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S D Detera-Wadleigh

Publications and source records attributed to S D Detera-Wadleigh.

At least 19 recordsLinked to original sources
PubMed2006

Fine mapping of a susceptibility locus for bipolar and genetically related unipolar affective disorders, to a region containing the C21ORF29 and TRPM2 genes on chromosome 21q22.3.

Linkage analyses of bipolar families have confirmed that there is a susceptibility locus near the telomere on chromosome 21q. To fine map this locus we carried out tests of allelic association using 30 genetic markers near the telomere at 21q22.3 in 600 bipolar research subjects and 450 ancestrally matched supernormal control subjects. We found significant allelic association with the microsatellite markers D21S171 (P=0.016) and two closely linked single-nucleotide polymorphisms, rs1556314 (P=0.008) and rs1785467 (P=0.025). A test of association with a three locus haplotype across the susceptibility region was significant with a permutation test of P=0.011. A two SNP haplotype was also significantly associated with bipolar disorder (P=0.01). Only two brain expressed genes, TRPM2 and C21ORF29 (TSPEAR), are present in the associated region. TRPM2 encodes a calcium channel receptor and TSPEAR encodes a peptide with repeats associated with epilepsy in the mouse. DNA from subjects who had inherited the associated marker alleles was sequenced. A base pair change (rs1556314) in exon 11 of TRPM2, which caused a change from an aspartic acid to a glutamic acid at peptide position 543 was found. This SNP showed the strongest association with bipolar disorder (P=0.008). Deletion of exon 11 of TRPM2 is known to cause dysregulation of cellular calcium homeostasis in response to oxidative stress. A second nonconservative change from arginine to cysteine at position 755 in TRPM2 (ss48297761) was also detected. A third nonconservative change from histidine to glutamic acid was found in exon 8 of TSPEAR. These changes need further investigation to establish any aetiological role in bipolar disorder.

Amino Acid Substitution↗
PubMed2004

Findings in an independent sample support an association between bipolar affective disorder and the G72/G30 locus on chromosome 13q33.

Markers near the nested genes G72 and G30 on chromosome 13q33 have been implicated in the etiology of schizophrenia and, recently, bipolar affective disorder (BPAD). Hattori et al (2003) reported that single-nucleotide polymorphisms (SNPs) near the G72/G30 locus were associated with BPAD in a sample of 22 pedigrees, and that SNP haplotypes were associated in a second, larger sample of triads. The present study attempts to replicate this finding in an independent case-control sample. Six SNPs near the G72/G30 locus, including the most strongly associated markers in the previous study, were tested in 139 cases and 113 ethnically matched controls. Significant association was detected between BPAD and two adjacent SNPs (smallest P=0.007; global P=0.024). Haplotype analysis produced additional support for association (smallest P=0.004; global P=0.004). Analysis of 31 unlinked microsatellite markers detected no population stratification in the cases or controls studied. Although the associated alleles and haplotypes differ from those previously reported, these new results provide further evidence, in an independent sample, for an association between BPAD and genetic variation in the vicinity of the genes G72 and G30.

Bipolar Disorder↗
PubMed2002

Expression of the smoothelin gene is mediated by alternative promoters.

OBJECTIVE: Two major isoforms of smoothelin have been reported, a 59-kDa smoothelin-A in visceral smooth muscle cells and a 110-kDa smoothelin-B in vascular smooth muscle cells. The present study was undertaken to investigate the expression of these smoothelin isoforms in different smooth muscle tissues and to determine how they are generated. METHODS: Western blotting with a new, well-defined, smoothelin antibody was used to confirm the existence of two major smoothelin isoforms. Northern blotting, RT-PCR, primer extension and 5'RACE were applied to analyse the expression of these isoforms in human and mouse. Promoter reporter assays were carried out to establish the existence of a dual promoter system governing the expression pattern of the gene. RESULTS: Antibody C6G confirmed the existence of two smoothelin proteins. Northern blotting showed that in vascular tissues a larger smoothelin transcript is generated than in visceral tissue. The cDNA of this larger smoothelin-B was cloned. Computer analysis of the open reading frame suggests an alpha-helical structure of 130 amino acids at the amino terminus of smoothelin-B. The smoothelin gene was cloned and sequenced. It comprises about 25 kb and contains 21 exons. The translational start of smoothelin-B is located in exon 2, whereas transcription and translation of the previously described smoothelin-A starts inside exon 10. Smoothelin-A and -B were demonstrated to be generated by two physically separated promoters. Splice variants within the calponin homology domain at the 3' end of the gene were found for both isoforms. CONCLUSIONS: Two major smoothelin isoforms are generated from a single gene by a dual promoter system in a tissue specific manner. Further variation in the smoothelin proteins is achieved by alternative splicing in the calponin homology domain.

