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. 2011;231-42.
doi: 10.1142/9789814335058_0025.

The Reference Human Genome Demonstrates High Risk of Type 1 Diabetes and Other Disorders

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Free PMC article

The Reference Human Genome Demonstrates High Risk of Type 1 Diabetes and Other Disorders

Rong Chen et al. Pac Symp Biocomput. .
Free PMC article

Abstract

Personal genome resequencing has provided promising lead to personalized medicine. However, due to the limited samples and the lack of case/control design, current interpretation of personal genome sequences has been mainly focused on the identification and functional annotation of the DNA variants that are different from the reference genome. The reference genome was deduced from a collection of DNAs from anonymous individuals, some of whom might be carriers of disease risk alleles. We queried the reference genome against a large high-quality disease-SNP association database and found 3,556 disease-susceptible variants, including 15 rare variants. We assessed the likelihood ratio for risk for the reference genome on 104 diseases and found high risk for type 1 diabetes (T1D) and hypertension. We further demonstrated that the risk of T1D was significantly higher in the reference genome than those in a healthy patient with a whole human genome sequence. We found that the high T1D risk was mainly driven by a R260W mutation in PTPN22 in the reference genome. Therefore, we recommend that the disease-susceptible variants in the reference genome should be taken into consideration and future genome sequences should be interpreted with curated and predicted disease-susceptible loci to assess personal disease risk.

Figures

Fig. 1
Fig. 1
The disease risk comparison between the personal genome of a healthy male and the reference genome. Each circle represents the genetic risk of a disease for the patient and the reference genome.
Fig. 2
Fig. 2
Contribution of individual alleles to overall risk LR of T1D of the reference genome. Alleles and their associated genes are listed on the left, ordered from top to bottom by the number of studies in which each was published and the total sum of cohort sizes across those papers. The LR of each independent SNP/allele is listed. A user of this figure could draw a horizontal line at a given threshold of belief, include and exclude alleles, and retrieve the accumulated LR at the right column and shown graphically in the middle. The central graph displays the change in accumulated LR, with darker squares representing more publications and larger squares representing larger sample size.
Fig. 3
Fig. 3
Contribution of individual genotypes to the overall risk LR of T1D for a previously published 40-year-old healthy Caucasian male. See Figure 3 for details on the graphical elements.

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