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: 14.5). 03/2011; 17(4):421-32. DOI: 10.1038/mp.2011.8
Source: PubMed


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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Available from: Manuel Mattheisen, Jan 14, 2014
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    • "Schizophrenia Working Group of the PGC (2014) identified 108 loci significantly associated with schizophrenia at genome-wide level; some of these loci were involved not only in schizophrenia, but also in BP (Chen et al., 2013; Mühleisen et al., 2014). Evidence is growing that the contribution of genome-wide significantly associated risk loci to the genetic liability to major psychoses in different populations might depend on disorder subphenotype, in particular on the subphenotype generated by the age-of-onset (AO) (Mathieu et al., 2010; Priebe et al., 2012; Jamain et al., 2014). Several clinical studies showed that early-and lateonset forms of BP and schizophrenia are accompanied by different morbid risk for major psychoses to first degree relatives of probands (Rice et al., 1987; Schürhoff et al., 2000; Byrne et al., 2002; Grigoroiu-Serbanescu et al., 2001, 2014), which might suggest a different expression of the genetic propensity. "
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    ABSTRACT: We investigated the influence of the age-of-onset (AO) on the association of 45 loci conferring risk for bipolar disorder (BP) and schizophrenia with BP-type-I in a Romanian sample (461 patients, 436 controls). The AO-analysis implicated the EGFR gene, as well as loci in other genes, in the AO variation of BP-type-I and revealed for the first time the link between BP-type-I and risk variants considered specific to schizophrenia (polymorphisms in MMP16/RIPK2 and CNNM2 genes).
    11/2015; DOI:10.1016/j.psychres.2015.11.008
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    • "The Romanian and the German samples with AO means around 25 years and median at 24 years were similar to other published large samples of hospitalized patients (Tondo et al., 2010; Baldessarini et al., 2012) and to the world sample investigated by Merikangas et al. (2011). Similar to our preliminary report on a patient subgroup of the samples analyzed in the present study (Grigoroiu-Serbanescu et al., 2010, Priebe et al., 2012) and to Tozzi et al. (2011), we showed that both a three-AO-group distribution and a two-AOgroup distribution may fit the data equally well, as the AIC-score differences between the two models were close, only marginally favoring the three-AO-group model. We also showed that the upper limit of the EO group varies from sample to sample by two to four years, although the patients were recruited under similar conditions at the three sites, were diagnosed with the same instruments and the samples were large enough (354–882 cases). "

    Journal of Affective Disorders 10/2014; 168:197-204. DOI:10.1016/j.jad.2014.06.05 · 3.38 Impact Factor
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    • "All CNVs that passed the stringent filter criteria were presumed to be genuine CNVs. In two previous studies, 100% of our putative CNVs were shown to be technically verifiable when our filter criteria were employed [20], [23]. "
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    ABSTRACT: Large rare copy number variants (CNVs) have been recognized as significant genetic risk factors for the development of schizophrenia (SCZ). However, due to their low frequency (1∶150 to 1∶1000) among patients, large sample sizes are needed to detect an association between specific CNVs and SCZ. So far, the majority of genome-wide CNV analyses have focused on reporting only CNVs that reached a significant P-value within the study cohort and merely confirmed the frequency of already-established risk-carrying CNVs. As a result, CNVs with a very low frequency that might be relevant for SCZ susceptibility are lost for secondary analyses. In this study, we provide a concise collection of high-quality CNVs in a large German sample consisting of 1,637 patients with SCZ or schizoaffective disorder and 1,627 controls. All individuals were genotyped on Illumina's BeadChips and putative CNVs were identified using QuantiSNP and PennCNV. Only those CNVs that were detected by both programs and spanned ≥30 consecutive SNPs were included in the data collection and downstream analyses (2,366 CNVs, 0.73 CNVs per individual). The genome-wide analysis did not reveal a specific association between a previously unknown CNV and SCZ. However, the group of CNVs previously reported to be associated with SCZ was more frequent in our patients than in the controls. The publication of our dataset will serve as a unique, easily accessible, high-quality CNV data collection for other research groups. The dataset could be useful for the identification of new disease-relevant CNVs that are currently overlooked due to their very low frequency and lack of power for their detection in individual studies.
    PLoS ONE 07/2013; 8(7):e64035. DOI:10.1371/journal.pone.0064035 · 3.23 Impact Factor
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