52 Genetic Loci Influencing Myocardial Mass
Key result
Large GWAS meta-analysis links 32 novel genetic loci to electrocardiographic QRS phenotypes.
- P<1 × 10(-8)
- n=73,518
Why the study?
Myocardial mass is a key determinant of cardiac function and hypertrophy, but its genetic determinants remain to be clarified.
Do specific genetic loci influence QRS traits reflecting myocardial mass in individuals of European ancestry?
Population
Up to 73,518 individuals of European ancestry
Design
Genome-wide association meta-analysis
Authors
Discussion
Loading...
Member takes
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“This allowed us to discover 52 regions where 67 genes are located, which we now think are involved in the functioning of the cardiac muscle. We already knew that some of these genes cause serious cardiac diseases, but we did not realise that the majority of them also play a role in the way the heart functions.”
Implication
Advances understanding of genetic regulators of myocardial mass; leaves open translation to clinical risk prediction or targeted therapies.
Key Points
- To identify genetic determinants and biological pathways regulating myocardial mass and cardiac electrical conduction through electrocardiographic QRS traits.
- Conducted a genome-wide association meta-analysis across 4 QRS traits (Sokolow-Lyon, Cornell, 12-leadsum, and QRS duration) in up to 73,518 individuals of European ancestry.
- Mapped functional elements using DNase I hypersensitive site profiling across 349 cell lines and tissues, cardiac histone modification states, ChIP-seq transcription factor binding, and in silico candidate gene prioritization.
- Assessed in vivo regulatory enhancer activity in transgenic mouse embryos and validated functional variants in the SCN5A/SCN10A locus.
- Identified 52 genomic loci (32 novel) associated with QRS phenotypes at p < 1 × 10(-8), explaining between 2.7% (Sokolow-Lyon) and 5.0% (QRS duration) of trait variance.
- Demonstrated that sentinel variants were ~3.5-fold enriched in human fetal heart DNase I hypersensitive sites (p = 7.7 × 10 −12) and enriched in cardiac transcription factor binding sites including NKX2-5, GATA-4, TBX3, TBX5, and SRF.
- Prioritized 67 candidate genes enriched in cardiovascular system development (p = 1 × 10 −56) that showed preferential expression in cardiac tissue (p = 9.8 × 10 −6).
Study Design
Type
Meta-Analysis (n=73,518)
Multicenter
Yes
Structured PICO
Do specific genetic loci influence QRS traits reflecting myocardial mass in individuals of European ancestry?
P
Population
Up to 73,518 individuals of European ancestry from North America and Europe assessed for genetic determinants of 4 QRS traits.
E
Exposure
Genetic variants (SNPs) across the genome
C
Comparator
Reference alleles
O
Outcome
4 QRS traits: Sokolow-Lyon, Cornell, 12-lead-voltage duration products (12-leadsum), and QRS durationsurrogate
Main Result
p-value: p=< 1 × 10(-8)
Identifies 52 genetic loci associated with QRS traits, providing insights into the genetic determinants of myocardial mass and potential therapeutic targets for cardiac hypertrophy.
Limitations
- Finite number of markers studied
- Additional fine-mapping required
- eQTL sample size relatively small
- ECG indexes might reflect electrical remodeling rather than mass per se
Cite This Study
Harst et al. (2016) conducted a meta-analysis in General population (n=73,518). Genetic loci (SNPs) vs. Reference alleles was evaluated on Association with 1 or more QRS phenotypes (Sokolow-Lyon, Cornell, 12-leadsum, QRS duration) (p=< 1 × 10(-8)). Genome-wide association meta-analysis identified 52 genomic loci, of which 32 are novel, reliably associated with 1 or more QRS phenotypes at p < 1 × 10(-8).