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PubMed2006

HLA alleles and haplotypes in French North African immigrants.

Human leukocyte antigen (HLA) haplotypes (n = 187) were genotyped and assigned by the mode of inheritance in migrant families from North Africa who reside in the Paris, France, area. The distribution of alleles and haplotypes in that population was compared with the one obtained in a control population of ancient French natives residing in the same area (248 independent haplotypes also assigned by the mode of inheritance were studied). The results in migrants reveal the following: (1) a higher diversity in the distribution of HLA-A and -DRB1 alleles; (2) lower frequencies of alleles common in our region, such as A*0201 B*1501, B*4001, and DRB1*0401 and increased frequencies of minor subtypes, such as A*3002 and DRB1*0402; and (3) distinct distributions of B/Cw, DRB1/DQB1 or B/Cw/DRB1/DQB1 haplotypes. The results also revealed that the four most frequent five-allele haplotypes in controls i.e., HLA-A*0101/B*0801/Cw*0701/DRB1*0301/DQB1*0201; A*0301/B*0702/Cw*0702/DRB1*1501/DQB1*0602 (both of Indo-Celtic origin); A*2902/B*4403/Cw*1601/DRB1*0701/DQB1*0202 (frequent in Western-Europeans); and A*0201/B*1501/Cw*0304/DRB1*0401/DQB1*0302, represent 10.5% of the total haplotypes in controls but 1.6% in North Africans. Conversely, 9 five-allele haplotypes in multiple copy in North Africans (among which A*3002/B*1801/Cw*0501/DRB1*0301/DQB1*0201 of Paleo-North African origin and A*0201/B*0702/Cw*0702/DRB1*1501/DQB1*0602 of ancient European and Paleo-North African origin) represent 9.6% of the total haplotypes in North Africans but 2.4% in controls. These results thus suggest a low degree of admixture between the two populations.

Africa, Northern↗

PubMed2004

Low-activity haplotype of the microsomal epoxide hydrolase gene is protective against placental abruption.

OBJECTIVE: We wanted to determine whether genetic variability in the gene encoding microsomal epoxide hydrolase (EPHX) contributes to individual differences in susceptibility to the occurrence of placental abruption. METHODS: The study involved 117 women with placental abruption and 115 healthy control pregnant women who were genotyped for two single nucleotide polymorphisms (SNPs), T-->C (Tyr113His) in exon 3 and A-->G (His139Arg) in exon 4, in the EPHX gene. Chi-square analysis was used to assess genotype and allele frequency differences between the women with placental abruption and the control group. In addition, single-point analysis was expanded to pair of loci haplotype analysis to examine the estimated haplotype frequencies of the two SNPs, of unknown phase, among the women with placental abruption and the control group. Estimated haplotype frequencies were assessed using the maximum-likelihood method, employing an expectation-maximization algorithm. RESULTS: Single-point allele and genotype distributions in exons 3 and 4 of the EPHX gene were not statistically different between the groups. However, in the haplotype estimation analysis we observed a significantly decreased frequency of haplotype C-A (His113-His139) among the placental abruption group compared with the control group (P = .007). The odds ratio for placental abruption associated with the low-activity haplotype C-A (His113-His139) was 0.552 (95% confidence interval, 0.358 to 0.851). CONCLUSIONS: The use of two intragenic SNPs jointly in haplotype analysis of association demonstrated that the genetically determined low-activity haplotype C-A (His113-His139) was significantly less frequent in women with placental abruption.

Abruptio Placentae↗

PubMed2004

A haplotype constituted of four MMP-2 promoter polymorphisms (-1575G/A, -1306C/T, -790T/G and -735C/T) is associated with coronary triple-vessel disease.

