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At least 433 records · Page 24Linked to original sources
PubMed2007

The serotonin receptor HTR1B: gene polymorphisms in attention deficit hyperactivity disorder.

Serotonin plays an essential role in cognition, locomotor activity, and the regulation of sleep, pain, mood, and aggression. Polymorphisms of the HTR1B gene have been implicated in a variety of psychiatric disorders including attention deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). The objectives of this study were to: (i) expand our original investigation of the relationship between the HTR1B receptor gene and attention deficit/hyperactivity and; (ii) to investigate a possible association of obsessive behaviors/perfectionism and the HTR1B gene in a sample of 203 families with an ADHD proband. Six single nucleotide polymorphisms (SNPs) of the HTR1B receptor gene were genotyped using standard methods. Evidence for an association between the HTR1B gene and ADHD as a qualitative diagnosis, or the inattentive and hyperactive-impulsive quantitative traits was not supported by either TDT single marker analysis or haplotype analysis. In addition we did not find evidence to suggest an association between HTR1B and perfectionism in this sample of ADHD families.

Adolescent↗
PubMed1993

A gene for Stargardt's disease (fundus flavimaculatus) maps to the short arm of chromosome 1.

Stargardt's disease (fundus flavimaculatus) is one of the most frequent causes of macular degeneration in childhood and accounts for 7% of all retinal dystrophies. It is an autosomal recessive condition characterized by a bilateral loss of central vision occurring at age 7-12 years. Genetic linkage analysis of eight families has assigned the disease locus to chromosome 1p21-p13. Multipoint linkage analysis and haplotype analysis has allowed us to establish the best estimate for location of the gene over the locus D1S435 (maximum lod score of 12.66). Our results are consistent with the genetic homogeneity of this condition.

Child↗
PubMed1994

Apparent genetic homogeneity of the Treacher Collins-Franceschetti syndrome.

The Treacher Collins-Franceschetti syndrome (TCOF) or mandibulofacial dysostosis (MFD) is an autosomal dominant disorder characterized by craniofacial abnormalities and hearing loss. A refined genetic linkage map of the TCOF locus was established in 8 independent families, using 12 microsatellite DNA markers of the distal 5q. Positive lod score values were obtained for all markers with a maximum at the D5S413 locus (Zmax = 3.79 at theta = 0%). Multipoint linkage analysis and haplotype analysis supported the location of the gene between loci D5S434 and D5S412. These results are consistent with previous linkage analyses [Dixon et al.: Am J Hum Genet 49:17-22, 1991, Am J Hum Genet 52:907-914, 1993; Jabs et al.: Genomics 11:193-198, 1991, Genomics 18:7-13, 1993] and provide further evidence of genetic homogeneity in this syndrome.

Chromosomes, Human, Pair 5↗
PubMed2003

Molecular diagnosis and prophylactic therapy for presymptomatic Chinese patients with Wilson disease.

BACKGROUND: The potential for therapy for Wilson disease (WD) emphasizes the importance of presymptomatic diagnosis in families with WD (WD families). OBJECTIVES: To investigate the feasibility of presymptomatic DNA diagnosis and evaluate the efficacy of zinc sulfate therapy in WD families. METHODS: Seventy-eight clinically unaffected siblings were studied from 51 unrelated WD families that were ascertained by affected individuals. The diagnosis in presymptomatic patients was established by a combination of direct mutational analysis and haplotype analysis with 3 short tandem repeat markers. The presymptomatic patients were treated with 50 mg of elemental zinc sulfate twice a day from the time of molecular diagnosis and followed up for 3 to 5 years. RESULTS: Of the 78 siblings, 17 were diagnosed as presymptomatic patients. Kayser-Fleischer rings were absent in 7 and faint in 4 of the 17 presymptomatic patients. The serum ceruloplasmin values gradually increased and 24-hour urinary copper values gradually diminished during zinc therapy, which indicate effective control of copper metabolism. None of the siblings developed clinical symptoms of WD or adverse effects from zinc therapy. CONCLUSION: We conclude that presymptomatic DNA diagnosis and zinc therapy are effective treatment of patients with WD.

