The Wellcome trust UK–Irish bipolar affective disorder sibling-pair genome screen: first stage report

Bennett, Philip C.; Segurado, Ricardo; Jones, Ian; Bort, S.; McCandless, F.; Lambert, David; Heron, Jessica; Comerford, Claire; Middle, F.; Corvin, Aiden; Pelios, G.; Kirov, George; Larsen, Bo; Mulcahy, T.; Williams, Nigel; O’Connell, R.M.; O’Mahony, Edmond; Payne, Annette; Holmans, Peter Alan; Craddock, Nicholas John; Gill, Michael

doi:10.1038/sj.mp.4000957

Cited by 62 publications

(42 citation statements)

References 74 publications

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“…Modest support for linkage to 17q was observed in a series of UK-Irish families. 47 We also note that reported linkages to other chromosomal regions, including 1q, 4p, 6p, 10p, 12q, 18p, 18q and Xq (see Introduction), are not clearly supported by our data. We found, though, modest support for a previously reported linkage on 18q.…”

Section: Discussioncontrasting

confidence: 55%

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Evidence for a putative bipolar disorder locus on 2p13–16 and other potential loci on 4q31, 7q34, 8q13, 9q31, 10q21–24, 13q32, 14q21 and 17q11–12

et al. 2003

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Bipolar disorder (BP) is a severe and common psychiatric disorder characterized by extreme mood swings. Family, twin and adoption studies strongly support a genetic component. The mode of inheritance is complex and likely involves multiple, as yet unidentified genes. To identify susceptibility loci, we conducted a genome-wide scan with 343 microsatellite markers in one of the largest, well-characterized pedigree samples assembled to date (373 individuals in 40 pedigrees). To increase power to detect linkage, scan statistics were used to examine the logarithm of odds (lod) scores based on evidence at adjacent chromosomal loci. This analysis yielded significant evidence of linkage (genome-wide Po0.05) for markers on 2p13-16. Standard linkage analysis was also supportive of linkage to 2p13-16 (lod ¼ 3.20), and identified several other interesting regions: 4q31 (lod ¼ 3.16), 7q34 (lod ¼ 2.78), 8q13 (lod ¼ 2.06), 9q31 (lod ¼ 2.07), 10q24 (lod ¼ 2.79), 13q32 (lod ¼ 2.2), 14q21 (lod ¼ 2.36) and 17q11-12 (lod ¼ 2.75). In this systematic, large-scale study, we identified novel putative loci for BP (on 2p13-16, 8q13 and 14q21) and found support for previously proposed loci (on 4q31, 7q34, 9q31, 10q21-24, 13q32 and 17q11-12). Two of the regions implicated in our study, 2p13-14 and 13q32, have also been linked to schizophrenia, suggesting that the two disorders may have susceptibility genes in common.

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Section: Discussioncontrasting

confidence: 55%

“…A more proximal location, on 4q12-13, was reported in UK-Irish families. 47 Possible linkage to 7q was observed in the NIMH genetics initiative pedigree series 48 and in another series of US pedigrees. 5 Modest support for linkage to 9q was observed in the NIMH genetics initiative pedigree sample.…”

Section: Discussionmentioning

confidence: 99%

Evidence for a putative bipolar disorder locus on 2p13–16 and other potential loci on 4q31, 7q34, 8q13, 9q31, 10q21–24, 13q32, 14q21 and 17q11–12

et al. 2003

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“…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. 26,31 We established a comprehensive transcript map encompassing this candidate region, 31 which corresponds with the transcript maps for this region from the UCSC, Ensembl and NCBI genome annotation projects.…”

Section: Introductionmentioning

confidence: 99%

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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“…39 The second focus of findings (F-2) is at 105 Mb, mainly in BPD, with one significant study 42 and several supporting studies, 37,38,46 but also studies on SCZ, 24 autism 52 and multiple sclerosis. 53 The third focus (F-3) is for BPD and is located at 126 Mb with a very significant finding from one study of Portuguese pedigrees.…”

Section: Discussionmentioning

confidence: 99%

Excitement and confusion on chromosome 6q: the challenges of neuropsychiatric genetics in microcosm

Kohn¹,

Lerer²

2005

Mol Psychiatry

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The search for genes that are implicated in the pathogenesis of schizophrenia (SCZ), bipolar disorder (BPD) and other complex neuropsychiatric phenotypes has yielded a plethora of positive findings, but has also engendered a substantial degree of confusion. Exciting findings include positive linkage results in a number of chromosomal regions and the identification of several genes that have been associated with SCZ and to a lesser extent with BPD. Confusing aspects include the difference between studies in localization of linkage peaks in the same chromosomal regions, raising the possibility that these regions may harbor more than one gene, the fact that positive linkage findings as well as associated genes appear in several cases to be shared by more than one disorder, and the failure to identify thus far the precise pathogenic variants in associated genes. Recent findings of linkage and association studies on chromosome 6q illustrate the current status of neuropsychiatric genetics in intriguing microcosm. Positive findings from linkage and association studies are reviewed in order to identify approaches that may help to settle apparent contradictions and allow an interpretation of the results that may prove useful in application to findings from other chromosomal regions. Not only SCZ and BPD but also other psychiatric and neurological phenotypes are considered. Taking a topographic approach, we identify five foci of positive findings on chromosome 6q and suggest that each may harbor gene(s) that confer susceptibility to SCZ or BPD or may modify their onset or clinical course. We further suggest that in searching for these genes the possibility that they may be implicated in more than one disorder should be taken into account. We also discuss the potential contribution of rare genetic variants identified in homogeneous, isolated populations to the subsequent identification of common variants in the same gene that contribute to disease susceptibility in outbred populations. Keywords: schizophrenia; bipolar disorder; chromosome 6q; molecular genetics; linkageThe last three decades have seen considerable advances in the field of psychiatric genetics. First, family twin and adoption studies conclusively established that genes play a major role in the etiology of many psychiatric disorders. Then, an increasing number of groups embarked on linkage studies aiming at localizing these genes. With ever improving technology, whole genome scans became the standard vehicle for these endeavors. Studies became more and more sophisticated, involving larger samples of carefully characterized affected individuals, using denser maps of markers and employing increasingly powerful statistical tools. Over the years, linkage studies have repeatedly implicated several chromosomal regions as linked to major psychiatric disorders, particularly schizophrenia (SCZ) and bipolar disorder (BPD) (for reviews, see Riley and McGuffin, 1 Berrettini,2 Kohn and Lerer 3 and Mathews and Reus 4 ). Recent meta-analyses of linkage studies have establi...

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The Wellcome trust UK–Irish bipolar affective disorder sibling-pair genome screen: first stage report

Cited by 62 publications

References 74 publications

Evidence for a putative bipolar disorder locus on 2p13–16 and other potential loci on 4q31, 7q34, 8q13, 9q31, 10q21–24, 13q32, 14q21 and 17q11–12

Evidence for a putative bipolar disorder locus on 2p13–16 and other potential loci on 4q31, 7q34, 8q13, 9q31, 10q21–24, 13q32, 14q21 and 17q11–12

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

Excitement and confusion on chromosome 6q: the challenges of neuropsychiatric genetics in microcosm

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