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PubMed2006

Parsing the genetic heterogeneity of chromosome 12q susceptibility genes for Alzheimer disease by family-based association analysis.

Previous linkage studies have suggested that chromosome 12 may harbor susceptibility genes for late-onset Alzheimer disease (LOAD). No risk genes on chromosome 12 have been conclusively identified yet. We have reported that the linkage evidence for LOAD in a 12q region was significantly increased in autopsy-confirmed families particularly for those showing no linkage to alpha-T catenin gene, a LOAD candidate gene on chromosome 10 [LOD score increased from 0.1 in the autopsy-confirmed subset to 4.19 in the unlinked subset (optimal subset); p<0.0001 for the increase in LOD score], indicating a one-LOD support interval spanning 6 Mb. To further investigate this finding and to identify potential candidate LOAD risk genes for follow-up analysis, we analyzed 99 single nucleotide polymorphisms in this region, for the overall sample, the autopsy-confirmed subset, and the optimal subset, respectively, for comparison. We saw no significant association (p<0.01) in the overall sample. In the autopsy-confirmed subset, the best finding was obtained in the activation transcription factor 7 (ATF7) gene (single-locus association, p=0.002; haplotype association global, p=0.007). In the optimal subset, the best finding was obtained in the hypothetical protein FLJ20436 (FLJ20436) gene (single-locus association, p=0.0026). These results suggest that subset and covariate analyses may be one approach to help identify novel susceptibility genes on chromosome 12q for LOAD.

Alzheimer Disease↗

PubMed2005

Association analysis of brain-derived neurotrophic factor (BDNF) gene 196 A/G polymorphism with Alzheimer's disease (AD) in mainland Chinese.

A functional polymorphism in the coding region of brain-derived neurotrophic factor (BDNF) gene (196 A/G, Met66Val) has recently been reported to be associated with Alzheimer's disease (AD) and with an overrepresentation of G allele in AD patients, but different results have also been presented. We conducted a case-control study to analyze the association between the BDNF A/G polymorphism and sporadic AD in a sample composed of 203 AD patients and 239 controls from Mainland Chinese Han population. No association between the polymorphism and AD, no association between the polymorphism and age at onset in AD, and no significant interaction between BDNF and apolipoprotein E (APOE) genotype were detected in either the total or the male samples. However, a significantly high frequency of the GG genotype in the female controls compared with the female patients was detected. A postponed age at onset in the female patients with the GG genotype was also observed. These results suggest that the GG genotype has a protection effect from AD development in females. A significant low frequency of AD patients with the BDNF GG genotype in the AD APOEepsilon4 carriers compared with the frequency of the controls with the BDNF GG genotype in the control APOEepsilon4 carriers was also detected in the female individuals, suggesting that the BDNF GG genotype may reduce the effect of APOEepsilon4 on AD risk in females. Additionally, low frequencies of BDNF G allele and GG genotype were revealed in Chinese when compared with that in the other race populations so far reported.

Adult↗

PubMed2001

Association analysis of polymorphism in the promoter region of the alpha2a-adrenoceptor gene with schizophrenia and clozapine response.

There exists considerable evidence implicating the alpha (alpha) adrenergic system in the superior therapeutic effects of clozapine for the treatment of schizophrenia, as also its associated adverse hypersalivation side effect. It would seem plausible for variants of the adrenoceptors to be associated with the clozapine response. The present study tested the hypothesis that a biallelic polymorphism in the promoter region of the alpha2a-adrenoceptor gene confers susceptibility to schizophrenia, and is associated with a clozapine-induced (favorable) therapeutic response and/or a clozapine-induced hypersalivation. Ninety-seven treatment-resistant schizophrenic patients were assessed using the Brief Psychiatric Rating Scale before and after clozapine treatment. The results of clozapine treatment demonstrated that the alpha2a-adrenoceptor gene variants did not play a major role in the susceptibility, hypersalivation adverse effect or clozapine response of patients with schizophrenia. The polymorphism of the alpha2a-adrenoceptor gene investigated is not likely to play a major role in the pathogenesis of schizophrenic disorders or clozapine response, although the hypothesis that these genes are implicated in the cognitive deficit and polydipsia associated with schizophrenic disorders may, however, still warrant further study.