Alternative Splicing↗
PubMed2002

Association between serotonin 4 receptor gene polymorphisms and bipolar disorder in Japanese case-control samples and the NIMH Genetics Initiative Bipolar Pedigrees.

Possible irregularities in serotonergic neurotransmission have been suggested as causes of a variety of neuropsychiatric diseases. We performed mutation and association analyses of the HTR4 gene, on 5q32, encoding the serotonin 4 receptor in mood disorders and schizophrenia. Mutation analysis was performed on the HTR4 exons and exon/intron boundaries in 48 Japanese patients with mood disorders and 48 patients with schizophrenia. Eight polymorphisms and four rare variants were identified. Of these, four polymorphisms at or in close proximity to exon d, g.83097C/T (HTR4-SVR (splice variant region) SNP1), g.83159G/A (HTR4-SVRSNP2), g.83164 (T)9-10 (HTR4-SVRSNP3), and g.83198A/G (HTR4-SVRSNP4), showed significant association with bipolar disorder with odds ratios of 1.5 to 2. These polymorphisms were in linkage disequilibrium, and only three common haplotypes were observed. One of the haplotypes showed significant association with bipolar disorder (P = 0.002). The genotypic and haplotypic associations with bipolar disorder were confirmed by transmission disequilibrium test in the NIMH Genetics Initiative Bipolar Pedigrees with ratios of transmitted to not transmitted alleles of 1.5 to 2.0 (P = 0.01). The same haplotype that showed association with bipolar disorder was suggested to be associated with schizophrenia in the case-control analysis (P = 0.003) but was not confirmed when Japanese schizophrenia families were tested. The polymorphisms associated with mood disorder were located within the region that encodes the divergent C-terminal tails of the 5-HT(4) receptor. These findings suggest that genomic variations in the HTR4 gene may confer susceptibility to mood disorder.

Adolescent↗
PubMed2001

Fine mapping supports previous linkage evidence for a bipolar disorder susceptibility locus on 13q32.

A region between D13S71 and D13S274 on 13q32 showed linkage to bipolar disorder (BP) based on a genome scan using markers with an average spacing of approximately 6 cM and an average heterozygosity of approximately 60% [Detera-Wadleigh et al., 1999: Proc Natl Acad Sci USA 96:5604-5609]. In an attempt to confirm this finding and achieve fine mapping of the susceptibility region, nine additional microsatellite markers with average heterozygosity of approximately 86%, located between D13S71 and D13S274, were typed in the same sample. The strongest linkage evidence was detected by multipoint linkage analysis (ASPEX program) around D13S779-D13S225 with maximum LOD score of 3.25 under Affection Status Model II (ASM II; P = 0.0000546). Data from additional nine markers resulted in a decrease of the 95% confidence interval of the linkage region. Association analyses with GASSOC TDT and ASPEX/sib_tdt detect potential linkage disequilibrium with several markers, including D13S280 (ASPEX TDT P = 0.0033, ASM I). These data generated using a higher marker density within the proposed susceptibility region strengthen the validity of our previous findings and suggest a finer localization of the susceptibility gene(s) on 13q32.

Bipolar Disorder↗
PubMed2001

Evidence for association of the myo-inositol monophosphatase 2 (IMPA2) gene with schizophrenia in Japanese samples.

In our search for candidate genes for affective disorder on the short arm of chromosome 18, we cloned IMPA2, a previously unreported myo-inositol monophosphatase gene, that maps to 18p11.2. We determined its genomic structure and detected three new single nucleotide polymorphisms (SNPs). In the present study, we screened the gene further to search for additional polymorphisms in Japanese samples and identified seven other SNPs, including a novel missense mutation. These polymorphisms clustered into three regions of the gene. Three relatively informative SNPs, 58G>A, IVS1--15G>A and 800C>T from clusters 1, 2 and 3, respectively, were selected for association tests using a case-control design. The Japanese cohort included 302 schizophrenics, 205 patients with affective disorder and 308 controls. Genotyping was done either by melting curve analysis on the LightCycler or by sequencing. All three SNPs showed significant genotypic association (nominal P = 0.031--0.0001) with schizophrenia, but not with affective disorder. These findings increase the relevance of 18p11.2 to schizophrenia susceptibility because GNAL, which has been shown previously to be implicated in schizophrenia in an independent study, is in close physical proximity to IMPA2. Our findings suggest that IMPA2 or a gene nearby may contribute to the overall genetic risk for schizophrenia among Japanese.

