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The genetic etiology of schizophrenia, a common and debilitating psychiatric disorder, is supported by a wealth of data. Review of the current findings suggests that considerable progress has been made in recent years, with a number of chromosomal regions consistently implicated by linkage analysis. Three groups have shown linkage to 1q21-22 using similar models, with HLOD scores of 6.5, 3.2, and 2.4. Other replicated loci include 13q32 that has been implicated by two independent groups with significant HLOD scores (4.42) or NPL values (4.18), and 5pl4.1-13.1, 5q21-33, 8p2l-22, and 10p11-15, each of which have been reported as suggestive by at least three separate groups. Different studies have also replicated evidence for a modest number of candidate genes that were not ascertained through linkage. Of these, the greatest support exists for the DRD3 (3q13.3), HTR2A (13q14.2), and CHRNA7 (15q13-q14) genes. The refinement of phenotypes, the use of endophenotypes, reduction of heterogeneity, and extensive genetic mapping have all contributed to this progress. The rapid expansion of information from the human genome project will likely further accelerate this progress and assist in the discovery of susceptibility genes for schizophrenia. A greater understanding of disease mechanisms and the application of pharmacogenetics should also lead to improvements in therapeutic interventions.
Cell Mol Life Sci 2002 Feb
PMID:Recent advances in the genetics of schizophrenia. 1191 47

From our linkage study of Irish families with a high density of schizophrenia, we have previously reported evidence for susceptibility genes in regions 5q21-31, 6p24-21, 8p22-21, and 10p15-p11. In this report, we describe the cumulative results from independent genome scans of three a priori random subsets of 90 families each, and from multipoint analysis of all 270 families in ten regions. Of these ten regions, three (13q32, 18p11-q11, and 18q22-23) did not generate scores above the empirical baseline pairwise scan results, and one (6q13-26) generated a weak signal. Six other regions produced more positive pairwise and multipoint results. They showed the following maximum multipoint H-LOD (heterogeneity LOD) and NPL scores: 2p14-13: 0.89 (P = 0.06) and 2.08 (P = 0.02), 4q24-32: 1.84 (P = 0.007) and 1.67 (P = 0.03), 5q21-31: 2.88 (P= 0.0007), and 2.65 (P = 0.002), 6p25-24: 2.13 (P = 0.005) and 3.59 (P = 0.0005), 6p23: 2.42 (P = 0.001) and 3.07 (P = 0.001), 8p22-21: 1.57 (P = 0.01) and 2.56 (P = 0.005), 10p15-11: 2.04 (P = 0.005) and 1.78 (P = 0.03). The degree of 'internal replication' across subsets differed, with 5q, 6p, and 8p being most consistent and 2p and 10p being least consistent. On 6p, the data suggested the presence of two susceptibility genes, in 6p25-24 and 6p23-22. Very few families were positive on more than one region, and little correlation between regions was evident, suggesting substantial locus heterogeneity. The levels of statistical significance were modest, as expected from loci contributing to complex traits. However, our internal replications, when considered along with the positive results obtained in multiple other samples, suggests that most of these six regions are likely to contain genes that influence liability to schizophrenia.
Mol Psychiatry 2002
PMID:Genome-wide scans of three independent sets of 90 Irish multiplex schizophrenia families and follow-up of selected regions in all families provides evidence for multiple susceptibility genes. 1214 Jul 77