Adult↗

PubMed2005

Association analysis of serotonin transporter promoter gene polymorphism with ADHD and related symptomatology.

Attention deficit hyperactivity disorder (ADHD) is one of the most common childhood behavioral disorders. Genetic factors contribute to the underlying liability to develop attention deficit hyperactivity disorder. Several investigations have reported associations between ADHD and serotonin transporter promoter polymorphisms, but the results have been inconsistent. The present study did not find significant association between ADHD and serotonin transporter promoter polymorphisms, but did find an effect of serotonin transporter promoter polymorphisms on some ADHD symptomatology. Patients homozygous for the short allele showed more Withdrawn or Somatic complaint scores than subjects with the long allele.

Alleles↗

PubMed1999

Linkage and association analysis of susceptibility regions on chromosomes 5 and 6 in 106 Scandinavian sibling pair families with multiple sclerosis.

In the genetically homogeneous Scandinavian population, we have investigated chromosome 5 and the HLA (human leukocyte antigen) region on chromosome 6p21 by applying linkage and association analyses on 106 white sibling pair families with multiple sclerosis. The importance of genes within the HLA region for the susceptibility of multiple sclerosis has previously been reported. More recently, findings have suggested importance of regions on chromosome 5. Half of chromosome 5 was analyzed by using 14 microsatellite markers and a susceptibility region with a maximum LOD score of 1.1 was identified. Chromosome 6 was analyzed by HLA-DR typing and using the TNF alpha microsatellite marker. A peak maximum LOD score of 2.0 was found at the HLA-DR marker. Association studies were made for all the markers, comparing 106 probands from the sibling pairs with 100 unrelated controls. None of the markers on chromosome 5 showed significant association with multiple sclerosis, whereas strong association between multiple sclerosis and DR2 was found, with an odds ratio of 3.7 (p < 10(-5)). It is surprising that association was not seen for any of the TNF alpha alleles including the 121-bp allele, although this allele was in positive linkage disequilibrium with DR2 in both patients and controls. Our results support the existence of multiple sclerosis susceptibility loci on chromosomes 5p and 6p21.

Chromosome Mapping↗

PubMed2002

Allelic association analysis of the dopamine D2, D3, 5-HT2A, and GABA(A)gamma2 receptors and serotonin transporter genes with heroin abuse in Chinese subjects.

Five candidate genes, the receptors DRD2, DRD3, HTR2A and GABA(A)gamma2, and the serotonin transporter (5-HTT) were analyzed for association with heroin abuse. We examined three polymorphisms (promoter - 141DeltaC, Ser311Cys, and TaqI) in the DRD2 gene, one polymorphism (Ser9Gly) in the DRD3 gene, two polymorphisms (promoter - 1438G/A and T102C) in the HTR2A gene, two polymorphisms (VNTR and Del/Ins) in 5-HTT gene, and one polymorphism (G3145A) in GABA(A)gamma2 gene in 121 Chinese heroin addicts and 194 controls. None of the polymorphisms differed significantly for allele, genotype, or haplotype frequencies, except for the DRD2 promoter polymorphism - 141DeltaC (genotype-wise and allele-wise, P = 0.05, uncorrected). An additional 344 subjects with heroin abuse and 104 controls were investigated for the - 141DeltaC polymorphism. In the second sample, there were no significant difference of genotype or allele frequencies between subjects with heroin abuse and normal controls. When we divided the sample by route of administration into nasal inhalers and IM or IV injectors, however, it produced a significant difference between inhalers of heroin and controls (genotype-wise, P = 0.006, allele-wise, P = 0.016) but not for injectors of heroin (genotype-wise, P = 0.81, allele-wise, P = 0.69). We also found that LD between all polymorphisms we examined in the gene was weak, possibly explaining why we see association of this polymorphism with heroin abuse but not with other markers in the gene. Overall our results indicates that the HTR2A, 5-HTT, DRD3 and GABA(A)gamma2 genes are not likely to be a major genetic risk factor for heroin abuse in this population, with the exception of possible association between nasal inhalation and DRD2 promoter - 141DeltaC polymorphism.

