Genomewide Linkage Disequilibrium Mapping of Severe Bipolar Disorder in a Population Isolate

Neurogenetics Laboratory, University of California, San Francisco, CA, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 10/2002; 71(3):565-74. DOI: 10.1086/342291
Source: PubMed


Genomewide association studies may offer the best promise for genetic mapping of complex traits. Such studies in outbred populations require very densely spaced single-nucleotide polymorphisms. In recently founded population isolates, however, extensive linkage disequilibrium (LD) may make these studies feasible with currently available sets of short tandem repeat markers, spaced at intervals as large as a few centimorgans. We report the results of a genomewide association study of severe bipolar disorder (BP-I), using patients from the isolated population of the central valley of Costa Rica. We observed LD with BP-I on several chromosomes; the most striking results were in proximal 8p, a region that has previously shown linkage to schizophrenia. This region could be important for severe psychiatric disorders, rather than for a specific phenotype.

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Available from: Dar Meshi, Sep 30, 2015
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    • "This mainly urban population can trace its origin to a trihybrid admixture of Iberian Europeans, Amerindians and sub-Saharan Africans, albeit with a predominant Caucasian component [17]. Interesting historic, demographic and genetic characteristics of this hybrid population have attracted researchers interested in testing genetic associations for various diseases [18] [19] [20] [21] [22] [23] [24] [25] [26]. However, as for most Latin American countries, pharmacogenetic studies are still lacking. "
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    ABSTRACT: HLA-B∗57:01 is a well-known and cost-effective pharmacogenetic marker for abacavir hypersensitivity. As with other HLA alleles, there is widespread variation in its frequency across populations. The Costa Rica Central Valley Population (CCVP) is the major population in this country. The frequency of HLA-B∗57:01 in this population has not been described yet. Thus, our aim was to determine the frequency of this allele in the CCVP. 200 unrelated healthy volunteer donors born in the CCVP were typed. HLA-B∗57-positive samples identified by HLA intermediate resolution typing methods were further typed by SBT to high resolution. An HLA-B∗57:01 carrier frequency of 5.00% was determined in this sample. This frequency is relatively high in comparison to reports from other populations in Latin America. These results suggest that there is a considerable frequency of HLA-B∗57:01 in the CCVP and that pharmacogenetic testing for HIV+ patients who are going to receive abacavir-based treatment should be considered in this country.
    Human Immunology 10/2014; 75(11). DOI:10.1016/j.humimm.2014.09.011 · 2.14 Impact Factor
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    • "reported [ Ewald et al . , 1998a ] . The regions identified in the present study in other chromosomes that have already been linked to BD were located on chromosomes 2q24 [ Zandi et al . , 2007 ] ; 5p15 , a region containing the Dopamine Transporter gene , with the same D5S417 marker [ Kelsoe et al . , 2001 ] ; 7q34 [ Liu et al . , 2003 ] ; 8p23 [ Ophoff et al . , 2002 ; Walss - Bass et al . , 2006 ] and 8q24 [ Cichon et al . , 2001b ; Badenhop et al . , 2002 ] ; 9q21 [ Friddle et al . , 2000 ] with the D9S264 marker used in the former study only 0 . 33 Mb apart from the D9S167 marker yielding a positive result for the present genome scan ; 10q26 [ Kelsoe et al . , 2001 ; Cichon et al . , 2001a ; Ewal"
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    ABSTRACT: The discovery of the genetic factors implicated in the predisposition to complex diseases may greatly profit from genetic studies in isolated populations. In this perspective, we performed a genome-wide scan using 507 microsatellite markers, with an average interval size of 7.6 cM, on a sample of 88 nuclear families with at least two affected sibs with bipolar disorder recruited in the Sardinian population. An initial analysis yielded non-parametric linkage exceeding 3.4 with P-values <0.0003 at two adjacent markers, D1S206 and D1S435 in the 1p22-p21 chromosomal region. Moreover, positive linkage ranging between 2.0 and 3.0 was obtained for other loci in several cases in regions that have already been linked to predisposition to bipolar disorder, such as 5p15.33, 8q24.13, and 11q14.3. A subsequent analysis of the 1p22-p21 region using the same set of families and a dense panel of 20 new microsatellite markers, spaced at 1.2 cM on average, reinforced the finding of suggestive linkage for this region. Interestingly, NPL values above 2.1 and P-values <0.02 were obtained for a cluster of 10 markers comprising D1S435. Thus, this study suggests that the 1p22-p21 region may contain a new locus participating to the genetic susceptibility to bipolar disorder and reproduces positive linkage for several other loci already implicated in this pathology. Since the Sardinian population presents a peculiar genetic homogeneity, these results may pave the way to further studies for replication in this population contributing to the rapid discovery of the genetic factors predisposing to bipolar disorder.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 09/2010; 153B(6):1200-8. DOI:10.1002/ajmg.b.31092 · 3.42 Impact Factor
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    • "Park et al. (2004) have shown significant genome-wide linkage of bipolar disorder with psychotic symptoms to 8p21 (lod = 3.46) and suggestive linkage to 8p12, as for several other regions shared with schizophrenia. Earlier to Park et al. (2004); Ophoff et al. (2002) had also found the strongest linkage in their bipolar I family sample to be in chromosome 8p. Furthermore, Green et al. (2005) found that the NRG1 core haplotype was associated with bipolar disorder. "
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    ABSTRACT: As evidence of partial aetiological overlap between bipolar affective disorder and schizophrenia is accumulating, it is important to determine whether genes implicated in the aetiology of schizophrenia play a role in bipolar disorder, and vice versa. As the neuregulin 1 (NRG1) gene has been associated with schizophrenia, we set out to investigate whether it is also associated with bipolar affective disorder, using a sample from Scotland, UK. We tested four single nucleotide polymorphisms (SNPs), SNP8NRG221533 (rs35753505), SNP8NRG241930, SNP8NRG243177 (rs6994992) and SNPNRG222662 (rs4623364) for allelic and haplotypic association with bipolar disorder and the presence of psychotic or mood-incongruent psychotic features. We found nominal allele-wise significant association (P = 0.02) for SNP8NRG221533, with the T allele being overrepresented in cases. This is the opposite allelic association to the original association study where the C allele was associated with schizophrenia. Allele-wise significance increased when we tested for association with the subgroups of bipolar disorder with psychotic features (chi2 = 8.53; P = 0.003; odds ratio = 1.49) and, more specifically, with mood-incongruent psychotic features (chi2 = 7.13; P = 0.008; odds ratio = 1.57). Furthermore, both these subphenotypes were significantly associated with the SNP8NRG221533(T)-SNP8NRG241930(G) haplotype (chi2 = 11.94, global P = 0.027 and chi2 = 11.88, global P = 0.019, respectively) and with the SNP8NRG221533(T)-SNP8NRG222662(C)-SNP8NRG241930(G) haplotype (chi2 = 19.98, global P = 0.009) in case of the broader subphenotype of psychotic bipolar. This study supports the hypothesis that NRG1 may play a role in the development of bipolar disorder, especially in psychotic subtypes, albeit with different alleles to previous association reports in schizophrenia and bipolar disorder.
    Psychiatric genetics 04/2009; 19(3):113-6. DOI:10.1097/YPG.0b013e32832a4f69 · 1.94 Impact Factor
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