Bipolar affective disorder is a severe mood disorder that afflicts approximately 1% of the population worldwide. Twin and adoption studies have indicated that genetic factors contribute to the disorder and while many chromosomal regions have been implicated, no susceptibility genes have been identified. We undertook a combined analysis of 10 cM genome screen data from a single large bipolar affective disorder pedigree, for which we have previously reported linkage to chromosome 13q14 (Badenhop et al, 2001) and 12 pedigrees independently screened using the same 400 microsatellite markers. This 13-pedigree cohort consisted of 231 individuals, including 69 affected members. Two-point LOD score analysis was carried out under heterogeneity for three diagnostic and four genetic models. Non-parametric multipoint analysis was carried out on regions of interest. Two-point heterogeneity LOD scores (HLODs) greater than 1.5 were obtained for 11 markers across the genome, with HLODs greater than 2.0 obtained for four of these markers. The strongest evidence for linkage was at 3q25-26 with a genome-wide maximum score of 2.49 at D3S1279. Six markers across a 50 cM region at 3q25-26 gave HLODs greater than 1.5, with three of these markers producing scores greater than 2.0. Multipoint analysis indicated a 20 cM peak between markers D3S1569 and D3S1614 with a maximum NPL of 2.8 (P= 0.004). Three other chromosomal regions yielded evidence for linkage: 9q31-q33, 13q14 and 19q12-q13. The regions on chromosomes 3q and 13q have previously been implicated in other bipolar and schizophrenia studies. In addition, several individual pedigrees gave LOD scores greater than 1.5 for previously reported bipolar susceptibility loci on chromosomes 18p11, 18q12, 22q11 and 8p22-23.
Mol Psychiatry 2002
PMID:A genome screen of 13 bipolar affective disorder pedigrees provides evidence for susceptibility loci on chromosome 3 as well as chromosomes 9, 13 and 19. 1214 Jul 82

The present study reports a genomewide scan using linkage analysis for risk genes involved in bipolar disorder with 613 microsatellite markers including additional testing of promising regions. As previously published significant linkage was obtained at chromosome 12q24.3 with a two-point parametric lod score of 3.42 at D12S1639 including all members in both families (empirical P-value 0.00004, genome-wide P-value 0.0417). The multipoint parametric lod score at D12S1639 was 3.63 (genome-wide P-value 0.0265). At chromosome 1p22-p21 a parametric, affecteds-only two-point lod score of 2.75 at marker D1S216 was found (empirical P-value 0.0002, genome-wide P-value 0.1622). A three-point lod score of 2.98 (genome-wide P-value 0.1022) at D1S216, and a multipoint non-parametric analysis with a maximum NPL-all score of 17.60 (P-value 0.00079) at D1S216 further supported this finding. A number of additional loci on chromosomes 4p16, 6q14-q22, 10q26 and 16p13.3 yielded parametric lod scores around or above 2.
Mol Psychiatry 2002
PMID:A genome-wide scan shows significant linkage between bipolar disorder and chromosome 12q24.3 and suggestive linkage to chromosomes 1p22-21, 4p16, 6q14-22, 10q26 and 16p13.3. 1219 18

Genome-wide linkage analyses performed in a Finnish study sample have identified four potential predisposing loci for multiple sclerosis (MS). Here we made an effort to restrict the wide linkage region on chromosome 17 with a dense set of 31 markers using multipoint linkage analyses and monitoring for shared marker alleles in MS chromosomes. We carried out the linkage analyses in 22 Finnish multiplex MS families originating from a regional subisolate that shows an exceptionally high prevalence of MS in order to minimize the genetic and environmental heterogeneity of the study sample. Thirty markers on the 23 cM initial interval gave positive pairwise LOD scores. We monitored for shared haplotypes among affected family members within a family, and identified an approximately 4 cM region flanked by the markers D17S1792 and ATA43A10 in 17 out of the 22 families (77.3%). The multipoint linkage analyses using Genehunter and SIMWALK 2.40 provided further evidence for the same 4 cM region, for example a maximal multipoint NPL score of 5.98 (P<0.0002). We observed nominal evidence for association to MS, with one marker flanking the shared region, and this association was replicated in the additional set of families. Using the combined power of linkage, association and shared haplotype analyses, we were thus able to restrict the MS locus on chromosome 17q from 23 cM to a 4 cM region covering a physical interval of approximately 2.5 Mb. Thus, this study describes the restriction of an MS locus outside the HLA region into a segment approachable by molecular tools.
Hum Mol Genet 2002 Sep 15
PMID:Fine mapping of a multiple sclerosis locus to 2.5 Mb on chromosome 17q22-q24. 1221 54

