Allelic Spectra of Risk SNPs Are Different for Environment/Lifestyle Dependent versus Independent Diseases

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Abstract

Genome-wide association studies (GWAS) have generated sufficient data to assess the role of selection in shaping allelic diversity of disease-associated SNPs. Negative selection against disease risk variants is expected to reduce their frequencies making them overrepresented in the group of minor (<50%) alleles. Indeed, we found that the overall proportion of risk alleles was higher among alleles with frequency <50% (minor alleles) compared to that in the group of major alleles. We hypothesized that negative selection may have different effects on environment (or lifestyle)-dependent versus environment (or lifestyle)-independent diseases. We used an environment/lifestyle index (ELI) to assess influence of environmental/lifestyle factors on disease etiology. ELI was defined as the number of publications mentioning “environment” or “lifestyle” AND disease per 1,000 disease-mentioning publications. We found that the frequency distributions of the risk alleles for the diseases with strong environmental/lifestyle components follow the distribution expected under a selectively neutral model, while frequency distributions of the risk alleles for the diseases with weak environmental/lifestyle influences is shifted to the lower values indicating effects of negative selection. We hypothesized that previously selectively neutral variants become risk alleles when environment changes. The hypothesis of ancestrally neutral, currently disadvantageous risk-associated alleles predicts that the distribution of risk alleles for the environment/lifestyle dependent diseases will follow a neutral model since natural selection has not had enough time to influence allele frequencies. The results of our analysis suggest that prediction of SNP functionality based on the level of evolutionary conservation may not be useful for SNPs associated with environment/lifestyle dependent diseases.

Figures

  • Fig 1. Proportions of SNPs with the signature of recent positive selection on the most commonly used genotyping platforms. The red horizontal line shows the proportion of SNPs with signature of recent positive selection among GWAS-detected SNPs associated with risk of common human diseases.
  • Table 1. Absolute number and the proportion of selected SNPs on the most popular genotyping platforms.
  • Table 2. Proportions of minor risk alleles (MiRA) in GWAS studied diseases.
  • Table 3. Environmental and lifestyle indexes (ELIs) for the GWAS-studied diseases.
  • Fig 2. The proportions of minor risk alleles (MiRA) in the first, second and third tertiles defined based on the environment/lifestyle index (ELI).
  • Fig 3. Frequency binned distributions of the risk alleles for different common diseases. F—frequency of the risk-associated allele. Area under each curve equals 1. Black line shows the distribution expected under the assumption that the probability of the allele to be risk associated is independent of its frequency. a) Proportions of the risk alleles in the 5 frequency categories for diseases stratified by the ELI tertiles. b) Proportions of the risk alleles for 3 individual diseases from the first tertile (environment/lifestyle independent diseases). c) Distributions of risk alleles for 3 individual diseases from the third ELI tertile (environment/lifestyle dependent diseases). d) Proportions of the risk alleles averaged for the 3 environment/lifestyle dependent (red line) and 3 environment/lifestyle independent (blue line) diseases.
  • Fig 4. Expected evolutionary dynamics of currently deleterious, recently neutral risk associated alleles.Upper panel shows the distribution of selection coefficients: negative values imply negative and positive values positive selection. A change in the environment or life style leads to changes in selective values of existing variants making some of previously neutral variants deleterious and others advantageous. The lower panel shows frequency distributions of risk alleles immediately after changes in environment/life style and after the negative selection took place.

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APA

Gorlov, I. P., Gorlova, O. Y., & Amos, C. I. (2015). Allelic Spectra of Risk SNPs Are Different for Environment/Lifestyle Dependent versus Independent Diseases. PLoS Genetics, 11(7). https://doi.org/10.1371/journal.pgen.1005371

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