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A R Sanders

Publications and source records attributed to A R Sanders.

At least 19 recordsLinked to original sources
PubMed2005

Haplotypic association spanning the 22q11.21 genes COMT and ARVCF with schizophrenia.

Catechol-O-methyltransferase (COMT) has been implicated in schizophrenia by its function through its roles in monoamine neurotransmitter metabolism and its impact on prefrontal cognition, and also by its position through linkage scans and a strong cytogenetic association. Further support comes from association studies, especially family-based ones examining the COMT variant, Val(108/158)Met. We have studied eight markers spanning COMT and including portions of the two immediately adjacent genes, thioredoxin reductase 2 and armadillo repeat deleted in velocardiofacial syndrome (ARVCF), using association testing in 136 schizophrenia families. We found nominal evidence for association of illness to rs165849 (P=0.051) in ARVCF, and a stronger signal (global P=0.0019-0.0036) from three-marker haplotypes spanning the 3' portions of COMT and ARVCF, including Val(108/158)Met with Val(108/158) being the overtransmitted allele, consistent with previous studies. We also find Val(108/158)Met to be in linkage disequilibrium with the markers in ARVCF. These findings support previous association signals of schizophrenia to COMT markers, and suggest that ARVCF might contribute to this signal. ARVCF, a member of the catenin family, besides being a positional candidate, is also one due to its function, that is, its potential role in neurodevelopment, which is implicated in schizophrenia pathogenesis by several lines of evidence.

Adult↗
PubMed2004

Multicenter linkage study of schizophrenia loci on chromosome 22q.

The hypothesis of the existence of one or more schizophrenia susceptibility loci on chromosome 22q is supported by reports of genetic linkage and association, meta-analyses of linkage, and the observation of elevated risk for psychosis in people with velocardiofacial syndrome, caused by 22q11 microdeletions. We tested this hypothesis by evaluating 10 microsatellite markers spanning 22q in a multicenter sample of 779 pedigrees. We also incorporated age at onset and sex into the analysis as covariates. No significant evidence for linkage to schizophrenia or for linkage associated with earlier age at onset, gender, or heterogeneity across sites was observed. We interpret these findings to mean that the population-wide effects of putative 22q schizophrenia susceptibility loci are too weak to detect with linkage analysis even in large samples.

Chromosome Mapping↗
PubMed2004

Complexities in psychiatric genetics.

A substantial contribution of genetic factors to the risk of psychiatric disorders such as schizophrenia, bipolar disorder, autism, and drug and alcohol dependence has already been established. However, the familial transmission of these disorders cannot be explained by simple Mendelian models of inheritance, and non-genetic factors must also play a substantial role in their etiologies. Furthermore, the prevalence of any major psychiatric disorder is a great deal higher than that of Mendelian disorders. It has been suggested that evolutionary forces would rapidly eliminate large gene effects, which would suggest that mental disorders, which are highly prevalent, are associated with minor gene effects (Risch, 1994). The current paradigm is that genes with small interacting genetic effects, in conjunction with environmental factors, affect the risk for psychiatric disease. New laboratory and statistical methodology and database tools, and the availability of large clinical samples for the study of linkage and association sustain optimism that genes involved with these diseases will be characterized in the near future. This accomplishment should in turn lead not only to a better understanding of the primary molecular pathophysiology and to more specific and effective therapies, but also to a better understanding of non-genetic risk factors that could be targets for preventive strategies.

Alleles↗
PubMed2003

Polymorphisms in the 5'-untranslated region of the human serotonin receptor 1B (HTR1B) gene affect gene expression.

We present evidence of complex balancing regulation of HTR1B transcription by common polymorphisms in its promoter. Computational analysis of the HTR1B gene predicted that a 5' segment, spanning common DNA sequence variations, T-261G, A-161T, and -182INS/DEL-181, contained a putative functional promoter. Using a secreted alkaline phosphatase (SEAP) reporter gene system, we found that the haplotype -261G_-182INS-181_A-161 enhanced transcriptional activity 2.3-fold compared with the haplotype T-261_-182INS-181_A-161. Conversely, -161T reversed this, and the net effect when -261G and -161T were in the same haplotype (-261G_-182INS-181_-161T) was equivalent to the major haplotype (T-261_-182INS-181_A-161). Electrophoretic mobility shift experiments showed that -261G and -161T modify the binding of transcription factors (TFs): -261G generates a new AP2 binding site, while alleles A-161 and -161T exhibit different binding characteristics to AP1. T-261G and A-161T were found to be in linkage disequilibrium (LD) with G861C in a European ancestry population. Interestingly, G861C has been reported to be associated with several psychiatric disorders. Our results indicate that HTR1B is the target of substantial transcriptional genetic regulation by common haplotypes, which are in LD with the HTR1B single-nucleotide polymorphism (SNP) most commonly used in association studies.

