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Quantitative and Qualitative Role of Antagonistic Heterogeneity in Genetics of Blood Lipids.

Publication ,  Journal Article
Kulminski, AM; Loika, Y; Nazarian, A; Culminskaya, I
Published in: The journals of gerontology. Series A, Biological sciences and medical sciences
September 2020

Prevailing strategies in genome-wide association studies (GWAS) mostly rely on principles of medical genetics emphasizing one gene, one function, one phenotype concept. Here, we performed GWAS of blood lipids leveraging a new systemic concept emphasizing complexity of genetic predisposition to such phenotypes. We focused on total cholesterol, low- and high-density lipoprotein cholesterols, and triglycerides available for 29,902 individuals of European ancestry from seven independent studies, men and women combined. To implement the new concept, we leveraged the inherent heterogeneity in genetic predisposition to such complex phenotypes and emphasized a new counter intuitive phenomenon of antagonistic genetic heterogeneity, which is characterized by misalignment of the directions of genetic effects and the phenotype correlation. This analysis identified 37 loci associated with blood lipids but only one locus, FBXO33, was not reported in previous top GWAS. We, however, found strong effect of antagonistic heterogeneity that leaded to profound (quantitative and qualitative) changes in the associations with blood lipids in most, 25 of 37 or 68%, loci. These changes suggested new roles for some genes, which functions were considered as well established such as GCKR, SIK3 (APOA1 locus), LIPC, LIPG, among the others. The antagonistic heterogeneity highlighted a new class of genetic associations emphasizing beneficial and adverse trade-offs in predisposition to lipids. Our results argue that rigorous analyses dissecting heterogeneity in genetic predisposition to complex traits such as lipids beyond those implemented in current GWAS are required to facilitate translation of genetic discoveries into health care.

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Published In

The journals of gerontology. Series A, Biological sciences and medical sciences

DOI

EISSN

1758-535X

ISSN

1079-5006

Publication Date

September 2020

Volume

75

Issue

10

Start / End Page

1811 / 1819

Related Subject Headings

  • White People
  • Triglycerides
  • Phenotype
  • Multifactorial Inheritance
  • Male
  • Lipids
  • Humans
  • Gerontology
  • Genotype
  • Genome-Wide Association Study
 

Citation

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Kulminski, A. M., Loika, Y., Nazarian, A., & Culminskaya, I. (2020). Quantitative and Qualitative Role of Antagonistic Heterogeneity in Genetics of Blood Lipids. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 75(10), 1811–1819. https://doi.org/10.1093/gerona/glz225
Kulminski, Alexander M., Yury Loika, Alireza Nazarian, and Irina Culminskaya. “Quantitative and Qualitative Role of Antagonistic Heterogeneity in Genetics of Blood Lipids.The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 75, no. 10 (September 2020): 1811–19. https://doi.org/10.1093/gerona/glz225.
Kulminski AM, Loika Y, Nazarian A, Culminskaya I. Quantitative and Qualitative Role of Antagonistic Heterogeneity in Genetics of Blood Lipids. The journals of gerontology Series A, Biological sciences and medical sciences. 2020 Sep;75(10):1811–9.
Kulminski, Alexander M., et al. “Quantitative and Qualitative Role of Antagonistic Heterogeneity in Genetics of Blood Lipids.The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, vol. 75, no. 10, Sept. 2020, pp. 1811–19. Epmc, doi:10.1093/gerona/glz225.
Kulminski AM, Loika Y, Nazarian A, Culminskaya I. Quantitative and Qualitative Role of Antagonistic Heterogeneity in Genetics of Blood Lipids. The journals of gerontology Series A, Biological sciences and medical sciences. 2020 Sep;75(10):1811–1819.
Journal cover image

Published In

The journals of gerontology. Series A, Biological sciences and medical sciences

DOI

EISSN

1758-535X

ISSN

1079-5006

Publication Date

September 2020

Volume

75

Issue

10

Start / End Page

1811 / 1819

Related Subject Headings

  • White People
  • Triglycerides
  • Phenotype
  • Multifactorial Inheritance
  • Male
  • Lipids
  • Humans
  • Gerontology
  • Genotype
  • Genome-Wide Association Study