Cis-epistasis at the LPA locus and risk of cardiovascular diseases.

Abstract

AIMS:

Coronary artery disease (CAD) has a strong genetic predisposition. However, despite substantial discoveries made by genome-wide association studies (GWAS), a large proportion of heritability awaits identification. Non-additive genetic effects might be responsible for part of the unaccounted genetic variance. Here, we attempted a proof-of-concept study to identify non-additive genetic effects, namely epistatic interactions, associated with CAD.

METHODS AND RESULTS:

We tested for epistatic interactions in 10 CAD case-control studies and UK Biobank with focus on 8068 SNPs at 56 loci with known associations with CAD risk. We identified a SNP pair located in cis at the LPA locus, rs1800769 and rs9458001, to be jointly associated with risk for CAD [odds ratio (OR) = 1.37, P = 1.07 × 10-11], peripheral arterial disease (OR = 1.22, P = 2.32 × 10-4), aortic stenosis (OR = 1.47, P = 6.95 × 10-7), hepatic lipoprotein(a) (Lp(a)) transcript levels (beta = 0.39, P = 1.41 × 10-8), and Lp(a) serum levels (beta = 0.58, P = 8.7 × 10-32), while individual SNPs displayed no association. Further exploration of the LPA locus revealed a strong dependency of these associations on a rare variant, rs140570886, that was previously associated with Lp(a) levels. We confirmed increased CAD risk for heterozygous (relative OR = 1.46, P = 9.97 × 10-32) and individuals homozygous for the minor allele (relative OR = 1.77, P = 0.09) of rs140570886. Using forward model selection, we also show that epistatic interactions between rs140570886, rs9458001, and rs1800769 modulate the effects of the rs140570886 risk allele.

CONCLUSIONS:

These results demonstrate the feasibility of a large-scale knowledge-based epistasis scan and provide rare evidence of an epistatic interaction in a complex human disease. We were directed to a variant (rs140570886) influencing risk through additive genetic as well as epistatic effects. In summary, this study provides deeper insights into the genetic architecture of a locus important for cardiovascular diseases.

• Authors: Lingyao Zeng, Sylvain Moser, Nazanin Mirza-Schreiber, Claudia Lamina, Stefan Coassin, Christopher P Nelson, Tarmo Annilo, Oscar Franzén, Marcus E Kleber, Salome Mack, Till F M Andlauer, Beibei Jiang, Barbara Stiller, Ling Li, Christina Willenborg, Matthias Munz, Thorsten Kessler, Adnan Kastrati, Karl-Ludwig Laugwitz, Jeanette Erdmann, Susanne Moebus, Markus M Nöthen, Annette Peters, Konstantin Strauch, Martina Müller-Nurasyid, Christian Gieger, Thomas Meitinger, Elisabeth Steinhagen-Thiessen, Winfried März, Andres Metspalu, Johan L M Björkegren, Nilesh J Samani, Florian Kronenberg, Bertram Müller-Myhsok, Heribert Schunkert
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 118 Issue 4 Pg. 1088-1102 (03 16 2022) ISSN: 1755-3245 [Electronic] England
• PMID: 33878186 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Chemical References

• Lipoprotein(a)

Topics

• Cardiovascular Diseases (diagnosis, genetics)
• Coronary Artery Disease (diagnostic imaging, genetics)
• Epistasis, Genetic
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Humans
• Lipoprotein(a) (genetics)
• Polymorphism, Single Nucleotide