Janssens, A. C. et al. The impact of genotype frequencies on the clinical validity of genomic profiling for predicting common chronic diseases. Genet. Med. 9, 528-535

Erasmus University Rotterdam, Rotterdam, South Holland, Netherlands
Genetics in medicine: official journal of the American College of Medical Genetics (Impact Factor: 7.33). 08/2007; 9(8):528-35. DOI: 10.1097/GIM.0b013e31812eece0
Source: PubMed


Single genetic variants in multifactorial disorders typically have small effects, so major increases in disease risk are expected only from the simultaneous exposure to multiple risk genotypes. We investigated the impact of genotype frequencies on the clinical discriminative accuracy for the simultaneous testing of 40 independent susceptibility genetic variants.
In separate simulation scenarios, we varied the genotype frequency from 1% to 50% and the odds ratio for each genetic variant from 1.1 to 2.0. Population size was 1 million and the population disease risk was 10%. Discriminative accuracy was quantified as the area under the receiver-operating characteristic curve. Using an example of genomic profiling for type 2 diabetes, we evaluated the area under the receiver-operating characteristic curve when the odds ratios and genotype frequencies varied between five postulated genetic variants.
When the genotype frequency was 1%, none of the subjects carried more than six of 40 risk genotypes, and when risk genotypes were frequent (> or =30%), all carried at least six. The area under the receiver-operating characteristic curve did not increase above 0.70 when the odds ratios were modest (1.1 or 1.25), but higher genotype frequency increased the area under the receiver-operating characteristic curve from 0.57 to 0.82 and from 0.63 to 0.93 when odds ratios were 1.5 or 2.0. The example of type 2 diabetes showed that the area under the receiver-operating characteristic curve did not change when differences in the odds ratios were ignored.
Given that the effects of susceptibility genes in complex diseases are small, the feasibility of future genomic profiling for predicting common diseases will depend substantially on the frequencies of the risk genotypes.