5' Untranslated Regions↗
PubMed2001

Linkage analysis of schizophrenia to chromosome 15.

We have mapped a sample of 68 families consisting of one or more affected sibling pairs with schizophrenia or schizoaffective disorder with 20 markers spanning all of chromosome 15 to investigate whether there is a locus on chromosome 15 that confers an increased susceptibility to schizophrenia using parametric and nonparametric linkage analyses. Allele sharing identical by descent and multipoint maximum likelihood score (MLS) statistics were employed. Results show excess allele sharing for multiple markers in 15q11.2-q25, a chromosomal region previously found linked to a decrease in the normal inhibition of the P50 auditory-evoked response to the second of paired stimuli, a decrease associated with schizophrenia. Excess allele sharing was found for markers spanning about 48 cM in 15q11.2-q25 (D15S1002-D15S1023). The greatest single point allele sharing was found at D15S659 (62.6%). The multipoint MLS scores were greater than 1.0 in the 30-52 cM interval delimited by ACTC and D15S150, with a maximum value of 2.0 with GENEHUNTER PLUS near D15S1039.

Alleles↗
PubMed2001

Genetic diversity of the human serotonin receptor 1B (HTR1B) gene.

We systematically and comprehensively investigated polymorphisms of the HTR1B gene as well as their linkage disequilibrium and ancestral relationships. We have detected the following polymorphisms in our sample via denaturing gradient gel electrophoresis, database comparisons, and/or previously published assays: G-511T, T-261G, -182INS/DEL-181, A-161T, C129T, T371G, T655C, C705T, G861C, A1099G, G1120A, and A1180G. The results of the intermarker analyses showed strong linkage disequilibrium between the C129T and the G861C polymorphisms and revealed four common haplotypes: ancestral (via chimpanzee comparisons), 129T/861C, -161T, and -182DEL-181. The results of association tests with schizophrenia were negative, although A-161T had a nominal P = 0.04 via ASPEX/sib_tdt. The expressed missense substitutions, Phe124Cys, Phe219Leu, Ile367Val, and Glu374Lys, could potentially affect ligand binding or interaction with G proteins and thus modify drug response in carriers of these variants. On average, the human cSNPs and differences among other primates clustered in the more thermodynamically unstable regions of the mRNA, which suggests that the evolutionary survival of nucleotide sequence variation may be influenced by the mRNA structure of this gene.

Alleles↗
PubMed2000

Multicenter linkage study of schizophrenia candidate regions on chromosomes 5q, 6q, 10p, and 13q: schizophrenia linkage collaborative group III.

Schizophrenia candidate regions 33-51 cM in length on chromosomes 5q, 6q, 10p, and 13q were investigated for genetic linkage with mapped markers with an average spacing of 5.64 cM. We studied 734 informative multiplex pedigrees (824 independent affected sibling pairs [ASPs], or 1,003 ASPs when all possible pairs are counted), which were collected in eight centers. Cases with diagnoses of schizophrenia or schizoaffective disorder (DSM-IIIR criteria) were considered affected (n=1,937). Data were analyzed with multipoint methods, including nonparametric linkage (NPL), ASP analysis using the possible-triangle method, and logistic-regression analysis of identity-by-descent (IBD) sharing in ASPs with sample as a covariate, in a test for intersample heterogeneity and for linkage with allowance for intersample heterogeneity. The data most supportive for linkage to schizophrenia were from chromosome 6q; logistic-regression analysis of linkage allowing for intersample heterogeneity produced an empirical P value <.0002 with, or P=.0004 without, inclusion of the sample that produced the first positive report in this region; the maximum NPL score in this region was 2.47 (P=.0046), the maximum LOD score (MLS) from ASP analysis was 3.10 (empirical P=.0036), and there was significant evidence for intersample heterogeneity (empirical P=.0038). More-modest support for linkage was observed for chromosome 10p, with logistic-regression analysis of linkage producing an empirical P=. 045 and with significant evidence for intersample heterogeneity (empirical P=.0096).

