Genomewide Scan and Fine-Mapping Linkage Studies in Four European Samples with Bipolar Affective Disorder Suggest a New Susceptibility Locus on Chromosome 1p35-p36 and Provides Further Evidence of Loci on Chromosome 4q31 and 6q24

Philipps University of Marburg, Marburg, Hesse, Germany
The American Journal of Human Genetics (Impact Factor: 10.93). 01/2006; 77(6):1102-11. DOI: 10.1086/498619
Source: PubMed


We present the findings of a large linkage study of bipolar affective disorder (BPAD) that involved genomewide analysis of 52 families (448 genotyped individuals) of Spanish, Romany, and Bulgarian descent and further fine mapping of the 1p34-p36, 4q28-q31, and 6q15-q24 regions. An additional sample of 56 German families (280 individuals) was included for this fine-mapping step. The highest nonparametric linkage scores obtained in the fine mapping were 5.49 for 4q31 and 4.87 for 6q24 in the Romany families and 3.97 for 1p35-p36 in the Spanish sample. MOD-score (LOD scores maximized over genetic model parameters) analysis provided significant evidence of linkage to 4q31 and at least borderline significance for the 1p and 6q regions. On the basis of these results and previous positive research findings, 4q31 and 6q24 should now be considered confirmed BPAD susceptibility loci, and 1p35-p36 is proposed as a new putative locus that requires confirmation in replication studies.

