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PubMed2005

Three haplotypes associated with CYP2A6 phenotypes in Caucasians.

The human cytochrome P450 2A6 (CYP2A6) enzyme metabolizes several xenobiotic compounds of clinical or toxicological importance. We aimed to identify genetic variants and major CYP2A6 haplotypes associated with CYP2A6 phenotypic variation. CYP2A6 mRNA level, protein level, activity and haplotypes were determined in Caucasian liver samples via real-time polymerase chain reaction, Western blot, coumarin 7-hydroxylation, DNA sequencing and genotyping, respectively. Phenotypes were then analyzed for associations with haplotypes. CYP2A6 transcript, protein and activity levels were correlated among each other. In 45 African-American, 156 Caucasian, 47 Chinese, 50 Japanese and 47 Korean DNA samples, we detected 95 different polymorphisms in the CYP2A6 gene, 49 of which had not been described previously. Caucasian variants formed 33 haplotypes which built four clades. Allele *9B and the CYP2A7/2A6 partial deletion allele CYP2A6*12B were both associated with decreased expression. The latter haplotype extends at least over 147 kb up into the CYP2B6 gene. A haplotype almost identical to allele *1A was associated with decreased expression and activity of CYP2A6 compared to all other haplotypes. In summary A CYP2A6*1A-like allele, *9B and *12B are major genetic determinants of CYP2A6 phenotype variation in Caucasians.

Alleles↗

PubMed2006

Functional single nucleotide polymorphism haplotypes in the human equilibrative nucleoside transporter 1.

The human equilibrative nucleoside transporter 1 gene (hENT1) is the primary nucleoside transporter for cytosine arabinoside (AraC), a deoxycytidine analog used for treatment of acute leukemias and lymphomas. We screened approximately 1.6 kb upstream of the transcription initiation site of hENT1 for single nucleotide polymorphisms (SNPs) that affect gene expression. We identified one SNP at position -706G>C with a frequency of 21% in whites and 5% in African-Americans. In African-Americans, we observed two SNPs at positions -1345C>G and -1050G>A with allele frequencies of 8% and 19%, respectively. TRANSFAC analysis suggested that -1345C>G and -706G>C may alter transcription factor binding sites. Four naturally occurring haplotypes (CGG, CAG, CGC and GAG) were cloned into a luciferase expression plasmid, transfected into Cos-1 cells, and reporter activity measured at 24 and 48 h. Three haplotypes, CAG, CGC and GAG, respectively, showed average expression that was approximately two-fold (P<0.05), 1.4-fold (P<0.05) and 1.1-fold (P>0.05) higher than lowest expression haplotype CGG at 48 h. When reanalysed as single SNPs, the differences in expression were significant for -1345C>G and -1050G>A genotypes, and not for -706G>C. However, the magnitude of difference was reduced, suggesting that no single SNP completely accounts for the expression differences observed at the haplotype level. By real-time quantitative reverse transcriptase-polymerase chain reaction assay, individuals with CGG/CGC haplotypes showed 1.37-fold higher median expression of hENT1 transcript than those with common CGG/CGG haplotypes. Although not statistically significant (P=0.12), this difference is in the direction predicted by the in vitro data. hENT1 promoter region haplotypes may influence gene expression and alter AraC chemosensitivity.

Black or African American↗

PubMed2006

Four novel defective alleles and comprehensive haplotype analysis of CYP2C9 in Japanese.

Genetic variations in cytochrome P450 2C9 (CYP2C9) are known to contribute to interindividual and interethnic variability in response to clinical drugs such as warfarin. In the present study, CYP2C9 from 263 Japanese subjects was resequenced, resulting in the discovery of 62 variations including 32 novel ones. In addition to the two known non-synonymous single nucleotide polymorphisms (SNPs), Ile359Leu (*3; allele frequency=0.030) and Leu90Pro (*13; 0.002), seven novel non-synonymous SNPs, Leu17Ile (0.002), Lys118ArgfsX9 (*25; 0.002), Thr130Arg (*26; 0.002), Arg150Leu (*27; 0.004), Gln214Leu (*28; 0.002), Pro279Thr (*29; 0.002) and Ala477Thr (*30; 0.002), were found. Functional characterization of novel alleles using a mammalian cell expression system in vitro revealed that *25 was a null allele and that *26, *28 and *30 were defective alleles. The *26 product showed a 90% decrease in the Vmax value but little change in the Km value towards diclofenac. Both *28 and *30 products showed two-fold higher Km values and three-fold lower Vmax values than the *1 allele, suggesting the importance of Gln214 and Ala477 for substrate recognition. Linkage disequilibrium and haplotype analyses were performed using the detected variations. Only five haplotypes (frequency >0.02) accounted for most (>87%) of the inferred haplotypes, and they were closely associated with the haplotypes of CYP2C19 in Japanese. Although the haplotype structure of CYP2C9 was rather simple in Japanese, the haplotype distribution was quite different from those previously reported in Caucasians and Africans. Taken together, novel defective alleles and detailed haplotype structures would be useful for determining metabolic phenotypes of CYP2C9 substrate drugs in Japanese and probably Asians.

