Unraveling Genetic Origin of Aging-Related Traits: Evolving Concepts

Kulminski, Alexander M.

doi:10.1089/rej.2013.1441

Cited by 24 publications

(29 citation statements)

References 111 publications

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“…Potential mechanisms of genetic trade-offs are discussed in references 18, 34, and 46. Our results contribute to the discussion that the traditional concept regarding replication of association of the same allele, in the same direction with the same aging-related trait in different populations, has inherent limitations. 41,[47][48][49][50][51] Additionally, our results support the view that more insight into the genetic origin of traits in late life and analyses of mechanisms linking genes to such traits are needed.…”

Section: The E4 Allele and Onset Of Ndsupporting

confidence: 78%

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Trade-Offs in the Effects of the Apolipoprotein E Polymorphism on Risks of Diseases of the Heart, Cancer, and Neurodegenerative Disorders: Insights on Mechanisms from the Long Life Family Study

Kulminski

Arbeev²,

Culminskaya³

et al. 2015

Rejuvenation Research

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The lack of evolutionary established mechanisms linking genes to age-related traits makes the problem of genetic susceptibility to health span inherently complex. One complicating factor is genetic trade-off. Here we focused on long-living participants of the Long Life Family Study (LLFS), their offspring, and spouses to: (1) Elucidate whether trade-offs in the effect of the apolipoprotein E e4 allele documented in the Framingham Heart Study (FHS) are a more general phenomenon, and (2) explore potential mechanisms generating age- and gender-specific trade-offs in the effect of the e4 allele on cancer, diseases of the heart, and neurodegenerative disorders assessed retrospectively in the LLFS populations. The e4 allele can diminish risks of cancer and diseases of the heart and confer risks of diseases of the heart in a sex-, age-, and LLFS-population-specific manner. A protective effect against cancer is seen in older long-living men and, potentially, their sons (>75 years, relative risk [RR]>75=0.48, p=0.086), which resembles our findings in the FHS. The protective effect against diseases of the heart is limited to long-living older men (RR>76=0.50, p=0.016), as well. A detrimental effect against diseases of the heart is characteristic for a normal LLFS population of male spouses and is specific for myocardial infarction (RR=3.07, p=2.1×10(-3)). These trade-offs are likely associated with two inherently different mechanisms, including disease-specific (detrimental; characteristic for a normal male population) and systemic, aging-related (protective; characteristic for older long-living men) mechanisms. The e4 allele confers risks of neurological disorders in men and women (RR=1.98, p=0.046). The results highlight the complex role of the e4 allele in genetic susceptibility to health span.

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Section: The E4 Allele and Onset Of Ndsupporting

confidence: 78%

“…41 As a result, one has to assume indirect (conditional) linkage of genes with age-related traits. 42 This change in the paradigm from unconditional to conditional risks requires a change in analytic strategies.…”

Section: Apoe Gene and Trade-offs 131mentioning

confidence: 99%

Trade-Offs in the Effects of the Apolipoprotein E Polymorphism on Risks of Diseases of the Heart, Cancer, and Neurodegenerative Disorders: Insights on Mechanisms from the Long Life Family Study

Kulminski

Arbeev²,

Culminskaya³

et al. 2015

Rejuvenation Research

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“…A fundamental difficulty in elucidating the genetics of AD and other complex age‐related diseases characteristic of postreproductive life is the undefined role of evolution in establishing the disease mechanisms (Nesse, Ganten, Gregory & Omenn, 2012). This problem is complicated by recent changes in human life expectancy (Oeppen & Vaupel, 2002) and the fitness landscape (Corella & Ordovas, 2014; Crespi, Stead & Elliot, 2010; Kulminski, 2013; Vijg & Suh, 2005). Evolution‐related factors are inevitable sources of genetic heterogeneity in determining predisposition to ADs.…”

