TY - JOUR

T1 - Inclusion of endophenotypes in a standard GWAS facilitate a detailed mechanistic understanding of genetic elements that control blood lipid levels

AU - Zhang, Qianqian

AU - Cai, Zexi

AU - Lhomme, Marie

AU - Sahana, Goutam

AU - Lesnik, Philippe

AU - Guerin, Maryse

AU - Fredholm, Merete

AU - Karlskov-Mortensen, Peter

PY - 2020

Y1 - 2020

N2 - Dyslipidemia is the primary cause of cardiovascular disease, which is a serious human health problem in large parts of the world. Therefore, it is important to understand the genetic and molecular mechanisms that regulate blood levels of cholesterol and other lipids. Discovery of genetic elements in the regulatory machinery is often based on genome wide associations studies (GWAS) focused on end-point phenotypes such as total cholesterol level or a disease diagnosis. In the present study, we add endophenotypes, such as serum levels of intermediate metabolites in the cholesterol synthesis pathways, to a GWAS analysis and use the pig as an animal model. We do this to increase statistical power and to facilitate biological interpretation of results. Although the study population was limited to ~ 300 individuals, we identify two genome-wide significant associations and ten suggestive associations. Furthermore, we identify 28 tentative associations to loci previously associated with blood lipids or dyslipidemia associated diseases. The associations with endophenotypes may inspire future studies that can dissect the biological mechanisms underlying these previously identified associations and add a new level of understanding to previously identified associations.

AB - Dyslipidemia is the primary cause of cardiovascular disease, which is a serious human health problem in large parts of the world. Therefore, it is important to understand the genetic and molecular mechanisms that regulate blood levels of cholesterol and other lipids. Discovery of genetic elements in the regulatory machinery is often based on genome wide associations studies (GWAS) focused on end-point phenotypes such as total cholesterol level or a disease diagnosis. In the present study, we add endophenotypes, such as serum levels of intermediate metabolites in the cholesterol synthesis pathways, to a GWAS analysis and use the pig as an animal model. We do this to increase statistical power and to facilitate biological interpretation of results. Although the study population was limited to ~ 300 individuals, we identify two genome-wide significant associations and ten suggestive associations. Furthermore, we identify 28 tentative associations to loci previously associated with blood lipids or dyslipidemia associated diseases. The associations with endophenotypes may inspire future studies that can dissect the biological mechanisms underlying these previously identified associations and add a new level of understanding to previously identified associations.

U2 - 10.1038/s41598-020-75612-6

DO - 10.1038/s41598-020-75612-6

M3 - Journal article

C2 - 33116219

AN - SCOPUS:85094211699

VL - 10

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 18434

ER -