Psychosis and the genetic spectrum of bipolar disorder: evidence from linkage analysis

Cheng, Rong; Park, N; Juo, Suh Hang Hank; Liu, Jing; Loth, Jo Ellen; Endicott, Jean; Gilliam, T. Conrad; Baron, Miron

doi:10.1038/sj.mp.4001745

Cited by 5 publications

(4 citation statements)

References 10 publications

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“…We previously reported a significant bipolar locus at 8q24 in a cohort of persons of Latin American ancestry (Gonzalez et al, ), which replicates findings from other BD linkage studies (Avramopoulos et al, ; Cheng et al, ; Cichon et al, ; McInnis et al, ; McQueen et al, ; Park et al, ). The present fine mapping of markers in this region pinpoint one specific gene that has evidence of significant association in this sample of persons responsible for the original linkage finding.…”

Section: Discussionsupporting

confidence: 83%

Fine‐mapping scan of bipolar disorder susceptibility loci in Latino pedigrees

Gonzalez

Villa

Rodriguez

et al. 2019

American J of Med Genetics Pt B

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We previously identified bipolar disorder (BD) susceptibility loci on 8q24, 14q32, and 2q12-14 in a genome-wide nonparametric linkage screen in a Latino cohort. We now perform a fine mapping analysis using a dense map of additional SNPs to identify BD susceptibility genes within these regions. One thousand nine hundred and thirty-eight individuals with Latino ancestry (880 individuals with BD Type I or Schizoaffective, Bipolar Type) from 416 Latino pedigrees from the United States, Mexico, Costa Rica, and Guatemala were genotyped with 3,074 SNPs to provide dense coverage of the 8q24 (11.5 cM), 14q32 (7.5 cM), and 2q12-14 (6.5 cM) chromosomal loci. Single-marker association tests in the presence of linkage were performed using the LAMP software. The top linkage peak (rs7834818; LOD = 5.08, p = 3.30E − 5) and associated single marker (rs2280915, p = 2.70E − 12) were located within FBXO32 on 8q24. On chromosome 2, the top linkage peak (rs6750326; LOD = 5.06, p = 3.50E − 5) and associated single marker (rs11887088, p = 2.90E − 6) were located in intragenic regions near ACTR3 and DPP10.None of the additional markers in the region around chromosome 14q32 met significance levels for linkage or association. We identified six SNPs on 2q12-q14 and one SNP in FBXO32 on 8q24 that were significantly associated with BD in this Latino cohort. K E Y W O R D SACTR3, bipolar disorder, DPP10, FBXO32, Latino ancestry

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Section: Discussionsupporting

confidence: 83%

Fine‐mapping scan of bipolar disorder susceptibility loci in Latino pedigrees

Gonzalez

Villa

Rodriguez

et al. 2019

American J of Med Genetics Pt B

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“…However, we cannot determine from this analysis whether the differences found between child and adolescent age of onset subgroups are an independent effect of age when illness begins, or are affected by susceptibility genes that confer early age of onset. However, interestingly, studies of adult BP have noted heterogeneity of linkage associated with psychotic features and anxiety (38), as well as familiality of a range of phenotypic characteristics in families with BP (39). Whatever the reason for these differences, it will be crucial for ongoing molecular, genetic, neuroimaging, and treatment studies to take into account the age of BP onset, maturational effects, and the presence of comorbid disorders and differential exposure to stress to fully explicate research findings.…”

Section: Discussionmentioning

confidence: 99%

Comparison of manic and depressive symptoms between children and adolescents with bipolar spectrum disorders

et al. 2009

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Objective: To compare the most severe lifetime (current or past) mood symptoms, duration of illness, and rates of lifetime comorbid disorders among youth with bipolar spectrum disorders [BP (bipolar-I, bipolar-II and bipolar-not otherwise specified)].Methods: A total of 173 children (<12 years) with BP, 101 adolescents with childhood-onset BP, and 90 adolescents with adolescent-onset BP were evaluated with standardized instruments.Results: Depression was the most common initial and frequent episode for both adolescent groups, followed by mania ⁄ hypomania. Adolescents with childhood-onset BP had the longest illness, followed by children and then adolescents with adolescent-onset BP. Adjusting for sex, socioeconomic status, and duration of illness, while manic, both adolescent groups showed more ÔtypicalÕ and severe manic symptoms. Mood lability was more frequent in childhood-onset and adolescents with early-onset BP. While depressed, both adolescent groups showed more severe depressive symptoms, higher rates of melancholic and atypical symptoms, and suicide attempts than children. Depressed children had more severe irritability than depressed adolescents. Early BP onset was associated with attention-deficit hyperactivity disorder, whereas later BP onset was associated with panic, conduct, and substance use disorders. Above-noted results were similar when each BP subtype was analyzed separately. Conclusions:Older age was associated with more severe and typical mood symptomatology. However, there were differences and similarities in type, intensity, and frequency of BP symptoms and comorbid disorders related to age of onset and duration of BP and level of psychosocial development. These factors and the normal difficulties youth have expressing and modulating their emotions may explain existing complexities in diagnosing and treating BP in youth, particular in young children, and suggest the need for developmentally sensitive treatments.

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“…FKBP5 has not been identified as a risk gene by genome-wide association studies (GWAS). However, chromosome 6, which houses the FKBP5 gene, was associated with psychosis by GWAS . Instead, candidate gene studies, which use a hypothesis driven approach, have identified common FKBP5 single nucleotide polymorphisms (SNPs) that combine with environmental factors to increase risk for multiple neuropsychiatric disorders. − In PTSD, multiple studies have reported that FKBP5 SNPs combine with early life stress to increase risk; however, GWAS studies have not supported this .…”

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confidence: 99%

Targeting the FKBP51/GR/Hsp90 Complex to Identify Functionally Relevant Treatments for Depression and PTSD

et al. 2018

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Genetic and epigenetic alterations in FK506-binding protein 5 ( FKBP5) have been associated with increased risk for psychiatric disorders, including post-traumatic stress disorder (PTSD). Some of these common variants can increase the expression of FKBP5, the gene that encodes FKBP51. Excess FKBP51 promotes hypothalamic-pituitary-adrenal (HPA) axis dysregulation through altered glucocorticoid receptor (GR) signaling. Thus, we hypothesized that GR activity could be restored by perturbing FKBP51. Here, we screened 1280 pharmacologically active compounds and identified three compounds that rescued FKBP51-mediated suppression of GR activity without directly activating GR. One of the three compounds, benztropine mesylate, disrupted the association of FKBP51 with the GR/Hsp90 complex in vitro. Moreover, we show that removal of FKBP51 from this complex by benztropine restored GR localization in ex vivo brain slices and primary neurons from mice. In conclusion, we have identified a novel disruptor of the FKBP51/GR/Hsp90 complex. Targeting this complex may be a viable approach to developing treatments for disorders related to aberrant FKBP51 expression.

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Psychosis and the genetic spectrum of bipolar disorder: evidence from linkage analysis

Cited by 5 publications

References 10 publications

Fine‐mapping scan of bipolar disorder susceptibility loci in Latino pedigrees

Fine‐mapping scan of bipolar disorder susceptibility loci in Latino pedigrees

Comparison of manic and depressive symptoms between children and adolescents with bipolar spectrum disorders

Targeting the FKBP51/GR/Hsp90 Complex to Identify Functionally Relevant Treatments for Depression and PTSD

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