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Specific Haplotypes (specific + haplotype)
Selected AbstractsA Haplotype of the DRD1 Gene Is Associated With Alcohol DependenceALCOHOLISM, Issue 4 2008P. Batel Background:, The D1 dopamine receptor has been involved in a number of brain functions, including motor control, inattentive symptoms and reward and reinforcement mechanisms. Indeed, DRD1 antagonists may reduce cocaine-seeking behavior and the acquisition of cocaine-cue associations. The D1.1/r4532 marker of the DRD1 gene has been associated with a large set of phenotypes including addictive behaviors, but none with alcohol dependence per se. Methods:, We analyzed a population of 134 patients with alcohol dependence, also assessing more homogeneous (severe) phenotypes, comparing this sample with a healthy control population, assessing two SNPs within the DRD1 gene in order to depict the role of DRD1 polymorphisms and haplotypes. Results:, The T allele of the rs686 polymorphism within DRD1 gene was significantly more frequent in patients with alcohol dependence (p = 0.0008), with a larger excess for patients with severe dependence (p = 6 × 10,6), and even more for patients with severe complications such as withdrawal seizures (p = 7 × 10,7). A specific haplotype rs686*T-rs4532*G within the DRD1 gene was significantly more precisely associated with alcohol dependence in our sample (p = 5 × 10,6). Conclusions:, Even though chance finding cannot be ruled out, convergent evidence is given that the DRD1 gene is a susceptibility gene in alcohol dependence, regarding the fact that relying on more homogeneous phenotypes (i.e., more severe patients) and more informative genetic markers (i.e., haplotypes) reinforce the initial association. [source] The 3, Part of the Dopamine Transporter Gene DAT1/SLC6A3 Is Associated With Withdrawal Seizures in Patients With Alcohol DependenceALCOHOLISM, Issue 1 2008Yann Le Strat Background: Some studies have reported that the A9 allele of the variable nucleotide tandem repeat (VNTR) of the gene which encodes the dopamine transporter (DAT1/SLC6A3) is associated with alcoholism withdrawal symptoms such as alcohol withdrawal seizures (WSs), whereas others did not. We investigated whether polymorphisms within the DAT1 gene are associated with WS taking into account some of the confounding factors such as the severity of alcohol dependence. Methods: To further assess the role of this gene in WS, we genotyped the VNTR and 7 single nucleotide polymorphisms (SNPs) encompassing the DAT1 gene in a sample of 250 alcohol-dependent subjects (175 men and 75 women), of whom 24% exhibited WSs, taking into account the severity of alcohol dependence. Results: The VNTR is associated with an increased risk of WSs (odd ratio = 3.5; p = 0.019), even when controlling for confounding factors (p = 0.031). As 2 SNPs, in roughly the same location of the gene (namely rs27072 and rs27048), are also associated with WSs, it is possible that the initial association of the VNTR polymorphism was tagging a specific haplotype of this gene. Indeed, in our sample of alcohol-dependent patients, 2 haplotypes were associated with a significantly different risk of WSs. Conclusions: The present study adds evidence for a significant role of the 3, part of the DAT1 gene in WS of alcohol-dependent patients, not only because it is in accordance with previous work, but also because of larger statistical power (as relying on a sample over sampled with the studied phenotype), as it gives a more precise analysis of different SNPs within the DAT1 gene, and as it confirms the association when major potentially confounding factors are taken into account in a logistical regression analysis. [source] Genetic diversity and historical population structure in the New Zealand mayfly Acanthophlebia cruentataFRESHWATER BIOLOGY, Issue 1 2006PETER J. SMITH Summary 1. Nucleotide sequences of a 280 base pair region of the cytochrome b gene were used to assess genetic diversity and to infer population histories in the New Zealand mayfly Acanthophlebia cruentata. 2. A hierarchial examination of populations from 19 streams at different spatial scales in the central and northern North Island of New Zealand found 34 haplotypes. A common haplotype was found in all central region streams and unique haplotypes in northern streams. Several central streams had region specific haplotypes with genetically differentiated populations at the 70,100 km scale. 3. Haplotype diversity was high (0.53,0.8) at most sites, but low (0,0.22) in some central sites. amova analyses found significant genetic diversity among regions (69%) and among catchments (58%). Most population pairwise FST tests were significant, with non-significant pairwise tests among sites in the central region and pairs of sites between neighbouring streams. 