• Communications for Statistical Applications and Methods
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• v.24 no.6
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• pp.663-671
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• 2017

Some genetic association tests include an unidentifiable nuisance parameter under the null hypothesis of no association. When the mode of inheritance (MOI) is not specified in a case-control design, the Cochran-Armitage (CA) trend test contains an unidentifiable nuisance parameter. The transmission disequilibrium test (TDT) in a family-based association study that includes the unaffected also contains an unidentifiable nuisance parameter. The hypothesis tests that include an unidentifiable nuisance parameter are typically performed by taking a supremum of the CA tests or TDT over reasonable values of the parameter. The p-values of the supremum test statistics cannot be obtained by a normal or chi-square distribution. A common method is to use a Davies's upper bound of the p-value instead of an exact asymptotic p-value. In this paper, we provide a unified sine-cosine process expression of the CA trend test that does not specify the MOI and the TDT that includes the unaffected. We also present a closed form expression of the exact asymptotic formulas to calculate the p-values of the supremum tests when the score function can be written as a linear form in an unidentifiable parameter. We illustrate how to use the derived formulas using a pharmacogenetics case-control dataset and an attention deficit hyperactivity disorder family-based example.

• The Korean Journal of Applied Statistics
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• v.21 no.1
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• pp.81-94
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• 2008

Family-based tests such as the transmission and disequilibrium tests(TDT) have proved to be powerful tools in the search for disease genes. Unlike case-control studies, the tests are not affected by population admixture, which can lead to spurious association of multiple highly linked makers with disease-susceptible genes. Those tests have largely required knowledge of parental marker genotypes. However, parental data are often not available for late-onset diseases. In this article we propose sib-TDTs that overcome this problem by use of marker data from unaffected sib(s) instead of parents. To do this end, we fist defined a Mantel-Haenszel-type statistic for each haplotype and then proposed two tests based on this statistic. Simulation studies suggest that the proposed tests are robust to population admixture and are monotone increasing as a relative risk increases irrespective of mode of inheritance. We also illustrated the proposed tests with data adopted from Yonsei Cardiovascular Genome Center.

• Journal of Preventive Medicine and Public Health
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• v.37 no.4
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• pp.366-372
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• 2004

Objectives : This study was conducted to propose a new transmission/disequilibrium test(TDT) to test the linkage between genetic markers and disease-susceptibility genes based on haplotypes. Simulation studies were performed to compare the proposed method with that of Zhao et al. in terms of type I error probability and powers. Methods : We estimated the haplotype frequencies using the expectation-maximization(EM) algorithm with parents genotypes taken from a trio dataset, and then constructed a two-way contingency table containing estimated frequencies to all possible pairs of parents haplotypes. We proposed a score test based on differences between column marginals and their corresponding row marginals. The test also involved a covariance structure of marginal differences and their variances. In simulation, we considered a coalescent model with three genetic markers of biallele to investigate the performance of the proposed test under six different configurations. Results : The haplotype-based TDT statistics, our test and Zhao et al.'s test satisfied a type I error probability, but the TDT test based on single locus showed a conservative trend. As expected, the tests based on haplotypes also had better powers than those based on single locus. Our test and that of Zhao et al. were comparable in powers. Conclusion : We proposed a TDT statistic based on haplotypes and showed through simulations that our test was more powerful than the single locus-based test. We will extend our method to multiplex data with affected and/or unaffected sibling(s) or simplex data having only one parent s genotype.

• The Korean Journal of Applied Statistics
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• v.23 no.6
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• pp.1103-1113
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• 2010

An extensively used approach for family based association test(FBAT) is compared with the sib transmission/disequilibrium test(S-TDT), and in particular the adjusted S-TDT, in which the covariance among related siblings is taken into consideration, can provide a more sensitive test statistic for association. A simulation study comparing the three test statistics demonstrates that the type I error rates of all three tests are larger than the prespecified significance level and the power of the FBAT is lower than those of the other two tests. More detailed studies are required in order to assess the influence of the assumed conditions in FBAT on the efficiency of the test.

• Communications for Statistical Applications and Methods
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• v.17 no.5
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• pp.733-743
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• 2010

Recently, disease-genetic association analyses using single nucleotide polymorphisms(SNPs) and haplotypes in family-based genetic study have come into the spotlight. In binary trait, the classic transmission disequilibrium test(TDT) can only be applied if genetic information of parents and their offspring is available. However, in case of diseases having a late age of onset such as dementia, the TDT cannot be applied due to the fact that parental genotype data are unavailable. For this reason, alternate methods using genetic sib information instead of parental genotype data are proposed. In this study, methods using genetic sib information are reviewed and power of analysis tests is also compared throughout simulation experiment.

• Journal of Preventive Medicine and Public Health
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• v.42 no.1
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• pp.1-4
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• 2009

Objectives : Isolated cleft lip with or without cleft palate(CL/P) is among the most common human birth defects, with a prevalence of approximately 1 in 700 live births. The B-Cell Leukemia/lymphoma 3(BCL3) gene has been suggested as a candidate gene for CL/P based on association and linkage studies in some populations. This study tests for an association between markers in BCL3 and isolated, non-syndromic CL/P using a case-parent trio design, while considering parent-of-origin effects. Methods : Forty case-parent trios were genotyped for two single nucleotide polymorphisms(SNPs) in the BCL3 gene. We performed a transmission disequilibrium test(TDT) on individual SNPs, and the FAMHAP package was used to estimate haplotype frequencies and to test for excess transmission of multi-SNP haplotypes. Results : The odds ratio for transmission of the minor allele, OR(transmission), was significant for SNP rs8100239(OR=3.50, p=0.004) and rs2965169(OR=2.08, p=0.027) when parent-of-origin was not considered. Parentspecific TDT revealed that SNP rs8100239 showed excess maternal transmission. Analysis of haplotypes of rs2965169 and rs8100239 also suggested excess maternal transmission. Conclusions : BCL3 appears to influence risk of CL/P through a parent-of-origin effect with excess maternal transmission.