Alleles↗

PubMedDate not supplied

Determination and use of haplotypes: ethnic comparison and association of the lipoprotein lipase gene and coronary artery disease in Mexican-Americans.

PURPOSE: To illustrate an approach of deriving haplotypes for genetic association studies, using the lipoprotein lipase (LPL) gene and coronary artery disease. METHODS: Six polymorphisms sufficient to distinguish the most common haplotypes in the 3' end of LPL were identified by genotyping 10 polymorphisms in a small pilot population. These were used to haplotype LPL in large family samples of Mexican-Americans and non-Hispanic Caucasians. A case-control association study was performed comparing Mexican-Americans with and without coronary artery disease. RESULTS: The two ethnic groups exhibited significant genetic differences. Among Mexican-Americans, homozygosity for LPL haplotype 1 was protective against coronary artery disease (OR = 0.50, 95% CI 0.27-0.91). CONCLUSION: This study outlines the haplotype structure of the LPL gene, illustrates the utility of haplotype-based analysis in association studies, and demonstrates the importance of defining haplotype frequencies for different ethnic groups.

Alleles↗

PubMed2005

P2Y12 gene H2 haplotype is not associated with increased adenosine diphosphate-induced platelet aggregation after initiation of clopidogrel therapy with a high loading dose.

A large variability in the antiplatelet response to clopidogrel has been consistently reported. Recently, a P2Y12 haplotype was shown to be associated with enhanced adenosine diphosphate (ADP)-induced platelet aggregation in healthy volunteers. The aim of this study was to test in patients (n = 416) scheduled for coronary artery stenting whether P2Y12 haplotype H2 carriage is associated with increased ADP-induced platelet aggregation after administration of a 600 mg loading dose of clopidogrel. Blood was drawn from the arterial sheath at least 2 h after administration of 100 mg aspirin and 600 mg clopidogrel. ADP-induced platelet aggregation was assessed in platelet-rich plasma with light-transmission aggregometry. P2Y12 haplotypes (H1/H2) and P2Y12 C32T genotypes were determined with TaqMan assays. Haplotype combinations and genotypes were not associated with parameters of ADP-induced platelet aggregation after administration of a 600 mg loading dose of clopidogrel. Maximal ADP (5 mumol/l)-induced platelet aggregation was similar in patients carrying haplotype H2 and homozygous carriers of haplotype H1 (43.9 +/- 21.4 versus 43.2 +/- 21.1%, respectively; P = 0.77). Carriage of P2Y12 H2 haplotype does not seem to affect the platelet response to a 600 mg loading dose of clopidogrel in coronary artery disease patients prior to stenting.

Adenosine Diphosphate↗

PubMed2003

Linkage disequilibrium and haplotype diversity in the genes of the renin-angiotensin system: findings from the family blood pressure program.

Association studies of candidate genes with complex traits have generally used one or a few single nucleotide polymorphisms (SNPs), although variation in the extent of linkage disequilibrium (LD) within genes markedly influences the sensitivity and precision of association studies. The extent of LD and the underlying haplotype structure for most candidate genes are still unavailable. We sampled 193 blacks (African-Americans) and 160 whites (European-Americans) and estimated the intragenic LD and the haplotype structure in four genes of the renin-angiotensin system. We genotyped 25 SNPs, with all but one of the pairs spaced between 1 and 20 kb, thus providing resolution at small scale. The pattern of LD within a gene was very heterogeneous. Using a robust method to define haplotype blocks, blocks of limited haplotype diversity were identified at each locus; between these blocks, LD was lost owing to the history of recombination events. As anticipated, there was less LD among blacks, the number of haplotypes was substantially larger, and shorter haplotype segments were found, compared with whites. These findings have implications for candidate-gene association studies and indicate that variation between populations of European and African origin in haplotype diversity is characteristic of most genes.

