000-0002-0267-7811","position":1,"is_corresponding":false},{"id":753666,"name":"Jesse Jones","orcid":"0000-0002-2682-9736","position":2,"is_corresponding":false},{"id":36205,"name":"Andrew T. Hale","orcid":"0000-0003-3182-2966","position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:32:48.984902Z","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":[]}