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Journal Article

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

MPS-Authors
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Moser,  Sylvain
RG Statistical Genetics, Max Planck Institute of Psychiatry, Max Planck Society;
IMPRS Translational Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Mirza-Schreiber,  Nazanin
RG Statistical Genetics, Max Planck Institute of Psychiatry, Max Planck Society;

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Andlauer,  Till F. M.
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Jiang,  Beibei
RG Statistical Genetics, Max Planck Institute of Psychiatry, Max Planck Society;

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Mueller-Myhsok,  Bertram
RG Statistical Genetics, Max Planck Institute of Psychiatry, Max Planck Society;

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Citation

Zeng, L., Moser, S., Mirza-Schreiber, N., Lamina, C., Coassin, S., Nelson, C. P., et al. (2022). Cis-epistasis at the LPA locus and risk of cardiovascular diseases. CARDIOVASCULAR RESEARCH, 118(4), 1088-1102. doi:10.1093/cvr/cvab136.


Cite as: https://hdl.handle.net/21.11116/0000-000A-3C0F-4
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 x 10(-11)], peripheral arterial disease (OR = 1.22, P = 2.32 x 10(-4)), aortic stenosis (OR = 1.47, P = 6.95 x 10(-7)), hepatic lipoprotein(a) (Lp(a)) transcript levels (beta = 0.39, P = 1.41 x 10(-8)), and Lp(a) serum levels (beta = 0.58, P = 8.7 x 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 x 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.