Vascular lesion development is associated with an accumulation of extracellular matrix proteins within the vessel wall. The proteins are degraded by matrix metalloproteinases (MMPs). There is also evidence indicating a participation of the MMPs in the weakening of atherosclerotic plaque that predisposes to lesion disruption. The aim of the study was to test an association among haplotypes of four single nucleotide MMP-2 promoter polymorphisms and the angiographically confirmed coronary triple-vessel disease (TVD). Incidence of haplotypes of four MMP-2 promoter polymorphisms (-1575G/A, -1306C/T, -790T/G and -735C/T) determined by PCR reactions with restriction analyses in 187 patients with coronary TVD (153 men, 34 women, age median 65 years) was compared to 196 control subjects without clinical signs of coronary heart disease (131 men and 65 women, age median 60 years). The incidence of two similar haplotypes was found to be different between patients and healthy subjects. The haplotype GCTC was more frequent in the TVD patients (P=0.01) though the haplotype GCGC was identified only in healthy subjects (P=0.001). Interestingly, the GCTC is the most frequent polymorphic haplotype composed of four promoter SNPs localized in the MMP-2 gene (53% in healthy subjects vs. 66% in patients with TVD) and the haplotype GCGC is the least frequent polymorphic one (4.4% in healthy subjects vs. 0% in patients with TVD). Two different MMP-2 promoter haplotypes differing only in -790T/G allele are significantly more or less frequent in coronary TVD compared to non-ischemic persons. Thus, the -790T/G MMP-2 genotype might be used as a genetic marker representing MMP-2 promoter variability for the TVD with odds ratio for TT and TG genotypes 2.59, 95% confidential interval 1.21-5.55, P=0.009. The analysis of promoter MMP-2 gene variability could help us to understand individual susceptibility to MMP inhibitor treatment of the coronary artery disease.

Adenine↗

PubMed2004

Analysis of MDR1 haplotypes in Parkinson's disease in a white population.

The MDR1 multidrug transporter is important in regulating environmental xenobiotics and hence may play a causative role in Parkinson's disease (PD). MDR1 haplotype comprising 2677 G > T/A and 3435 C > T may be protective against PD. Using a case control methodology, we investigated the association of MDR1 haplotypes (single nucleotide polymorphisms (SNPs) 2677 G > T/A and 3435 C > T) in a Polish PD population. Seven SNPs, extending from the promoter to exon 28 of the MDR1 gene in 158 PD patients and 139 healthy controls were evaluated. Specifically we examined the association of haplotypes containing SNPs 2677 G > T/A and 3435 C > T and risk of PD. The multivariate logistic regression model was used to evaluate the effects of the covariates on the phenotypes. Haplotypes' frequencies were estimated using the Expectation-Maximization algorithm. The frequency of each individual SNPs; -41 A > G (intron -1), -145 C > G (exon 1), -129 T > C (exon 1), 1236 T > C (exon 12), 2677 G > T/A (exon 21), 3435 C > T (exon 26), and 4036 A > G (exon 28) did not differ between PD and controls. However, there was a trend towards significance in PD patients having the haplotype 2677G-3435C (p < 0.09, chi-square 2.85, odds ratio 0.25, 95% CI 0.06-1.08). Haplotype constructs of the other loci did not differ significantly between the two groups. There was a weak protective effect of the haplotype 2677G-3435C in our white population. However, the MDR1 haplotypes did not generally modulate the risk of PD.

Adult↗

PubMed1987

Correlation between polymorphic DNA haplotypes at phenylalanine hydroxylase locus and clinical phenotypes of phenylketonuria.

Eight polymorphic sites for seven restriction endonucleases have been reported at the human phenylalanine hydroxylase locus. The composite profile of the presence or absence for each of the eight polymorphic sites within an allele defines the haplotype of the corresponding allele. Twelve such haplotypes associated with normal and mutant phenylalanine hydroxylase alleles have been identified in 33 Danish families with children with phenylketonuria. Of the 66 mutant alleles analyzed, 59 (89%) were associated with only four haplotypes. The identification of individual phenylalanine hydroxylase alleles by haplotype analysis enables correlation of the hyperphenylalaninemic phenotypes of the patients with their genotypes. Patients who were either homozygous or heterozygous for the mutant alleles of haplotypes 2 and 3 had a severe clinical course. Patients who had a mutant allele of either haplotype 1 or 4 usually had a less severe clinical phenotype. The recent demonstration that the mutation responsible for classic phenylketonuria associated with haplotype 3 is not present in mutant alleles of other haplotypes provides unambiguous evidence that there are multiple mutations in the phenylalanine hydroxylase gene and supports the hypothesis that different combinations of mutant alleles may be responsible for the clinical diversity of phenylketonuria.

Child↗

PubMed1991

C4 Chido 3 and 6 distinguish two diabetogenic haplotypes: HLA-B49, SC01,DR4,DQw8 and B8,SC01,DR3,DQw2.