Adolescent↗
PubMed2005

Commonality of TRIM32 mutation in causing sarcotubular myopathy and LGMD2H.

Sarcotubular myopathy (OMIM 268950) is a rare autosomal recessive myopathy first described in two Hutterite brothers from South Dakota and in two non-Hutterite brothers from Germany. We report that sarcotubular myopathy (STM) is caused by mutation in TRIM32, the gene encoding the tripartite motif-containing protein 32. TRIM32 was found to be the gene mutated in limb girdle muscular dystrophy type 2H (LGMD2H [OMIM 254110]), a disorder that has been confined to the Hutterite population. The TRIM32 mutation found in the STM patients is identical to the causative mutation for LGMD2H (D487N), Haplotype analysis shows that the disease chromosomes share common ancestry.

Adult↗
PubMed2006

Genetic variation in the COX-2 gene and the association with prostate cancer risk.

COX-2 is a key enzyme in the conversion of arachidonic acid to prostaglandins. The prostaglandins produced by COX-2 are involved in inflammation and pain response in different tissues in the body. Accumulating evidence from epidemiologic studies, chemical carcinogen-induced rodent models and clinical trials indicate that COX-2 plays a role in human carcinogenesis and is overexpressed in prostate cancer tissue. We examined whether sequence variants in the COX-2 gene are associated with prostate cancer risk. We analyzed a large population-based case-control study, cancer prostate in Sweden (CAPS) consisting of 1,378 cases and 782 controls. We evaluated 16 single nucleotide polymorphisms (SNPs) spanning the entire COX-2 gene in 94 subjects of the control group. Five SNPs had a minor allele frequency of more than 5% in our study population and these were genotyped in all case patients and control subjects and gene-specific haplotypes were constructed. A statistically significant difference in allele frequency between cases and controls was observed for 2 of the SNPs (+3100 T/G and +8365 C/T), with an odds ratio of 0.78 (95% CI=0.64-0.96) and 0.65 (95% CI=0.45-0.94) respectively. In the haplotype analysis, 1 haplotype carrying the variant allele from both +3100 T/G and +8365 C/T, with a population frequency of 3%, was also significantly associated with decreased risk of prostate cancer (p=0.036, global simulated p-value=0.046). This study supports the hypothesis that inflammation is involved in prostate carcinogenesis and that sequence variation within the COX-2 gene influence the risk of prostate cancer.

Aged↗
PubMed1993

Analysis of a second family with hereditary non-chromaffin paragangliomas locates the underlying gene at the proximal region of chromosome 11q.

The gene for autosomal, dominantly inherited, non-chromaffin paragangliomas has previously been mapped at 11q23-qter by linkage analysis of a single family. In the present study, we have used genetic markers from 11q for the analysis of two distantly related pedigrees with the same disorder. Linkage analysis and haplotyping indicate that the gene underlying the disorder in the present family is located on chromosome 11q proximal to the tyrosinase gene locus (11q14-q21). Closely linked markers are the human homologue of the murine INT2 protooncogene and the anonymous DNA marker D11S527. A maximum lod score of 5.4 (theta = 0.0) has been obtained for linkage between the disorder and the chromosomal region defined by these markers. The human INT2 gene can be regarded as a candidate for the disorder on the basis of its expression pattern during embryogenesis in the mouse. However, haplotype analysis indicates that this gene is probably not the predisposing genetic factor in the present family.

Chromosome Mapping↗
PubMed2003

Non-radioactive detection of five common microsatellite markers for ATP7B gene in Wilson disease patients.