Adult↗

PubMed2005

Ancient haplotypes resulting from extensive molecular rearrangements in the wheat A genome have been maintained in species of three different ploidy levels.

Plant genomes, in particular grass genomes, evolve very rapidly. The closely related A genomes of diploid, tetraploid, and hexaploid wheat are derived from a common ancestor that lived <3 million years ago and represent a good model to study molecular mechanisms involved in such rapid evolution. We have sequenced and compared physical contigs at the Lr10 locus on chromosome 1AS from diploid (211 kb), tetraploid (187 kb), and hexaploid wheat (154 kb). A maximum of 33% of the sequences were conserved between two species. The sequences from diploid and tetraploid wheat shared all of the genes, including Lr10 and RGA2 and define a first haplotype (H1). The 130-kb intergenic region between Lr10 and RGA2 was conserved in size despite its activity as a hot spot for transposon insertion, which resulted in >70% of sequence divergence. The hexaploid wheat sequence lacks both Lr10 and RGA2 genes and defines a second haplotype, H2, which originated from ancient and extensive rearrangements. These rearrangements included insertions of retroelements and transposons deletions, as well as unequal recombination within elements. Gene disruption in haplotype H2 was caused by a deletion and subsequent large inversion. Gene conservation between H1 haplotypes, as well as conservation of rearrangements at the origin of the H2 haplotype at three different ploidy levels indicate that the two haplotypes are ancient and had a stable gene content during evolution, whereas the intergenic regions evolved rapidly. Polyploidization during wheat evolution had no detectable consequences on the structure and evolution of the two haplotypes.

Chromosome Deletion↗

PubMed2005

Genome-wide definitive haplotypes determined using a collection of complete hydatidiform moles.

We present genome-wide definitive haplotypes, determined using a collection of 74 Japanese complete hydatidiform moles, each carrying a genome derived from a single sperm. The haplotypes incorporate 281,439 common SNPs, genotyped with a high throughput array-based oligonucleotide hybridization technique. Comparison of haplotypes inferred from pseudoindividuals (constructed from randomized mole pairs) with those of moles showed some switch errors in resolution of phases by the computational inference method. The effects of these errors on local haplotype structure and selection of tag SNPs are discussed. We also show that definitive haplotypes of moles may be useful for elucidation of long-range haplotype structure, and should be more effective for detecting extended haplotype homozygosity indicative of positive selection.

Female↗

PubMed2026

The Neanderthal-Derived 3p21 Haplotype at LZTFL1 in Modern-Day Moroccans Is Associated With COVID-19 Severity and Further Suggests the Presence of Neanderthals in North Africa.

There is considerable variability in the clinical presentation of COVID-19 among patients infected with SARS-CoV-2. Genome-wide association studies (GWASs) have identified the 12q24.13 and 3p21.31 regions, derived from Neanderthal DNA, as the human genetic loci most strongly associated with COVID-19 severity. We examined in this study the 3p locus in the Moroccan population by analysing allele and haplotype frequencies at the LZTFL1 gene and their associations with COVID-19 outcomes. Three SNPs at LZTFL1, tagging the Neanderthal-derived COVID-19 risk haplotype, were sequenced by Sanger's method in 102 ambulatory participants and 105 hospitalized patients and have been compared to 118 controls negative for SARS-CoV-2 infection using logistic regression analysis. Results showed that the prevalence of the lead variant rs11385942 in this locus was 8.9%, whereas the variants rs35044562 and rs13078854, which tag the Neanderthal haplotype, were present in only 6.3%. Our study showed that only the rs35044562-T and rs13078854-A alleles were associated with a 2.5-fold increased risk of severe COVID-19 (p = 0.028). These two alleles, in LD with the rs11385942-AA one, form the haplotype inherited from the Neanderthal, the only haplotype associated with COVID-19 severity in the Moroccan population (p = 0.030), whereas sub-Saharan African and the rare local haplotype also containing the rs11385942 variant do not influence the COVID-19 outcomes 19 (p > 0.05). Furthermore, our study showed that the Neanderthal haplotype at 3p21 locus exists in the inhabitants of Morocco at a frequency close to that of Europeans and suggests a close connection between North Africa and Eurasia.