Adult↗
PubMed2001

Lithium-related genetics of bipolar disorder.

Lithium is a potent prophylactic medication and mood stabilizer in bipolar disorder. However, clinical outcome is variable, and its therapeutic effect manifests after a period of chronic treatment, implying a progressive and complex biological response process. Signal transduction systems known to be perturbed by lithium involve phosphoinositide (PI) turnover, activation of the Wnt pathway via inhibition of glycogen synthase kinase-3beta (GSK-3beta), and a growth factor-induced, Akt-mediated signalling that promotes cell survival. These pathways, acting in synergy, probably prompt the amplification of lithium signal causing such immense impact on the neuronal network. The sequencing of the human genome presents an unparallelled opportunity to uncover the full molecular repertoire involved in lithium action. Interrogation of high-resolution expression microarrays and protein profiles represents a strategy that should help accomplish this goal. A recent microarray analysis on lithium-treated versus untreated PC12 cells identified multiple differentially altered transcripts. Lithium-perturbed genes, particularly those that map to susceptibility regions, could be candidate risk-conferring factors for mood disorders. Transcript and protein profiling in patients could reveal a lithium fingerprint for responsiveness or nonresponsiveness, and a signature motif that may be diagnostic of a specific phenotype. Similarly, lithium-sensitive gene products could provide a new generation of pharmacological targets.

Bipolar Disorder↗
PubMed2001

A human glucocorticoid receptor gene variant that increases the stability of the glucocorticoid receptor beta-isoform mRNA is associated with rheumatoid arthritis.

OBJECTIVE: To study the occurrence and function of polymorphism in the human glucocorticoid receptor (hGR) gene in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). METHODS: We used single stranded conformation polymorphism (SSCP) and direct sequencing to study the hGR gene in 30 patients with RA, 40 with SLE, and 24 controls. A newly identified polymorphism was transfected in COS-1 cells and the stability of the mRNA containing the polymorphism was tested using real-time PCR. RESULTS: A polymorphism in the hGR gene in exon9beta, in an "ATTTA" motif, was found to be significantly associated with RA. Introduction of this polymorphism in the hGRb mRNA was found to significantly increase stability in vitro compared to the wild-type sequence. CONCLUSION: Our findings show an association between RA and a previously unreported polymorphism in the hGR gene. This polymorphism increased stability of hGRbeta mRNA, which could contribute to an altered glucocorticoid sensitivity since the hGRbeta is thought to function as an inhibitor of hGRalpha activity.

Animals↗
PubMed2000

Suggestive evidence of a locus on chromosome 10p using the NIMH genetics initiative bipolar affective disorder pedigrees.

As part of a four-center NIMH Genetics Initiative on Bipolar Disorder, a genome screen using 365 markers was performed on 540 DNAs from 97 families, enriched for affected relative pairs. This is the largest uniformly ascertained and assessed linkage sample for this disease, and includes 232 subjects diagnosed with bipolar I (BPI), 32 with schizo-affective, bipolar type (SABP), 72 with bipolar II (BPII), and 88 with unipolar recurrent depression (UPR). A hierarchical set of definitions of affected status was examined. Under Model I, affected individuals were those with a diagnosis of BPI or SABP, Model II included as affected those fitting Model I plus BPII, and Model III included those fitting Model II plus UPR. This data set was previously analyzed using primarily affected sib pair methods. We report the results of nonparametric linkage analyses of the extended pedigree structure using the program Genehunter Plus. The strongest finding was a lod score of 2.5 obtained on chromosome 10 near the marker D10S1423 with diagnosis as defined under Model II. This region has been previously implicated in genome-wide studies of schizophrenia and bipolar disorder. Other chromosomal regions with lod scores over 1.50 for at least one Model Included chromosomes 8 (Model III), 16 (Model III), and 20 (Model I). Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:18-23, 2000

Bipolar Disorder↗
PubMed2000

Genomic structure and novel variants of myo-inositol monophosphatase 2 (IMPA2).

