D2 dopamine receptor gene (DRD2) allele and haplotype frequencies in alcohol dependent and control subjects: no association with phenotype or severity of phenotype. (65/12035)

Possible association between polymorphisms at the D2 dopamine receptor gene (DRD2) and alcohol dependence has been controversial since first proposed in 1990. The most studied polymorphisms to date are the TaqI "A" and "B" systems; they are unlikely to convey a physiological effect directly, and have not been demonstrated to be in linkage disequilibrium with any common polymorphism more likely to convey such an effect, in populations of European ancestry. A recently-described polymorphism in the promoter region of the DRD2 gene with possible effects on gene regulation is the first functional polymorphism described at this locus frequent enough in European-Americans (EAs) to have the potential to explain the positive findings. The goals of this study were to determine if we could replicate any previously reported associations particularly with the "A" and "B" systems and alcohol dependence or severity of alcohol dependence, using a screened control group design. We also studied the promoter system, "D" system, and 3 locus haplotypes. To test the hypothesis of an association rigorously, we studied four DRD2 polymorphic systems in 160 EA alcohol dependent subjects and 136 screened EA control subjects. To increase our potential to detect association with other polymorphisms at the locus, we also constructed 3 locus haplotypes including the DRD2 "A," "D," and promoter systems in both samples. There were no significant differences in allele frequencies between alcohol dependent and screened control subjects for any of the four systems studied. There were also no differences in 3-locus haplotype frequencies between these groups. Analysis based on severity of alcohol dependence also yielded no significant association. The screened control allele frequencies did not differ from allele frequencies we reported previously in unscreened controls. Thus, we replicated previous findings of no association between DRD2 alleles and alcohol dependence. These results can now be extended to include haplotypes containing the possibly-functional promoter system polymorphism. Explanations previously offered to explain lack of association (regarding alcohol dependence severity, and use of screened vs. unscreened controls) were not validated. These results are consistent with no effect of DRD2 polymorphisms on behavioral phenotypes related to alcohol dependence.  (+info)

Risk of developing diabetic nephropathy is not associated with synergism between the angiotensin II (type 1) receptor C1166 allele and poor glycaemic control. (66/12035)

BACKGROUND: It has recently been reported that the risk of developing nephropathy in patients with insulin dependent (type 1) diabetes mellitus is strongly associated with synergism between poor glycaemic control and carriage of the hypertension associated angiotensin II (type 1) receptor C1166 allele. The same report also revealed an increase in risk of nephropathy in diabetic patients carrying a specific angiotensin II (type 1) receptor haplotype, i.e. C1166/140-bp microsatellite allele (major allele). METHODS: In order to replicate these findings we performed PCR-based genotyping for the A1166-->C DNA polymorphism and the CA repeat at the 3' end of the angiotensin II (type 1) receptor gene employing validated groups of type 1 diabetic patients with (cases, n = 95) and without (controls, n = 97) nephropathy. HbA1 values above the median (10.5) were used as an index of poor glycaemic control. RESULTS: The risk of nephropathy in carriers of the C1166 allele with HbA1 > 10.5 was 2.1 (95% CI 0.8-5.2) compared to 1.1 (95% CI 0.4-2.6) for non-carriers of the C1166 allele; however, these odds ratios were not significantly different. No difference in the frequency of the high-risk haplotype was found in cases compared to controls (12.4 vs 11.5%; chi2=0.0, P=0.938 with 1 df). CONCLUSIONS: The results of this study do not support previous findings that the risk of diabetic nephropathy is associated with synergism between poor glycaemic control and carriage of the C1166 allele or inheritance of the C1166/major microsatellite haplotype.  (+info)

A unique point mutation in the PMP22 gene is associated with Charcot-Marie-Tooth disease and deafness. (67/12035)

Charcot-Marie-Tooth disease (CMT) with deafness is clinically distinct among the genetically heterogeneous group of CMT disorders. Molecular studies in a large family with autosomal dominant CMT and deafness have not been reported. The present molecular study involves a family with progressive features of CMT and deafness, originally reported by Kousseff et al. Genetic analysis of 70 individuals (31 affected, 28 unaffected, and 11 spouses) revealed linkage to markers on chromosome 17p11.2-p12, with a maximum LOD score of 9.01 for marker D17S1357 at a recombination fraction of .03. Haplotype analysis placed the CMT-deafness locus between markers D17S839 and D17S122, a approximately 0.6-Mb interval. This critical region lies within the CMT type 1A duplication region and excludes MYO15, a gene coding an unconventional myosin that causes a form of autosomal recessive deafness called DFNB3. Affected individuals from this family do not have the common 1.5-Mb duplication of CMT type 1A. Direct sequencing of the candidate peripheral myelin protein 22 (PMP22) gene detected a unique G-->C transversion in the heterozygous state in all affected individuals, at position 248 in coding exon 3, predicted to result in an Ala67Pro substitution in the second transmembrane domain of PMP22.  (+info)

Molecular and clinical study of 18 families with ADCA type II: evidence for genetic heterogeneity and de novo mutation. (68/12035)

