Susceptibility loci for bipolar affective disorder on chromosome 18? A review and a study of Danish families

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 Pvalue 0.0002, genome-wide P-value 0.1622). A three-point lod score of 2.98 (genome-wide Pvalue 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.

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“…The parametric lod scores and haplotypes or marker alleles on chromosomes 12q24.3, 16p13.3, and 4p16 have been published previously. 8,10,41 …”

Section: Resultsmentioning

confidence: 99%

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

Ewald¹,

Flint²,

Kruse

et al. 2002

Mol Psychiatry

127

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“…Linkage to chromosome 18q was found in several independent studies. [15][16][17][18][19][20][21] Therefore, the 18q region might harbour a susceptibility gene for BP spectrum disorders. This was the starting point for our chromosome 18 genetic and physical mapping studies.…”

Section: Discussionmentioning

confidence: 99%

“…At the 1997 (Sante Fe, USA) and the 1998 World Congress on Psychiatric Genetics (Bonn, Germany), several other groups also reported evidence for linkage of BP to 18p and 18q. [16][17][18][19][20][21] Considering the complexity of BP disorder and the different methodologies applied, the independent studies focusing on 18q21-q23 might reflect the presence of the same susceptibility gene. In particular the regions implicated by Coon et al, 17 McInnes et al, 20 McMahon et al 21 overlap partially with the candidate region derived by us.…”

Section: Introductionmentioning

confidence: 99%

Genetic refinement and physical mapping of a chromosome 18q candidate region for bipolar disorder

et al. 1999

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Recent genetic studies have implicated chromosome 18 in bipolar disorder (BP) with putative loci in the pericentromeric region and on 18q. We reported linkage to chromosome 18q21.33-q23 in a large family. In this study we typed additional markers in the family and were able to reduce the candidate region significantly. All affected family members are sharing alleles for markers spanning a genetic distance of maximal 8.9 cM. Haplotype analysis provided a marker order in agreement with published genetic and physical maps. Using yeast artificial chromosomes, we constructed a contig map that will help to identify positional candidate genes for bipolar disorder.

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“…TTR represents 25% of all protein made in the cerebrospinal fluid and contained in the brain ventricles and is a major transporter of retinoid across the choroid plexus into the brain (10,105,106). The 18q12 locus containing TTR has very recently been linked to both bipolar illness (53) and schizophrenia (55). Determination of TTR expression, as well as the expression of other schizophrenia candidates in this pedigree, will be of interest.…”

Section: Expression Of Schizophrenia Candidate Genes Is Regulated By mentioning

confidence: 99%

Three independent lines of evidence suggest retinoids as causal to schizophrenia

Goodman

1998

Proc. Natl. Acad. Sci. U.S.A.

185

125

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Retinoid dysregulation may be an important factor in the etiology of schizophrenia. This hypothesis is supported by three independent lines of evidence that triangulate on retinoid involvement in schizophrenia: (i) congenital anomalies similar to those caused by retinoid dysfunction are found in schizophrenics and their relatives; (ii) those loci that have been suggestively linked to schizophrenia are also the loci of the genes of the retinoid cascade (convergent loci); and (iii) the transcriptional activation of the dopamine D2 receptor and numerous schizophrenia candidate genes is regulated by retinoic acid. These findings suggest a close causal relationship between retinoids and the underlying pathophysiological defects in schizophrenia. This leads to specific strategies for linkage analyses in schizophrenia. In view of the heterodimeric nature of the retinoid nuclear receptor transcription factors, e.g., retinoid X receptor ␤ at chromosome 6p21.3 and retinoic acid receptor ␤ at 3p24.3, two-locus linkage models incorporating genes of the retinoid cascade and their heterodimeric partners, e.g., peroxisome proliferatoractivated receptor ␣ at chromosome 22q12-q13 or nuclearrelated receptor 1 at chromosome 2q22-q23, are proposed. New treatment modalities using retinoid analogs to alter the downstream expression of the dopamine receptors and other genes that are targets of retinoid regulation, and that are thought to be involved in schizophrenia, are suggested.

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Susceptibility loci for bipolar affective disorder on chromosome 18? A review and a study of Danish families

Cited by 34 publications

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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

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

Genetic refinement and physical mapping of a chromosome 18q candidate region for bipolar disorder

Three independent lines of evidence suggest retinoids as causal to schizophrenia

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