TY - JOUR
T1 - Cis-epistasis at the LPA locus and risk of cardiovascular diseases
AU - Zeng, Lingyao
AU - Moser, Sylvain
AU - Mirza-Schreiber, Nazanin
AU - Lamina, Claudia
AU - Coassin, Stefan
AU - Nelson, Christopher P
AU - Annilo, Tarmo
AU - Franzén, Oscar
AU - Kleber, Marcus E
AU - Mack, Salome
AU - Andlauer, Till F M
AU - Jiang, Beibei
AU - Stiller, Barbara
AU - Li, Ling
AU - Willenborg, Christina
AU - Munz, Matthias
AU - Kessler, Thorsten
AU - Kastrati, Adnan
AU - Laugwitz, Karl-Ludwig
AU - Erdmann, Jeanette
AU - Moebus, Susanne
AU - Nöthen, Markus M
AU - Peters, Annette
AU - Strauch, Konstantin
AU - Müller-Nurasyid, Martina
AU - Gieger, Christian
AU - Meitinger, Thomas
AU - Steinhagen-Thiessen, Elisabeth
AU - März, Winfried
AU - Metspalu, Andres
AU - Björkegren, Johan L M
AU - Samani, Nilesh J
AU - Kronenberg, Florian
AU - Müller-Myhsok, Bertram
AU - Schunkert, Heribert
N1 - Publisher Copyright:
© 2021 The Author(s). Published by Oxford University Press on behalf of the European Society of Cardiology.
PY - 2022/3/16
Y1 - 2022/3/16
N2 - 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.
AB - 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.
UR - https://www.mendeley.com/catalogue/85caacb2-de4d-33ad-a634-e45cf5ceb81b/
UR - http://www.scopus.com/inward/record.url?scp=85113250552&partnerID=8YFLogxK
U2 - 10.1093/cvr/cvab136
DO - 10.1093/cvr/cvab136
M3 - Journal articles
C2 - 33878186
SN - 0008-6363
VL - 118
SP - 1088
EP - 1102
JO - Cardiovascular Research
JF - Cardiovascular Research
IS - 4
ER -
