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

BACKGROUND: TAP1 and TAP2 are two ABC transporter genes located within the class II region of the human MHC. Their protein products form a heterodimer whose function is to transport peptides from the cytoplasm into the endoplasmic reticulum. This study was performed to examine the polymorphism of TAP genes and the distribution of HLA-TAP haplotypes in the Korean population through family analysis. METHODS: The subjects used in this study were 50 healthy Korean families consisting of 233 individuals. TAP1 (codons 333 and 637) and TAP2 (codons 379, 565, 577, 651, 665, and 687) typings were carried out by the PCR-restriction fragment length polymorphism (RFLP) method. HLA-DRB1 and DQB1 genotyping results from a previous study were used for HLA-TAP haplotype analysis. RESULTS: The number (gene frequency) of TAP1 and TAP2 alleles detected were 3 for TAP1 (A 81.5%, B 17.0%, and C 1.5%) and 8 for TAP2 (A1 32.0%, A2 12.5%, B 34.0%, Bky2 6.5%, C 7.0%, D 3.0%, E 4.5%, and G 0.5%). Eleven TAP1-TAP2 haplotypes were observed with frequency 1%, among which 4 haplotypes (A-B, B-A1, A-Bky2, and C-E) showed weak but significant positive linkage disequilibrium (P<0.05). When DRB1-DQB1 haplotypes were extended to TAP1 and TAP2 loci, much diversification of haplotypes was observed: 19 different DRB1- DQB1 haplotypes formed 58 different haplotypes extended to TAP1 and TAP2 loci. These results add more evidence to the view that recombination hotspot is present within and around TAP gene region. CONCLUSION: The allele frequencies of TAP1 and TAP2 genes and the distribution of TAP1-TAP2 and HLA-TAP haplotypes were studied in Koreans based on a family study.
Alleles ; Cytoplasm ; Endoplasmic Reticulum ; Gene Frequency ; Haplotypes* ; HLA-DRB1 Chains ; Humans ; Linkage Disequilibrium ; Peptides ; Recombination, Genetic

BACKGROUND AND OBJECTIVES: Apolipoprotein A-I is the major lipoprotein constituent of high density lipoprotein in plasma. In this study, the role of two polymorphisms in the apo A-I gene was investigated on the serum lipid profiles and apo A-I levels in healthy men and women. SUBJECTS AND METHODS: Blood samples were obtained from 417 subjects (M : F=169 : 248, mean age 47.2 years). The apo A-I genotypes were determined by SNP-IT assays using the SNPstream 25KTM system. RESULTS: The frequencies of the A allele at the XmnI restriction site and position -75 bp were 0.25/0.23 and 0.19/0.17 in men and women, respectively. A strong positive linkage disequilibrium (D'=0.990) between two polymorphisms was detected. In men, the A allele at the XmnI restriction site was associated with significantly lower levels of triglyceride (p=0.028) compared to the G/G subjects, but no significant associations were detected between the G-75A polymorphism and any of the lipid traits examined. In women, each A allele for the XmnI restriction site and -75 bp polymorphisms were significantly associated with higher levels of apo A-I (p=0.032 and p=0.012). In the multiple regression analysis, the HDL, being a current drinker and the A allele of the XmnI restriction site polymorphism were major determinants of the serum apo A-I levels in women (R2=0.272, p<0.05). CONCLUSION: Our study showed that the A allele at XmnI restriction site in the apo A-I gene was associated with decreased triglyceride levels in men. Each A allele of two polymorphisms was associated with an elevated apo A-I level in women.
Alleles ; Apolipoprotein A-I* ; Apolipoproteins* ; Female ; Genotype ; Humans ; Linkage Disequilibrium ; Lipoproteins ; Male ; Middle Aged* ; Plasma ; Triglycerides

BACKGROUND AND OBJECTIVES : The common methods of genetic association analysis are sensitive to population stratification, which may easily lead to a spurious association result. We used a regression approach based for linkage disequilibrium to perform a high resolution genetic association analysis. SUBJECTS AND METHODS : We applied a regression approach that can increase the resolution of quantitative traits that are related with cardiovascular diseases. The population data was composed of 543 males and 876 females without cardiovascular diseases, and it was obtained from a cardiovascular genome center. We used information about linkage disequilibrium between the marker and trait locus, and we added the covariates to model their effects. RESULTS : We found that this regression approach has the merit of analyzing genetic association based on linkage disequilibrium. In the analysis of the male group, the total cholesterol was significantly in linkage disequilibrium with CETP3 (p=0.002), and triglyceride was significantly in linkage disequilibrium with ACE8 (p=0.037), APOA1-1 (p=0.031), APOA5-1 (p=0.001), APOA5-2 (p=0.001) and LIPC4 (p=0.022). HDL-cholesterol was significantly in linkage disequilibrium with ACE7 (p=0.002), ACE8 (p=0.008), ACE10 (p=0.003), APOA5-2 (p=0.022), and MTP1 (p=0.001). In the female group, total cholesterol was significantly associated with APOA5-1 (p=0.020), APOA5-2 (p=0.001), and LIPC1 (p=0.016), and triglyceride was significantly associated with APOA5-1 (p=0.009), APOA5-2 (p=0.001), and CETP5 (p=0.049). LDL-cholesterol was significantly associated with APOA5-2 (p=0.004), and HDL-cholesterol was significantly associated with LIPC1 (p=0.004). CONCLUSION : We used a regression-based method to perform high resolution linkage disequilibrium analysis of a quantitative trait locus that's associated with lipid profiles. This method of using a single marker, as applied in this paper, was well suited for analysis of genetic association. Because of the simplicity, the method can also be easily performed by routine statistical analysis software.
Cardiovascular Diseases ; Cholesterol ; Female ; Genome ; Humans ; Linkage Disequilibrium* ; Male ; Quantitative Trait Loci* ; Triglycerides

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

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

Genome-wide association (GWA) studies have found many important genetic variants that affect various traits. Since these studies are useful to investigate untyped but causal variants using linkage disequilibrium (LD), it would be useful to explore the haplotypes of single-nucleotide polymorphisms (SNPs) within the same LD block of significant associations based on high-density variants from population references. Here, we tried to make a haplotype catalog affecting body mass index (BMI) through an integrative analysis of previously published whole-genome next-generation sequencing (NGS) data of 7 representative Korean individuals and previously known Korean GWA signals. We selected 435 SNPs that were significantly associated with BMI from the GWA analysis and searched 53 LD ranges nearby those SNPs. With the NGS data, the haplotypes were phased within the LDs. A total of 44 possible haplotype blocks for Korean BMI were cataloged. Although the current result constitutes little data, this study provides new insights that may help to identify important haplotypes for traits and low variants nearby significant SNPs. Furthermore, we can build a more comprehensive catalog as a larger dataset becomes available.
Body Mass Index* ; Dataset ; Genome-Wide Association Study ; Haplotypes* ; Korea ; Linkage Disequilibrium ; Polymorphism, Single Nucleotide