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.

World-wide distributions of lactase persistence alleles and the complex effects of recombination and selection.

The genetic trait of lactase persistence (LP) is associated with at least five independent functional single nucleotide variants in a regulatory region about 14 kb upstream of the lactase gene [-13910*T (rs4988235), -13907*G (rs41525747), -13915*G (rs41380347), -14009*G (rs869051967) and -14010*C (rs145946881)]. These alleles have been inferred to have spread recently and present-day frequencies have been attributed to positive selection for the ability of adult humans to digest lactose without risk of symptoms of lactose intolerance. One of the inferential approaches used to estimate the level of past selection has been to determine the extent of haplotype homozygosity (EHH) of the sequence surrounding the SNP of interest.

High-Resolution Genetic Maps Identify Multiple Type 2 Diabetes Loci at Regulatory Hotspots in African Americans and Europeans.

Interpretation of results from genome-wide association studies for T2D is challenging. Only very few loci have been replicated in African ancestry populations and the identification of the implicated functional genes remain largely undefined. We used genetic maps that capture detailed linkage disequilibrium information in European and African Americans and applied these to large T2D case-control samples in order to estimate locations for putative functional variants in both populations.

The genomic and phenotypic diversity of Schizosaccharomyces pombe.

Natural variation within species reveals aspects of genome evolution and function. The fission yeast Schizosaccharomyces pombe is an important model for eukaryotic biology, but researchers typically use one standard laboratory strain. To extend the usefulness of this model, we surveyed the genomic and phenotypic variation in 161 natural isolates.

ABCC5 transporter is a novel type 2 diabetes susceptibility gene in European and African American populations.

Numerous functional studies have implicated PARL in relation to type 2 diabetes (T2D). We hypothesised that conflicting human association studies may be due to neighbouring causal variants being in linkage disequilibrium (LD) with PARL. We conducted a comprehensive candidate gene study of the extended LD genomic region that includes PARL and transporter ABCC5 using three data sets (two European and one African American), in relation to healthy glycaemic variation, visceral fat accumulation and T2D disease.

Refinement in localization and identification of gene regions associated with Crohn disease.

The risk of Crohn disease (CD) has a large genetic component. A recent meta-analysis of 6 genome-wide association studies reported 71 chromosomal intervals but does not account for all of the known genetic contribution. Here, we refine localization of the previously reported intervals and also identify additional CD susceptibility genes using a mapping approach that localizes causal variants based on genetic maps in linkage disequilibrium units (LDU maps).

A candidate-gene association study for berry colour and anthocyanin content in Vitis vinifera L.

Anthocyanin content is a trait of major interest in Vitis vinifera L. These compounds affect grape and wine quality, and have beneficial effects on human health. A candidate-gene approach was used to identify genetic variants associated with anthocyanin content in grape berries.

Dissecting the genetics of complex inheritance: linkage disequilibrium mapping provides insight into Crohn disease.

Family studies for Crohn disease (CD) report extensive linkage on chromosome 16q and pinpoint NOD2 as a possible causative locus. However, linkage is also observed in families that do not bear the most frequent NOD2 causative mutations, but no other signals on 16q have been found so far in published genome-wide association studies. Our aim is to identify this missing genetic contribution.

Identification and replication of three novel myopia common susceptibility gene loci on chromosome 3q26 using linkage and linkage disequilibrium mapping.

Refractive error is a highly heritable quantitative trait responsible for considerable morbidity. Following an initial genome-wide linkage study using microsatellite markers, we confirmed evidence for linkage to chromosome 3q26 and then conducted fine-scale association mapping using high-resolution linkage disequilibrium unit (LDU) maps. We used a preliminary discovery marker set across the 30-Mb region with an average SNP density of 1 SNP/15 kb (Map 1).

Impact of marker density on the accuracy of association mapping.

We studied the impact of marker density on the accuracy of association mapping using Genetic Analysis Workshop 15 simulated dense single-nucleotide polymorphism (SNP) data on chromosome 6. A total of 1500 cases and 2000 unaffected controls genotyped for 17,820 SNPs were analyzed. We applied the approach that combines information from multiple SNPs under the framework of the Malecot model and composite likelihood to non-overlapping regions of the chromosome.

Association mapping of susceptibility loci for rheumatoid arthritis.

We analyzed a case-control data set for chromosome 18q from the Genetic Analysis Workshop 15 to detect susceptibility loci for rheumatoid arthritis (RA). A total number of 460 cases and 460 unaffected controls were genotyped on 2300 single-nucleotide polymorphisms (SNPs) by the North American Rheumatoid Arthritis Consortium. Using a multimarker approach for association mapping under the framework of the Malecot model and composite likelihood, we identified a region showing significant association with RA (p < 0.

CHROMSCAN: genome-wide association using a linkage disequilibrium map.

CHROMSCAN implements a composite likelihood model for the analysis of association data. Disease-gene localisation is on a linkage disequilibrium unit (LDU) map, and locations and standard errors, for putatively causal polymorphisms, are determined by the programme. Distortions of the probability distribution created by auto-correlation are avoided by implementation of a permutation test.

LDMAP: the construction of high-resolution linkage disequilibrium maps of the human genome.

The precise characterization of the linkage disequilibrium (LD) landscape from high-density single-nucleotide polymorphism (SNP) data underpins the association mapping of diseases and other studies. We describe the algorithm and implementation of a powerful approach for constructing LD genetic maps with meaningful map distances. The computational problems posed by the enormous number of SNPs typed in the HapMap data are addressed by developing segmental map construction with the potential for parallelization, which we are developing.

Exploiting large scale computing to construct high resolution linkage disequilibrium maps of the human genome.

Unlabelled: Linkage disequilibrium (LD) maps increase power and precision in association mapping, define optimal marker spacing and identify recombination hot-spots and regions influenced by natural selection. Phase II of HapMap provides approximately 2.8-fold more single nucleotide polymorphisms (SNPs) than phase I for constructing higher resolution maps.

Mapping genes for common diseases: the case for genetic (LD) maps.

We examine the current effort to develop a haplotype map of the human genome and suggest an alternative approach which represents linkage disequilibrium patterns in the form of a metric LD map. LD maps have some of the useful properties of genetic linkage maps but have a much higher resolution which is optimal for SNP-based association mapping of common diseases. The studies that have been undertaken to date suggest that LD and recombination maps show some close similarities because of abundant, narrow, recombination hot spots.