Chromosome Mapping↗
PubMed1999

Follow-up study on a susceptibility locus for schizophrenia on chromosome 6q.

Evidence for suggestive linkage to schizophrenia with chromosome 6q markers was previously reported from a two-stage approach. Using nonparametric affected sib pairs (ASP) methods, nominal p-values of 0.00018 and 0.00095 were obtained in the screening (81 ASPs; 63 independent) and the replication (109 ASPs; 87 independent) data sets, respectively. Here, we report a follow-up study of this 50cM 6q region using 12 microsatellite markers to test for linkage to schizophrenia. We increased the replication sample size by adding an independent sample of 43 multiplex pedigrees (66 ASPs; 54 independent). Pairwise and multipoint nonparametric linkage analyses conducted in this third data set showed evidence consistent with excess sharing in this 6q region, though the statistical level is weaker (p=0.013). When combining both replication data sets (total of 141 independent ASPs), an overall nominal p-value=0.000014 (LOD=3. 82) was obtained. The sibling recurrence risk (lambdas) attributed to this putative 6q susceptibility locus is estimated to be 1.92. The linkage region could not be narrowed down since LOD score values greater than three were observed within a 13cM region. The length of this region was only slightly reduced (12cM) when using the total sample of independent ASPs (204) obtained from all three data sets. This suggests that very large sample sizes may be needed to narrow down this region by ASP linkage methods. Study of the etiological candidate genes in this region is ongoing.

Chromosomes, Human, Pair 6↗
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↗
PubMed1998

Multiple transcriptional variants and RNA editing in C18orf1, a novel gene with LDLRA and transmembrane domains on 18p11.2.

C18orf1 is a novel brain-expressed transcript, mapping to 18p11.2. Upon further characterization, we found multiple and differentially expressed transcriptional variants. C18orf1 alpha 1, an 8.5-kb transcript, was predicted to code for a 306-amino-acid protein and a 7.1-kb 3'-untranslated region (UTR). This variant was encoded by at least six exons. Alternative transcripts included alpha 2, identical to alpha 1 but missing 18 residues, and N-terminal-truncated variants termed beta 1 and beta 2. A motif search suggested the presence of a transmembrane domain in both alpha and beta and a low-density lipoprotein receptor class A (LDLRA) domain in the alpha-specific N-terminal. In LDLR, LDLRA has been shown to be involved in binding Ca2+ and LDL, raising the possibility that C18orf1 might bind Ca2+ and an unknown ligand. We also present evidence of RNA editing in the 5'-UTR of beta 2, the first demonstration of this phenomenon in 5'-UTR.

Adult↗
PubMed1998

Closing in on genes for manic-depressive illness and schizophrenia.

Advances in the human genetic map, and in genetic analysis of linkage and association in complex inheritance traits, have led to genetic progress in the major psychoses. For chromosome 6 in schizophrenia, and chromosomes 18 and 21 in manic-depressive illness, there are reports of linkage in several independent data sets. These are small effect genes, best detected with affected-relative-pair linkage methods. Association with candidate genes is an alternative strategy to uncovering susceptibility genes for these illnesses, but convincing associations remain to be demonstrated. New clinical and laboratory investigation methods are being developed. Testing every gene in the human genome for association with illness has recently been proposed (Risch and Merikangas 1996). This would require further progress in characterizing the genome and in automated large-scale genotyping. The best type of pedigree sampling for common disease studies, whether for linkage or association, is not yet established. An endophenotype hybrid strategy can combine genetic linkage, association, and pathophysiologic studies. As clinical molecular investigation methods advance, identification of disease susceptibility mutations and delineation of their pathophysiological roles may be expected.

Bipolar Disorder↗
PubMed1997

Suggestive evidence for a schizophrenia susceptibility locus on chromosome 6q and a confirmation in an independent series of pedigrees.