Adult↗

PubMed2005

Fine mapping of the psoriasis susceptibility gene PSORS1: a reassessment of risk associated with a putative risk haplotype lacking HLA-Cw6.

Human leukocyte antigen (HLA)-Cw6 has long been associated with psoriasis, and PSORS1 (psoriasis susceptibility 1), a major gene for psoriasis susceptibility, has been mapped to its vicinity. A previous analysis identified multiple risk haplotypes carrying HLA-Cw6 and one haplotype (cluster 17, HLA-Cw8-B65) that appeared to carry risk for psoriasis but did not carry HLA-Cw6. This haplotype was very similar to other risk haplotypes for at least 60 kb telomeric to HLA-C, suggesting identity by descent with the remaining risk chromosomes. The association, however, between psoriasis and this haplotype as assessed by the transmission/disequilibrium test (TDT) was of borderline significance (p-value 0.048). In order to better assess the risk associated with cluster 17, a multicenter collaboration typed additional subjects for a single marker (M6S161) for which one allele (249 bp) was found only on cluster 17. The new sample included 1275 pedigrees as well as 300 cases and 913 controls. Transmission of this allele to affected individuals was examined using the TDT and the pedigree disequilibrium test (PDT), and case-control samples were analyzed by a trend test across genotype categories. By all methods, the newly acquired genotypes failed to confirm the association originally reported, despite adequate power. In contrast, the 248 bp allele, which is found on all HLA-Cw6-positive risk haplotypes as well as several non-risk haplotypes, shows significant excess transmission for all cohorts. Taken together, these results indicate that cluster 17 does not carry a psoriasis-susceptibility allele, and expand the PSORS1 risk interval to approximately 300 kb.

Case-Control Studies↗

PubMed1995

Casein haplotypes and their association with milk production traits in the Finnish Ayrshire cattle.

Polymorphism of casein genes was studied in half-sib families of artificial insemination bulls of the Finnish Ayrshire dairy breed. Ten grandsires and 300 of their sons were genotyped for the following polymorphisms: alpha s1-casein (B, C), beta-casein (A1, A2), the microsatellite within the kappa-casein gene (ms5, ms4) and kappa-casein (A, B, E). Nine different combinations of these alleles, casein haplotypes, were found. Associations between casein haplotypes and milk production traits (milk and protein yield, fat and protein percentage and milking speed) were studied with ordinary least-squares analysis to find a direct effect of the haplotypes or an association within individual grandsire families using the granddaughter design. Estimated breeding values of sons were obtained from cow evaluation by animal model. No direct effect of the casein haplotypes on the traits was found. Within grandsire families, in one out of four families the chromosomal segment characterized by haplotype 3 (B-A2-ms4-A) was associated with an increase in milk yield (P < 0.01) and a decrease in fat percentage (P < 0.01) when contrasted with haplotype 8 (B-A1-ms4-E). The results provide evidence that in the Finnish Ayrshire breed at least one quantitative trait locus affecting the genetic variation in yields traits is segregating linked to either haplotype 3 (B-A2-ms4-A) or 8 (B-A1-ms4-E).

Animals↗

PubMed2005

Falciparum malaria in the north of Laos: the occurrence and implications of the Plasmodium falciparum chloroquine resistance transporter (pfcrt) gene haplotype SVMNT.

OBJECTIVE: The Pfcrt-gene encodes a transmembrane protein located in the Plasmodium falciparum digestive vacuole. Chloroquine resistant (CQR) strains of African and Southeast Asian origin carry the Pfcrt-haplotype (c72-76) CVIET, whereas most South American and Papua New Guinean CQR stains carry the SVMNT haplotype. METHOD: Eighty-eight samples from an area with reported in vivo Chloroquine and in vitro Amodiaquine-resistance were screened for the K76T mutation and their Pfcrt-haplotype (c72-76) using a new SSOP-ELISA. RESULTS: Hundred percent of the analysed samples showed the K76T mutation which is highly associated with in vivo drug failure. This very high rate of a CQR-marker is alarming in an area were CQ is still used as first line drug. The distribution of the three main Pfcrt-haplotypes was as follows: 68% CVIET, 31% SVMNT, 0% CVMNT. CONCLUSIONS: These data show, for the first time, the South American/PNG -haplotype (SVMNT) on mainland Southeast Asia. SVMNT-haplotype and others might be associated with a decreased efficacy of Amodiaquine and could therefore be potential markers for of amodiaquine resistance (AQR). If there is a correlation between AQR and the SVMNT-haplotype as suggested, 31% prevalence of a potential resistance marker is cause for concern.

