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PLoS Genet. 2015 Jul 22;11(7):e1005371. doi: 10.1371/journal.pgen.1005371. eCollection 2015 Jul.

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

Author information

1
The Geisel School of Medicine, Dartmouth College, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, United States of America.

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.

PMID:
26201053
PMCID:
PMC4511800
DOI:
10.1371/journal.pgen.1005371
[Indexed for MEDLINE]
Free PMC Article

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