Recently, we cloned the human myo-inositol monophosphatase 2 (IMPA2) cDNA and established its map location to chromosome 18p11.2, a region previously implicated in bipolar disorder. Because the myo-inositol monophosphatase enzyme has been shown to be inhibited by lithium, an effective therapeutic agent for bipolar disorder, IMPA2 is a plausible positional and functional candidate gene. To permit comprehensive screening for variants we characterized the genomic structure and isolated the potential promoter of IMPA2. The gene was found to encode eight exons spanning;27 kb. The proximal 1-kb 5' flanking region did not contain an obvious TATA box but multiple potential binding sites for Sp1 and consensus motifs for AP2 and other transcription factors were evident. Sequencing of the coding region and splice junctions in unrelated bipolar disorder patients detected novel variants. A missense mutation in exon 2, His76Tyr, was found in one patient. His76 is evolutionarily conserved and replacement with Tyr introduces a potential site for phosphorylation. The other polymorphisms included an RsaI polymorphism, IVS1-15G>A, and a T --> C silent mutation in the third nucleotide of codon 53 in exon 2. By Fisher's exact test the silent mutation showed a trend for association (P = 0.051) with bipolar disorder suggesting that further scrutiny of this gene is warranted.

Alternative Splicing↗
PubMed2000

Refinement of regions with allelic loss on chromosome 18p11.2 and 18q12.2 in esophageal squamous cell carcinoma.

Esophageal cancer ranks among the 10 most common cancers worldwide and is almost invariably fatal. The detailed genetic repertoire involved in esophageal carcinogenesis has not been defined. We have shown previously that the esophageal squamous cell carcinoma genome exhibits a frequent loss of heterozygosity (LOH) in the pericentromeric region of chromosome 18. To construct a fine deletion map, we screened 76 new samples composed of microdissected esophageal squamous cell carcinoma and matched morphologically normal epithelial cells using closely spaced markers. Maximal LOH frequency (54%) was displayed by D18S542 on 18p11.2. The pattern of LOH in selected patients indicated that the short region of overlap extends 3 cM on either side of D18S542. On the long arm of chromosome 18, the highest frequency of allelic loss (42%) was detected by D18S978 on 18q12.2-q21.1. This analysis revealed a short region of overlap of approximately 0.8 cM. These findings further implicate unreported tumor suppressor genes encoded by 18p11.2 and 18q12.2 in esophageal squamous cell carcinogenesis and they indicate a refinement of their map location.

Adult↗
PubMed2000

Association study on the DUSP6 gene, an affective disorder candidate gene on 12q23, performed by using fluorescence resonance energy transfer-based melting curve analysis on the LightCycler.

We introduced a new genotyping method, fluorescence resonance energy transfer-based melting curve analysis on the LightCycler, for the analysis of the gene, DUSP6 (dual specificity MAP kinase phosphatase 6), in affective disorder patients. The DUSP6 gene is located on chromosome 12q22-23, which overlaps one of the reported bipolar disorder susceptibility loci. Because of its role in intracellular signalling pathways, the gene may be involved in the pathogenesis of affective disorders not only on the basis of its position but also of its function. We performed association analysis using a T>G polymorphism that gives rise to a missense mutation (Leu114Val). No evidence for a significant disease-causing effect was found in Japanese unipolars (n = 132) and bipolars (n = 122), when compared with controls (n = 299). More importantly, this study demonstrates that melting curve analysis on the LightCycler is an accurate, rapid and robust method for discriminating genotypes from biallelic markers. This strategy has the potential for use in high throughput scanning for and genotyping of single nucleotide polymorphisms (SNPs).

Adult↗
PubMed1999

Do schizophrenia and affective disorder share susceptibility genes?

Schizophrenia and affective disorders are relatively common neuropsychiatric diseases with a complex genetic etiology. A multigenic inheritance with variable influence of unknown environmental factors may be involved. Family studies have demonstrated the existence of both phenotypes in the same kindreds, and in certain cases, a transition from one phenotype to another occurs. In addition, intermediate phenotypes such as schizoaffective disorders are found in families with schizophrenia and affective illness. Recent genome and chromosomal scans appear to support these epidemiologic data, since susceptibility regions for both schizophrenia and affective disorders have been found to overlap, on chromosomes 10p13-p12, 13q32, 18p and 22q11-q13. These studies were performed in independently ascertained family samples with index patients afflicted either with schizophrenia or bipolar disorder. Taken together, these findings imply shared loci for schizophrenia and affective disorders among those required for the full expression of the phenotype. Identification and molecular characterization of the genetic components conferring risk to both disorders would impact positively on diagnosis, prevention, and treatment.

