Dataset Information

IRS1 G972R polymorphism and type 2 diabetes: a paradigm for the difficult ascertainment of the contribution to disease susceptibility of 'low-frequency-low-risk' variants.

ABSTRACT: The aim of the study was to determine the association between IRS1 G972R polymorphism and type 2 diabetes; published data concerning this association have been conflicting. To obtain further insight into this topic, we performed a meta-analysis of all available case-control studies.We performed a meta-analysis of 32 studies (12,076 cases and 11,285 controls).The relatively infrequent R972 variant was not significantly associated with type 2 diabetes (OR 1.09, 95% CI 0.96-1.23, p = 0.184 under a dominant model). Some evidence of heterogeneity was observed across studies (p = 0.1). In the 14 studies (9,713 individuals) in which the mean age at type 2 diabetes diagnosis was available, this variable explained 52% of the heterogeneity (p = 0.03). When these studies were subdivided into tertiles of mean age at diagnosis, the OR for diabetes was 1.48 (95% CI 1.17-1.87), 1.22 (95% CI 0.97-1.53) and 0.88 (95% CI 0.68-1.13) in the youngest, intermediate and oldest tertile, respectively (p = 0.0022 for trend of ORs).Our findings illustrate the difficulties of ascertaining the contribution of 'low-frequency-low-risk' variants to type 2 diabetes susceptibility. In the specific context of the R972 variant, approximately 200,000 study individuals would be needed to have 80% power to identify a 9% increase in diabetes risk at a genome-wide significance level. Under these circumstances, a strategy aimed at improving outcome definition and decreasing its heterogeneity may critically enhance our ability to detect genetic effects, thereby decreasing the required sample size. Our data suggest that focusing on early-onset diabetes, which is characterised by a stronger genetic background, may be part of such a strategy.

SUBMITTER: Morini E

PROVIDER: S-EPMC2782547 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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IRS1 G972R polymorphism and type 2 diabetes: a paradigm for the difficult ascertainment of the contribution to disease susceptibility of 'low-frequency-low-risk' variants.

Morini E E Prudente S S Succurro E E Chandalia M M Zhang Y-Y YY Mammarella S S Pellegrini F F Powers C C Proto V V Dallapiccola B B Cama A A Sesti G G Abate N N Doria A A Trischitta V V

Diabetologia 20090626 9

<h4>Aims/hypothesis</h4>The aim of the study was to determine the association between IRS1 G972R polymorphism and type 2 diabetes; published data concerning this association have been conflicting. To obtain further insight into this topic, we performed a meta-analysis of all available case-control studies.<h4>Methods</h4>We performed a meta-analysis of 32 studies (12,076 cases and 11,285 controls).<h4>Results</h4>The relatively infrequent R972 variant was not significantly associated with type 2 ...[more]

PMID: 19557384

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Project description:BackgroundWhole-genome sequencing and imputation methodologies have enabled the study of the effects of genomic variants with low to very low minor allele frequency (MAF) on variation in complex traits. Our objective was to estimate the proportion of variance explained by imputed sequence variants classified according to their MAF compared with the variance explained by the pedigree-based additive genetic relationship matrix for 17 traits in Nordic Holstein dairy cattle.ResultsImputed sequence variants were grouped into seven classes according to their MAF (0.001-0.01, 0.01-0.05, 0.05-0.1, 0.1-0.2, 0.2-0.3, 0.3-0.4 and 0.4-0.5). The total contribution of all imputed sequence variants to variance in deregressed estimated breeding values or proofs (DRP) for different traits ranged from 0.41 [standard error (SE) = 0.026] for temperament to 0.87 (SE = 0.011) for milk yield. The contribution of rare variants (MAF < 0.01) to the total DRP variance explained by all imputed sequence variants was relatively small (a maximum of 12.5% for the health index). Rare and low-frequency variants (MAF < 0.05) contributed a larger proportion of the explained DRP variances (>13%) for health-related traits than for production traits (<11%). However, a substantial proportion of these variance estimates across different MAF classes had large SE, especially when the variance explained by a MAF class was small. The proportion of DRP variance that was explained by all imputed whole-genome sequence variants improved slightly compared with variance explained by the 50 k Illumina markers, which are routinely used in bovine genomic prediction. However, the proportion of DRP variance explained by imputed sequence variants was lower than that explained by pedigree relationships, ranging from 1.5% for milk yield to 37.9% for the health index.ConclusionsImputed sequence variants explained more of the variance in DRP than the 50 k markers for most traits, but explained less variance than that captured by pedigree-based relationships. Although in humans partitioning variants into groups based on MAF and linkage disequilibrium was used to estimate heritability without bias, many of our bovine estimates had a high SE. For a reliable estimate of the explained DRP variance for different MAF classes, larger sample sizes are needed.

Dataset Information

IRS1 G972R polymorphism and type 2 diabetes: a paradigm for the difficult ascertainment of the contribution to disease susceptibility of 'low-frequency-low-risk' variants.

Publications

IRS1 G972R polymorphism and type 2 diabetes: a paradigm for the difficult ascertainment of the contribution to disease susceptibility of 'low-frequency-low-risk' variants.

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