TnF-funded project: Reducing the missing heritability of the cardiovascular risk factor Lipoprotein(a): A novel computational approach for LPA allele size estimation
About
Variable number tandem repeats (VNTRs) are repetitive genomic regions that remain unresolved in large biobanks and therefore contribute to the missing heritability of human traits. The LPA gene almost monogenically controls lipoprotein(a) [Lp(a)], a strong cardiovascular risk factor. However, most LPA variation remains uncharacterized because of a VNTR in its sequence, the KIV-2 VNTR. Its size explains 40–70% of the Lp(a) variance, but this information is missing from biobanks.
This project, funded by the Tiroler Nachwuchsforscher*innenförderung (TnF; PI: Silvia Di Maio), develops a novel computational approach to determine the KIV-2 VNTR size at scale.
The project has three main aims:
- Develop a novel computational approach, supported by machine learning, to determine VNTR size from short-read sequencing data and apply it to ~500,000 UK Biobank samples.
- Disentangle the individual effects of known and novel LPA variants on Lp(a) and cardiovascular disease risk.
- Explore ancestry-specific LPA features.
The pipeline will be publicly available and builds on our existing workflows (vntr-calling-nf, nf-gwas). The project will help to further explain Lp(a) heritability, improve cardiovascular risk stratification, and pave the way for exploring other VNTRs and traits.
Team
Professor of Digital and Computational Genetics
+43 512 9003 70579
sebastian.schoenherr@i-med.ac.at
Related publications
Di Maio S, Zöscher P, Weissensteiner H, Forer L, Schachtl-Riess JF, Amstler S, Streiter G, Pfurtscheller C, Paulweber B, Kronenberg F, Coassin S, Schönherr S: Resolving intra-repeat variation in medically relevant VNTRs from short-read sequencing data using the cardiovascular risk gene LPA as a model. Genome Biol. 25:167, 2024. PMID: 38926899 Journal Article