Section: Introductionmentioning

confidence: 99%

Apolipoprotein E region molecular signatures of Alzheimer's disease

et al. 2018

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SummaryAlthough the APOE region is the strongest genetic risk factor for Alzheimer's diseases (ADs), its pathogenic role remains poorly understood. Elucidating genetic predisposition to ADs, a subset of age‐related diseases characteristic for postreproductive period, is hampered by the undefined role of evolution in establishing molecular mechanisms of such diseases. This uncertainty is inevitable source of natural‐selection–free genetic heterogeneity in predisposition to ADs. We performed first large‐scale analysis of linkage disequilibrium (LD) structures characterized by 30 polymorphisms from five genes in the APOE 19q13.3 region (BCAM,NECTIN2,TOMM40,APOE, and APOC1) in 2,673 AD‐affected and 16,246 unaffected individuals from five cohorts. Consistent with the undefined role of evolution in age‐related diseases, we found that these structures, being highly heterogeneous, are significantly different in subjects with and without ADs. The pattern of the difference represents molecular signature of AD comprised of single nucleotide polymorphisms (SNPs) from all five genes in the APOE region. Significant differences in LD in subjects with and without ADs indicate SNPs from different genes likely involved in AD pathogenesis. Significant and highly heterogeneous molecular signatures of ADs provide unprecedented insight into complex polygenetic predisposition to ADs in the APOE region. These findings are more consistent with a complex haplotype than with a single genetic variant origin of ADs in this region.

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“…An important challenge is a special type of heterogeneity attributed to the elusive role of evolution in shaping the genetic basis of age-related traits. This heterogeneity is the result of age-related processes in an organism and compositional changes in a population in changing environment [9,14,15]. …”

Section: Introductionmentioning

confidence: 99%

Pleiotropic Associations of Allelic Variants in a 2q22 Region with Risks of Major Human Diseases and Mortality

Kulminski

Culminskaya

et al. 2016

PLoS Genet

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Gaining insights into genetic predisposition to age-related diseases and lifespan is a challenging task complicated by the elusive role of evolution in these phenotypes. To gain more insights, we combined methods of genome-wide and candidate-gene studies. Genome-wide scan in the Atherosclerosis Risk in Communities (ARIC) Study (N = 9,573) was used to pre-select promising loci. Candidate-gene methods were used to comprehensively analyze associations of novel uncommon variants in Caucasians (minor allele frequency~2.5%) located in band 2q22.3 with risks of coronary heart disease (CHD), heart failure (HF), stroke, diabetes, cancer, neurodegenerative diseases (ND), and mortality in the ARIC study, the Framingham Heart Study (N = 4,434), and the Health and Retirement Study (N = 9,676). We leveraged the analyses of pleiotropy, age-related heterogeneity, and causal inferences. Meta-analysis of the results from these comprehensive analyses shows that the minor allele increases risks of death by about 50% (p = 4.6×10−9), CHD by 35% (p = 8.9×10−6), HF by 55% (p = 9.7×10−5), stroke by 25% (p = 4.0×10−2), and ND by 100% (p = 1.3×10−3). This allele also significantly influences each of two diseases, diabetes and cancer, in antagonistic fashion in different populations. Combined significance of the pleiotropic effects was p = 6.6×10−21. Causal mediation analyses show that endophenotypes explained only small fractions of these effects. This locus harbors an evolutionary conserved gene-desert region with non-coding intergenic sequences likely involved in regulation of protein-coding flanking genes ZEB2 and ACVR2A. This region is intensively studied for mutations causing severe developmental/genetic disorders. Our analyses indicate a promising target region for interventions aimed to reduce risks of many major human diseases and mortality.

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Unraveling Genetic Origin of Aging-Related Traits: Evolving Concepts

Cited by 24 publications

References 111 publications

Trade-Offs in the Effects of the Apolipoprotein E Polymorphism on Risks of Diseases of the Heart, Cancer, and Neurodegenerative Disorders: Insights on Mechanisms from the Long Life Family Study

Trade-Offs in the Effects of the Apolipoprotein E Polymorphism on Risks of Diseases of the Heart, Cancer, and Neurodegenerative Disorders: Insights on Mechanisms from the Long Life Family Study

Apolipoprotein E region molecular signatures of Alzheimer's disease

Pleiotropic Associations of Allelic Variants in a 2q22 Region with Risks of Major Human Diseases and Mortality

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