Full-Genome Scan for Linkage in 50 Families Segregating the Bipolar Affective Disease Phenotype

Friddle, Carl; Koskela, Rebecca; Ranade, Koustubh; Hebert, Joan M.; Cargill, Michele; Clark, C D; McInnis, Melvin G.; Simpson, Sylvia G.; McMahon, Francis J.; Stine, O. Colin; Meyers, Deborah A.; Xu, Jianfeng; MacKinnon, Dean F.; Swift‐Scanlan, Theresa; Jamison, Kay Redfield; Folstein, Susan E.; Daly, Mark J.; Kruglyak, Leonid; Marr, Thomas G.; DePaulo, J. Raymond; Botstein, David

doi:10.1086/302697

Cited by 76 publications

(82 citation statements)

References 38 publications

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“…27 Similarly, McInnis et al 28 reported evidence of linkage to 4q35 (NPL of 2.43) after linkage analysis in 65 bipolar pedigrees. The Dana Consortium (Johns Hopkins University) also reported evidence of linkage to chromosome 4q35 (maximum multipoint HLOD of 2.11) following linkage analysis in 50 bipolar families, 29 although this cohort was also contained within the larger cohort studied by McInnis et al 28 In addition, data from the Wellcome Trust funded UK-Irish Bipolar Sib-pair study also indicates support for a 4q35 locus. 30 The 43 cM genetic interval that harbors a bipolar susceptibility gene on chromosome 4q35 corresponds to 4.8 Mb of DNA.…”

Section: Introductionmentioning

confidence: 93%

Positional cloning, association analysis and expression studies provide convergent evidence that the cadherin gene FAT contains a bipolar disorder susceptibility allele

et al. 2006

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A susceptibility locus for bipolar disorder was previously localized to chromosome 4q35 by genetic linkage analysis. We have applied a positional cloning strategy, combined with association analysis and provide evidence that a cadherin gene, FAT, confers susceptibility to bipolar disorder in four independent cohorts (allelic P-values range from 0.003 to 0.024). In two case-control cohorts, association was identified among bipolar cases with a family history of psychiatric illness, whereas in two cohorts of parent-proband trios, association was identified among bipolar cases who had exhibited psychosis. Pooled analysis of the case-control cohort data further supported association (P = 0.0002, summary odds ratio = 2.31, 95% CI: 1.49-3.59). We localized the bipolar-associated region of the FAT gene to an interval that encodes an intracellular EVH1 domain, a domain that interacts with Ena/VASP proteins, as well as putative b-catenin binding sites. Expression of Fat, Catnb (b-catenin), and the three genes (Enah, Evl and Vasp) encoding the Ena/VASP proteins, were investigated in mice following administration of the mood-stabilizing drugs, lithium and valproate. Fat was shown to be significantly downregulated (P = 0.027), and Catnb and Enah were significantly upregulated (P = 0.0003 and 0.005, respectively), in response to therapeutic doses of lithium. Using a protein interaction map, the expression of genes encoding murine homologs of the FAT (ft)-interacting proteins was investigated. Of 14 interacting molecules that showed expression following microarray analysis (including several members of the Wnt signaling pathway), eight showed significantly altered expression in response to therapeutic doses of lithium (binomial P = 0.004). Together, these data provide convergent evidence that FAT and its protein partners may be components of a molecular pathway involved in susceptibility to bipolar disorder.

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Section: Introductionmentioning

confidence: 93%

Positional cloning, association analysis and expression studies provide convergent evidence that the cadherin gene FAT contains a bipolar disorder susceptibility allele

et al. 2006

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“…However, some strong and recent studies had negative results for chromosome 18 in SZ 4,6,33,34 and for BP. 35 Differences among samples in terms of racial and ethnic characteristics and in terms of diagnostic procedure might explain different results across studies. For instance, the latter negative studies on 6p used SZ plus SZA as phenotypes, 4,6,34 or used schizophrenia related psychoses, 33 and some used DSM-III-R diagnoses whereas others used DSM-IV criteria.…”