Haplotype analysis using microsatellite markers is a useful indicator of specific mutations and is often exploited as the first large-scale screening technique to carry out the molecular characterization of the disease gene in probands from a specific population. However, the methodologies available are still cumbersome and require the use of either radioactive compounds or specialized equipment suitable to follow fluorescent dyes. Both these techniques may not be available for newly developing clinical laboratories. We have set up a sensitive and easy-to-use protocol to characterize five closely spaced, highly polymorphic microsatellite polymorphisms (CA repeats) that span the Wilson disease (WD) region, i.e. D13S316, D13S133, D13S301, D13S314, D13S315. The technique described here for the analysis of the WD gene microsatellite system relies on the quick detection method of silver staining, avoiding the use of toxic or sophisticated equipment. This approach could be the method of choice to implement molecular genetic testing in clinical laboratories, even those not especially equipped for DNA analysis and in particular in newly developed molecular genetics centers in countries whose population has not yet been characterized for WD-causing ATP7B gene mutations.

Adenosine Triphosphatases↗
PubMed2005

[Digenic association of RHO and RP1 genes with retinitis pigmentosa among Chinese population in Hong Kong].

OBJECTIVE: To identify the mutation patterns of RHO and RP1 genes in the Chinese patients with retinitis pigmentosa (RP) and to explore their potential interactions in the pathogenesis of RP. METHODS: Sequence alterations in the entire coding region and splice sites of RHO and RP1 gene were screened in 151 RP affected probands and 150 unrelated controls who were all Hong Kong Chinese. Additional 46 relatives of 12 RP probands carrying possible mutations in RHO or RP1 were recruited for segregation analysis. Univariate analysis, multivariate analysis and genotype-pedigree disequilibrium test were used to examine the associations of polymorphisms in these two genes with RP. RESULTS: Two mutations in the RHO gene, 5211delC and P347L, were identified each in one proband from the 151 probands, accounting for 1.3% of the RP patients. Two mutations in the RP1 gene, R677X and D984G, were identified each in one proband from the 151 probands, also accounting for 1.3% of the RP patients. In univariate analysis, non-coding sequence variants in the RHO gene, -26G > A, was found to increase the risk of RP, while R872H in the RP1 gene was likely to be a protective factor for RP. Multivariable logistic regression analysis and haplotype analysis confirmed these associations. CONCLUSION: The prevalences of RHO and RP1 mutations among the RP patients in Chinese population are both less than reported in other populations. Besides the disease-causing mutations, non-coding sequence alterations may also be a modifier for RP. The potential interactions between RHO and RP1 suggest a digenic etiology for RP.

Adolescent↗
PubMed1991

Geographical distribution gradients of the major PKU mutations and the linked haplotypes.

Analysis of 81 phenylketonuria families from Bulgaria, Lithuania and eastern Germany demonstrated a high frequency of haplotype 2 and the associated Arg408----Trp408 substitution. Haplotype 3 and the splicing mutation in intron 12 are rare or absent in the groups studies. Pooling the data on European populations suggests a Balto-Slavic origin of the defect in codon 408 of the phenylalanine hydroxylase gene and a geographical gradient in the distribution of both major PKU mutations which may contribute to the higher incidence of classic PKU in northern Europeans.

Bulgaria↗
PubMed1992

The Huntington's disease candidate region exhibits many different haplotypes.

Analysis of 78 Huntington's disease (HD) chromosomes with multi-allele markers revealed 26 different haplotypes, suggesting a variety of independent HD mutations. The most frequent haplotype, accounting for about one third of disease chromosomes, suggests that the disease gene is between D4S182 and D4S180. However, the paucity of an expected class of chromosomes that can be related to this major haplotype by assuming single crossovers may reflect the operation of other mechanisms in creating haplotype diversity. Some of these mechanisms sustain alternative scenarios that do not require a multiple mutational origin for HD and/or its positioning between D4S182 and D4S180.

Alleles↗
PubMed2005

Gene SNPs and mutations in clinical genetic testing: haplotype-based testing and analysis.

