research-review:prospective-analysis-of-genetic-variants-associated-with-human-lifespan
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research-review:prospective-analysis-of-genetic-variants-associated-with-human-lifespan [2019/10/10 19:18] marcos |
research-review:prospective-analysis-of-genetic-variants-associated-with-human-lifespan [2019/11/13 21:08] marcos |
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| + | // This paper was covered at a journal club called [[https://www.meetup.com/New-York-Science-Journal-Club |Deep Dive]], part of [[http://www.biotechwithoutborders.org/|Biotech without Borders]]. // | ||
| ===== A Prospective Analysis of Genetic Variants Associated with Human Lifespan ===== | ===== A Prospective Analysis of Genetic Variants Associated with Human Lifespan ===== | ||
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| ==== Abstract ==== | ==== Abstract ==== | ||
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| + | A GWA (genome wide association) study was conducted using the AncestryDNA and UK Biobank. Previous studies had been done before on the individual data sets. This study increased the statistical power by increasing the total number of subjects. | ||
| The challenge of correlating lifespan with genetics, is that "genotypes are generally gathered from living persons, whereas lifespan (total elapsed time between birth and death) is a property of deceased persons. Due to this challenge, current age has been used as a lifespan proxy trait in many human aging studies." However, as decades go by and additional studies are done using age as a lifespan proxy, there will be confounding factors having to do with such things as the advancement of medicine or increases in pollution. | The challenge of correlating lifespan with genetics, is that "genotypes are generally gathered from living persons, whereas lifespan (total elapsed time between birth and death) is a property of deceased persons. Due to this challenge, current age has been used as a lifespan proxy trait in many human aging studies." However, as decades go by and additional studies are done using age as a lifespan proxy, there will be confounding factors having to do with such things as the advancement of medicine or increases in pollution. | ||
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| Variants where a single nucleotide in the DNA is altered often result in the same allele. These single nucleotide differences are referred to as SNP (single nucleotide polymorphism) variants. SNP's can arise in any of the cells of the body due to mutations. While mutations are infrequent, they occur because the DNA copying process is imperfect. | Variants where a single nucleotide in the DNA is altered often result in the same allele. These single nucleotide differences are referred to as SNP (single nucleotide polymorphism) variants. SNP's can arise in any of the cells of the body due to mutations. While mutations are infrequent, they occur because the DNA copying process is imperfect. | ||
| - | As a population grows older, members of the same age with alleles that reduce lifespan, will die off first. The cells within an individual also mutate, but at a very slow rate. So slow, that DNA samples from the same person, taken 80 years apart, would still show a [[https://www.quora.com/If-you-take-a-DNA-sample-from-a-newborn-would-it-match-a-DNA-sample-from-when-the-same-person-is-80 |majority of cells]] having the original DNA. | + | As a population grows older, members of the same age with alleles that reduce lifespan, will die off first. The cells within an individual also mutate, but at a very slow rate. So slow, that DNA samples from the same person, taken 80 years apart, would still show a [[https://www.quora.com/If-you-take-a-DNA-sample-from-a-newborn-would-it-match-a-DNA-sample-from-when-the-same-person-is-80 |majority of cells]] having the original DNA. However, there are cases of [[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5446794 |clonal mosaicism]], where a mutation can give rise to body regions with a different genome. |
| There may be some cases, however, where mutations have a survival advantage compared to neighboring cells, and are able to gain majority. An example of this is cancer. However, it is unlikely that DNA samples will be composed of a majority of mutated cells. | There may be some cases, however, where mutations have a survival advantage compared to neighboring cells, and are able to gain majority. An example of this is cancer. However, it is unlikely that DNA samples will be composed of a majority of mutated cells. | ||
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| However, 3 loci had no known disease associations. Namely the genes WAPL, SRRM3, and IP6K1 are associated with longevity but not with life-shortening diseases. | However, 3 loci had no known disease associations. Namely the genes WAPL, SRRM3, and IP6K1 are associated with longevity but not with life-shortening diseases. | ||
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| + | WAPL was only found to be significant in the narrower birth cohort. Analyzing the same data in a different way, they used a wider birth cohort to increase statistical power. The downside to doing this was increased uncertainty in terms of censorship of long lived individuals. Censorship of long lived individuals means that the individuals could have lived longer than is recorded. | ||
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| + | Below you see the effect on lifespan based on the cohort data used, where the horizontal lines represent the range of uncertainty. The effect of the WAPL gene, while not related to any known disease, appears to be, on average, detrimental to lifespan. However, the effect is less than one year of life, or many years of life for some of those with the allele? | ||
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| + | {{:research-review:f5.jpg|WAPL loci effect by birth cohort}} | ||
| === Heterogeneity of GWA results across analyses === | === Heterogeneity of GWA results across analyses === | ||
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| When research finds loci associated with a phenotype, the odds of the heritability of these loci is less than the odds of inheriting the phenotype. The issue of "missing heritability" is the failure of research to find all the genetic factors for heritability (hg2 is less than h2). | When research finds loci associated with a phenotype, the odds of the heritability of these loci is less than the odds of inheriting the phenotype. The issue of "missing heritability" is the failure of research to find all the genetic factors for heritability (hg2 is less than h2). | ||
| - | Studies have estimated h2 to be between 15-30%, while h2g is less than 10% as deduced from the heritability of the lifespan loci found in this analysis. | + | Studies have estimated lifespan h2 to be between 15-30%, while h2g is less than 10% as deduced from the heritability of the lifespan loci found in this analysis. |
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| + | The authors explain in this and a [[https://www.genetics.org/content/210/3/1109 |past study]] that the discrepancy is not a failure to find the genetic components of lifespan, but instead the sociological phenomenon of assortative mating. Assortative mating is where individuals of similar phenotype or within the same culture mate with each other more frequently than would be expected from random mating. Even with their efforts to include assortative mating into the statistical analysis, they state that: "It is worth considering that the inflation of h2 estimates due to assortative mating may be more generally responsible for the recurrence of sizable “missing heritability” gaps." | ||
| - | The authors explain that the discrepancy is not a failure to find the genetic components of lifespan, but instead the sociological phenomenon of assortative mating. Assortative mating is where individuals of similar phenotype or within the same culture mate with each other more frequently than would be expected from random mating. | + | The significance of this conclusion, and of the GWA studies for lifespan phenotypes, is that there are no individual alleles that produce a long lived individual, only alleles that reduce lifespan. |
| + | --- //[[user:marcos|Marcos Reyes]] 2019/10/27 03:39// | ||
research-review/prospective-analysis-of-genetic-variants-associated-with-human-lifespan.txt · Last modified: 2019/11/13 21:08 by marcos
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