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

Leiden University, Leyden, South Holland, Netherlands
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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    • "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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    • "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.
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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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