Adolescent↗

PubMed1995

Association analysis of a polymorphism of the monoamine oxidase B gene with Parkinson's disease in a Japanese population.

The polymorphic allele of the monoamine oxidase B (MAO-B) gene detected by polymerase chain reaction (PCR) and single-stranded conformation polymorphism (SSCP) was associated with Parkinson's disease (PD) in Caucasians. We characterized this polymorphic allele, allele 1, of the MAO-B gene using direct sequencing of PCR products. A single DNA substitution (G-A), resulting gain of Mae III restriction site was detected in intron 13 of the MAO-B gene. The allele associated with PD in Caucasians was twice as frequent as in healthy Japanese, but the association of the allele of the MAO-B gene was not observed in Japanese patients with PD.

Adult↗

PubMed2003

Association analysis of polymorphisms in the upstream region of the human dopamine D4 receptor gene in schizophrenia.

Several studies have suggested that the transcriptional activity of the DRD4 gene may exert an important role in susceptibility to schizophrenia. To address this issue, we studied the association of schizophrenia and polymorphisms including -616C>G, -603T>del, -602G>del, 600G>C, -521C>T, -376C>T and a 120 bp tandem duplication polymorphism (120 bp repeat) in 1.2 kb upstream from the initiation codon in the promoter region of the DRD4 gene with 210 schizophrenic cases and 206 healthy controls. The results showed a significant excess of allele L of the 120 bp repeat in the schizophrenic patients compared to the controls (X(2)=8.585, df=1, P=0.003, OR=1.546, 95% CI=1.154-2.070). No significant difference was detected in the frequencies of genotype and allele of six other polymorphisms between the two groups. However, haplotypic distribution of 120 bp repeat, -616C>G, -602G>del, -521C>T and -376C>T was significantly different between case and control groups (P=0.005). This might cause the alteration of the transcriptional regulation of the DRD4 gene, as the consensus sequences of binding sites for several known transcription factors are involved in this region.

Adult↗

PubMed1999

Association analysis between a Cys23Ser substitution polymorphism of the human 5-HT2c receptor gene and neuronal hyperexcitability.

Transgenic mice lacking a functional 5-HT2c receptor gene are extremely susceptible to audiogenic seizures, suggesting that 5-HT2c receptors mediate inhibition of neuronal network excitability. The present association study tested the hypothesis that a Cys23Ser substitution polymorphism within the human 5-HT2c receptor gene modulates neuronal excitability. Genotypes of the Cys23Ser polymorphism were assessed in 454 subjects of German descent, comprising: 1) 93 severely affected alcohol-dependent males with a history of alcohol withdrawal seizure or delirium, 2) 119 patients affected by an idiopathic generalized epilepsy, and 3) 242 controls. Both sexes were analyzed separately because of the X-chromosomal location of the 5-HT2c receptor gene. The allele frequencies of the Cys23Ser variants did not differ significantly between the controls and either the severely affected alcohol-dependent males (P = 0.34), or patients with idiopathic generalized epilepsy (P > 0.57). Our results suggest that the common Cys23Ser substitution polymorphism of the human 5-HT2c receptor gene does not confer susceptibility to neuronal hyperexcitability in either idiopathic generalized epilepsy or alcohol withdrawal seizure or delirium.

Adult↗

PubMed2002

Characterisation, mutation detection, and association analysis of alternative promoters and 5' UTRs of the human dopamine D3 receptor gene in schizophrenia.

