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Uncoupling associations of risk alleles with endophenotypes and phenotypes: insights from the ApoB locus and heart‐related traits

Traditionally, genomewide association studies (GWAS) have emphasized the benefits of large samples in the analyses of age‐related traits rather than their specific properties. We adopted a realistic concept of genetic susceptibility to inherently heterogeneous, age‐related traits driven by the elusi...

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Autores principales: Kulminski, Alexander M., Kernogitski, Yelena, Culminskaya, Irina, Loika, Yury, Arbeev, Konstantin G., Bagley, Olivia, Duan, Matt, Arbeeva, Liubov, Ukraintseva, Svetlana V., Wu, Deqing, Stallard, Eric, Yashin, Anatoliy I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5242299/
https://www.ncbi.nlm.nih.gov/pubmed/27683205
http://dx.doi.org/10.1111/acel.12526
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author Kulminski, Alexander M.
Kernogitski, Yelena
Culminskaya, Irina
Loika, Yury
Arbeev, Konstantin G.
Bagley, Olivia
Duan, Matt
Arbeeva, Liubov
Ukraintseva, Svetlana V.
Wu, Deqing
Stallard, Eric
Yashin, Anatoliy I.
author_facet Kulminski, Alexander M.
Kernogitski, Yelena
Culminskaya, Irina
Loika, Yury
Arbeev, Konstantin G.
Bagley, Olivia
Duan, Matt
Arbeeva, Liubov
Ukraintseva, Svetlana V.
Wu, Deqing
Stallard, Eric
Yashin, Anatoliy I.
author_sort Kulminski, Alexander M.
collection PubMed
description Traditionally, genomewide association studies (GWAS) have emphasized the benefits of large samples in the analyses of age‐related traits rather than their specific properties. We adopted a realistic concept of genetic susceptibility to inherently heterogeneous, age‐related traits driven by the elusive role of evolution in their properties. We analyzed in detail the associations of rs693 and rs562338 polymorphisms representing the Apolipoprotein B locus with endophenotypes (total cholesterol [TC] and high‐density lipoprotein cholesterol) and phenotypes (myocardial infarction [MI] and survival) in four large‐scale studies, which include 20 748 individuals with 2357 MI events. We showed that a strong, robust predisposition of rs693 and rs562338 to TC (β = 0.72, P = 7.7 × 10(−30) for rs693 and β = −1.08, P = 9.8 × 10(−42) for rs562338) is not translated into a predisposition to MI and survival. The rs693_A allele influences risks of MI and mortality after MI additively with lipids. This allele shows antagonistic effects—protecting against MI risks (β = −0.18, P = 1.1 × 10(−5)) or increasing MI risks (β = 0.15, P = 2.8 × 10(−3)) and mortality after MI, in different populations. Paradoxically, increased TC concentrations can be protective against MI for the rs693_A allele carriers. Our results uncouple the influences of the same alleles on endophenotypes and phenotypes despite potential causal relationships among the latter. Our strategy reveals virtually genomewide significance for the associations of rs693 with MI (P = 5.5 × 10(−8)) that is contrasted with a weak estimate following the traditional, sample‐size‐centered GWAS strategy (P = 0.16) in the same sample. These results caution against the use of the traditional GWAS strategy for gaining profound insights into genetic predisposition to healthspan and lifespan.
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spelling pubmed-52422992017-02-03 Uncoupling associations of risk alleles with endophenotypes and phenotypes: insights from the ApoB locus and heart‐related traits Kulminski, Alexander M. Kernogitski, Yelena Culminskaya, Irina Loika, Yury Arbeev, Konstantin G. Bagley, Olivia Duan, Matt Arbeeva, Liubov Ukraintseva, Svetlana V. Wu, Deqing Stallard, Eric Yashin, Anatoliy I. Aging Cell Original Articles Traditionally, genomewide association studies (GWAS) have emphasized the benefits of large samples in the analyses of age‐related traits rather than their specific properties. We adopted a realistic concept of genetic susceptibility to inherently heterogeneous, age‐related traits driven by the elusive role of evolution in their properties. We analyzed in detail the associations of rs693 and rs562338 polymorphisms representing the Apolipoprotein B locus with endophenotypes (total cholesterol [TC] and high‐density lipoprotein cholesterol) and phenotypes (myocardial infarction [MI] and survival) in four large‐scale studies, which include 20 748 individuals with 2357 MI events. We showed that a strong, robust predisposition of rs693 and rs562338 to TC (β = 0.72, P = 7.7 × 10(−30) for rs693 and β = −1.08, P = 9.8 × 10(−42) for rs562338) is not translated into a predisposition to MI and survival. The rs693_A allele influences risks of MI and mortality after MI additively with lipids. This allele shows antagonistic effects—protecting against MI risks (β = −0.18, P = 1.1 × 10(−5)) or increasing MI risks (β = 0.15, P = 2.8 × 10(−3)) and mortality after MI, in different populations. Paradoxically, increased TC concentrations can be protective against MI for the rs693_A allele carriers. Our results uncouple the influences of the same alleles on endophenotypes and phenotypes despite potential causal relationships among the latter. Our strategy reveals virtually genomewide significance for the associations of rs693 with MI (P = 5.5 × 10(−8)) that is contrasted with a weak estimate following the traditional, sample‐size‐centered GWAS strategy (P = 0.16) in the same sample. These results caution against the use of the traditional GWAS strategy for gaining profound insights into genetic predisposition to healthspan and lifespan. John Wiley and Sons Inc. 2016-09-28 2017-02 /pmc/articles/PMC5242299/ /pubmed/27683205 http://dx.doi.org/10.1111/acel.12526 Text en © 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Kulminski, Alexander M.
Kernogitski, Yelena
Culminskaya, Irina
Loika, Yury
Arbeev, Konstantin G.
Bagley, Olivia
Duan, Matt
Arbeeva, Liubov
Ukraintseva, Svetlana V.
Wu, Deqing
Stallard, Eric
Yashin, Anatoliy I.
Uncoupling associations of risk alleles with endophenotypes and phenotypes: insights from the ApoB locus and heart‐related traits
title Uncoupling associations of risk alleles with endophenotypes and phenotypes: insights from the ApoB locus and heart‐related traits
title_full Uncoupling associations of risk alleles with endophenotypes and phenotypes: insights from the ApoB locus and heart‐related traits
title_fullStr Uncoupling associations of risk alleles with endophenotypes and phenotypes: insights from the ApoB locus and heart‐related traits
title_full_unstemmed Uncoupling associations of risk alleles with endophenotypes and phenotypes: insights from the ApoB locus and heart‐related traits
title_short Uncoupling associations of risk alleles with endophenotypes and phenotypes: insights from the ApoB locus and heart‐related traits
title_sort uncoupling associations of risk alleles with endophenotypes and phenotypes: insights from the apob locus and heart‐related traits
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5242299/
https://www.ncbi.nlm.nih.gov/pubmed/27683205
http://dx.doi.org/10.1111/acel.12526
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