Adolescent↗

PubMed1988

Italian extended HLA haplotypes in congenital adrenal hyperplasia.

In order to complete the data on human 21-Hydroxylase deficiency, we present a study on HLA markers in 35 Italian families (14 from Northern, eight from Central and 13 from Southern Italy) with one affected child. Three children from the issue of first cousin marriages were homozygous for the whole HLA haplotype. Extended haplotypes shared by unrelated patients were not found, and a total absence of the HLA Bw47 allele among the haplotypes carrying the disease as well as normal haplotypes was observed. The absence of A1 Cw7 B8 BfS C4AQ0 C4B1 DR3 extended haplotype was instead confirmed. Allele frequencies in the different clinical forms were analyzed: BfSO7 allele frequency was significantly increased on haplotypes of the salt-wasting form (p less than 0.01). We noticed two duplications (C4B1-2) of C4B genes, on haplotypes involved in the disease. Allele distribution in the regions studied showed that Bw22 (w55), Cw3 and DR2 were characteristic of Northern patients, while B15 was found in patients from Central Italy.

Adrenal Hyperplasia, Congenital↗

PubMed1994

Multi-locus analysis of HLA class II genes in DR2-positive IDDM haplotypes in Finland. The "Childhood Diabetes in Finland" (DiMe) Study Group.

In this study we characterized the haplotypes found in IDDM patients that normally confer resistance to the disease in order to localize the polymorphisms relevant for the protection. We studied 15 DR2-positive subjects with IDDM for their DRB1, DRB5 and DQB1 genes using RFLP, polymerase chain reaction (PCR), oligonucleotide typing, and in some specific cases direct sequencing after allele-specific PCR. In addition we analyzed 39 DR2-positive, IDDM non-associated haplotypes representing those haplotypes that are not inherited to probands and hence are present only in healthy family members. The frequency of the DRB1*1501-DRB5*0101-DQB1*0602 haplotype was slightly decreased among diabetic patients (80% vs. 92%). In addition, two unconventional haplotypes DRB1*1501-DRB5*0101-DQB1*05031 and DRB1*1501-DRB5*0101-DQB1*0502 were found in patients with IDDM while all the control ones were conventional. The sequencing of the DQB1*0602 allele present in IDDM haplotypes showed no differences when compared to the controls. These results support the primary but not absolute role of DQ in the protection against IDDM. An additional role of factors centromeric to DQB1 gene was suggested by findings based on the bi-allelic TaqI RFLP polymorphism of the DQA2 gene. All DR2-DQB1*0602 IDDM haplotypes were associated with the 2.1-kb fragment while in the control group the 2.1-kb and 1.9-kb fragments were evenly distributed.

Alleles↗

PubMed1997

Striking diversity of DR15 haplotypes in Croatians.

Analysis of HLA class II polymorphism revealed DR2 as the most frequent antigen in Croatians (20, 9%). The observed DR2 subtypes and their frequencies were as follows: DRB1*1601-9.9%; 1501-8.5%; 1602-1.8%, 1502-1.4% and 1503-0.7%. Furthermore, analysis of probable DRB1-DQA1-DQB1 haplotype associations in unrelated individuals revealed a high diversity of DR15 haplotype associations. Now, to confirm this observation from unrelated individuals, family studies have been performed. Sixty-eight families, with at least one parent and one offspring DR2 positive, have been studied. DRB1*1601-DQA1*0102-DQB1*0502 seems to be conserved haplotype in Croatians while DRB1*15 haplotypes showed extremely high diversity. Seven rare DR15 haplotypes are observed; six of these appear twice and one only once. Two haplotypes appear to be unique to Croatians: DRB1*1501-DQA1*0102-DQB1*0501 and DRB1*1501-DQA1*0102-DQB1*0604. This confirmation of extremely high diversity of DR15 haplotypes in Croatians is a valuable tool for unrelated bone marrow transplantation and DR2 disease association studies.