4. The levels of sequence divergence are interpreted as the result of Pleistocene divergence in multiple refugia, leading to the evolution of regionally unique haplotypes. The low diversity in some central region populations may result from recent colonisation following local extinctions, associated with volcanic events. [source] Estimating haplotype relative risks in complex disease from unphased SNPs data in families using a likelihood adjusted for ascertainmentGENETIC EPIDEMIOLOGY, Issue 8 2006J. Carayol Abstract The understanding of complex diseases and insights to improve their medical management may be achieved through the deduction of how specific haplotypes may play a joint effect to change relative risk information. In this paper we describe an ascertainment adjusted likelihood-based method to estimate haplotype relative risks using pooled family data coming from association and/or linkage studies that were used to identify specific haplotypes. Haplotype-based analysis tends to require a large amount of parameters to capture all the information that leads to efficiency problems. An adaptation of the Stochastic Expectation Maximization algorithm is used for haplotypes inference from genotypic data and to reduce the number of nuisance parameters for risk estimation. Using different simulations, we show that this method provides unbiased relative risk estimates even in case of departure from Hardy-Weinberg equilibrium. Genet. Epidemiol. 2006. © 2006 Wiley-Liss, Inc. [source] Canine diabetes mellitus: from phenotype to genotypeJOURNAL OF SMALL ANIMAL PRACTICE, Issue 1 2008B. Catchpole Breed differences in susceptibility to diabetes mellitus in dogs suggest an underlying genetic component to the pathogenesis of the disease. There is little evidence for an equivalent of human type 2 diabetes in dogs, and it has been proposed that canine diabetes is more comparable to the type 1 form of the disease. Certain immune response genes, particularly those encoding major histocompatibility complex molecules involved in antigen presentation, are important in determining susceptibility to human type 1 diabetes. We tested the hypothesis that canine major histocompatibility complex genes (known as the dog leucocyte antigen) are associated with diabetes in dogs. A total of 530 diabetic dogs and more than 1000 controls were typed for dog leucocyte antigen, and associations were found with three specific haplotypes. The DLA-DRB1*009/DQA1*001/DQB1*008 haplotype shows the strongest association with diabetes in the UK dog population. This haplotype is common in diabetes-prone breeds (Samoyed, cairn terrier and Tibetan terrier) but rare in diabetes-resistant breeds (boxer, German shepherd dog and golden retriever), which could explain differences in the prevalence of diabetes in these different breeds. There is evidence that the DLA-DQA1*001 allele is also associated with hypothyroidism, suggesting that this could represent a common susceptibility allele for canine immune-mediated endocrinopathies. [source] Identification of 25 new mutations in 40 unrelated Spanish Niemann-Pick type C patients: genotype-phenotype correlationsCLINICAL GENETICS, Issue 3 2005EM Fernandez-Valero To better characterize Niemann-Pick type C (NPC) in Spain and improve genetic counselling, molecular analyses were carried out in 40 unrelated Spanish patients. The search identified 70/80 alleles (88%) involving 38 different NPC1 mutations, 26 of which are described for the first time. No patient with NPC2 mutations was identified. The novel NPC1 mutations include 14 amino acid substitutions [R372W (c.1114C > T), P434L (c.1301C > T), C479Y (c.1436G > A), K576R (c.1727G > A), V727F (c.2179G > T), M754K (c.2261T > A), S865L (c.2594C > T), A926T (c.2776G > A), D948H (c.2842G > C), V959E (c.2876T > A), T1036K (c.3107C > A), T1066N (c.3197C > A), N1156I (c.3467A > T) and F1224L (c.3672C > G)], four stop codon [W260X (c.780G > A), S425X (c.1274C > A), C645X (c.1935T > A) and R1059X (c.3175C > T)], two donor splice-site mutations [IVS7+1G > A (g.31432G > A) and IVS21+2insG (g.51871insG)], one in-frame mutation [N961_F966delinsS (c.2882del16bpins1bp)] and five frameshift mutations [V299fsX8 (c.895insT), A558fsX11 (c.1673insG), C778fsX10 (c.2334insT), G993fsX3 (c.2973_78delG) and F1221fsX20 (c.3662delT)]. We also identified three novel changes [V562V (c.1686G > A), A580A (c.1740C > G) and A1187A (c.3561G > T)] in three independent NPC patients and five polymorphisms that have been described previously. The combination of these polymorphisms gave rise to the establishment of different haplotypes. Linkage disequilibrium was detected between mutations C177Y and G993fsX3 and specific haplotypes, suggesting a unique origin for these mutations. In contrast, I1061T mutation showed at least two different origins. The most prevalent mutations in Spanish patients were I1061T, Q775P, C177Y and P1007A (10, 7, 7 and 5% of alleles, respectively). Our data in homozygous patients indicate that the Q775P mutation correlates with a severe infantile neurological form and the C177Y mutation with a late infantile clinical phenotype. [source] | |||||||||||||