The combination of the HLA complement allotypes BFS, C2C, C4AQ0 (deleted gene) and C4B1, termed SC01 complotype, usually present in the HLA-B8,DR3,DQw2 diabetogenic haplotype, has also been found in a novel "low frequency" HLA-B49,DR4,DQw8 haplotype associated with Spanish insulin-dependent diabetes mellitus (IDDM). Family studies of C4 antigenic determinants Rodgers/Chido and their specific C4d nucleotide sequences confirm that this novel haplotype bearing Chido -3, -6 is not due to a recent recombination from the common HLA-B8,DR3 haplotype bearing Chido 3,6; moreover, Chido analysis at the serological or DNA level is presently the only way to distinguish both SC01 complotypes, since BF, C2, steroid 21-hydroxylase and C4 genes do not reveal other differences by restriction fragment analysis. On the other hand, HLA-B49,SC01,DR4 is the first DR4-bearing IDDM-susceptible haplotype with a deleted C4 gene described so far and the only DR4-bearing haplotype found in the Spanish population. This report further supports the fact that extended haplotypes with deleted (or "not duplicated") genes in the class III region contain IDDM-susceptibility more often than non-deleted (or "duplicated") haplotypes in the Spanish and other Mediterranean populations.

Base Sequence↗

PubMed2004

A haplotype of the methylenetetrahydrofolate reductase gene is protective against late-onset Alzheimer's disease.

Epidemiological studies have shown that elevated plasma homocysteine (Hcy) levels play an important role in the pathogenesis of Alzheimer's disease (AD). In spite of the evidence that a C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene elevates plasma Hcy levels, the impact of the C677T polymorphism on the development of AD is controversial. Here, we performed a genetic case-control study in a Japanese population to investigate whether three polymorphisms of the MTHFR gene, C677T (Ala222Val), A1298C (Glu429Ala), and A1793G (Arg594Gln), are associated with the development of late-onset AD (LOAD). In our study, the MTHFR gene had four major regional haplotypes: Haplotype A (677C-1298A-1793G), Haplotype B (677T-1298A-1793G), Haplotype C (677C-1298C-1793G), and Haplotype D (677C-1298C-1793A). The frequency of Haplotype C in LOAD was significantly lower than that in control group. Furthermore, the benefit conferred by the presence of at least one Haplotype C was stronger in LOAD patients who lacked the ApoE 4 allele (OR=0.293; 95% CI=0.115-0.744; P=0.010). The results indicate that Haplotype C of the MTHFR gene is protective against the development of LOAD.

Aged↗

PubMed2002

Pediatric celiac disease in India is associated with multiple DR3-DQ2 haplotypes.

The role of human leukocyte antigen (HLA) DQ2 heterodimer (DQA1*0501-DQB1*0201) in presenting gluten peptides to effector T cells in celiac disease (CD) has been well documented. Because HLA-DQ2 is carried on DR3 haplotypes due to linkage disequilibrium, such haplotypes are encountered more frequently in patients with autoimmune disease. This study analyzed 35 North Indian children below 15 years of age and diagnosed to have CD as per the ESPGAN criteria, which included histopathologic alterations in duodenal biopsies, clinical response to gluten withdrawal, and presence of antiendomysial antibodies. The HLA class I and class II alleles were determined by polymerase chain reaction-sequence-specific primers, sequence-specific oligonucleotide probe, and reverse line strip molecular techniques. A statistically significant positive association of the disease with HLA-DRB1*03 (94.2% versus 22.1% in controls, chi(2) = 73.4, p = 7.54E-11), and a negative association with DRB1*15 (chi(2) = 7.4, p = 6.5E-03) and DRB1*13 alleles was observed. The HLA-DQB1*0201 was observed in all the 35 patients (100%), whereas the DQ2 heterodimer alpha(0)beta(0) occurred in 97.1% of CD patients (31.4% in double dose, 65.7% in single dose) and revealed significant deviation from healthy controls (chi(2) = 102.08, p = 7.56E-11). Further analysis revealed involvement of multiple DR3+ve haplotypes with CD in Indians, of which A26-B8-DR3 was the most common DR3 haplotype among patients (34.28%, chi(2) = 40.57, p = 2.65E-10) followed by Ax-B21-DR3 (11.4%) (chi(2) = 13.8, p = 2E-04) and the classical Caucasian haplotype A1-B8-DR3 (5.7%). The former two haplotypes are characteristic of Asian Indians and are involved in the development of CD. We conclude that the high risk DR3 haplotypes that play a crucial role in the development of CD are unique in Asian Indians. Detailed analysis of these haplotypes in Indian patients with autoimmune diseases may help understand the influence of other intervening genes within the major histocompatibility complex.

