Genome-wide scan in Portuguese Island families implicates multiple loci in bipolar disorder: Fine mapping adds support on chromosomes 6 and 11

Veterans Affairs Medical Center, Washington, DC 20422, USA.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics (Impact Factor: 3.42). 05/2004; 127B(1):30-4. DOI: 10.1002/ajmg.b.30001
Source: PubMed

ABSTRACT As part of an extensive study in the Portuguese Island population of families with multiple patients suffering from bipolar disorder and schizophrenia, we performed an initial genome-wide scan of 16 extended families with bipolar disorder that identified three regions on chromosomes 2, 11, and 19 with genome-wide suggestive linkage and several other regions, including chromosome 6q, also approached suggestive levels of significance. Dick et al. [2003: Am J Hum Genet 73:107-114] recently reported in a study of 250 families with bipolar disorder a maxLOD score of 3.61 near marker D6S1021 on chromosome 6q. This study replicates this finding having detected a peak NPL = 2.02 (P = 0.025) with the same marker D6S1021(104.7 Mb). Higher-density mapping provided additional support for loci on chromosome 6 including marker D6S1021 with an NPL = 2.59 (P = 0.0068) and peaking at marker D6S1639 (125 Mb) with an NPL = 3.06 (P = 0.0019). A similar pattern was detected with higher-density mapping of chromosome 11 with an NPL = 3.15 (P = 0.0014) at marker D11S1883 (63.1 Mb). Simulations at the density of our fine mapping data indicate that less than 1 scan out of 10 would find two such scores genome-wide in the same scan by chance. Our findings provide additional support for a susceptibility locus for bipolar disorder on 6q, as well as, suggesting the importance of denser scans. Published 2004 Wiley-Liss, Inc.

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Available from: Christopher P. Morley, Sep 25, 2015
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    • "The initial 10,000 GPC participants drawn from earlier studies include our Portuguese Island Collection (PIC) of individuals and multiplex families with schizophrenia and/or bipolar disorder. The PIC sampled a homogeneous population founded 500 years ago on two island archipelagos off the coast of Portugal [Pato et al., 2004; Sklar et al., 2004]. The PIC has been an integral part of the International Schizophrenia Consortium (ISC). "
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    ABSTRACT: The Genomic Psychiatry Cohort (GPC) is a longitudinal resource designed to provide the necessary population-based sample for large-scale genomic studies, studies focusing on Research Domain Criteria (RDoC) and/or other alternate phenotype constructs, clinical and interventional studies, nested case-control studies, long-term disease course studies, and genomic variant-to-phenotype studies. We provide and will continue to encourage access to the GPC as an international resource. DNA and other biological samples and diagnostic data are available through the National Institute of Mental Health (NIMH) Repository. After appropriate review and approval by an advisory board, investigators are able to collaborate in, propose, and co-lead studies involving cohort participants. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 06/2013; 162(4). DOI:10.1002/ajmg.b.32160 · 3.42 Impact Factor
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    • "However, the genetic loci containing the genes RHEB, TMEM138, and CYBASC3 that are associated with TESI have shown linkage with bipolar disorder (Cassidy et al, 2007; Elashoff et al, 2007; Pato et al, 2004). PIK3C3 is considered as a candidate gene for schizophrenia (Carter, 2009; Tang et al, 2008) and was previously associated with bipolar "
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    ABSTRACT: Emergence of suicidal ideation (TESI) during treatment with antidepressants in major depression led to a black box warning. We performed a genome-wide association study to identify genetic markers, which increase the risk for this serious side effect. TESI was evaluated in depressed in-patients (N=397) and defined by an emergence of suicidal thoughts during hospitalization without suicidal thoughts at admission using the suicide item (3) of the Hamilton Depression Rating Scale. Genotype distribution of 405.383 single-nucleotide polymorphisms (SNPs) in patients with TESI (N=32/8.1%) was compared to patients without increase in suicidal ideation (N=329/82.9%) and to a subgroup never reported suicidal ideation (N=79/19.9%). Top results were analyzed in an independent sample (N=501). None variant reached genome-wide significance, the best associated SNP was rs1630535 (p-value=1.3 × 10(-7)). The top 79 SNPs could be analyzed in an independent sample, and 14 variants showed nominal significant association with the same risk allele in the replication sample. A discriminant analysis classifying patients using these 79 SNPs revealed a 91% probability to classify TESI vs non-TESI cases correctly in the replication sample. Although our data need to be interpreted carefully owing to the small numbers in both cohorts, they suggest that a combination of genetic markers might indeed be used to identify patients at risk for TESI.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 02/2012; 37(3):797-807. DOI:10.1038/npp.2011.257 · 7.05 Impact Factor
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    • "The initial sample included only 29 concordant EO-BPI sib-pairs, whereas 53 were included in this study. The region has been identified in three previous genome scans (Dick et al. 2003; Fallin et al., 2004; Pato et al., 2004) and by the meta-analysis reported by Segurado et al (Segurado et al., 2003); note that none of these studies considered AAO in their analyses. One of the four genome-wide association studies conducted for bipolar disorder (WTCCC, 2007; Baum et al., 2008, Ferreira et al., 2008, Sklar et al., 2008), the Wellcome Trust Case control consortium, reported moderate evidence for association of bipolar disorder in the 2q14 region (p=10 -6 ). "
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    ABSTRACT: Bipolar disorder has a genetic component, but the mode of inheritance remains unclear. A previous genome scan conducted in 70 European families led to detect eight regions linked to bipolar disease. Here, we present an investigation of whether the phenotypic heterogeneity of the disorder corresponds to genetic heterogeneity in these regions using additional markers and an extended sample of families. The MLS statistic was used for linkage analyses. The predivided sample test and the maximum likelihood binomial methods were used to test genetic homogeneity between early-onset bipolar type I (cut-off of 22 years) and other types of the disorder (later onset of bipolar type I and early-onset bipolar type II), using a total of 138 independent bipolar-affected sib-pairs. Analysis of the extended sample of families supports linkage in four regions (2q14, 3p14, 16p23, and 20p12) of the eight regions of linkage suggested by our previous genome scan. Heterogeneity testing revealed genetic heterogeneity between early and late-onset bipolar type I in the 2q14 region (P = 0.0001). Only the early form of the bipolar disorder but not the late form appeared to be linked to this region. This region may therefore include a genetic factor either specifically involved in the early-onset bipolar type I or only influencing the age at onset (AAO). Our findings illustrate that stratification according to AAO may be valuable for the identification of genetic vulnerability polymorphisms. © 2010 Wiley-Liss, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 12/2010; 153B(8):1425-33. DOI:10.1002/ajmg.b.31121 · 3.42 Impact Factor
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