Genome-wide survey implicates the influence of copy number variants (CNVs) in the development of early-onset bipolar disorder.

Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
Molecular Psychiatry (Impact Factor: 15.15). 03/2011; 17(4):421-32. DOI: 10.1038/mp.2011.8
Source: PubMed

ABSTRACT We used genome-wide single nucleotide polymorphism (SNP) data to search for the presence of copy number variants (CNVs) in 882 patients with bipolar disorder (BD) and 872 population-based controls. A total of 291 (33%) patients had an early age-at-onset < or =21 years (AO < or =21 years). We systematically filtered for CNVs that cover at least 30 consecutive SNPs and which directly affect at least one RefSeq gene. We tested whether (a) the genome-wide burden of these filtered CNVs differed between patients and controls and whether (b) the frequency of specific CNVs differed between patients and controls. Genome-wide burden analyses revealed that the frequency and size of CNVs did not differ substantially between the total samples of BD patients and controls. However, separate analysis of patients with AO < or =21 years and AO>21 years showed that the frequency of microduplications was significantly higher (P=0.0004) and the average size of singleton microdeletions was significantly larger (P=0.0056) in patients with AO < or =21 years compared with controls. A search for specific BD-associated CNVs identified two common CNVs: (a) a 160 kb microduplication on 10q11 was overrepresented in AO < or = 21 years patients (9.62%) compared with controls (3.67%, P=0.0005) and (b) a 248 kb microduplication on 6q27 was overrepresented in the AO< or = 21 years subgroup (5.84%) compared with controls (2.52%, P=0.0039). These data suggest that CNVs have an influence on the development of early-onset, but not later-onset BD. Our study provides further support for previous hypotheses of an etiological difference between early-onset and later-onset BD.

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    ABSTRACT: Objectives Copy number variants (CNVs) have been shown to affect susceptibility for neuropsychiatric disorders. To date, studies implicating the serotonergic system in complex conditions have just focused on single nucleotide polymorphisms (SNPs). We therefore sought to identify novel common genetic copy number polymorphisms affecting genes of the serotonergic system, and to assess their putative role in bipolar affective disorder (BPAD) and major depressive disorder (MDD).MethodsA selection of 41 genes of the serotonergic system encoding receptors, the serotonin transporter, metabolic enzymes and chaperones were investigated using a paired-end mapping (PEM) approach on next-generation sequencing data from the pilot project of the 1000 Genomes Project. For association testing, 593 patients with MDD, 1,145 patients with BPAD, and 1,738 healthy controls were included in the study.ResultsPEM led to the identification of a microdeletion in the gene encoding tryptophan hydroxylase 2 (TPH2), affecting an amygdala- and hippocampus-specific isoform. It was not associated with BPAD or MDD using a case–control association approach.Conclusions We did not find evidence for a role of the TPH2 microdeletion in the pathoetiology of affective disorders. Further studies examining its putative role in behavioral traits regulated by the limbic system are warranted.
    Bipolar Disorders 04/2014; · 4.62 Impact Factor
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    ABSTRACT: Background Age-of-onset (AO) is increasingly used in molecular genetics of bipolar I disorder (BP-I) as a phenotypic specifier with the goal of reducing genetic heterogeneity. However, questions regarding the cut-off age for defining early onset (EO), as well as the number of onset groups characterizing BP-I have emerged over the last decade with no definite conclusion. The aims of this paper are: 1) to see whether a mixture of three distributions better describes the AO of BP-I than a mixture of two distributions in different independent samples; 2) to compare the morbid risk (MR) for BP-I and for major affective disorders and schizophrenia in first degree relatives of BP-I probands by proband onset group derived from commingling analysis, since the MR to relatives is a trait with strong genetic background. Methods We applied commingling (admixture) analysis to the AO of three BP-I samples from Romania (n=621), Germany (n=882), and Poland (n=354). Subsequently, the morbid risk (MR) for BP-I and for major psychoses (BP-I, BP-II, Mdd-UP, schizoaffective disorders, schizophrenia) was estimated in first degree relatives by proband AO-group derived from admixture analysis in the Romanian sample. Results In the three independent samples and in the combined sample two- and three-AO-group distributions fitted the empirical data equally well. The upper EO limit varied between 21 and 25 years from sample to sample. The MR for both BP-I and for all major psychoses was similar in first degree relatives of EO probands (AO≤21) and in relatives of intermediate-onset probands (AO=22–34). Significant MR differences appeared only when comparing the EO group to the late-onset (LO) group (AO>34). Similar to Mdd-UP and schizophrenia, a significant MR decrease in proband first degree relatives was visible after proband AO of 34 years. Under the three-AO-group classification the MR for both BP-I and all major psychoses in first degree relatives did not differ by relative sex in any proband AO-group. Under the two-AO-group classification female relatives of LO probands (AO>24) had a significantly higher MR for all major psychoses than male relatives, while there was no sex difference for the relatives of EO probands. Limitations MR was not computed in the German and Polish samples because family data were not available and 34% of the relatives of the Romanian probands were not available for direct interview. Conclusion Similar to other clinical traits, the MR for major psychoses to relatives failed to support a three-AO-group classification in BP-I suggesting that this is not more useful for the molecular analysis than a two-AO-group classification.
    Journal of Affective Disorders. 01/2014; 168:197–204.
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    ABSTRACT: An increased rate of de novo copy number variants (CNVs) has been found in schizophrenia (SZ), autism and developmental delay. An increased rate has also been reported in bipolar affective disorder (BD). Here, in a larger BD sample, we aimed to replicate these findings and compare de novo CNVs between SZ and BD. We used Illumina microarrays to genotype 368 BD probands, 76 SZ probands and all their parents. CNVs were called by PennCNV and filtered for frequency (<1%) and size (>10kb). Putative de novo CNVs were validated with the z-score algorithm, manual inspection of log R ratios, and qPCR probes. We found 15 de novo CNVs in BD (4.1% rate) and six in SZ (7.9% rate). Combining results with previous studies and using a cut-off of >100kb, the rate of de novo CNVs in BD was intermediate between controls and SZ: 1.5% in controls, 2.2% in BD and 4.3% in SZ. Only the differences between SZ and BD and SZ and controls were significant. The median size of de novo CNVs in BD (448kb) was also intermediate between SZ (613kb) and controls (338kb), but only the comparison between SZ and controls was significant. Only one de novo CNV in BD was in a confirmed SZ locus (16p11.2). Sporadic or early onset cases were not more likely to have de novo CNVs. We conclude that de novo CNVs play a smaller role in BD compared to SZ. Patients with a positive family history can also harbour de novo mutations.
    Human Molecular Genetics 07/2014; · 7.69 Impact Factor

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Lutz Priebe