Quantitative trait loci (QTL) and their additive, dominance and epistatic effects play a critical role in complex trait variation. It is often infeasible to detect multiple interacting QTL due to main effects often being confounded by interaction effects. Positioning interacting QTL within a small region is even more difficult. We present a variance component approach nested in an empirical Bayesian method, which simultaneously takes into account additive, dominance and epistatic effects due to multiple interacting QTL. The covariance structure used in the variance component approach is based on combined linkage disequilibrium and linkage (LDL) information. In a simulation study where there are complex epistatic interactions between QTL, it is possible to simultaneously fine map interacting QTL using the proposed approach. The present method combined with LDL information can efficiently detect QTL and their dominance and epistatic effects, making it possible to simultaneously fine map main and epistatic QTL.
Chromosome Mapping ; Epistasis, Genetic ; Genetic Linkage ; Humans ; Linkage Disequilibrium ; Monte Carlo Method ; Quantitative Trait Loci ; genetics

Suitability of a specific population for linkage disequilibrium mapping studies of complex traits may be assessed by investigating the background linkage disequilibrium (BLD). We are unaware of studies for quantifying the degree of BLD in the Korean population, although the population may be a good candidate for mapping of complex trait genes through whole-genome association studies. It is useful to investigate the properties of genetic isolates in East Asia and to compare them to genetic isolates in Europe. We analyzed the extent of BLD in the Korean population using 735 microsatellite markers and compared the results with the Icelander population, which is one of the European expanded genetic isolates. The Korean population exhibited a level of BLD comparable with the Icelander population. The inference of population structure using the model with admixture showed that each individual has allele copies originating from K populations in equal proportions. Therefore, we believe that factors other than genetic distance, such as recent admixture, have not contributed to the level of BLD. Our results showed that the Korean population, which is an expanded population with no evidence of admixture, has a BLD level comparable with the Icelander population. Therefore, the Korean population can be used for fine mapping of either complex traits or monogenic diseases.
Microsatellite Repeats/*genetics ; Male ; Linkage Disequilibrium/*genetics ; Korea ; Humans ; *Heterozygote ; Female ; Chromosomes, Human/genetics ; Adult

OBJECTIVETo investigate the relationship between haplotypes of multilocus markers and ankylosing spondylitis (AS).

METHODSFive families with AS were recruited from Shanghai area. Eleven microsatellite markers around D6S276 were analyzed by Linkage package and by Cyrillic package.

RESULTSFine linkage analysis showed the significant Lod score values with D6S276 was 3.8821, Lod score values with D6S1691 and D6S1618 near D6S276 were larger than 1.5. The crossover value in 5 pedigrees was 14%. The haplotype analysis showed that the regions between D6S1691 and D6S1618 were associated with AS.

CONCLUSIONThe regions of D6S1691-D6S276-D6S1618 may harbor a susceptible gene of AS. The specific haplotypes of different pedigrees may play an important role in the presymptomatic diagnosis for AS.

Female ; Haplotypes ; genetics ; Humans ; Linkage Disequilibrium ; genetics ; Male ; Pedigree ; Spondylitis, Ankylosing ; genetics

OBJECTIVETo explore the relationship between the microsatellite markers on chromosome 6 and schizophrenia by linkage disequilibrium analysis.

METHODSTwenty-eight microsatellite markers on chromosome 6 were evaluated in 115 affected-sib-pair and trios families. Linkage disequilibrium analysis was conducted according to diagnostic categories, Positive and Negative Syndrome Scale (PANSS) and other clinical data by XDT and MAPMAKER/SIBS software system.

RESULTSSignificant P value (P<0.005) was found in all the four diagnostic categories. Only the locus of D6S1960 showed positive P value (P<0.05) in all the subgroups divided by PANSS scale and the age of onset.

CONCLUSIONThe area around D6S1960 in short arm of chromosome 6 may contain susceptibility gene of schizophrenia.

Age of Onset ; Chromosomes, Human, Pair 6 ; Humans ; Linkage Disequilibrium ; Microsatellite Repeats ; genetics ; Schizophrenia ; genetics

Human leukocyte antigen (HLA) is the most polymorphic genetic system found in human genome. The polymorphisms of different HLA genes and haplotypes in different ethnic and geographic populations are of high importance for investigation of their population genetic characteristics and searching for HLA matched unrelated hematopoietic stem cell transplantation donors, as well as in disease association studies. The HLA molecular genetic principals and the progress of HLA population investigation were reviewed, as well as the methods applied in the field.
Alleles ; Genetics, Population ; methods ; HLA Antigens ; genetics ; Haplotypes ; Humans ; Linkage Disequilibrium

Understanding with greater clearness the characteristics of recombination within the human leucocyte antigen(HLA) is of deep significance to gaining an insight into the evolutionary process of shaping HLA allelic diversity and ultimately the human resistance against diverse pathogens. Family studies and statistical analysis of recombination have provided estimations of recombination fractions across the major histocompatibility complex and have identified the potential recombination hotspots. Other characteristics such as haplotype specificity and sequence motifs have been intensively studied. The recombination fractions, hotspots and other characters are reviewed in this paper.
Gene Frequency ; HLA Antigens ; genetics ; Haplotypes ; Humans ; Linkage Disequilibrium ; Recombination, Genetic ; genetics

OBJECTIVESTo formulate an equation for fine mapping of disease loci under complex conditions and determine the marker-disease distance in a specific case using this equation.

