The hazards of genotype imputation when mapping disease susceptibility variants.

Background: The cost-free increase in statistical power of using imputation to infer missing genotypes is undoubtedly appealing, but is it hazard-free? This case study of three type-2 diabetes (T2D) loci demonstrates that it is not; it sheds light on why this is so and raises concerns as to the shortcomings of imputation at disease loci, where haplotypes differ between cases and reference panel.

Results: T2D-associated variants were previously identified using targeted sequencing. We removed these significantly associated SNPs and used neighbouring SNPs to infer them by imputation.

The hazards of genotype imputation in chromosomal regions under selection: A case study using the Lactase gene region.

Although imputation of missing SNP results has been widely used in genetic studies, claims about the quality and usefulness of imputation have outnumbered the few studies that have questioned its limitations. But it is becoming clear that these limitations are real-for example, disease association signals can be missed in regions of LD breakdown. Here, as a case study, using the chromosomal region of the well-known lactase gene, LCT, we address the issue of imputation in the context of variants that have become frequent in a limited number of modern population groups only recently, due to selection.

New Insights Into Mitochondrial Dysfunction at Disease Susceptibility Loci in the Development of Type 2 Diabetes.

This study investigated the potential genetic mechanisms which underlie adipose tissue mitochondrial dysfunction in Type 2 diabetes (T2D), by systematically identifying nuclear-encoded mitochondrial genes (NEMGs) among the genes regulated by T2D-associated genetic loci. The target genes of these 'disease loci' were identified by mapping genetic loci associated with both disease and gene expression levels (expression quantitative trait loci, eQTL) using high resolution genetic maps, with independent estimates co-locating to within a small genetic distance. These co-locating signals were defined as T2D-eQTL and the target genes as T2D genes.