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

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

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

Most common diseases are caused by multiple genetic and environmental factors. Among the genetic factors, single nucleotide polymorphisms (SNPs) are common DNA sequence variations in individuals and can serve as important genetic markers. Recently, investigations of gene-based and whole genome-based SNPs have been applied to association studies for marker discovery. However, SNPs are so population-specific that the association needs to be verified. Fifty-five genes and 384 SNPs were selected based on association with disease. Genotypes of 337 SNPs in candidate genes were determined using Illumina Sentrix Array Matrix (SAM) chips by an allelespecific extension method in 364 unrelated Korean individuals. Allelic frequencies of SNPs were compared with those of other populations obtained from the International HapMap database. Minor allele frequencies, linkage disequilibrium blocks, tagSNPs, and haplotypes of functional candidate SNPs in 55 genetic disease-associated genes were provided. Our data may provide useful information for the selection of genetic markers for genebased genetic disease-association studies of the Korean population.
Base Sequence ; Gene Frequency ; Genetic Markers ; Genotype ; Haplotypes ; HapMap Project ; Linkage Disequilibrium ; Polymorphism, Single Nucleotide*

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

OBJECTIVES: Previous studies on NOTCH4 gene and schizophrenia have not produced consistent results, and more studies with various ethnicities and populations were warranted. This study was performed with Korean population to find the role of the NOTCH4 gene in the development of schizophrenia. METHODS: 235 schizophrenics and 236 normal controls participated in the study. Two SNPs (-1725 A/G and -25 T/C) on the NOTCH4 gene were investigated. Genotyping was done by Taqman assay, and statistical analysis was done by contingency chi-square test for the allele and genotype frequencies and PowerMarker V3.0 for the haplotype. RESULTS: The two SNPs did not deviate from Hardy-Weinberg equilibrium in neither schizophrenics or normal controls. Two groups were not different in terms of allele and genotype distribution for both SNPs. Two SNPs were found to be in linkage disequilibrium. Haplotype analysis could not find an association between schizophrenia and these two SNPs. There was no association between the age at onset and the genotypes for both SNPs. CONCLUSION: We could not find any significant association between schizophrenia and the NOTCH4 gene in this Korean population. Although there are limitations in this study, this result supports the conclusion that the NOTCH4 gene is less likely to play a major role on the development of schizophrenia in the Asian population.
Alleles ; Asian Continental Ancestry Group ; Genotype ; Haplotypes ; Humans ; Linkage Disequilibrium ; Polymorphism, Single Nucleotide* ; Schizophrenia*

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