Genetic Determinants of Plasma Low-Density Lipoprotein Cholesterol Levels: Monogenicity, Polygenicity, and “Missing” Heritability

Changes in plasma low-density lipoprotein cholesterol (LDL-c) levels relate to a high risk of developing some common and complex diseases. LDL-c, as a quantitative trait, is multifactorial and depends on both genetic and environmental factors. In the pregenomic age, targeted genes were used to detec...

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Autor principal:	Jesús Maria Martín-Campos
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	plasma cholesterol levels autosomal dominant hypercholesterolemia genetic risk scores mosaicism maternal effect epigenetics Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/c4c241a5112a4a1790b22baefbe64060
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spelling	oai:doaj.org-article:c4c241a5112a4a1790b22baefbe640602021-11-25T16:51:28ZGenetic Determinants of Plasma Low-Density Lipoprotein Cholesterol Levels: Monogenicity, Polygenicity, and “Missing” Heritability10.3390/biomedicines91117282227-9059https://doaj.org/article/c4c241a5112a4a1790b22baefbe640602021-11-01T00:00:00Zhttps://www.mdpi.com/2227-9059/9/11/1728https://doaj.org/toc/2227-9059Changes in plasma low-density lipoprotein cholesterol (LDL-c) levels relate to a high risk of developing some common and complex diseases. LDL-c, as a quantitative trait, is multifactorial and depends on both genetic and environmental factors. In the pregenomic age, targeted genes were used to detect genetic factors in both hyper- and hypolipidemias, but this approach only explained extreme cases in the population distribution. Subsequently, the genetic basis of the less severe and most common dyslipidemias remained unknown. In the genomic age, performing whole-exome sequencing in families with extreme plasma LDL-c values identified some new candidate genes, but it is unlikely that such genes can explain the majority of inexplicable cases. Genome-wide association studies (GWASs) have identified several single-nucleotide variants (SNVs) associated with plasma LDL-c, introducing the idea of a polygenic origin. Polygenic risk scores (PRSs), including LDL-c-raising alleles, were developed to measure the contribution of the accumulation of small-effect variants to plasma LDL-c. This paper discusses other possibilities for unexplained dyslipidemias associated with LDL-c, such as mosaicism, maternal effect, and induced epigenetic changes. Future studies should consider gene–gene and gene–environment interactions and the development of integrated information about disease-driving networks, including phenotypes, genotypes, transcription, proteins, metabolites, and epigenetics.Jesús Maria Martín-CamposMDPI AGarticleplasma cholesterol levelsautosomal dominant hypercholesterolemiagenetic risk scoresmosaicismmaternal effectepigeneticsBiology (General)QH301-705.5ENBiomedicines, Vol 9, Iss 1728, p 1728 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	plasma cholesterol levels autosomal dominant hypercholesterolemia genetic risk scores mosaicism maternal effect epigenetics Biology (General) QH301-705.5
spellingShingle	plasma cholesterol levels autosomal dominant hypercholesterolemia genetic risk scores mosaicism maternal effect epigenetics Biology (General) QH301-705.5 Jesús Maria Martín-Campos Genetic Determinants of Plasma Low-Density Lipoprotein Cholesterol Levels: Monogenicity, Polygenicity, and “Missing” Heritability
description	Changes in plasma low-density lipoprotein cholesterol (LDL-c) levels relate to a high risk of developing some common and complex diseases. LDL-c, as a quantitative trait, is multifactorial and depends on both genetic and environmental factors. In the pregenomic age, targeted genes were used to detect genetic factors in both hyper- and hypolipidemias, but this approach only explained extreme cases in the population distribution. Subsequently, the genetic basis of the less severe and most common dyslipidemias remained unknown. In the genomic age, performing whole-exome sequencing in families with extreme plasma LDL-c values identified some new candidate genes, but it is unlikely that such genes can explain the majority of inexplicable cases. Genome-wide association studies (GWASs) have identified several single-nucleotide variants (SNVs) associated with plasma LDL-c, introducing the idea of a polygenic origin. Polygenic risk scores (PRSs), including LDL-c-raising alleles, were developed to measure the contribution of the accumulation of small-effect variants to plasma LDL-c. This paper discusses other possibilities for unexplained dyslipidemias associated with LDL-c, such as mosaicism, maternal effect, and induced epigenetic changes. Future studies should consider gene–gene and gene–environment interactions and the development of integrated information about disease-driving networks, including phenotypes, genotypes, transcription, proteins, metabolites, and epigenetics.
format	article
author	Jesús Maria Martín-Campos
author_facet	Jesús Maria Martín-Campos
author_sort	Jesús Maria Martín-Campos
title	Genetic Determinants of Plasma Low-Density Lipoprotein Cholesterol Levels: Monogenicity, Polygenicity, and “Missing” Heritability
title_short	Genetic Determinants of Plasma Low-Density Lipoprotein Cholesterol Levels: Monogenicity, Polygenicity, and “Missing” Heritability
title_full	Genetic Determinants of Plasma Low-Density Lipoprotein Cholesterol Levels: Monogenicity, Polygenicity, and “Missing” Heritability
title_fullStr	Genetic Determinants of Plasma Low-Density Lipoprotein Cholesterol Levels: Monogenicity, Polygenicity, and “Missing” Heritability
title_full_unstemmed	Genetic Determinants of Plasma Low-Density Lipoprotein Cholesterol Levels: Monogenicity, Polygenicity, and “Missing” Heritability
title_sort	genetic determinants of plasma low-density lipoprotein cholesterol levels: monogenicity, polygenicity, and “missing” heritability
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/c4c241a5112a4a1790b22baefbe64060
work_keys_str_mv	AT jesusmariamartincampos geneticdeterminantsofplasmalowdensitylipoproteincholesterollevelsmonogenicitypolygenicityandmissingheritability
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Genetic Determinants of Plasma Low-Density Lipoprotein Cholesterol Levels: Monogenicity, Polygenicity, and “Missing” Heritability

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