Subcutaneous adipose tissue splice quantitative trait loci reveal differences in isoform usage associated with cardiometabolic traits.
Am J Hum Genet
; 109(1): 66-80, 2022 01 06.
Article
em En
| MEDLINE
| ID: mdl-34995504
ABSTRACT
Alternate splicing events can create isoforms that alter gene function, and genetic variants associated with alternate gene isoforms may reveal molecular mechanisms of disease. We used subcutaneous adipose tissue of 426 Finnish men from the METSIM study and identified splice junction quantitative trait loci (sQTLs) for 6,077 splice junctions (FDR < 1%). In the same individuals, we detected expression QTLs (eQTLs) for 59,443 exons and 15,397 genes (FDR < 1%). We identified 595 genes with an sQTL and exon eQTL but no gene eQTL, which could indicate potential isoform differences. Of the significant sQTL signals, 2,114 (39.8%) included at least one proxy variant (linkage disequilibrium r2 > 0.8) located within an intron spanned by the splice junction. We identified 203 sQTLs that colocalized with 141 genome-wide association study (GWAS) signals for cardiometabolic traits, including 25 signals for lipid traits, 24 signals for body mass index (BMI), and 12 signals for waist-hip ratio adjusted for BMI. Among all 141 GWAS signals colocalized with an sQTL, we detected 26 that also colocalized with an exon eQTL for an exon skipped by the sQTL splice junction. At a GWAS signal for high-density lipoprotein cholesterol colocalized with an NR1H3 sQTL splice junction, we show that the alternative splice product encodes an NR1H3 transcription factor that lacks a DNA binding domain and fails to activate transcription. Together, these results detect splicing events and candidate mechanisms that may contribute to gene function at GWAS loci.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Regulação da Expressão Gênica
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Processamento Alternativo
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Característica Quantitativa Herdável
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Locos de Características Quantitativas
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Gordura Subcutânea
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Fatores de Risco Cardiometabólico
Tipo de estudo:
Etiology_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Humans
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Male
País/Região como assunto:
Europa
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article