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Strong impact of natural-selection-free heterogeneity in genetics of age-related phenotypes.

Publication ,  Journal Article
Kulminski, AM; Huang, J; Loika, Y; Arbeev, KG; Bagley, O; Yashkin, A; Duan, M; Culminskaya, I
Published in: Aging
March 2018

A conceptual difficulty in genetics of age-related phenotypes that make individuals vulnerable to disease in post-reproductive life is genetic heterogeneity attributed to an undefined role of evolution in establishing their molecular mechanisms. Here, we performed univariate and pleiotropic genome-wide meta-analyses of 20 age-related phenotypes leveraging longitudinal information in a sample of 33,431 individuals and dealing with the natural-selection-free genetic heterogeneity. We identified 142 non-proxy single nucleotide polymorphisms (SNPs) with phenotype-specific (18 SNPs) and pleiotropic (124 SNPs) associations at genome-wide level. Univariate meta-analysis identified two novel (11.1%) and replicated 16 SNPs whereas pleiotropic meta-analysis identified 115 novel (92.7%) and nine replicated SNPs. Pleiotropic associations for most novel (93.9%) and all replicated SNPs were strongly impacted by the natural-selection-free genetic heterogeneity in its unconventional form of antagonistic heterogeneity, implying antagonistic directions of genetic effects for directly correlated phenotypes. Our results show that the common genome-wide approach is well adapted to handle homogeneous univariate associations within Mendelian framework whereas most associations with age-related phenotypes are more complex and well beyond that framework. Dissecting the natural-selection-free genetic heterogeneity is critical for gaining insights into genetics of age-related phenotypes and has substantial and unexplored yet potential for improving efficiency of genome-wide analysis.

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Published In

Aging

DOI

EISSN

1945-4589

ISSN

1945-4589

Publication Date

March 2018

Volume

10

Issue

3

Start / End Page

492 / 514

Related Subject Headings

  • Polymorphism, Single Nucleotide
  • Humans
  • Genotype
  • Genome-Wide Association Study
  • Gene Expression Regulation
  • Developmental Biology
  • Computational Biology
  • Aging
  • 1112 Oncology and Carcinogenesis
  • 0606 Physiology
 

Citation

APA
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ICMJE
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Kulminski, A. M., Huang, J., Loika, Y., Arbeev, K. G., Bagley, O., Yashkin, A., … Culminskaya, I. (2018). Strong impact of natural-selection-free heterogeneity in genetics of age-related phenotypes. Aging, 10(3), 492–514. https://doi.org/10.18632/aging.101407
Kulminski, Alexander M., Jian Huang, Yury Loika, Konstantin G. Arbeev, Olivia Bagley, Arseniy Yashkin, Matt Duan, and Irina Culminskaya. “Strong impact of natural-selection-free heterogeneity in genetics of age-related phenotypes.Aging 10, no. 3 (March 2018): 492–514. https://doi.org/10.18632/aging.101407.
Kulminski AM, Huang J, Loika Y, Arbeev KG, Bagley O, Yashkin A, et al. Strong impact of natural-selection-free heterogeneity in genetics of age-related phenotypes. Aging. 2018 Mar;10(3):492–514.
Kulminski, Alexander M., et al. “Strong impact of natural-selection-free heterogeneity in genetics of age-related phenotypes.Aging, vol. 10, no. 3, Mar. 2018, pp. 492–514. Epmc, doi:10.18632/aging.101407.
Kulminski AM, Huang J, Loika Y, Arbeev KG, Bagley O, Yashkin A, Duan M, Culminskaya I. Strong impact of natural-selection-free heterogeneity in genetics of age-related phenotypes. Aging. 2018 Mar;10(3):492–514.

Published In

Aging

DOI

EISSN

1945-4589

ISSN

1945-4589

Publication Date

March 2018

Volume

10

Issue

3

Start / End Page

492 / 514

Related Subject Headings

  • Polymorphism, Single Nucleotide
  • Humans
  • Genotype
  • Genome-Wide Association Study
  • Gene Expression Regulation
  • Developmental Biology
  • Computational Biology
  • Aging
  • 1112 Oncology and Carcinogenesis
  • 0606 Physiology