Analysis of Brugada syndrome loci reveals that fine-mapping clustered GWAS hits enhances the annotation of disease-relevant variants

Genome-wide association studies (GWASs) are instrumental in identifying loci harboring common single-nucleotide variants (SNVs) that affect human traits and diseases. GWAS hits emerge in clusters, but the focus is often on the most significant hit in each trait- or disease-associated locus. The rema...

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Detalles Bibliográficos
Autores: Pinsach Abuin, Mel·lina, Olmo, Bernat del, Pérez Agustín, Adrian, Matés Ramírez, Jesús, Allegue Toscano, Catarina, Iglesias, Anna, Ma, Qi, Merkurjev, Daria, Konovalov, Sergiy, Zhang, Jing, Sheikh, Farah, Telenti, Amalio, Brugada Terradellas, Josep, Brugada, Ramon, Gymrek, Melissa, Di Iulio, Julia, Garcia-Bassets, Ivan, Pagans i Lista, Sara
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10256/19629
Acceso en línea:http://hdl.handle.net/10256/19629
Access Level:acceso abierto
Palabra clave:Mort sobtada
Arrítmia
Sudden death
Arrhythmia
Brugada, Síndrome de
Brugada syndrome
Cor -- Malalties -- Aspectes genètics
Heart -- Diseases -- Genetic aspects
Descripción
Sumario:Genome-wide association studies (GWASs) are instrumental in identifying loci harboring common single-nucleotide variants (SNVs) that affect human traits and diseases. GWAS hits emerge in clusters, but the focus is often on the most significant hit in each trait- or disease-associated locus. The remaining hits represent SNVs in linkage disequilibrium (LD) and are considered redundant and thus frequently marginally reported or exploited. Here, we interrogate the value of integrating the full set of GWAS hits in a locus repeatedly associated with cardiac conduction traits and arrhythmia, SCN5A-SCN10A. Our analysis reveals 5 common 7-SNV haplotypes (Hap1-5) with 2 combinations associated with life-threatening arrhythmia-Brugada syndrome (the risk Hap1/1 and protective Hap2/3 genotypes). Hap1 and Hap2 share 3 SNVs; thus, this analysis suggests that assuming redundancy among clustered GWAS hits can lead to confounding disease-risk associations and supports the need to deconstruct GWAS data in the context of haplotype composition

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