The dopamine D(3) receptor gene (DRD3) is a candidate for a number of psychiatric conditions including schizophrenia, bipolar disorder and alcohol and drug abuse. Previous studies have reported associations between polymorphisms in DRD3 and these disorders, but these findings may have reflected linkage disequilibrium with pathogenic variants that are further upstream. We have isolated and sequenced approximately 9 kb of genomic sequence upstream of the human DRD3 translational start site. Using 5' RACE, we have identified within this region three additional exons and two putative promoter regions which show promoter activity in three different cell lines. A 5' UTR identified only in lymphoblasts is spread over three exons and is 353 bp long. A second 5' UTR, found in adult and fetal brain, lymphocytes, kidney and placenta is spread over two exons and is 516 bp long. A 260-bp sequence within this 9 kb corresponds to a previously reported EST, but corresponding mRNA could not be found in the tissues above. The EST, 5' UTRs and putative promoter regions have been analysed for polymorphisms, revealing 10 single nucleotide polymorphisms, seven of which were tested for association in a large sample of unrelated patients with schizophrenia and matched controls. No associations were observed with schizophrenia. In addition we failed to replicate previous findings of association with homozygosity of the Ser9Gly variant. The results from this study imply that neither the coding nor the regulatory region of DRD3 plays a major role in predisposition to schizophrenia.

5' Untranslated Regions↗

PubMed2003

Mutation screening of the Homer gene family and association analysis in schizophrenia.

Homer proteins are a group of proteins that regulate group 1 metabotropic glutamate receptor function. As altered glutamate function has been implicated in many neuro psychiatric disorders, particularly schizophrenia, we have screened all three known Homer genes for sequence variation for use under the candidate gene association paradigm. We found seven SNPs, including three in exons. Of these, none was non-synonymous. Allele frequencies of all the detected SNPs were estimated in DNA pools of 368 schizophrenics and 368 controls. Only one (Homer 1 IVS4 + 18A > G) was associated with schizophrenia in this sample, a finding confirmed by individual genotyping (P = 0.01). However, in our extended sample of 680 cases and 671 controls, the evidence for association diminished (P = 0.05). Our results suggest it is unlikely that sequence variants in the Homer genes contribute to the aetiology of schizophrenia, but the variants we identified are plausible candidates for other neuropsychiatric phenotypes.

Adult↗

PubMed2005

Identification, characterization, and association analysis of novel genes from the bipolar disorder susceptibility locus on chromosome 4q35.

The cause of bipolar disorder remains unknown, with little knowledge of the underlying biological, anatomical, biochemical, or genetic defect. The disorder is genetically complex, with an increasing number of loci being implicated through genetic linkage studies. We previously identified a bipolar disorder susceptibility locus on chromosome 4q35 and refined the interval harboring this susceptibility gene to approximately 5 Mb, a size that is amenable to positional cloning. Several independent studies have reported the presence of a susceptibility gene at this locus. To identify candidate genes for testing for association with bipolar disorder, we previously established a transcript map that encompasses the candidate interval. We have continued to seek novel genes from this region in order to expand this transcript map. Here, we describe the further identification and characterization of eight novel genes from the chromosome 4q35 bipolar candidate interval. Expression analysis determined that six of these novel genes are expressed in the brain, and these genes were therefore analyzed for association with bipolar disorder. Single nucleotide polymorphisms were identified from the candidate genes and tested for association in our case-control cohort. Our data suggest that the six candidate genes analyzed can be excluded from involvement in the disorder.

Bipolar Disorder↗

PubMed2005

Linkage and association analysis in pedigrees from different populations.

Using the Genetic Analysis Workshop 14 simulated datasets we carried out nonparametric linkage analyses and applied a log-linear method for analysis of case-parent-triad data with stratification on parental mating type. We proposed and applied a random effect modelling approach to explore the impact of population heterogeneity on tests of association between genetic markers and disease status. The estimated genetic effect may appear to be strongly significant in one population but nonsignificant in another population, leading to confusion about interpretation. However, when results are interpreted in the light of a random effects model, both studies may be making similar statements about a genetic effect that varies depending on environment and background.