Adolescent↗

PubMed2000

A new method for the evaluation of matches in non-recombining genomes: application to Y-chromosomal short tandem repeat (STR) haplotypes in European males.

A 9-locus microsatellite framework (minimal haplotype), previously developed for forensic purposes so as to facilitate stain analysis, personal identification and kinship testing, has been adopted for the establishment of a large reference database of male European Y-chromosomal haplotypes. The extent of population stratification pertaining to this database, an issue crucial for its practical forensic application, was assessed through analysis of molecular variance (AMOVA) of the 20 regional samples included. Despite the notion of some significant haplotype frequency differences, which were found to correlate with known demographic and historic features of Europeans, AMOVA generally revealed a high level of genetic homogeneity among the populations analyzed. Owing to their high diversity, however, accurate frequency estimation is difficult for Y-STR haplotypes when realistic (i.e. moderately sized) datasets are being used. As expected, strong pair-wise and higher order allelic associations were found to exist between all markers studied, implying that haplotype frequencies cannot be estimated as products of allele frequencies. A new extrapolation method was therefore developed which treats haplotype frequencies as random variables and generates estimates of the underlying distribution functions on the basis of closely related haplotypes. This approach, termed frequency 'surveying', is based upon standard population genetics theory and can in principle be applied to any combination of markers located on the Y-chromosome or in the mitochondrial genome. Application of the method to the quality assured reference Y-STR haplotype database described herein will prove very useful for the evaluation of positive trace-donor matches in forensic casework.

Alleles↗

PubMed2002

Mismatch distribution analysis of Y-STR haplotypes as a tool for the evaluation of identity-by-state proportions and significance of matches--the European picture.

We suggest the use of the mismatch distribution methodology as an easy way to estimate the distance between all pairs of haplotypes present in a sample. This approach allows the evaluation of the proportion of pairs of Y-STR haplotypes that are prone to become identical by state (IBS), in one generation, by recurrent mutation, a statistic of major importance in the forensic field. The mismatch approach presents some advantages alternatively to the empirical one, since it is not necessary to have simultaneous information on STRs and SNPs, and it allows the evaluation of IBS also within-haplogroups. The estimation of IBS at an European scale showed that there is a high population substructuring for this parameter, increasing from southern-central European countries towards west and north, in accordance to what was found for Y-biallelic markers. This result seems to imply a more careful use of large databases for matching evaluation, even in the absence of population structure for general Y-STR diversity. Furthermore, mismatch distribution can be used to measure the distance between a particular haplotype and all the haplotypes in a sample. When applied to the most frequent haplotypes in Europe it revealed that the opportunity for IBS is not directly related to the frequency of a haplotype, but highly dependent on the proportion of neighbouring haplotypes--so, that reporting on the haplotype frequency for evaluating the significance of a match can be misleading.

Chromosomes, Human, Y↗

PubMed2004

Identity of the mtDNA haplotype(s) of Phytophthora infestans in historical specimens from the Irish potato famine.

The mtDNA haplotypes of the plant pathogen Phytophthora infestans present in dried potato and tomato leaves from herbarium specimens collected during the Irish potato famine and later in the 19th and early 20th century were identified. A 100 bp fragment of ribosomal DNA (rDNA) specific for P. infestans was amplified from 90% of the specimens (n = 186), confirming infection by P. infestans. Primers were designed that distinguish the extant mtDNA haplotypes. 86% percent of the herbarium specimens from historic epidemics were infected with the Ia mtDNA haplotype. Two mid-20th century potato leaves from Ecuador (1967) and Bolivia (1944) were infected with the Ib mtDNA haplotype of the pathogen. Both the Ia and IIb haplotypes were found in specimens collected in Nicaragua in the 1950s. The data suggest that the Ia haplotype of P. infestans was responsible for the historic epidemics during the 19th century in the UK, Europe, and the USA. The Ib mtDNA haplotype of the pathogen was dispersed later in the early 20th century from Bolivia and Ecuador. Multiple haplotypes were present outside Mexico in the 1940s-60s, indicating that pathogen diversity was greater than previously believed.

