The balance between heritable and environmental aetiology of human disease.

Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany.
Nature Reviews Genetics (Impact Factor: 39.79). 01/2007; 7(12):958-65. DOI: 10.1038/nrg2009
Source: PubMed

ABSTRACT The Human Genome Project and the ensuing International HapMap Project were largely motivated by human health issues. But the distance from a DNA sequence variation to a novel disease gene is considerable; for complex diseases, closing this gap hinges on the premise that they arise mainly from heritable causes. Using cancer as an example of complex disease, we examine the scientific evidence for the hypothesis that human diseases result from interactions between genetic variants and the environment.

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    ABSTRACT: Several genome-wide association studies on colorectal cancer (CRC) have reported similar findings of a new susceptibility locus, 15q13.3. After that, a number of studies have reported that the rs4779584 and rs10318 polymorphisms at chromosome 15q13.3 have been implicated in CRC and colorectal adenoma (CRA) risk; however, these studies have yielded inconsistent results. To investigate this inconsistency, we performed a meta-analysis of 22 studies involving a total of 48,468 CRC cases, 4,189 CRA cases, and 85,105 controls for the two polymorphisms to evaluate its effect on genetic susceptibility for CRC/CRA. Potential sources of heterogeneity and publication bias were also systematically explored. Overall, the summary odds ratio (OR) of rs4779584-T variant for CRC was 1.13 (95 % CI 1.09-1.16, P < 10(-5)) and 1.15 (95 % CI 1.04-1.28, P = 0.006) for CRA. After stratified by ethnicity, significantly increased CRC risks were found for rs4779584 polymorphism among East Asians and Caucasians, while no significant associations were detected among African American and other ethnic populations. A meta-analysis of studies on the rs10318 polymorphism also showed significant overall association with CRC, yielding a per-allele OR of 1.13 (95 % CI 1.02-1.24, P = 0.02). In the subgroup analysis by ethnicity, significantly increased CRC risks were found in Caucasians; whereas no significant associations were found among East Asians and African Americans. This meta-analysis demonstrated that the rs4779584 and rs10318 polymorphism at 15q13.3 is a risk factor associated with increased CRC/CRA susceptibility, but these associations vary in different ethnic populations.
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    ABSTRACT: BACKGROUND: Decreased renal function is an established risk factor for cardiovascular disease (CVD). Causal mechanisms between estimates of renal function and CVD are intricate and investigation of the relative importance of genetic and environmental factors for the variability of these phenotypes could provide new knowledge. METHODS AND RESULTS: Cystatin C and creatinine levels in 12 313 twins were analyzed. Uni- and bivariate heritability for these traits and CVD was estimated through structured equation modelling and genome-wide complex trait analysis (GCTA) in order to independently confirm additive genetic effects. Twin model-estimated heritability of Cystatin C was 0.55 (95% confidence interval [CI], 0.49 to 0.60) in men, 0.63 (0.59 to 0.66) in women, and 0.60 (0.56 to 0.63) in both sexes combined. For creatinine, heritability estimates were in the same range. Heritability of CVD was 0.39 (0.02 to 0.67) in men and 0.20 (0.00 to 0.61) in women. The phenotypic correlation between Cystatin C and CVD correlation was 0.16 (0.12 to 0.20) in men and 0.17 (0.13 to 0.21) in women, whereas the genetic correlation in males was 0.41 (0.21 to 0.62) while it was non-significant in females. Trough GCTA, the heritability of Cystatin C and creatinine in both sexes combined was estimated to 0.40 (SE 0.07, P=8E(-9)) and 0.19 (SE 0.07, P=0.003), respectively. CONCLUSIONS: Twin model-based heritability of Cystatin C was higher compared to previous studies. Co-variation between Cystatin C and CVD in males was partly explained by additive genetic components, indicating that Cystatin C and CVD share genetic influences. The GCTA provided independent evidence for significant contribution of additive genetics to trait variance of Cystatin C.
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    ABSTRACT: Inconclusive results of the association between genetic polymorphisms involved in folate metabolism and maternal risk for Down syndrome (DS) have been reported. Therefore, this meta-analysis was conducted. We searched electronic databases through May, 2014, for eligible studies. Pooled odds ratios with 95% confidence intervals were used to assess the strength of the association, which was estimated by fixed or random effects models. Heterogeneity among studies was evaluated using Q-test and I (2) statistic. Subgroup and sensitivity analyses were also conducted. Publication bias was estimated using Begg's and Egger's tests. A total of 17 case-controls studies were included. There was evidence for an association between the MTRR c.66A>G (rs1801394) polymorphism and maternal risk for DS. In the subgroup analysis, increased maternal risk for DS was found in Caucasians. Additionally, the polymorphic heterozygote MTHFD1 1958GA genotype was associated significantly with maternal risk for DS, when we limit the analysis by studies conformed to Hardy-Weinberg equilibrium. Finally, considering MTR c.2756A>G (rs1805087), TC2 c.776C>G (rs1801198), and CBS c.844ins68, no significant associations have been found, neither in the overall analyses nor in the stratified analyses by ethnicity. In conclusion, our meta-analysis suggested that the MTRR c.66A>G (rs1801394) polymorphism and MTHFD1 c.1958G>A (rs2236225) were associated with increased maternal risk for DS.
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