METHODSLewontin's linkage disequilibrium (LD) measure D' was used to formulate an equation for mapping disease genes in the presence of phenocopies, locus heterogeneity, gene-gene and gene-environment interactions, incomplete penetrance, uncertain liability and threshold, incomplete initial LD, natural selection, recurrent mutation, high disease allele frequency and unknown mode of inheritance. This equation was then used to determine the distance between a marker ( epsilon 4 within the apolipoprotein E gene, APOE) and Alzheimer's disease (AD) loci using published data.

RESULTSAn equation was formulated for mapping disease genes under the above conditions.If these conditions are present but ignored, then recombination fraction theta between marker and disease loci will be either overestimated or estimated with little bias. Therefore, an upper limit of theta can be obtained. AD has been found to be associated with the marker allele epsilon 4 in Africans, Asians, and Caucasians. This suggests that the AD- epsilon 4 allelic LD predates the divergence of peoples occurring 100 000 years ago. With the age of AD- epsilon 4 allelic LD so estimated, the maximal distance was calculated to be 23.2 kb (mean 5.8 kb).

CONCLUSIONS(1) A method is developed for LD mapping of susceptibility genes. (2) A mutation within the APOE gene itself, among others, is responsible for the susceptibility to AD, which is supported by recent evidence from studies using transgenic mice.

Alzheimer Disease ; genetics ; Chromosome Mapping ; Confidence Intervals ; Genetic Predisposition to Disease ; genetics ; Humans ; Linkage Disequilibrium ; Mutation

Rheumatoid arthritis (RA) is a systemic inflammatory disease associated with both genetic and environmental factors. The DRB1 gene at the human leukocyte antigen (HLA) locus of chromosome 6p21.3 was the first genetic factor associated with RA to be identified in the 1980s; however, identification of causative genes other than those at the HLA locus has been challenging for geneticists because of the strong linkage disequilibrium in this locus and the non-Mendelian inheritance pattern of RA. Recent advances in high-throughput single nucleotide polymorphism genotyping technologies and bioinformatic analysis tools have facilitated the identification of positive associations of hundreds of genes with RA using family-based linkage analyses and genome wide association studies. Some of the RA associated genes at non-HLA loci are as follows: PADI4, PTPN22, STAT4, and TNFAIP3. In this paper, we describe the pathological mechanisms mediated by these genes. In addition, we review results of previous genetic studies of RA and future challenges in connecting the dots of missing heritability in the post-genome-wide association study era.
Arthritis, Rheumatoid* ; Genetics ; Genome-Wide Association Study ; Humans ; Inheritance Patterns ; Leukocytes ; Linkage Disequilibrium ; Polymorphism, Single Nucleotide

Antigen processing (TAP, HLA-DM and LMP) genes map within the major histocompatibility complex (MHC) class II region between the HLA-DQB1 and -DPB1 loci, and are involved in the processing of peptides bound to HLA class I or class II molecules. In order to determine the allele frequencies of antigen processing genes and the various linkage disequilibria existing among these genes, we have analyzed TAP1, TAP2, HLA-DMA, and HLA-DMB, LMP2, LMP7 polymorphisms in 184 unrelated healthy Koreans using the rnethod of PCR-SSCP, ARMS-PCR and PCR-RFLP. The frequencies of antigen processing genes were TAP1A (77.7%), TAP1*B (17.1%), TAP1*C (5.2%), TAP2*A (41.6%), TAP2*B (31.3%), TAP2*C (3.3%), TAP2*D (0.8%), TAP2*E (6.5%), TAP2*G (0.8%), HLA-DMA*0101 (81.5%), HLA-DMA*0102 (18.2%), HLA-DMA*0103 (0.3%), HLA-DMB*0101 (42.9%), HLA-DMB*0102 (19.0%), HLA-DMB*0103 (38.0%), LMP2*R (78.8%), LMP2*H (21.2%), LMP7*A (35.3%), LMP7*B (56.0%), LMP7*C (4.9%), and LMP7*D (3.8%). We also analysed two- locus association among each locus. Many significant positive associations were observed between these two loci, such as between HLA-DMB and TAP1, between HLA-DMA and HLA-DMB, between LMP2 and LMP7, and between TAP1 and LMP7. Conversely, any significant linkage disequilibrium was not detected between HLA-DMB and LMP2. These results could be used as control data for disease association and population genetics studies in Korean population.
Antigen Presentation* ; Gene Frequency ; Genetics, Population ; Linkage Disequilibrium ; Major Histocompatibility Complex ; Peptides

With the rapid development of human genome project, increased genetic and population-based association studies are focused on the identification of the underlying susceptibility genes and contributions from gene-environment interaction to common complex diseases. Whole-genome association study with high-density single nucleotide polymorphisms is one of the most important milestones in that process. However, problems still exist in study design, data processing, and results interpretation. Large-scale cohort study or population-based case-control design with sufficient statistical power, new approaches to assess the gene-gene and gene-environment interactions, as guarantee of the consistency and replicability of these researches are crucial in the exploration of the causes of these common complex diseases.
Genetic Markers ; Genetic Predisposition to Disease ; Genetics, Population ; Humans ; Linkage Disequilibrium ; Molecular Epidemiology ; Phenotype