Biological Specimen Banks↗

PubMed2000

Allele frequencies and haplotypic associations defined by allelic DNA typing at HLA class I and class II loci in the Japanese population.

HLA class I and class II allelic genotypes were determined in 371 unrelated individuals and 309 members of 81 families inhabiting the central Japan area. A total of 20 HLA-A alleles, 16 HLA-Cw alleles, 38 HLA-B alleles, 27 HLA-DRB1 alleles, 15 HLA-DQB1 alleles and 12 HLA-DPB1 alleles were detected. By the two-, three-, four-, five- and six-locus allelic association analyses extracted from the HLA-A to -DPB1 locus, 26 HLA-Cw-B haplotypes, 25 HLA-DRB1-DQB1 haplotypes, 42 HLA-Cw-B-DRB1 haplotypes, 37 HLA-Cw-B-DRB1-DQB1 haplotypes, 29 HLA-A-Cw-B-DRB1-DQB1 haplotypes and 21 HLA-A-Cw-B-DRB1-DQB1-DPB1 haplotypes with the frequencies of higher than 0.005 were recognized. Among 19 HLA-B alleles with the high allele frequencies (above 0.007), 9 HLA-B alleles, B*0702, B*1301, B*3701, B*3901, B*4006, B*4403, B*5201, B*5901 and B*6701 were found to be tightly associated with single HLA-Cw alleles. Most of HLA-DRB1 alleles showed strong associations with single HLA-DQB1 alleles, but DRB1*0802 and DRB1*1401 were associated with two different DQB1 alleles. Extended haplotypes carrying infrequent class I alleles with the allele frequencies of lower than 0.007 were defined by family studies. Gene frequencies and haplotypic associations within the entire HLA classical loci elucidated at the high resolution (four-digital) allelic level will provide useful information on anthropology, marrow donor registry, legal medicine and disease-association studies.

Family↗

PubMed2003

Identification of three genomic haplotypes 5' to the human CD1D gene and their distribution in four ethnic groups.

CD1d presents lipid antigen to a conserved population of natural killer (NK) T cells, which participate in host immune defense, tumor cell rejection and suppression of autoimmunity. The levels of human CD1d expression vary significantly between individuals. To understand such variation, we sequenced the region up to 1.7 kb 5' upstream of the translation start site and partially through exon 2 in 44 white Americans. We also studied two tagged single nucleotide polymorphisms (SNP) in 112 white Americans, 60 African-Americans, 88 Europeans, and 84 Chinese people from the region. Six SNP present in the region (-836C-->T, -773C-->T, -764C-->G, -713A-->T, -365A-->G and +363A-->G) were found to be in a complete linkage disequilibrium and comprised three haplotypes. Haplotype 1 had -836C, -773C, -764C, -713A, -365A and +363A. Haplotype 2 had -836C, -773T, -764C, -713A, -365A and +363A. Haplotype 3 had -836T, -773C, -764G, -713T, -365G and +363G. -773C-->T and -764C-->G can serve as the tagged SNP to differentiate the three haplotypes. The frequency of haplotype 1 was significantly higher in African Americans than in the other three ethnic groups, whereas the frequency of haplotype 3 was significantly higher in the Chinese people than those in the other three groups. The finding of the three haplotypes provides a genetic marker for CD1d and facilitates the study of the functional role of the genetic variations in human CD1d expression and regulation.

Antigens, CD1↗

PubMed2001

Some specific human leukocyte antigen (HLA)-DR/DQ haplotypes are more important than individual HLA-DR and -DQ phenotypes for the development of mucocutaneous type of Behçet's disease and for disease shift from recurrent aphthous stomatitis to mucocutaneous type of Behçet's disease.