Chromosomes, Human↗

PubMed2004

Association analysis of FEZ1 variants with schizophrenia in Japanese cohorts.

BACKGROUND: DISC1 has been suggested as a causative gene for psychoses in a large Scottish family. We recently identified FEZ1 as an interacting partner for DISC1. To investigate the role of FEZ1 in schizophrenia and bipolar disorder, case-control association analyses were conducted in Japanese cohorts. METHODS: We performed a mutation screen of the FEZ1 gene and detected 15 polymorphisms. Additional data on informative polymorphisms were obtained from public databases. Eight single nucleotide polymorphisms (SNPs) were analyzed in 119 bipolar disorder and 360 schizophrenic patients and age- and gender-matched control subjects. All genotypes were determined with the TaqMan assay, and selected samples were confirmed by sequencing. RESULTS: The two adjacent polymorphisms displayed a nominally significant association with schizophrenia (IVS2+ 1587G>A, p = .014; 396T<A or Asp123Glu, p = .024). Homozygotes with the Glu123 allele were observed in only a small portion (2%) of schizophrenia patients but not in control subjects or bipolar patients. Conversely, no SNPs displayed allelic, genotypic, or haplotypic associations with bipolar disorder. CONCLUSIONS: A modest association between FEZ1 and schizophrenia suggests that this gene and the DISC1-mediated molecular pathway might play roles in the development of schizophrenia, with FEZ1 affecting only a small subset of Japanese schizophrenia patients.

Adaptor Proteins, Signal Transducing↗

PubMed2000

Laryngeal cancer cost analysis: association of case-mix and treatment characteristics with medical charges.

OBJECTIVES: To examine the relationship of various pretreatment case-mix characteristics and treatment modalities with medical charges incurred during diagnosis, treatment, and 2-year follow-up for patients with laryngeal cancer. DESIGN: Retrospective chart review and billing record analysis. METHODS: The charts and billing records of patients diagnosed with laryngeal cancer at the University of Iowa Hospitals and Clinics (UIHC) between January 1, 1991 and December 31, 1994 were reviewed. The independent variables included various pretreatment patient-mix and tumor characteristics (age, AJCC TNM clinical stage, smoking history, ASA class, and comorbidity as defined by Kaplan-Feinstein grade) as well as type of treatment. The dependent variables included total physician, office, and university hospital-based charges incurred during the pretreatment evaluation and 0- to 3-, 3- to 12, and 12- to 24-month billing periods after the initiation of cancer-directed therapy. Total 1-year and 2-year charges were also evaluated. Univariate and multivariate analyses were used to investigate the relationships between dependent and independent variables and to develop models predictive of management charges during the individual and total billing periods. RESULTS: Pretreatment charges showed no significant associations (P < .05) with any of the independent variables. Multiple regression analyses indicated that comorbidity, stage, and initial treatment modality were significant variables in one or more of the models predicting charges incurred during the 0- to 3-month, 3- to 12-month, total 1-year, and total 2-year billing periods. The models yielded R2 values for the total 1- and 2-year billing periods of 0.5246 and 0.5055, respectively. CONCLUSIONS: This work supports continued study of measures that may result in earlier detection of laryngeal cancer as a potential means of reducing management charges. These results also indicate that a more accurate method of stratifying the disease severity of laryngeal cancer patients for reimbursement purposes would include measurements of the severity of the index disease as well as comorbid diseases.

Aged↗

PubMed2006

The genetic background of osteoporosis in cystic fibrosis: association analysis with polymorphic markers in four candidate genes.

