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Birth Cohort, Age, and Sex Strongly Modulate Effects of Lipid Risk Alleles Identified in Genome-Wide Association Studies.

Publication ,  Journal Article
Kulminski, AM; Culminskaya, I; Arbeev, KG; Arbeeva, L; Ukraintseva, SV; Stallard, E; Wu, D; Yashin, AI
Published in: PloS one
January 2015

Insights into genetic origin of diseases and related traits could substantially impact strategies for improving human health. The results of genome-wide association studies (GWAS) are often positioned as discoveries of unconditional risk alleles of complex health traits. We re-analyzed the associations of single nucleotide polymorphisms (SNPs) associated with total cholesterol (TC) in a large-scale GWAS meta-analysis. We focused on three generations of genotyped participants of the Framingham Heart Study (FHS). We show that the effects of all ten directly-genotyped SNPs were clustered in different FHS generations and/or birth cohorts in a sex-specific or sex-unspecific manner. The sample size and procedure-therapeutic issues play, at most, a minor role in this clustering. An important result was clustering of significant associations with the strongest effects in the youngest, or 3rd Generation, cohort. These results imply that an assumption of unconditional connections of these SNPs with TC is generally implausible and that a demographic perspective can substantially improve GWAS efficiency. The analyses of genetic effects in age-matched samples suggest a role of environmental and age-related mechanisms in the associations of different SNPs with TC. Analysis of the literature supports systemic roles for genes for these SNPs beyond those related to lipid metabolism. Our analyses reveal strong antagonistic effects of rs2479409 (the PCSK9 gene) that cautions strategies aimed at targeting this gene in the next generation of lipid drugs. Our results suggest that standard GWAS strategies need to be advanced in order to appropriately address the problem of genetic susceptibility to complex traits that is imperative for translation to health care.

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Published In

PloS one

DOI

EISSN

1932-6203

ISSN

1932-6203

Publication Date

January 2015

Volume

10

Issue

8

Start / End Page

e0136319

Related Subject Headings

  • Sex Factors
  • Quantitative Trait, Heritable
  • Polymorphism, Single Nucleotide
  • Male
  • Humans
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • General Science & Technology
  • Female
  • Cholesterol
 

Citation

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Kulminski, A. M., Culminskaya, I., Arbeev, K. G., Arbeeva, L., Ukraintseva, S. V., Stallard, E., … Yashin, A. I. (2015). Birth Cohort, Age, and Sex Strongly Modulate Effects of Lipid Risk Alleles Identified in Genome-Wide Association Studies. PloS One, 10(8), e0136319. https://doi.org/10.1371/journal.pone.0136319
Kulminski, Alexander M., Irina Culminskaya, Konstantin G. Arbeev, Liubov Arbeeva, Svetlana V. Ukraintseva, Eric Stallard, Deqing Wu, and Anatoliy I. Yashin. “Birth Cohort, Age, and Sex Strongly Modulate Effects of Lipid Risk Alleles Identified in Genome-Wide Association Studies.PloS One 10, no. 8 (January 2015): e0136319. https://doi.org/10.1371/journal.pone.0136319.
Kulminski AM, Culminskaya I, Arbeev KG, Arbeeva L, Ukraintseva SV, Stallard E, et al. Birth Cohort, Age, and Sex Strongly Modulate Effects of Lipid Risk Alleles Identified in Genome-Wide Association Studies. PloS one. 2015 Jan;10(8):e0136319.
Kulminski, Alexander M., et al. “Birth Cohort, Age, and Sex Strongly Modulate Effects of Lipid Risk Alleles Identified in Genome-Wide Association Studies.PloS One, vol. 10, no. 8, Jan. 2015, p. e0136319. Epmc, doi:10.1371/journal.pone.0136319.
Kulminski AM, Culminskaya I, Arbeev KG, Arbeeva L, Ukraintseva SV, Stallard E, Wu D, Yashin AI. Birth Cohort, Age, and Sex Strongly Modulate Effects of Lipid Risk Alleles Identified in Genome-Wide Association Studies. PloS one. 2015 Jan;10(8):e0136319.

Published In

PloS one

DOI

EISSN

1932-6203

ISSN

1932-6203

Publication Date

January 2015

Volume

10

Issue

8

Start / End Page

e0136319

Related Subject Headings

  • Sex Factors
  • Quantitative Trait, Heritable
  • Polymorphism, Single Nucleotide
  • Male
  • Humans
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • General Science & Technology
  • Female
  • Cholesterol