The phenotype and haplotype frequencies of human leukocyte antigens (HLA)-DR and -DQ in 32 Chinese patients with the mucocutaneous (MC) type of Behçet's disease (BD) were calculated and compared with those in 310 healthy control Chinese and with those in 80 Chinese patients with recurrent aphthous stomatitis (RAS). We found that the phenotype frequency of HLA-DRw8 [corrected P (Pc)<0.005] and the haplotype frequencies of HLA-DRw8/DQw1 (Pc<0.005), -DRw8/DQw5(w1) (Pc<0.0005), -DRw12(5)/DQw1 (Pc<0.005), -DRw12(5)/DQw6(w1) (Pc< 0.0005), and -DRw52/DQw1 (Pc<0.005) in patients with the MC type of BD were significantly greater than those in healthy control subjects. This finding suggests that individual Chinese with HLA-DRw8 antigen and HLA-DRw8/DQw1, -DRw8/DQw5(w1), -DRw12(5)/DQw1, -DRw12(5)/DQw6(w1) and -DRw52/DQw1 haplotypes are more likely to have the MC type of BD. Furthermore, the relative risks (RRs) of HLA-DRw8/DQw1 (5.6), -DRw8/ DQw5 (w1) (10.0), and -DRw12(5)/DQw6(w1) (14.4) haplotypes in patients with the MC type of BD were equal to or higher than the RR of HLA-DRw8 phenotype (5.6), suggesting that some of the HLA-DR/DQ haplotypes may play more important roles than the individual HLA-DR and -DQ phenotypes for the development of the MC type of BD. The phenotype frequencies of HLA-DR5 (Pc<0.01), -DRw8 (Pc<0.005) and -DQw1 (Pc<0.05) as well as the haplotype frequencies of HLA-DR5/DQw1 (P<0.005) and -DRw8/DQw1 (Pc<0.00005) in patients with the MC type of BD were significantly higher than those in patients with RAS. Moreover, the RRs of HLA-DR5/DQw1 (29.1) and -DRw8/DQw1 (47.4) haplotypes were greater than the RRs of HLA-DR5 (10.4), -DRw8 (23.4) and -DQw1 (4.0) antigens. These results suggest that some specific HLA-DR/DQ haplotypes may be more important than the individual HLA-DR and -DQ phenotypes in the disease shift from RAS to the MC type of BD.

Adolescent↗

PubMed2001

Y-chromosome SNP haplotypes suggest evidence of gene flow among caste, tribe, and the migrant Siddi populations of Andhra Pradesh, South India.

From observations of lack of haplotype sharing based on Y-chromosome specific short tandem repeat (STR) loci, previous reports suggested negligible gene flow among different geographic populations of India. Using Single Nucleotide Polymorphism (SNP) sites in combination with STRs, we observed evidence of haplotype sharing across caste-tribe boundaries in South India. We examined 27 SNPs in the non-recombining region of the Y chromosome to investigate gene flow in 204 individuals belonging to three caste groups (Vizag Brahmins, Peruru Brahmins, Kammas), three tribes (Bagata, Poroja, Valmiki) and an additional group (the Siddis) of African ancestry. Principal component and AMOVA analyses show that the between group component of variation is non-significant (P>0.05), while that among populations within the caste and tribal groups is significant (P<0.001). In particular, the Valmikis and Siddis are close to the caste groups. Of a total of 11 distinct SNP-haplotypes observed, the two tribal groups (Bagata and Poroja) lack the haplotypes H4, H4A, H5A and H16, which are seen in the caste groups. In contrast, all three tribal groups exhibit the Southeast Asian haplotype H11 that is absent in the caste populations. The presence of haplotypes H4, H5, H14, and H16 in the Siddis indicate that they have assimilated considerable non-African admixture. The evidence of haplotype sharing between castes and tribes is also found when the H14 lineage was further subdivided by five STR loci. We conclude that even though these SNP-based Y-haplotypes are able to distinguish the populations, gene flow in these South Indian populations is not as negligible as that inferred from other studies based on Y-specific short tandem repeat markers.

Alleles↗

PubMed2001

Haplotype analysis in Icelandic and Finnish BRCA2 999del5 breast cancer families.