Haplotype-based analysis using high-density single nucleotide polymorphism (SNP) markers have gained increasing attention in evaluating candidate genes in various clinical situations. For example, haplotype information is useful for predicting the severity and prognosis of certain genetic disorders. The intragenic cis-interactions between the common polymorphisms and the pathogenic mutations of prion protein (PRNP) and cystic fibrosis transmembrane conductance regulator (CFTR) genes greatly influence the phenotypes and the disease penetrance of hereditary Creutzfeldt-Jakob disease and cystic fibrosis. Merits of haplotype study are more evident in the fine mapping of complex diseases and in identifying genetic variations that influence individual's response to drugs. Knowledge-based approaches and/or linkage analyses using SNP tagged haplotypes are effective tools in detecting genetic associations. For example, haplotype studies in the inflammatory bowel disease susceptibility loci revealed diverse cis and trans gene-gene interactions, which can affect the clinical outcomes. Although currently, we have very limited knowledge on haplotype-phenotypic characterizations of most genes, these examples demonstrate that increased understanding of the clinically relevant haplotypes will provide better results in the diagnosis and possibly in the treatment of both monogenic and polygenic diseases.

Amyloid↗
PubMed2000

Nine polymorphisms of angiotensinogen gene in the susceptibility to essential hypertension.

Even if the importance of angiotensinogen (AGT) gene has been known in gene targeting animals and humans genetic studies, its precise mechanism and the interaction among AGT gene variants, plasma AGT concentration and risk for hypertension remain uncertain. We examined whether AGT gene variants predispose to hypertension via an increase of plasma AGT concentration. Plasma AGT concentration was estimated from plasma angiotensin I which was cleaved by an excess amount of human renin and measured by RIA. Using 9 AGT gene variants which included new polymorphisms (G-152A and T+31C), we examined the association with hypertension and with plasma concentration by a case-control study. Haplotype analysis revealed that G-6A, T+31C and M235T polymorphisms were in absolute linkage disequilibrium and were associated with hypertension but not with plasma AGT level. On the other hand, -1074t;T235 haplotype was associated with an increase of AGT level but not with hypertension. In the haplotype analysis, only H3 haplotype frequency, which contained G-6, T+31 and M235 alleles, was significantly increased in normotensive subjects, suggesting that this haplotype is associated with a hypotensive effect. According to combined haplotype analysis of diallele and microsatellite markers, it remains a possibility that M235T, T+31C, G-6A, A-20C and G-1074T polymorphisms may play an important role in increased risk for essential hypertension. Our results suggest that the positive association between AGT polymorphism and hypertension is not simply explained by an increase of plasma AGT concentration.

Alleles↗
PubMed2004

Linkage disequlibrium in the DTNBP1 (dysbindin) gene region and on chromosome 1p36 among psychotic patients from a genetic isolate in Israel: findings from identity by descent haplotype sharing analysis.

Several genes have been reported recently to be associated with schizophrenia and bipolar disorder. Because of the complexity of the inheritance of these disorders, there is an urgent need to replicate these findings and to search for additional candidate genes. The study of genetic isolates is a powerful technique that may overcome some of the obstacles caused by genetic heterogeneity and ambiguity of phenotype definition. Identity by descent (IBD) haplotype sharing analysis in these populations may be used to detect mutations within shared haplotypes in smaller samples of affected individuals. In this study, we used IBD haplotype sharing analysis to replicate positive linkage and association findings in psychotic disorders, and to identify other regions of interest. Fifty-two patients with major psychiatric disorders from a genetically isolated village in Israel were studied. By studying eight Y chromosome markers, we were able to confirm the oral tradition of members of this isolate regarding a common paternal origin. Three hundred fifty nine microsatellite markers on 9 candidate chromosomes were genotyped, and haplotypes were reconstructed using information from family members. Two highly significant (P < 0.0001) peaks of haplotype sharing were found. One was for psychotic patients with any diagnosis at the location of dysbindin, a gene previously associated with schizophrenia. The other peak was for patients with schizophrenia on chromosome 1p36. Thus, this study both replicates an earlier finding and points to a novel region of interest, which might be unique to this population.

Carrier Proteins↗
PubMed2004

Haplotype association analysis of discrete and continuous traits using mixture of regression models.