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Available from: Muin J Khoury, Aug 29, 2014
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    • "To identify cumulative effects of these SNPs, we created a genetic risk score (GRS) for each individual by summing up the number of effect alleles of the SNPs. We did not weight the risk alleles on the basis of their individual effect sizes because no well-accepted effect sizes were available for each of the SNPs, and it has been shown that weighting of risk alleles may have only limited effects[23]. Again logistic regression was used to calculate odds ratio (OR) of the GRS-32 from all 32 SNPs that met our minor-allele frequency cut-off (see above) for the risk of obesity or overweight. "
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    ABSTRACT: Background: Large-scale genome-wide association studies have identified multiple genetic variants that are associated with elevated body mass index (BMI) or the risk of obesity in Caucasian or Asian populations. We examined whether these variants are individually associated with obesity in Chinese children, and also assessed their cumulative effects and predictive value for obesity risk in Chinese children. Methods: We genotyped 40 single nucleotide polymorphisms (SNPs) and conducted association analyses for 32/40 SNPs with an estimated minor allele frequency >1 % in 2 030 unrelated Chinese children, including 607 normal-weight, 718 overweight, and 705 obese individuals from two cross-sectional study groups. Logistic regression and linear regression under the additive model were used to examine associations, and the area under the receiver operating characteristic curve (AUCROC) was reported as prediction summary. Results: We identified obesity association for 6 SNPs near SEC16B, RBJ, CDKAL1, TFAP2B, MAP2K5 and FTO (odds ratios (ORs) ranged from 1.19 to 1.41, nominal two-sided P-values < 0.05). Association (Bonferroni corrected) of rs543874 near SEC16B and rs2241423 near MAP2K5 had presumably stronger effects on obesity in Chinese children than in Caucasian populations. Their risk alleles were also associated with BMI standard deviation score (BMI-SDS) variability. We demonstrated the cumulative effects of the 32 SNPs on obesity risk (per risk allele: OR = 1.06, 95 % CI: 1.03-1.11, P = 4.84 × 10(-4)) and BMI-SDS (β = 0.04, 95 % CI: 0.02-0.06, P = 3.69 × 10(-7)). The difference in AUCROC for a model with covariates (age, age square, sex and study group) and the model including covariates and all 32 SNPs was 2.8 % (P = 0.0002). Conclusion: While six SNPs were individually associated with obesity in Chinese children, the 32 common variants identified by recent GWA studies had cumulative effects and resulted in a limited increase in the AUCROC predictive value for childhood obesity.
    Preview · Article · Dec 2016 · BMC Medical Genetics
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    • "The other issue was the GRS calculation method24252627. Similar to previous reports212223, we did not observe a highly significant difference between the two methods (uwGRS and wGRS) in disease prediction power, as shown by slightly different AUC (difference < 0.05) and Nagelkerke's pseudo R2 (difference < 0.01) scores using the same number of risk alleles. The data was consistent with previous reports: it mattered little in terms of discriminative accuracy whether genetic scores were constructed using the count method or the log odds procedure for most complex diseases with ORs for disease risk alleles similar and close to 1212223. "
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    ABSTRACT: The effect of genetic markers associated with IgA nephropathy on risk of disease in sub-phenotype and progression is uncertain. Data from 2096 Chinese patients were used to create both un-weighted (uw) and weighted (w) genetic risk score (GRS). The association between GRS with disease susceptibility and clinical parameters were assessed. All nine selected single nucleotide polymorphisms (SNPs) were associated with susceptibility to IgAN. uwGRS and wGRS showed a similar fit in disease associations. With every 1-unit increase in the uwGRS, the disease risk increased by approximately 20%; whereas every one standard deviation increase in the wGRS, disease risk increased by approximately 40% ~ 60%. Association between rs3803800 and serum IgA was replicated, and risk groups in GRSs were associated with increased IgA/IgA1 levels. uwGRS9 ≥ 16 was an independent predictor for end stage renal disease (ESRD) in IgAN, with a relative risk of 2.52 (p = 6.68 × 10(-3)). In conclusion, we observed that GRSs comprising nine SNPs identified in a GWAS of IgAN were strongly associated with susceptibility to IgAN. The high risk GRS9 group had a high risk of ESRD in follow-up.
    Full-text · Article · May 2014 · Scientific Reports
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    • "We did not weight the risk alleles on basis of their individual effect sizes because no well-accepted effect sizes were available for each of the SNPs. It is previously demonstrated that weighting of risk alleles may have limited effect [59]. "
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    ABSTRACT: Background Environment, health behavior, and genetic background are important in the development of obesity. Adolescents spend substantial part of daily leisure time on cultural and social activities, but knowledge about the effects of participation in such activities on weight is limited. Methods A number of 1450 adolescents from the Norwegian HUNT study (1995–97) were followed-up in 2006–08 as young adults. Phenotypic data on lifestyle and anthropometric measures were assessed using questionnaires and standardized clinical examinations. Genotypic information on 12 established obesity-susceptibility loci were available for analyses. Generalized estimating equations were used to examine the associations between cultural and social activities in adolescence and adiposity measures in young adulthood. In addition, interaction effects of a genetic predisposition score by leisure time activities were tested. Results In girls, participation in cultural activities was negatively associated with waist circumference (WC) (B = −0.04, 95%CI: -0.08 to −0.00) and with waist-hip ratio (WHR) (B = −0.058, 95%CI: -0.11 to −0.01). However, participation in social activities was positively associated with WC (B = 0.040, CI: 0.00 to 0.08) in girls and with BMI (B = 0.027, CI: 0.00 to 0.05) in boys. The effect of the obesity-susceptibility genetic variants on anthropometric measures was lower in adolescents with high participation in cultural activities compared to adolescents with low participation. Conclusion This study suggests that the effects of cultural activities on body fat are different from the effects of participation in social activities. The protective influence of cultural activities in female adolescents against overweight in adulthood and their moderating effect on obesity-susceptibility genes suggest that even cultural activities may be useful in public health strategies against obesity.
    Full-text · Article · Sep 2012 · BMC Public Health
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