Croatia↗

PubMed2006

HLA-A, HLA-B, and HLA-DRB1 alleles and haplotypes in Naxi and Han populations in southwestern China (Yunnan province).

The frequencies of the human leukocyte antigen alleles HLA-A, HLA-B, and HLA-DRB1 and the A-B-DRB1, A-B, and B-DRB1 haplotypes were studied in Naxi and Yunnan Han populations using polymerase chain reaction (PCR)-sequence-specific amplification for alleles A and B and a PCR-microtiter plate hybridization method for the DRB1 allele. A total of 8 A, 19 B, and 30 DRB1 alleles were found in the Naxi population, and 15 A, 21 B, and 36 DRB1 alleles were found in Yunnan Han population. The common A-B-DRB1 haplotypes in the Naxi population were A*24-B*15-DRB1*1202, A*11-B*15-DRB1*0405, A*11-B*15-DRB1*1202, A*11-B*38-DRB1*08032, and A*11-B*55-DRB1*0405; the common A-B haplotypes were A*11-B*15, A*11-B*38, and A*24-B*15; and the common B-DRB1 haplotypes were B*15-DRB1*1202, B*38-DRB1*08032, and B*48-DRB1*1201. In the Yunnan Han population, the common A-B-DRB1 haplotypes were A*24-B*15-DRB1*1501, A*24-B*46-DRB1*08032, and A*24-B*15-DRB1*1201; the common A-B haplotypes were A*24-B*15, A*24-B*46, and A*34-B*46; and the common B-DRB1 haplotypes were B*15-DRB1*1501, B*46-DRB1*09012, and B*46-DRB1*1401. Phylogenetic tree and principal component analyzes based on HLA-A, HLA-B, and DRB1 allele frequencies suggested that the Naxi ethnic group belongs to the southern Chinese groups, while the Yunnan Han population is a characteristic population located intermediate between northern and southern Chinese groups, although they live in the southwest of China.

Alleles↗

PubMed1996

Multiple founder haplotypes of mitochondrial DNA in Amerindians revealed by RFLP and sequencing.

The mitochondrial DNA (mtDNA) of 139 individuals from eight tribes which belong to four linguistic groups of the Brazilian Amazon Region was studied both by RFLP and by sequencing of the D-loop region. RFLP analysis showed that 41 haplotypes (29%) belonged to haplogroup A, 39 (28%) to haplogroup B, 38 (27%) to haplogroup C, 19 (14%) to haplogroup D, and 2 (< 2%) could not be assigned to any of the four haplogroups. Among the 92 individuals analyzed by direct sequencing of the D-loop region, we observed 43 different haplotypes defined by 48 polymorphic points, while one haplotype could not be assigned to any of the clusters previously described. Joint analysis of data obtained by RFLP and by sequencing of mtDNA demonstrated that, regardless of the method of analysis, the mtDNA haplotypes of contemporary Amerindians cluster into four groups, similar to those previously described, even though 7% of the total sample or 12% of the haplotypes have discrepancies between results obtained by RFLP and sequencing. In addition to supporting the prevalence of four major haplogroups among contemporary Amerindians, our data are compatible with multiple founder haplotypes in each haplogroup, based on: i) a high prevalence of unusual haplotypes: ii) presence of multiple polymorphic sites shared by different haplogroups; iii) relative differences in nucleotide diversity based on RFLP or sequencing within the different haplogroups.

Base Sequence↗

PubMed2005

Tests of association between quantitative traits and haplotypes in a reduced-dimensional space.

Candidate gene association tests are currently performed using several intragenic SNPs simultaneously, by testing SNP haplotype or genotype effects in multifactorial diseases or traits. The number of haplotypes drastically increases with an increase in the number of typed SNPs. As a result, large numbers of haplotypes will introduce large degrees of freedom in haplotype-based tests, and thus limit the power of the tests. In this study we propose using the principal component method to reduce the dimension, and then construct association tests on the lower-dimensional space to test the association between haplotypes and a quantitative trait using population-based samples. The proposed method allows ambiguous haplotypes. We use simulation studies to evaluate the type I error rate of the tests, and compare the power of the proposed tests with that of the tests without dimension reduction, and the tests with dimension reduction by merging rare haplotypes. The simulation results show that the proposed tests have correct type I error rates and are more powerful than other tests in most cases considered in our simulation studies.

Computer Simulation↗