Bipolar affective disorder is a severe mood disorder that afflicts approximately 1% of the population worldwide. Twin and adoption studies have indicated that genetic factors contribute to the disorder and while many chromosomal regions have been implicated, no susceptibility genes have been identified. We undertook a combined analysis of 10 cM genome screen data from a single large bipolar affective disorder pedigree, for which we have previously reported linkage to chromosome 13q14 (Badenhop et al, 2001) and 12 pedigrees independently screened using the same 400 microsatellite markers. This 13 pedigree cohort consisted of 231 individuals, including 69 affected members. Two-point LOD score analysis was carried out under heterogeneity for three diagnostic and four genetic models. Non-parametric multipoint analysis was carried out on regions of interest. Two-point heterogeneity LOD scores (HLODs) greater than 1.5 were obtained for 11 markers across the genome, with HLODs greater than 2.0 obtained for four of these markers. The strongest evidence for linkage was at 3q25-26 with a genome-wide maximum score of 2.49 at D3S1279. Six markers across a 50 cM region at 3q25-26 gave HLODs greater than 1.5, with three of these markers producing scores greater than 2.0. Multipoint analysis indicated a 20 cM peak between markers D3S1569 and D3S1614 with a maximum NPL of 2.8 (P = 0.004). Three other chromosomal regions yielded evidence for linkage: 9q31-q33, 13q14 and 19q12-q13. The regions on chromosomes 3q and 13q have previously been implicated in other bipolar and schizophrenia studies. In addition, several individual pedigrees gave LOD scores greater than 1.5 for previously reported bipolar susceptibility loci on chromosomes 18p11, 18q12, 22q11 and 8p22-23.
Mol Psychiatry 2002
PMID:A genome screen of 13 bipolar affective disorder pedigrees provides evidence for susceptibility loci on chromosome 3 as well as chromosomes 9, 13 and 19. 1223 78

The purpose of this study was to assess 65 pedigrees ascertained through a Bipolar I (BPI) proband for evidence of linkage, using nonparametric methods in a genome-wide scan and for possible parent of origin effect using several analytical methods. We identified 15 loci with nominally significant evidence for increased allele sharing among affected relative pairs. Eight of these regions, at 8q24, 18q22, 4q32, 13q12, 4q35, 10q26, 2p12, and 12q24, directly overlap with previously reported evidence of linkage to bipolar disorder. Five regions at 20p13, 2p22, 14q23, 9p13, and 1q41 are within several Mb of previously reported regions. We report our findings in rank order and the top five markers had an NPL>2.5. The peak finding in these regions were D8S256 at 8q24, NPL 3.13; D18S878 at 18q22, NPL 2.90; D4S1629 at 4q32, NPL 2.80; D2S99 at 2p12, NPL 2.54; and D13S1493 at 13q12, NPL 2.53. No locus produced statistically significant evidence for linkage at the genome-wide level. The parent of origin effect was studied and consistent with our previous findings, evidence for a locus on 18q22 was predominantly from families wherein the father or paternal lineage was affected. There was evidence consistent with paternal imprinting at the loci on 13q12 and 1q41.
Mol Psychiatry 2003 Mar
PMID:Genome-wide scan of bipolar disorder in 65 pedigrees: supportive evidence for linkage at 8q24, 18q22, 4q32, 2p12, and 13q12. 1266 Aug 1

Serotonergic and opioidergic neurotransmitter system alterations have been observed in people with eating disorders; the genes for the serotonin 1D receptor (HTR1D) and the opioid delta receptor (OPRD1) are found on chr1p36.3-34.3, a region identified by our group in a linkage analysis of anorexia nervosa (AN). These candidate genes were evaluated for sequence variation and for linkage and association of this sequence variation to AN in family and case : control data sets. Resequencing of the HTR1D locus and a portion of the OPRD1 locus identified novel SNPs and confirmed existing SNPs. Genotype assay development and genotyping of nine SNPs (four at HTR1D and five at OPRD1) was performed on 191 unrelated individuals fulfilling DSM-IV criteria (w/o amenorrhea criterion) for AN, 442 relatives of AN probands and 98 psychiatrically screened controls. Linkage analysis of these candidate gene SNPs with 33 microsatellite markers in families including relative pairs concordantly affected with restricting AN (N=37) substantially increased the evidence for linkage of this region to restricting AN to an NPL score of 3.91. Statistically significant genotypic, allelic, and haplotypic association to AN in the case : control design was observed at HTR1D and OPRD1 with effect sizes for individual SNPs of 2.63 (95% CI=1.21-5.75) for HTR1D and 1.61 (95% CI=1.11-2.44) for OPRD1. Using genotype data on parents and AN probands, three SNPs at HTR1D were found to exhibit significant transmission disequilibrium (P&<0.05). The combined statistical genetic evidence suggests that HTR1D and OPRD1 or linked genes may be involved in the etiology of AN.
Mol Psychiatry 2003 Apr
PMID:Candidate genes for anorexia nervosa in the 1p33-36 linkage region: serotonin 1D and delta opioid receptor loci exhibit significant association to anorexia nervosa. 1274 May 97

