Complex phenotypes and phenomenon of genome-wide inter-chromosomal linkage disequilibrium in the human genome

Kulminski, Alexander M.

doi:10.1016/j.exger.2011.08.010

Cited by 13 publications

(14 citation statements)

References 55 publications

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“…This is an important result implying that genes for these SNPs can work together in a coordinated fashion. This result is in line with recent findings in the mouse (Graber et al 2006;Petkov et al 2005Petkov et al , 2007 and it deserves separate detail analyses (Kulminski 2011).…”

Section: Developmental Process 14supporting

confidence: 81%

Genomics of human health and aging

Kulminski

Culminskaya

2011

AGE

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Despite notable progress of the candidategene and genome-wide association studies (GWAS), understanding the role of genes contributing to human health and lifespan is still very limited. We use the Framingham Heart Study to elucidate if recognizing the role of evolution and systemic processes in an aging organism could advance such studies. We combine throughput methods of GWAS with more detail methods typical for candidate-gene analyses and show that both lifespan and ages at onset of CVD and cancer can be controlled by the same allelic variants. The risk allele carriers are at highly significant risk of premature death (e.g., RR02.9, p 05.0× 10 −66 ), onset of CVD (e.g., RR01.6, p04.6×10 −17 ), and onset of cancer (e.g., RR01.6, p01.5×10 −6 ). The mechanism mediating the revealed genetic associations is likely associated with biological aging. These aging-related phenotypes are associated with a complex network which includes, in this study, 62 correlated SNPs even so these SNPs can be on non-homologous chromosomes. A striking result is three-fold, highly significant (p03.6×10 −10 ) enrichment of non-synonymous SNPs (N027) in this network compared to the entire qualified set of the studied SNPs. Functional significance of this network is strengthened by involvement of genes for these SNPs in fundamental biological processes related to aging (e.g., response to stimuli, protein degradation, apoptosis) and by connections of these genes with neurological (20 genes) and cardiovascular (nine genes) processes and tumorigenesis (10 genes). These results document challenging role of gene networks in regulating human health and aging and call for broadening focus on genomics of such phenotypes.

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Section: Developmental Process 14supporting

confidence: 81%

Genomics of human health and aging

Kulminski

Culminskaya

2011

AGE

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“…Unfortunately, the authors did not provide conventional quality control metrics for these SNPs, such as genotyping call rate, deviation from Hardy-Weinberg Equilibrium, and crucially whether visual examination of the cluster plots of two allele intensity values to determine whether the genotype calling by the software used was appropriate. As previously stated (Paterson 2012), a study on the sample size analysed by would be unlikely to have good power to detect any loci apart from the chromosome 9p21 locus for cardiovascular disease at alpha <5×10 −8 .…”

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confidence: 89%

“…In a recent letter to the editor of the Experimental Gerontology, I brought up similar criticisms (Paterson 2012) of an earlier paper published by the same author . However, in their reply (Kulminski 2012), none of the specific criticisms were addressed. Until the authors address the issues of genotyping quality, any conclusions that SNPs on different chromosomes are associated with each other is premature.…”

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confidence: 90%

Letter to the editor: expression of concern, reaffirmed

Paterson

2013

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“…Our recent findings suggest that inter-chromosomal LD can be caused by bio-genetic mechanisms possibly associated with favorable or unfavorable epistatic evolution in humans (Kulminski 2011). In this work, we address two research questions.…”

Section: Introductionmentioning

confidence: 98%

Inter-chromosomal level of genome organization and longevity-related phenotypes in humans

Kulminski

Culminskaya

Yashin

2012

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Studies focusing on unraveling the genetic origin of health span in humans assume that polygenic, aging-related phenotypes are inherited through Mendelian mechanisms of inheritance of individual genes. We use the Framingham Heart Study (FHS) data to examine whether non-Mendelian mechanisms of inheritance can drive linkage of loci on non-homologous chromosomes and whether such mechanisms can be relevant to longevity-related phenotypes. We report on genome-wide inter-chromosomal linkage disequilibrium (LD) and on chromosome-wide intra-chromosomal LD and show that these are real phenomena in the FHS data. Genetic analysis of inheritance in families based on Mendelian segregation reveals that the alleles of single nucleotide polymorphisms (SNPs) in LD at loci on non-homologous chromosomes are inherited as a complex resembling haplotypes of a genetic unit. This result implies that the inter-chromosomal LD is likely caused by non-random assortment of non-homologous chromosomes during meiosis. The risk allele haplotypes can be subject to dominant-negative selection primary through the mechanisms of non-Mendelian inheritance. They can go to extinction within two human generations. The set of SNPs in inter-chromosomal LD (N=68) is nearly threefold enriched, with high significance (p=1.6 × 10(-9)), on non-synonymous coding variants (N=28) compared to the entire qualified set of the studied SNPs. Genes for the tightly linked SNPs are involved in fundamental biological processes in an organism. Survival analyses show that the revealed non-genetic linkage is associated with heritable complex phenotype of premature death. Our results suggest the presence of inter-chromosomal level of functional organization in the human genome and highlight a challenging problem of genomics of human health and aging.

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Complex phenotypes and phenomenon of genome-wide inter-chromosomal linkage disequilibrium in the human genome

Cited by 13 publications

References 55 publications

Genomics of human health and aging

Genomics of human health and aging

Letter to the editor: expression of concern, reaffirmed

Inter-chromosomal level of genome organization and longevity-related phenotypes in humans

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