• Journal of the Korean Academy of Child and Adolescent Psychiatry
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• v.18 no.2
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• pp.123-129
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• 2007

Objectives: Autism is a complex neurodevelopmental spectrum disorder with a strong genetic component. Previous neurochemical and genetic studies have suggested the possible involvement of the serotonin system in autism. Tryptophan 2,3-dioxygenase(TDO2) is the rate-limiting enzyme in the catabolism of tryptophan, which is the precursor of serotonin synthesis. The aim of this study was to investigate the association between the TDO2 gene and autism spectrum disorders(ASD) in a Korean population. Methods: The patients were diagnosed with ASD on the basis of the DSM-IV diagnostic classification outlined in the Korean version of the Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule. The present study included the detection of four single nucleotide polymorphisms(SNPs) in the TDO2 gene(rs2292536, rs6856558, rs6830072, rs6830800) and the family-based association analysis of the single nucleotide polymorphisms in Korean ASD trios using a transmission disequilibrium test(TDT) and haplotype analysis. The family trios of 136 probands were included in analysis. 87.5% were male and 86.0% were diagnosed with autism. The mean age of the probands was $78.5{\pm}35.8$ months(range: 26-264 months). Results: Two SNPs showed no polymorphism, and there was no significant difference in transmission in the other two SNPs. We also could not find any significant transmission in the haplotype analysis(p>.05). Conclusion: We could not find any significant statistical association between the transmission of SNPs in the TDO2 gene and ASD in a Korean population. This result may not support the possible involvement of the TDO2 gene in the development of ASD, and further exploration might be needed to investigate other plausible SNP sites.

• Korean Journal of Biological Psychiatry
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• v.13 no.4
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• pp.289-298
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• 2006

Objectives : Autism is a complex neurodevelopmental spectrum disorder with a strong genetic component. Previous neurochemical and genetic studies suggested the possible involvement of glutamate N-methyl-D-aspartate(NMDA) receptor in autism. The aim of study was to investigate the association between the NMDA2B receptor gene(GRIN2B) and autism spectrum disorders(ASD) in the Korean population. Methods : The patients with ASD were diagnosed with Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule based on DSM-IV diagnostic classification. The present study was conducted with the detection of four single nucleotide polymorphisms(SNPs) in GRIK2 and family-based association analysis of the single nucleotide polymorphisms in Korean ASD trios using transmission disequilibrium test (TDT). Results : One hundred twenty six patients with ASD and their biological parents were analyzed. 86.5% were male and 85.1% were diagnosed as autistic disorder. The mean age was $71.9{\pm}31.6$ months(range : 26-185 months). We found that rs1805247 showed significantly preferential transmission(TDT ${\chi}^2$=12.8, p<0.001) in ASD. Conclusion : One SNP in GRIN2B gene was significantly associated with ASD in the Korean population. This result suggests the possible involvement of glutamate NMDA receptor gene in the development of ASD.

• Journal of the Korean Academy of Child and Adolescent Psychiatry
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• v.18 no.2
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• pp.154-161
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• 2007

Objectives: The aim of the current study is to test for the association of DRD4 exon III VNTR polymorphism with attention-deficit hyperactivity disorder(ADHD) in Korean children population. Methods: 113 Korean children with ADHD, 102 parents, and 133 control subjects participated with the current study. The distribution of genotypes and alleles of DRD4 exon III VNTR in children with ADHD was compared with that in control subjects. In addition, 69 children with ADHD and their parents were analyzed using the transmission disequilibrium test(TDT). Results: We could not find any significant differences in the distribution of genotypes and alleles at DRD4 exon III VNTR polymorphism between children with ADHD and control subjects. In addition, there was no preferential transmission of long allele of DRD4 exon III VNTR polymorphism. Conclusion: These results suggest that DRD4 is not associated with ADHD in Korean children population.

• Korean Journal of Biological Psychiatry
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• v.11 no.2
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• pp.146-154
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• 2004

Objective:Attention deficit hyperactivity disorder(ADHD) is the most common childhood psychiatric disorder, affecting 3-5% of school-aged children. Although the biological basis of ADHD is unknown, family studies provide strong evidence that ADHD has a genetic basis. Recent genetic studies have suggested associations between ADHD and serotonin 1B(5HT1B) receptor gene G861C polymorphism. The aim of this study is to test for the association between ADHD and 5HT1B receptor gene G861C polymorphism in Korean population. Method:We processed DNA extraction and genotyping. 106 Korean children with ADHD and their parents were analyzed using the transmission disequilibrium test(TDT) and haplotype-based haplotype relative risk (HHRR). And the ADHD children were compared with 212 age and gender matched normal controls. Results:There was no statistical difference of distributions between ADHD cases and controls. We did not observe any preferential transmission of alleles of 5HT1B receptor gene G861C polymorphism in ADHD. Conclusions:Though there is the possibility of failing to detect small genetic effects, our results show no evidence of an association between ADHD and 5HT1B receptor gene G861C polymorphism in the Korean population and indicate that it is unlikely that the 5HT1B receptor is implicated in the susceptibility to ADHD.