Section: Molecular Psychiatrymentioning

confidence: 99%

A search for specific and common susceptibility loci for schizophrenia and bipolar disorder: a linkage study in 13 target chromosomes

et al. 2001

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We report the first stage of a genome scan of schizophrenia (SZ) and bipolar disorder (BP) covering 18 candidate chromosomal areas. In addition to testing susceptibility loci that are specific to each disorder, we tested the hypothesis that some susceptibility loci might be common to both disorders. A total of 480 individuals from 21 multigenerational pedigrees of Eastern Qué bec were evaluated by means of a consensus best-estimate diagnosis made blind to diagnoses in relatives and were genotyped with 220 microsatellite markers. Two-point and multipoint model-based linkage analyses were performed and mod scores (Z, for max Z max ) are reported. The strongest linkage signals were detected at D18S1145 (in 18q12; Z = 4.03) for BP, and at D6S334 (in 6p 22-24; Z het = 3.47; ␣ = 0.66) for SZ. Three other chromosomal areas (3q, 10p, and 21q) yielded linkage signals. Chromosomes 3p, 4p, 5p, 5q, 6q, 8p, 9q, 11q, 11p, 12q, 13q, 18p and 22q showed no evidence of linkage. The 18q12 results met the Lander and Kruglyak (1995) criterion for a genome-wide significant linkage and suggested that this susceptibility region may be shared by SZ and BP. The 6p finding provided confirmatory evidence of linkage for SZ. Our results suggest that both specific and common susceptibility loci must be searched for SZ and BP. Molecular Psychiatry (2001) 6, 684-693.Keywords: schizophrenia; bipolar disorder; linkage analysis; psychiatric genetics; family studies Schizophrenia (SZ) and bipolar disorder (BP) are highly heritable disorders probably involving several genes and environmental factors. 1-3 Although previous linkage studies have yielded promising results for both disorders 4-6 (see Riley and McGuffin 7 and Pulver 8 for a recent comprehensive review), their results are often conflicting and difficult to interpret. Methodological obstacles to definitive findings include insufficient statistical power, unknown mode of inheritance, populational differences, uncertain phenotype definitions, 3,9 which also complicate the comparison of results across studies. In addition, studies suggested that some susceptibility loci such as 13q32 5,6 and 18p11 5,10 might be common to both disorders. 11,12 As discussed elsewhere, 2,13,14 such common loci are compatible with previous reports of some degree of coaggregation between SZ and mood disorders. 15 In this context, as a first stage of a genome scan for SZ and BP, we prioritized chromosomal areas based on previous linkage or association results before using, in the second stage, evenly spaced (7-10 cM) markers to cover the rest of the genome which is underway. Our criteria to select candidate areas were based on previous findings of a lod score of at least 2 in the case of parametric (model-based) analyses, or a P-value of at least 0.005 in the case of non-parametric (model-free) analyses. Two other regions were investigated as follow-ups of our own preliminary findings suggesting an association between adult onset SZ and the DRD3 locus 14 and of a suggestive linkage between SZ and 11q21-q24. 16 We r...

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“…Although current studies mainly focused on the role of classical cadherins and FAT in cancer, 5,6 there is consistent evidence suggesting a possible role of FAT in the development of psychiatric disorders. [7][8][9][10][11] Blair et al 8 recently reported FAT as a susceptibility gene for bipolar disorder. They found that a haplotype block at the 3¢ end of the cadherin gene FAT (rs2306987, rs1298865, rs2306990, rs2637777 and rs2304865) associated to bipolar disorder in an Australian patientcontrol sample of 137 families.…”

Section: Introductionmentioning

confidence: 99%

No influence of FAT polymorphisms in response to aripiprazole

et al. 2009

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The aim of this study was to investigate possible influences of a set of markers in the FAT gene (rs2306987, rs2306990, rs2637777 and rs2304865) on efficacy and tolerability of aripiprazole in the treatment of schizophrenic patients. Efficacy was assessed at baseline and weeks 1, 2, 4, 6, 8 and 12 using the Clinical Global Impression Severity and Improvement scale (CGI-S; CGI-I), the Brief Psychiatric Rating Scale and the Schedule for the Assessment of Negative Symptoms scale. Side effects were evaluated by means of the Simpson-Angus Scale for Extrapyramidal Symptoms, the Barnes Akathisia Scale and the Abnormal Involuntary Movement Scale. Multivariate analyses were employed to test possible influences of single nucleotide polymorphisms on clinical and safety variables. Analysis of haplotypes was also performed. No relevant association between FAT variants and clinical or safety scores was observed. Haplotype analysis did not reveal any significant association with clinical and safety scores at any time as well. Our data suggest no association between investigated alleles and genotypes in FAT and response to aripiprazole. However, because several limitations characterize the present study, further investigations on larger studies are required.

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Full-Genome Scan for Linkage in 50 Families Segregating the Bipolar Affective Disease Phenotype

Cited by 76 publications

References 38 publications

Positional cloning, association analysis and expression studies provide convergent evidence that the cadherin gene FAT contains a bipolar disorder susceptibility allele

Positional cloning, association analysis and expression studies provide convergent evidence that the cadherin gene FAT contains a bipolar disorder susceptibility allele

A search for specific and common susceptibility loci for schizophrenia and bipolar disorder: a linkage study in 13 target chromosomes

No influence of FAT polymorphisms in response to aripiprazole

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