The 999del5 mutation is the single, strong BRCA2 founder mutation in Iceland and the most common BRCA1/2 founder mutation in Finland. To evaluate the origin and time since spreading of the 999del5 mutation in Iceland and in Finland, we constructed haplotypes with polymorphic markers within and flanking the BRCA2 gene in a set of 18 Icelandic and 10 Finnish 999del5 breast cancer families. All Icelandic families analysed shared a common core haplotype of about 1.7 cM. The common ancestors for the Icelandic families studied were estimated to trace back to 340-1000 years, not excluding the possibility that the mutation was brought to Iceland during the settlement of the country. Analysis of the Finnish families revealed two distinct haplotypes. A rare one, found in three families in the old settlement region in southwestern Finland, shared a four-marker (0.5 cM) core haplotype with the Icelandic 999del5 haplotype. A distinct approximately 6 cM haplotype was shared by seven 999del5 Finnish families estimated to have a common ancestry 140-300 years ago. These families cluster in two geographical regions in Finland, in the very same area as those with the rare haplotype and also in the most eastern, late settlement region of Finland. The results may indicate a common ancient origin for the 999del5 mutation in Iceland and in Finland, but distinct mutational events cannot be ruled out. The surprising finding of the same mutation in two completely different haplotypes in a sparsely populated area in Finland may suggest gene conversion.

Breast Neoplasms↗

PubMed2000

Family-based linkage disequilibrium mapping using SNP marker haplotypes: application to a potential locus for schizophrenia at chromosome 22q11.

Family-based linkage disequilibrium mapping using SNP markers is expected to be a major route to the identification of susceptibility alleles for complex diseases. However there are a number of methodological issues yet to be resolved, including the handling of extended haplotype data and analysis of haplotype transmission in sib-pair or family trio samples. In the present study, we have analysed two dinucleotide repeat and six SNP markers at the COMT locus at chromosome 22q11, a region implicated in psychosis, for transmission distortion in 198 Chinese schizophrenic family trios. When individual markers were analysed using the TDT, two showed modest evidence of transmission distortion (186C/T, P = 0.04; Val158Met, P = 0.01). Using haplotypes of paired markers analysed by the program TRANSMIT, the most significant P value was 0.001, for the Met158Val and 900ins/delC polymorphisms in the COMT gene. The global P value for the haplotypes of all six SNP markers tested was 0.004, largely a result of the excess transmission of two extended haplotypes which differed at the marker 408C/G. The exclusion of this marker from the analysis gave a global P value of 0.002 and produced a five marker haplotype system which was significant at P = 0.0006. This haplotype consisted of the alleles -287G:186C:Val158:900insC:ARVCF930C, which may represent a background haplotype for the transmission of a schizophrenia susceptibility allele at chromosome 22q11. Our results support the hypotheses that either COMT is itself a susceptibility gene, or more likely that this region of chromosome 22 contains a susceptibility gene that is in linkage disequilibrium with COMT alleles. Molecular Psychiatry (2000) 5, 77-84.

Adolescent↗

PubMed2004

COMT haplotypes suggest P2 promoter region relevance for schizophrenia.

A recent study found, in a large sample of Ashkenazi Jews, a highly significant association between schizophrenia and a particular haplotype of three polymorphic sites in the catechol-O-methyl transferase, COMT, gene: an IVS 1 SNP (dbSNP rs737865), the exon 4 functional SNP (Val158Met, dbSNP rs165688), and a downstream SNP (dbSNP rs165599). Subsequently, this haplotype was shown to be associated with lower levels of COMT cDNA derived from normal cortical brain tissue, most likely due to cis-acting element(s). As a first step toward evaluating whether this haplotype may be relevant to schizophrenia in populations other than Ashkenazi Jews, we have studied this haplotype in 38 populations representing all major regions of the world. Adding to our previous data on four polymorphic sites in the COMT gene, including the Val158Met polymorphism, we have typed the IVS 1 rs737865 and 3' rs615599 sites and also included a novel IVS 1 indel polymorphism, yielding seven-site haplotype frequencies for normal individuals in the 38 globally distributed populations, including a sample of Ashkenazi Jews. We report that the schizophrenia-associated haplotype is significantly heterogeneous in populations worldwide. The three-site, schizophrenia-associated haplotype frequencies range from 0% in South America to 37.1% in Southwest Asia, despite the fact that schizophrenia occurs at roughly equal frequency around the world. Assuming that the published associations found between the exon 4 Val158Met SNP and schizophrenia are due to linkage disequilibrium, these new haplotype data support the hypothesis of a relevant cis variant linked to the rs737865 site, possibly just upstream in the P2 promoter driving transcription of the predominant form of COMT in the brain. The previously described HindIII restriction site polymorphism, located within the P2 promoter, varies within all populations and may provide essential information in future studies of schizophrenia.

Catechol O-Methyltransferase↗