A positive linkage of schizophrenia with chromosome 1q loci has been reported in Caucasian patients. This study was designed to evaluate the linkage of schizophrenia with markers of the 1q22-44 region in 52 Taiwanese families with at least two affected siblings. In the region 1q22-31 (17.8 cM), marker D1S1679 had a maximal proportion (0.57, P=0.03) of shared identity by descent (IBD) under a narrow phenotype (DSM-IV schizophrenia only). In the region 1q42-44 (26.8 cM), the marker D1S251, located near the breakpoint of a balanced translocation t (1;11) (q42.1;q14.3) segregated with schizophrenia, and also near the neurodevelopment-related 'Disrupted in Schizophrenia 1' gene, had a maximum NPL score of 1.73 (P=0.03) under the narrow phenotype model and 2.18 (P=0.01) under the broad phenotype model comprised of schizophrenia, schizoaffective disorder, and other nonaffective psychotic disorders as defined by DSM-IV criteria. The marker D1S2836 also had a maximal proportion (0.57, P=0.05) of shared IBD under the broad model. These findings may provide guidance for positional cloning studies on candidate genes in the 1q22-31 and 1q41-44 regions.
Mol Psychiatry 2003 Apr
PMID:Linkage of schizophrenia with chromosome 1q loci in Taiwanese families. 1274 Jun 2

Iodine deficiency is the most important etiological factor for euthyroid endemic goiter. However, family and twin pair studies also strongly indicate a genetic prediposition. In euthyroid goiters molecular defects in the thyroglobulin (TG), and Na+/I- symporter (NIS) gene have been identified. Numerous mutations in the Pendrin (PDS) gene have been found in families with PDS characterized by deafness and euthyroid goiter. Moreover, family studies indicated two major candidate loci MNG-1 on chromosome 14q31 and Xp22. However, all previous linkage studies investigated only one family. To clarify the general relevance of these previously identified two major candidate loci for the etiology of euthyroid goiter we investigated four families with a total number of 74 family members by linkage analysis with microsatellite markers. Moreover, we analyzed the thyroid candidate genes TG, thyroperoxidase (TPO), NIS, TSH receptor, and PDS. In a further family with 12 members in whom we have previously demonstrated linkage to the MNG-1 locus we investigated the Xp22 locus and the PDS gene in addition to our initial study. Linkage analysis results of our study are not significant enough to definitely exclude or confirm linkage to the investigated candidate genes and loci. Nevertheless, we obtained very weak indications for possible linkage to Xp22 in one family by a maximal multipoint LOD score of 1.15, and cosegregation of haplotypes among affected family members. Moreover, in another family linkage to PDS was indicated by a maximal multipoint LOD score of 1.87 as well as cosegregation of haplotypes. However, sequencing of the PDS gene did not reveal germline mutations. A significant total NPL score of 6.5 for PDS over all families most likely indicated linkage to a genomic region close to PDS. Furthermore, the likelihood of linkage to MNG-1 and Xp22 is reduced, because multipoint LOD scores were below 1 or negative. In all families there was no significant evidence for linkage for the thyroid candidate genes TG, TPO, NIS, or the TSH receptor. In conclusion, a general role of MNG-1 and Xp22 for the etiology of euthyroid goiter is unlikely but cannot clearly excluded. The multipoint parametric and nonparametric LOD scores further suggest genetic heterogeneity in the etiology of familial euthyroid goiter. To identify other susceptibility loci it is necessary to perform genome-wide linkage analysis studies with more families.
J Mol Med (Berl) 2003 Nov
PMID:Further indications for genetic heterogeneity of euthyroid familial goiter. 1456 11


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