Broad Paper Vids: Study of both common and rare variation yields insight into cardiac arrhythmia

In the search for genetic sources of disease risk or genes that control traits, scientists can look for a single mutant gene that causes a rare, Mendelian disease or common DNA alterations that influence the trait in the broader population. But often those approaches remain separate.

In this edition of Paper Vids, Broad researchers Kasper Lage, Chris Newton-Cheh, and Lizzy Rossin discuss their research to integrate those two approaches in the study of heart arrhythmias – irregularities in the rate or rhythm of the heartbeat. Newton-Cheh, along with Broad researcher Paul de Bakker, led a multi-national meta-analysis of genome-wide association studies, appearing in Nature Genetics, that uncovered several dozen genetic regions linked to variation in QT interval, a component of heart rhythm. Prolonged QT interval can cause heart arrhythmias and is a risk factor for sudden cardiac death. By studying 100,000 individuals, the researchers identified 35 common variants tied to QT interval that collectively explain up to 10 percent of QT-interval variation.

In a related paper released simultaneously in Nature Methods, the scientists describe a collaboration among Kasper Lage, Lizzy Rossin, and colleagues to analyze protein-protein interactions and merge those results with the findings on common variation in QT interval, revealing new insight into both the common trait and severe cardiac arrhythmias caused by prolonged QT interval. Taken together, the papers provide a useful analytical method and framework for integrating common (GWAS) and rare genetic (Mendelian mutations) variation.

This effort relied upon significant contributions from Broad researchers for genetic analysis, including Lage, Rossin, Newton-Cheh, de Bakker, and Mark Daly, in addition to Alicia Lundby, a postdoc at the Novo Nordisk Foundation Center for Protein Research at the University of Copenhagen who spent half a year at the Broad to work on this project.

Hear more about the power of merging discoveries from large-scale genetic studies with large-scale proteomics data:

Papers cited:

Arking*, Pulit*, et al. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. Nature Genetics. DOI: 10.1038/ng.3014.

Lundby*, Rossin*, et al. Proteomic annotation of loci from genome-wide association studies applied to QT interval variation. Nature Methods. DOI: 10.1038/nmeth.2997.