We present a regression-based method of haplotype association analysis for quantitative and dichotomous traits in samples consisting of unrelated individuals. The method takes account of uncertain phase by initially estimating haplotype frequencies and obtaining the posterior probabilities of all possible haplotype combinations in each individual, then using these as weights in a finite mixture of regression models. Using this method, different combinations of marker loci can be modeled, to find a parsimonious set of marker loci that are most predictive and therefore most likely to be closely associated with the a quantitative trait locus. The method has the additional advantage of being able to use individuals with some missing genotype data, by considering all possible genotypes at the missing markers. We have implemented this method using the SNPHAP and Mx programs and illustrated its use on published data on idiopathic generalized epilepsy.

Chromosome Mapping↗
PubMed1993

Germinal mosaicism in a Duchenne muscular dystrophy family: implications for genetic counselling.

In this study we describe a three-generation family in which two siblings were affected by Duchenne muscular dystrophy (DMD). Immunohistochemical analysis of muscle dystrophin and haplotype analysis of the DMD locus revealed that the X chromosome carrying the DMD gene was transmitted from the healthy maternal grandfather to his three daughters, including the proband's mother. These findings indicate that the grandfather was a germinal mosaic for the DMD gene. The definition of the carrier status in two possible carriers led us to give accurate genetic counselling and to prevent the birth of an affected boy. The results of this study demonstrate the usefulness of haplotype analysis and immunohistochemical muscle dystrophin studies to detect hidden germinal mosaicism and to improve genetic counselling.

Dystrophin↗
PubMed2004

Genetic association mapping under founder heterogeneity via weighted haplotype similarity analysis in candidate genes.

Taking advantage of increasingly available high-density single nucleotide polymorphism (SNP) markers within genes and across genomes, more and more genetic association studies began to use multiple closely linked markers in candidate genes. A practical analytical challenge arising in such studies is the possibility that not all case chromosomes have inherited disease-causing mutations from a common ancestral chromosome (founder heterogeneity). To alleviate the problem, we propose a method that applies a clustering algorithm to haplotype similarity analysis. The method identifies a sequence of nested subsets of case chromosomes by a peeling procedure, where each subset is relatively homogeneous. The average similarity score estimated from each subset in the sequence is compared to that estimated in controls, and a raw (unadjusted for multiple comparisons) P value is obtained. The test for the association between the trait and the candidate gene is based on the minimum raw P value observed in the comparison sequence, with its significance level estimated by a permutation procedure. The method can be applied to both haplotype and genotype data. Simulation studies suggest that our method has the correct type I error rate, and is generally more powerful than existing methods of haplotype similarity analysis.

Alleles↗
PubMed2003

Two exonic single nucleotide polymorphisms in the microsomal epoxide hydrolase gene are associated with polycystic ovary syndrome.

OBJECTIVE: To determine whether genetic variability in the gene encoding microsomal epoxide hydrolase (EPHX) contributes to individual differences in susceptibility to the development of polycystic ovary syndrome (PCOS). DESIGN: Retrospective case-control study. SETTING: University-based clinic. PATIENT(S): One hundred twelve white women with PCOS and 115 healthy controls. INTERVENTION(S): None. MAIN OUTCOME MEASURES: The presence of two single nucleotide polymorphisms (SNPs), T-->C (Tyr113His) in exon 3 and A-->G (His139Arg) in exon 4, in the EPHX gene. Single point analysis was expanded to pair of loci haplotype analysis to examine the estimated haplotype frequencies of the two SNPs, of unknown phase, in the PCOS and control groups. Estimated haplotype frequencies were assessed using the maximum-likelihood method, using an expectation-maximization algorithm. RESULT(S): Single point allele and genotype distributions in exon 3 and exon 4 of the EPHX gene were not statistically different between the groups. However, according to the haplotype estimation analysis, we observed a significantly elevated frequency of haplotype C-G (His113-Arg139) in the PCOS group versus the control group. The odds ratio for PCOS associated with the low activity haplotype C-G (His113-Arg139) was 2.28 (95% confidence interval 1.1-4.8). CONCLUSION(S): The use of two intragenic single nucleotide polymorphisms jointly in haplotype analysis of association demonstrated that the genetically determined low activity haplotype C-G (His113-Arg139) was significantly associated with PCOS.

Case-Control Studies↗