Genomic Linkage Disequilibrium Research Articles

The genetic differences with whole genome linkage disequilibrium mapping between responder and non‐responder in interferon‐α and ribavirin combined therapy for chronic hepatitis C patients

Interferon-alpha and ribavirin combined therapy has been a mainstream treatment for hepatitis C infection. The efficacy of this combined treatment is around 30% to 60%, and the factors affecting the responsiveness are still poorly defined. Our study is intended to investigate the genetic differences between responder and non-responder patients. The genome-wide linkage disequilibrium screening for loci associated with genetic difference between two patient groups was conducted by using 382 autosomal short tandem repeat (STR) markers involving 92 patients. We have identified 19 STR markers displaying different allele frequencies between the two patient groups. In addition, based on their genomic location and biological function, we selected the CD81 and IL15 genes to perform single nucleotide polymorphism genotyping. In conclusion, this study may provide a new approach for identifying the associated polymorphisms and the susceptible loci for interferon-alpha and ribavirin combined therapy in patients with chronic hepatitis C.

Whole genome linkage disequilibrium maps in cattle

BackgroundBovine whole genome linkage disequilibrium maps were constructed for eight breeds of cattle. These data provide fundamental information concerning bovine genome organization which will allow the design of studies to associate genetic variation with economically important traits and also provides background information concerning the extent of long range linkage disequilibrium in cattle.ResultsLinkage disequilibrium was assessed using r2 among all pairs of syntenic markers within eight breeds of cattle from the Bos taurus and Bos indicus subspecies. Bos taurus breeds included Angus, Charolais, Dutch Black and White Dairy, Holstein, Japanese Black and Limousin while Bos indicus breeds included Brahman and Nelore. Approximately 2670 markers spanning the entire bovine autosomal genome were used to estimate pairwise r2 values. We found that the extent of linkage disequilibrium is no more than 0.5 Mb in these eight breeds of cattle.ConclusionLinkage disequilibrium in cattle has previously been reported to extend several tens of centimorgans. Our results, based on a much larger sample of marker loci and across eight breeds of cattle indicate that in cattle linkage disequilibrium persists over much more limited distances. Our findings suggest that 30,000–50,000 loci will be needed to conduct whole genome association studies in cattle.

Discovery of genetic difference between asthmatic children with high IgE level and normal IgE level by whole genome linkage disequilibrium mapping using 763 autosomal STR markers

The genome-wide linkage disequilibrium screen for loci associated with genetic difference between allergic and nonallergic asthma was conducted with 763 autosomal STR markers and included 190 asthmatic children. Evidence for association with differences between the two forms of asthma was observed for 36 STR markers. Marker-to-marker synergetic effect and by simulation resampling tests revealed D5S2011, D6S305, and D9S286 were important loci in allergic asthma while D6S1574, D8S1769, and D19S226 were important in nonallergic asthma. Our results show strong genetic evidence that these markers play an important role in defining allergic and nonallergic asthma and provides important candidates of susceptible genes in these two categories of asthma. This study further shows that asthma is, indeed, a heterogeneous group of underlying diseases and, although with similar clinical phenotypes, may have different clinical severities, outcomes, and need more tailor-made management.

Linkage Disequilibrium and Haplotype Architecture for two ABC Transporter Genes (ABCC1 and ABCG2) in Chinese Population: Implications for Pharmacogenomic Association Studies

Information about linkage disequilibrium (LD) patterns and haplotype structures for candidate genes is instructive for the design and analysis of genetic association studies for complex diseases and drug response. ABCC1 and ABCG2 are genes coding for two multidrug resistance (MDR) associated transporters; they are also related to some pathophysiological traits. To pinpoint the LD profiles of these MDR genes in Chinese, we systemically screened 27 unrelated individuals for single nucleotide polymorphisms (SNPs) in the coding and regulatory regions of these genes, and thereby characterized their haplotype structures. Despite marked variations in haplotype diversity, LD pattern and intragenic recombination intensity between the two genes, both loci could be partitioned into several LD blocks, in which a modest number of haplotypes accounted for a high fraction of the sampled chromosomes. We concluded that each locus has its own genomic LD profile, but that they still share a common segmental LD architecture with low haplotype diversity. Our data will benefit genetic association studies of complex traits and drug response possibly related to these genes.

Family-based association study of schizophrenia with 444 markers and analysis of a new susceptibility locus mapped to 11q13.3.

Family-based linkage disequilibrium (LD) mapping has been suggested as a powerful and practical alternative to linkage analysis. We have performed a genome-wide LD survey of susceptibility loci for schizophrenia in a Japanese population. We first typed 119 schizophrenic pedigrees (357 individuals) using 444 microsatellite markers, and analyzed the data using the pedigree disequilibrium test. This analysis revealed 14 markers demonstrating significant transmission distortion. To corroborate these findings, the statistical methods were changed to the extended transmission disequilibrium test (ETDT), using 80 independent complete trios (schizophrenic proband and both parents), with 68 derived from initial pedigrees and 12 newly recruited trios. ETDT supported two markers for continued association, D11S987 on 11q13.3 (P = 0.00009) and D16S423 on 16p13.3 (P = 0.002). We scrutinized the most significant genomic locus on 11q11-13 by adding 26 new markers for analysis. Results of three-marker haplotype analysis in the region showed evidence of association with schizophrenia (most significant haplotype P = 0.0005, global P = 0.022). Although the present study may have missed other potential genomic intervals because of the sparse mapping density, we hope that it has identified promising anchor points for further studies to identify risk-conferring genes for schizophrenia in the Japanese population. In addition, we provide useful information on genomic LD structures in Japanese populations, which can be used for LD mapping of complex diseases.

Designing an optimum genetic association study using dense SNP markers and family-based sample.

Genetic association analysis using thousands of single nucleotide polymorphism (SNP) markers has become a promising alternative to genome-wide linkage scan. Analysis based on linkage-disequilibrium (LD) is more efficient because meiotic information of past generations is utilized. However, in addition to the physical distance between the disease locus and a marker locus, numerous other factors such as admixture, genetic drift, and multiple mutations can affect the observed value of LD. The effect of these factors in a genomic LD association study must be carefully analyzed to obtain an efficient study design. In the following review, we consider studies using family-based data and carefully study the effects of some of these important design factors, including the sample size, frequency of SNP markers, and marker density. For example, we conclude that (1) for reasonably frequent SNP markers, a moderately large sample of 500 families is appropriate for a moderately stringent significance level (alpha = 0.00009); (2) to maintain a power of 80%, maximal difference in allele frequencies between the disease gene and a SNP marker varies between 0.1 (under additive model) and 0.5 (multiplicative); (3) a map density of 10 cM is appropriate only under idea scenario (moderately large sample size, equal trait/marker allele frequencies, maximum LD strength etc.). Results shown here should have practical implications to designing efficient LD association studies using dense SNP markers.