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    • "Shared synteny for these regions is shown in Fig. 4.B. These regions include the following cytobands: murine 4qE, homologous to human 1p36, implicated in BPD in two studies with linkage scores of 3.97 [60] and 3.1 [61] and a region in which SNPs predict BPD susceptibility [62]; murine 5qF, homologous to human 12q24, implicated in BPD in multiple studies with linkage scores of 4.91 [63], 3.63 [64], 3.37 [65], 2.8 [61], and 2.08 [66] and a region in which SNPs and allele variants predict BPD susceptibility [44], [46], [67]; 8qE1, homologous to human 16q24, implicated in BPD in two studies with linkage scores of 3.51 [68] and 2.29 [69]; murine 11qE2, homologous to human 17q25, implicated in BPD in five studies with linkage scores of 3.11 [70], 2.4 [71], 2.4 [72], 2.1 [73], and 2.08 [74]; murine 13qA3 and 17qA3-17qB1, two cytobands with homology to human 6p21–22, implicated in BPD in multiple studies with linkage scores of 3.19 [68], 2.60 [75], 2.26 [72], and 1.91 [69]; murine 14qA1, homologous to human 3p14, implicated in BPD in two studies with linkage scores of 3.51 [76] and 2.31 [77]; and murine 16qB2–B3, homologous to human 3q29, implicated in BPD in two studies with linkage scores of 3.74 [78] and 2.0 [61]. Additional enriched genome regions showing weaker previous relationships to BPD included: murine 2qE, homologous to human 11p13, implicated in BPD in one study with a linkage score of 1.95 [79] and a region in which SNPs and allele variants predict BPD susceptibility [80], [81]; murine 8qB2–B3.1, "
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    ABSTRACT: Bipolar disorder (BPD) is a debilitating heritable psychiatric disorder. Contemporary rodent models for the manic pole of BPD have primarily utilized either single locus transgenics or treatment with psychostimulants. Our lab recently characterized a mouse strain termed Madison (MSN) that naturally displays a manic phenotype, exhibiting elevated locomotor activity, increased sexual behavior, and higher forced swimming relative to control strains. Lithium chloride and olanzapine treatments attenuate this phenotype. In this study, we replicated our locomotor activity experiment, showing that MSN mice display generationally-stable mania relative to their outbred ancestral strain, hsd:ICR (ICR). We then performed a gene expression microarray experiment to compare hippocampus of MSN and ICR mice. We found dysregulation of multiple transcripts whose human orthologs are associated with BPD and other psychiatric disorders including schizophrenia and ADHD, including: Epor, Smarca4, Cmklr1, Cat, Tac1, Npsr1, Fhit, and P2rx7. RT-qPCR confirmed dysregulation for all of seven transcripts tested. Using a novel genome enrichment algorithm, we found enrichment in genome regions homologous to human loci implicated in BPD in replicated linkage studies including homologs of human cytobands 1p36, 3p14, 3q29, 6p21-22, 12q24, 16q24, and 17q25. Using a functional network analysis, we found dysregulation of a gene system related to chromatin packaging, a result convergent with recent human findings on BPD. Our findings suggest that MSN mice represent a polygenic model for the manic pole of BPD showing much of the genetic systems complexity of the corresponding human disorder. Further, the high degree of convergence between our findings and the human literature on BPD brings up novel questions about evolution by analogy in mammalian genomes.
    Full-text · Article · Jun 2012 · PLoS ONE
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    • "A second linkage study found a LOD of 3.6 for linkage to unipolar affective disorder at 1p36 in a sample of 81 families [Zubenko et al., 2003]. A nonparametric LOD linkage score of 3.97 was found in a Spanish sample of bipolar affective disorder at 1p34-36 with 52 families of Spanish, Romanian and Bulgarian descent [Schumacher et al., 2005]. The 1p34-36 region has also been implicated with nominally significant LODs in linkage studies of bipolar disorder and related affective disorders in Gypsy families [Kaneva et al., 2009]. "
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    ABSTRACT: Three linkage studies of families with multiple cases of bipolar disorder and/or unipolar affective disorder have confirmed the involvement of the chromosome 1p36 region in the etiology of affective disorders with LOD scores of 2.7, 3.6, and 3.97. We investigated the protein kinase C zeta gene (PRKCZ) as a susceptibility locus for bipolar disorder because it is highly brain expressed and is localized close to the marker D1S243 which was linked to affective disorder in a single large UCL bipolar disorder family with a LOD of 3.1. PRKCZ encodes an unusual type of protein kinase which affects axonal differentiation through Wnt-signaling. We genotyped four microsatellite markers and nine single nucleotide polymorphism (SNP) markers within or near the PRKCZ gene in the UCL case-control sample of 600 bipolar disorder patients and up to 605 supernormal controls. Markers D1S243 and rs3128396 were significantly associated with bipolar disorder (empirical P = 0.037 and P = 0.040, respectively). We also included data from eight SNPs which were genotyped as part of our GWA study on bipolar disorder for association analysis. Tests of haplotypic association found that a haplotype block comprising markers rs3128296, rs2503706, and rs3128309 was associated with bipolar disorder (empirical P = 0.004). A previous linkage study had shown greater evidence for linkage within female cases compared to males. Therefore, to assess if the association was sex-specific, we performed a female-only allelic-association analysis, which resulted in SNPs rs3128296 and rs3128309 becoming associated with bipolar disorder (P = 0.004 and P = 0.016, respectively). PRKCZ may play a role in susceptibility to bipolar affective disorder.
    Full-text · Article · Mar 2012 · American Journal of Medical Genetics Part B Neuropsychiatric Genetics
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    • "The main aim of the current study was to re-assess the BPAD linkage findings in three large inter-related Gypsy families. Since the genome scan producing these findings [Schumacher et al., 2005], our sample has undergone the kind of changes that have contributed to non-replication in other studies, such as addition of more family members and re-evaluation of affection status. We FIG. 3. Haplotype analysis of GRM1 Exon 8 on Chromosome 6q24, located within the ''conserved'' haplotype D6S970–GATA184A08 (5-2). "
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    ABSTRACT: We report the results of follow-up analyses of 12 genomic regions showing evidence of linkage in a genome-wide scan (GWS) of Gypsy families with bipolar affective disorder (BPAD). The Gypsies are a young founder population comprising multiple genetically differentiated sub-isolates with strong founder effect and limited genetic diversity. The BPAD families belong to a single sub-isolate and are connected by numerous inter-marriages, resulting in a super-pedigree with 181 members. We aimed to re-assess the positive GWS findings and search for evidence of a founder susceptibility allele after the addition of newly recruited subjects, some changes in diagnostic assignment, and the use of denser genetic maps. Linkage analysis was conducted with SimWalk2, accommodating the full complexity of pedigree structure and using a conservative narrow phenotype definition (BPAD only). Six regions were rejected, while 1p36, 13q31, 17p11, 17q21, 6q24, and 4q31 produced nominally significant results in both the individual families and the super-pedigree. Haplotypes were reconstructed and joint tests for linkage and association were done for the most promising regions. No common ancestral haplotype was identified by sequencing a strong positional and functional candidate gene (GRM1) and additional STR genotyping in the top GWS region, 6q24. The best supported region was a 12 cM interval on 4q31, also implicated in previous studies, where we obtained significant results in the super-pedigree using both SimWalk2 (P = 0.004) and joint Pseudomarker analysis of linkage and linkage disequilibrium (P = 0.000056). The size of the region and the characteristics of the Gypsy population make it suitable for LD mapping.
    Full-text · Article · Mar 2009 · American Journal of Medical Genetics Part B Neuropsychiatric Genetics
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