BACKGROUND: Reduced Bone Mass Density (BMD) is frequent in Cystic Fibrosis (CF). Potentially, other genes than the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene may contribute to the bone phenotype variability in CF patients. METHODS: Four candidate genes likely associated with BMD variability were studied: the vitamin D receptor (VDR) gene, the estrogen receptor alpha (ESR1), the calcitonin receptor (CALCR) and the type I alpha 1 collagen (COL1A1) gene. A complete bone and CF evaluation was obtained for 82 subjects (39 m, 43 f): 15 had normal BMD (group 1), 46 were osteopenic (group 2), and 21 were osteoporotic (group 3). RESULTS: No statistical difference was found among the three groups for age, sex, pancreatic status, and vertebral fractures, nor for any of the biochemical markers. Weight, Body Mass Index (BMI), and FEV1, scored significantly worse in the two groups with the lowest T score. The CFTR mutations R1162X and F508del were more frequent in patients with lower BMD (p=0.044 and p=0.071). There was no significant difference in the distribution of the five marker genotypes among the 3 groups defined according to the unadjusted or adjusted (BMI and FEV1) BMD T score. No significant correlation was found between the VDR, CALCR, or COL1A1 gene polymorphisms and reduced BMD values. The individual ESR1 PvuII-XbaI haplotype C-A is associated to elevated u-calcium levels whereas the haplotype T-A is associated to lower values (p=0.00251). CONCLUSIONS: There was no evidence that the genes under study, with the possible exception of ESR1 gene variants, may modulate bone phenotype in CF.

Adult↗

PubMed2006

Genetic association analysis of functional impairment in chronic obstructive pulmonary disease.

RATIONALE: Patients with severe chronic obstructive pulmonary disease (COPD) may have varying levels of disability despite similar levels of lung function. This variation may reflect different COPD subtypes, which may have different genetic predispositions. OBJECTIVES: To identify genetic associations for COPD-related phenotypes, including measures of exercise capacity, pulmonary function, and respiratory symptoms. METHODS: In 304 subjects from the National Emphysema Treatment Trial, we genotyped 80 markers in 22 positional and/or biologically plausible candidate genes. Regression models were used to test for association, using a test-replication approach to guard against false-positive results. For significant associations, effect estimates were recalculated using the entire cohort. Positive associations with dyspnea were confirmed in families from the Boston Early-Onset COPD Study. RESULTS: The test-replication approach identified four genes-microsomal epoxide hydrolase (EPHX1), latent transforming growth factor-beta binding protein-4 (LTBP4), surfactant protein B (SFTPB), and transforming growth factor-beta1 (TGFB1)-that were associated with COPD-related phenotypes. In all subjects, single-nucleotide polymorphisms (SNPs) in EPHX1 (p < or = 0.03) and in LTBP4 (p < or = 0.03) were associated with maximal output on cardiopulmonary exercise testing. Markers in LTBP4 (p < or = 0.05) and SFTPB (p = 0.005) were associated with 6-min walk test distance. SNPs in EPHX1 were associated with carbon monoxide diffusing capacity (p < or = 0.04). Three SNPs in TGFB1 were associated with dyspnea (p < or = 0.002), one of which replicated in the family study (p = 0.02). CONCLUSIONS: Polymorphisms in several genes seem to be associated with COPD-related traits other than FEV(1). These associations may identify genes in pathways important for COPD pathogenesis.

Aged↗

PubMed2004

[Schizophrenia and ocular misalignment: phenotypic and genetic association analysis].

The increased incidence of minor physical anomalies (MPAs) in schizophrenia is the fundamental basis for the neurodevelopmental hypothesis of schizophrenia etiology. Ocular misalignment falls into the category of MPAs, but this phenotype has not been assessed in schizophrenia. This study reveals that constant exotropia displays marked association with schizophrenia. To assess the genetic mechanisms, we examined the transcription factor genes ARIX and its paralogue, PMX2B. We identified frequent deletion/insertion polymorphisms in the 20-alanine homopolymer stretch of PMX2B, with a modest association between these functional polymorphisms and constant exotropia in schizophrenia. The polymorphisms were also associated with overall schizophrenia and more specifically with schizophrenia manifesting strabismus. These results suggest a possible interaction between PMX2B and other schizophrenia-precipitating factors, increasing the risk of the combined phenotypes. This study also highlights the unique nature of the polyalanine length variations found in PMX2B.

Exotropia↗