The SCA7 mutation has been found in 54 patients and 7 at-risk subjects from 17 families who have autosomal dominant cerebellar ataxia (ADCA) II with progressive pigmentary maculopathy. In one isolated case, haplotype reconstruction through three generations confirmed a de novo mutation owing to paternal meiotic instability. Different disease-associated haplotypes segregated among the SCA7-positive kindreds, which indicated a multiple origin of the mutation. One family with the clinical phenotype of ADCA type II did not have the CAG expansion that indicated locus heterogeneity. The distribution of the repeat size in 944 independent normal chromosomes from controls, unaffected at-risk subjects, and one affected individual fell into two ranges. The majority of the alleles were in the first range of 7-19 CAG repeats. A second range could be identified with 28-35 repeats, and we provide evidence that these repeats represent intermediate alleles that are prone to further expansion. The repeat size of the pathological allele, the widest reported for all CAG-repeat disorders, ranged from 37 to approximately 220. The repeat size showed significant negative correlation with both age at onset and age at death. Analysis of the clinical features in the patients with SCA7 confirmed that the most frequently associated features are pigmentary maculopathy, pyramidal tract involvement, and slow saccades. The subjects with <49 repeats tended to have a less complicated neurological phenotype and a longer disease duration, whereas the converse applied to subjects with >/=49 repeats. The degree of instability during meiotic transmission was greater than in all other CAG-repeat disorders and was particularly striking in paternal transmission, in which a median increase in repeat size of 6 and an interquartile range of 12 were observed, versus a median increase of 3 and interquartile range of 3.5 in maternal transmission.  (+info)

Linkage-disequilibrium mapping of disease genes by reconstruction of ancestral haplotypes in founder populations. (69/12035)

Linkage disequilibrium (LD) mapping may be a powerful means for genome screening to identify susceptibility loci for common diseases. A new statistical approach for detection of LD around a disease gene is presented here. This method compares the distribution of haplotypes in affected individuals versus that expected for individuals descended from a common ancestor who carried a mutation of the disease gene. Simulations demonstrate that this method, which we term "ancestral haplotype reconstruction" (AHR), should be powerful for genome screening of phenotypes characterized by a high degree of etiologic heterogeneity, even with currently available marker maps. AHR is best suited to application in isolated populations where affected individuals are relatively recently descended (< approximately 25 generations) from a common disease mutation-bearing founder.  (+info)

The S15 self-incompatibility haplotype in Brassica oleracea includes three S gene family members expressed in stigmas. (70/12035)

Self-incompatibility in Brassica is controlled by a single, highly polymorphic locus that extends over several hundred kilobases and includes several expressed genes. Two stigma proteins, the S locus receptor kinase (SRK) and the S locus glycoprotein (SLG), are encoded by genes located at the S locus and are thought to be involved in the recognition of self-pollen by the stigma. We report here that two different SLG genes, SLGA and SLGB, are located at the S locus in the class II, pollen-recessive S15 haplotype. Both genes are interrupted by a single intron; however, SLGA encodes both soluble and membrane-anchored forms of SLG, whereas SLGB encodes only soluble SLG proteins. Thus, including SRK, the S locus in the S15 haplotype contains at least three members of the S gene family. The protein products of these three genes have been characterized, and each SLG glycoform was assigned to an SLG gene. Evidence is presented that the S2 and S5 haplotypes carry only one or the other of the SLG genes, indicating either that they are redundant or that they are not required for the self-incompatibility response.  (+info)

Partial sweeping of variation at the Fbp2 locus in a west African population of Drosophila melanogaster. (71/12035)

Departure of molecular variation from neutral equilibrium was studied in a highly recombining region of the Drosophila genome. A 2.2-kb region including the Fbp2 locus was sequenced for 10 chromosomes from a D. melanogaster sample from West Africa and for the related species D. simulans. Of the 33 variable sites present in the 1.3-kb transcription unit, 32 made up a single haplotype present in half of the D. melanogaster sample. This pattern significantly departed from predictions of the neutral drift-mutation equilibrium model. The major haplotype presented a diagnostic restriction site which was investigated in 226 chromosomes from three distant European and African populations. It was found at a high frequency (31%) in the population from which the sequenced sample originated, but was nearly absent from the other two (below 4%), suggesting that the major haplotype frequency resulted from a local selective sweep event. Partial sweeping of variation in regions of high recombination rates has previously been found for American and European populations of D. melanogaster. Our study shows that this phenomenon also occurs in African populations, which are in the ancestral range of this species.  (+info)

Incongruence in the diploid B-genome species complex of Glycine (Leguminosae) revisited: histone H3-D alleles versus chloroplast haplotypes. (72/12035)

Variation at the single-copy nuclear locus histone H3-D was surveyed in the diploid B-genome group of Glycine subgenus Glycine (Leguminosae: Papilionoideae), which comprises three named Australian species and a number of distinct but as yet not formally recognized taxa. A total of 23 alleles was identified in the 44 accessions surveyed. Only one individual was clearly heterozygous, which is not surprising given the largely autogamous breeding system of subgenus Glycine. Alleles differed by as many as 19 nucleotide substitutions, nearly all in the three introns; length variation was minimal. Phylogenetic analysis identified two shortest allele trees with very little homoplasy, suggesting that recombination has been rare. Both topological and data set incongruence were statistically significant between histone H3-D allele trees and trees inferred from chloroplast DNA haplotypes previously described from these same accessions. Whereas the distribution of H3-D alleles agrees well with morphologically based taxonomic groupings, chloroplast DNA haplotype polymorphisms transgress species boundaries, suggesting that the chloroplast genome is not tracking taxic relationships. Divergences among chloroplast DNA haplotypes involved in such transgressive patterns appear to be more recent than speciation events, suggesting hybridization rather than lineage sorting.  (+info)