SUMMARY: HapAnalyzer is an analysis system that provides minimum analysis methods for the SNP-based association studies. It consists of Hardy-Weinberg equilibrium (HWE) test, linkage disequilibrium (LD) computation, haplotype reconstruction, and SNP (or haplotype)-phenotype association assessment. It is well suited to a case-control association study for the unrelated population.
Case-Control Studies ; Haplotypes* ; Linkage Disequilibrium

An alternative way of constructing ancestral graphs, which is different from the coalescent-based approach, is proposed using population linkage disequilibrium (LD) data. The main difference from the existing method is the construction of the ancestral graphs based on variants instead of individual sequences. Therefore, the key of the proposed method is to use the order of allele ages in the graphs. Distinct from the previous age-estimation methods, allele ages are estimated from full haplotype information by examining the number of generations from the initial complete LD to the current decayed state for each two variants depending on the direction of LD decay between variants. Using a simple algorithmic procedure, an ancestral graph can be derived from the expected allele ages and current LD decay status. This method is different in many ways from previous methods, and, with further improvement, it might be a good replacement for the current approaches.
Alleles ; Family Characteristics ; Haplotypes ; Linkage Disequilibrium ; Recombination, Genetic

OBJECTIVE: Categorical syndromes such as schizophrenia may represent complexes of many continuous psychological structural phenotypes along several dimensions of personality development/degeneration. The present study investigated the heritability and familiality of personality dimensions in Korean families with schizophrenic linkage disequilibrium (LD). METHODS: We recruited 179 probands (with schizophrenia) as well as, whenever possible, their parents and siblings. We used the Temperament and Character Inventory (TCI) to measure personality and symptomatic dimensions. The heritability of personality dimensions in a total of 472 family members was estimated using Sequential Oligogenic Linkage Analysis Routines (SOLAR). To measure familiality, we compared the personality dimensions of family members with those of 336 healthy unrelated controls using analysis of variance (ANOVA) analysis. RESULTS: Three of the seven TCI variables were significantly heritable and were included in subsequent analyses. The three groups (control, unaffected first-degree relative, case) were found to significantly differ from one another, with the expected order of average group scores, for all heritable dimensions. CONCLUSION: Despite several study limitations with respect to family recruitment and phenotyping, our results show that aberrations in several personality dimensions related to genetic-environment coactions or interactions may underlie the complexity of the schizophrenic syndrome.
Humans ; Linkage Disequilibrium* ; Parents ; Phenotype ; Schizophrenia ; Siblings ; Temperament*

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

PURPOSE: Single-nucleotide polymorphism (SNP) markers within LIN28B have been reported to be related to the timing of pubertal growth. However, no study has investigated the frequency of genetic markers in girls with precocious puberty (PP) or early puberty (EP). This study aimed to determine the frequency of putative genetic markers in girls with PP or EP. METHODS: Genomic DNAs were obtained from 77 and 109 girls that fulfilled the criteria for PP and EP, respectively. The controls in this study were 144 healthy volunteers between 20 and 30 years of age. The haplotypes were reconstructed using 11 SNPs of LIN28B, and haplotype association analysis was performed. The haplotype frequencies were compared. Differences in the clinical and laboratory parameters were analyzed according to the haplotype dosage. RESULTS: Eleven SNPs in LIN28B were all located in a block that was in linkage disequilibrium. The haplotype could be reconstructed using 2 representative SNPs, rs4946651 and rs369065. The AC haplotype was less frequently observed in the PP group than in the controls (0.069 vs. 0.144, P=0.010). The trend that girls with non-AC haplotypes tended to have earlier puberty onset (P=0.037) was illustrated even in the EP+PP patient group by Kaplan-Meier analysis. CONCLUSION: The results of the present study showed that non-AC haplotypes of LIN28B had a significant association with PP in girls.
DNA ; Genetic Markers ; Haplotypes ; Humans ; Linkage Disequilibrium ; Polymorphism, Single Nucleotide ; Puberty ; Puberty, Precocious

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

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.

In order to find the disease susceptibility gene in these complex genetic trait, there have been much interests in association study using single nucleotide polymorphism (SNP). Association study can be divided into two approaches candidate gene approach and linkage disequilibrium mapping. Recently, the candidate gene approach also has attracted much attention with the possiblity of whole genome wide scan being widely discussed. In genome wide scan, the amount of information that a locus can provide about the other adjacent loci becomes an important matter. When a locus was found not to be associated with a trait, it is questionable that closely situated adjacent loci can also be excluded as disease susceptible loci. To approach this problem theoretically, this study tried to find a method to calculate power in case-control association study, and aimed to investigate the influence of hypothesized inheritance model to the obtainable power. In addition, this study investigated the implication of negative association results in other adjacent loci. METHOD: The power of associatiation study was calculated applying non-centrality chi-distribution approximated by Poisson distribution. Using this method, the powers in each inheritance model were calculated in candidate gene approach. The power of chi-square test in linkage disequilibrium mapping was also algebraically obtained. This method was applied to simulation data to verify the validity of the method. RESULT: The proportion of phenocopy and the allele frequency of candidate locus exert substantial influence to the power of the study rather than penetrance matrix or inheritance model. The power in linkage disequilibrium mapping exponentially decreased according to the degree of linkage disequilibrium as anticipated, however, the marker allele frequency exert enormous influence to the power. Without any a prior knowledge about which marker allele had linked with disease susceptibility allele, the marker with equal distribution of each allele showed the highest power. CONCLUSION: The implication of negative results obtained in association study can only be determined by power analysis. In linkage disequilibrium mapping, if favorable power had been obtained, exclusion analysis of specific gene segment could be attempted. Taking into account the probable inheritance model and the marker allele frequency in designing association study, more efficient and rigorous study can be possible.
Alleles ; Case-Control Studies ; Disease Susceptibility ; Gene Frequency ; Genome ; Linkage Disequilibrium ; Penetrance ; Polymorphism, Single Nucleotide* ; Wills

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