We have investigated whether there is a locus on chromosome 6 that confers an increased susceptibility to schizophrenia using a two-stage approach and nonparametric linkage analysis. Allele sharing identical by descent (IBD) and multipoint maximum likelihood score (MLS) statistics were employed. Results from two tested data sets, a first data set, or genome scanning data set, and a second replication data set, show excess allele sharing for multiple markers in 6q, a chromosomal region not previously reported as linked to schizophrenia. In our genome scanning data set, excess allele sharing was found for markers on 6q13-q26. The greatest allele sharing was at interval 6q21-q22.3 at marker D6S416 (IBD percentage 69; P = 0.00024). The multipoint MLS values were greater than 2.4 in the 11.4-cM interval delimited by D6S301 and D6S303, with a maximum value of 3.06 close to D6S278 and of 3.05 at D6S454/D6S423. We did not confirm, however, the previously described linkage in 6p, when tested in the systematic genome scanning data set. The replication data set also showed excess allele sharing in chromosomal area 6q13-q26, which overlapped with the aforementioned positive linkage area of the genome scanning data set. The highest sharing of the second data set was at D6S424 (IBD percentage 64; P = 0.0004), D6S283 (IBD percentage 62; P = 0.0009), and D6S423 (IBD percentage 63; P = 0.0009). Multipoint MLS analysis yielded MLS values greater than 1 in an area of about 35 cM, which overlaps with the MLS multipoint area of linkage from the genome scanning data set. The multipoint MLS at the D6S454/D6S423 locus was 2.05. In the second data set, the maximum multipoint MLS was located about 10 cM centromeric from the maximum of the genome scanning data set, at the interval D6S424-D6S275 (2.35). Our results provide very suggestive evidence for a susceptibility locus for schizophrenia in chromosome 6q from two independent data sets.

Alleles↗
PubMed1997

Initial genome scan of the NIMH genetics initiative bipolar pedigrees: chromosomes 4, 7, 9, 18, 19, 20, and 21q.

An initial genome scan was performed on 540 individuals from 97 families segregating bipolar disorder, collected through the National Institutes of Mental Health Genetics Initiative. We report here affected-sib-pair (ASP) data on 126 marker loci (approximately 68,000 genotypes) mapping to chromosomes 4, 7, 9, 18, 19, 20, and 21q, under three affection status models. Modest increases in identical-by-descent (IBD) allele sharing were found at the following loci: D4S2397 and D4S391 (P < 0.05) on 4p, D4S1647 (P < 0.05) on 4q, D7S1802 and D7S1869 (low P = 0.01) on 7p, D9S302 (P = 0.004) on 9q, and D20S604 on 20p and D20S173 on 20q (P < 0.05). In addition, five markers on 7q displayed increased IBD sharing (P = 0.046-0.002). Additional ASP analyses on chromosomes 18 and 21q marker data were performed using disease phenotype models defined previously. On chromosome 18, only D18S40 on 18p and D18S70 on 18q yielded a slight elevation in allele sharing (P = 0.02), implying that the reported linkages in these regions were not confirmed. On chromosome 21q, a cluster of markers within an approximately 9 cM interval: D21S1254, D21S65, D21S1440, and D21S1255 exhibited excess allele sharing (P = 0.041-0.008). Multilocus data on overlapping marker quartets, from D21S1265 to D21S1255, which were consistent with increased IBD sharing (P < 0.01, with a low of 0.0009), overlapped a broad interval of excess allele sharing reported previously, increasing support for a susceptibility locus for bipolar disorder on 21q.

Alleles↗
PubMed1997

Isolation of chromosome 18-specific brain transcripts as positional candidates for bipolar disorder.

Several studies have proposed the existence of susceptibility loci for bipolar disorder on chromosome 18. To identify possible candidate genes for this disease, we isolated brain-expressed transcripts by direct cDNA selection on chromosome 18-specific biotinylated cosmid clones. Longer cognate cDNA clones of the selected cDNAs were isolated from a normalized infant brain cDNA library. Physical mapping by PCR on a panel of somatic cell hybrids was conducted by the use of primers derived from partial sequences on either the 5' or 3' ends of the clones. In our initial analysis, 48 cDNA clones were found to be chromosome 18-specific, mapping to different subchromosomal regions. Sequence redundancy among these clones yielded 30 unique transcripts, five of which were represented in previously known genes. Further sequencing of the remaining 25 unique cDNA clones confirmed the absence of significant homology to known genes, indicating that these transcripts represented novel genes. Mapping with the use of a radiation hybrid panel positioned the brain cDNAs to within = 100 to 1100 kb from reference sequence tag sites (STSs) and assembled them into six high resolution linkage groups. The majority of the transcripts were found to cluster to discrete locations on 18p and 18q, previously hypothesized as susceptibility regions for bipolar disorder, identifying them as positional candidate genes.

Bipolar Disorder↗