Bipolar Disorder↗
PubMed1999

Chromosomes 12 and 16 workshop.

Recent linkage results independently derived from a large French Canadian pedigree and Danish kindreds coupled with supportive data from other studies provide compelling evidence for a bipolar disorder susceptibility locus on chromosome 12q23-q24. The idea is further strengthened by the finding that Darier's disease, which maps to this region, has been shown to cosegregate with affective disorder in a family. This linkage finding, however, was not supported in other independent genome scans. On chromosome 16, bipolar families from Denmark exhibited suggestive linkage with D16S510, on 16p13. Multipoint nonparametric analysis on the NIMH Genetics Initiative bipolar pedigrees yielded increased allele sharing that maximized approximately 18 cM proximal to the latter locus. In contrast, evidence of linkage was not detected in other panels of bipolar families that were presented. At 16p13, a maximum multipoint lod score of 4 for a latent class-derived phenotype that has aspects of alcohol dependence was found in a genome scan of 105 families from the Collaborative Study of the Genetics of Alcoholism, identifying a potential vulnerability locus.

Alcoholism↗
PubMed1999

A high-density genome scan detects evidence for a bipolar-disorder susceptibility locus on 13q32 and other potential loci on 1q32 and 18p11.2.

Bipolar disorder is a severe mental illness characterized by mood swings of elation and depression. Family, twin, and adoption studies suggest a complex genetic etiology that may involve multiple susceptibility genes and an environmental component. To identify chromosomal loci contributing to vulnerability, we have conducted a genome-wide scan on approximately 396 individuals from 22 multiplex pedigrees by using 607 microsatellite markers. Multipoint nonparametric analysis detected the strongest evidence for linkage at 13q32 with a maximal logarithm of odds (lod) score of 3.5 (P = 0. 000028) under a phenotype model that included bipolar I, bipolar II with major depression, schizoaffective disorder, and recurrent unipolar disorder. Suggestive linkage was found on 1q31-q32 (lod = 2. 67; P = 0.00022) and 18p11.2 (lod = 2.32; P = 0.00054). Recent reports have linked schizophrenia to 13q32 and 18p11.2. Our genome scan identified other interesting regions, 7q31 (lod = 2.08; P = 0. 00099) and 22q11-q13 (lod = 2.1; P = 0.00094), and also confirmed reported linkages on 4p16, 12q23-q24, and 21q22. By comprehensive screening of the entire genome, we detected unreported loci for bipolar disorder, found support for proposed linkages, and gained evidence for the overlap of susceptibility regions for bipolar disorder and schizophrenia.

Bipolar Disorder↗
PubMed1999

Mutation analysis of oculopharyngeal muscular dystrophy in Hispanic American families.

BACKGROUND: Oculopharyngeal muscular dystrophy (OPMD) is a late-onset autosomal dominant muscular dystrophy characterized by progressive ptosis, swallowing difficulties, and proximal limb weakness. Recently, the genetic basis of this disease has been characterized by mutations in the PABP2 gene that involve short expansions of the trinucleotide repeat GCG. OBJECTIVES: To independently confirm the presence and study the meiotic stability of the GCG expansion mutations in a distinct ethnic population with OPMD. SETTINGS: Hospital and university research laboratories in Los Angeles, Calif. SUBJECTS AND METHODS: Three unrelated families of Hispanic American descent were identified in whom OPMD was transmitted in an autosomal dominant pattern. All of these families can trace affected ancestors to the southwestern United States or to the bordering states of Mexico. In these families, 14 persons with OPMD were identified and studied. RESULTS: Our results confirm that in these families, expansion mutations characterized by a gain of 3 GCG repeats in the wild-type allele result in an abnormal nucleotide length of 9 GCG repeats in the PABP2 gene. In these families, these mutations are associated with the OPMD phenotype. The identical repeat mutation ([GCG]9) is found in all affected members of these unrelated families and shows relative meiotic stability. CONCLUSIONS: These results support and extend our study of haplotype analysis and suggest that a founder effect may have occurred for OPMD in this Hispanic American population.

Adult↗