Previously, Knight and colleagues reported a patient with schizophrenia (SCZ) who carried the complex chromosomal rearrangement inv(7)(p12.3;q21.11), t(7;8)(p12.3;p23). The translocation between chromosomes 7 and 8 resulted in a disruption of ABCA13, suggesting a possible role for this gene in the etiology of SCZ. This gene is member 13 of the ATP-binding cassette transporter subfamily A. Protein expression analyses in the adult mouse showed Abca13 expression in the brain (Knight et al., 2009).
Subsequent resequencing of functional domain exons identified rare variants that were associated with both SCZ and bipolar disorder (BPD; Knight et al., 2009). Furthermore, the same research group screened an SCZ and BPD sample for the presence of small copy number variants (CNVs) in this gene. Multiplex amplicon quantification assays were performed on DNA samples from 1004 patients with SCZ, on 428 patients with BPD, and on 1086 controls, and no over-representation of CNVs among patients compared with controls was identified (Pickard et al., 2012).
We sought to elucidate further the potential role of CNVs in ABCA13 and analyzed three clinically well-characterized data sets for the occurrence of CNVs in ABCA13: (i) 575 patients with major depressive disorder (MDD; Degenhardt et al., 2012), (ii) 882 patients with BPD (Priebe et al., 2012), and (iii) 1637 patients with SCZ or schizoaffective disorder. Of them, 487 patients with SCZ have previously been included in a GWA study by Rietschel et al. (2011). In addition, 1618 controls (described in detail in Degenhardt et al., 2012) were screened for the presence of CNVs in ABCA13. All participants were of German descent according to self-reported ancestry, and each participant provided written informed consent before inclusion.
All individuals were genotyped on HumanHap550v3, Human610-Quadv1, and Human660W-Quad arrays (Illumina, San Diego, California, USA). Detailed information on CNV detection and CNV quality control is provided elsewhere (Degenhardt et al., 2012). Only those markers common to all three chips were analyzed. Participants were excluded if their SD from the log R ratio calculated over all SNPs exceeded 0.30.
The three data sets were analyzed for the presence of both microdeletions and microduplications including the ABCA13 gene plus 10 kb upstream and downstream of the Refseq gene boundary (chr7: 48208389–48657637; hg18). All CNVs were required to span a minimum of 10 consecutive SNPs and have a log Bayes Factor (QuantiSNP) or confidence value (PennCNV) of at least 10.
No CNV including ABCA13 was identified in our three patient samples, nor in the controls. Hence, we did not find any evidence for CNVs in ABCA13 as a risk factor for the development of SCZ, BPD, or MDD. It cannot be excluded, however, that extremely rare CNVs might play a role in disease development, which would only be detectable in considerably larger samples. It is therefore important to gather data from several large studies before final conclusions regarding the involvement of CNVs in ABCA13 in SCZ, BPD, or MDD can be drawn.
The authors thank all the patients for participating in this study. They are grateful to Professor H.E. Wichmann for supplying the SNP-chip data from the KORA control cohort and to Professor S. Schreiber for providing access to the SNP-chip data from the PopGen control cohort. They acknowledge the support of Christine Esslinger, Claudia Schütz, Nina Seiferth, Sebastian Mohnke, and Leila Haddad in the recruitment of the MooDS controls. They thank all the probands from the Heinz Nixdorf Recall (HNR) study, and the MooDS Imaging controls.
This study was supported by the German Federal Ministry of Education and Research (BMBF), within the context of: the National Genome Research Network 2 (NGFN-2); the National Genome Research Network plus (NGFNplus); and the Integrated Genome Research Network (IG) MooDS (Grant 01GS08144 to S.C. and M.M.N., Grant 01GS08147 to M.R.). In addition, this work was supported by the European Union grant number HEALTH-F4-2009-242257 (Project ADAMS). J.S. was supported by the German Research Foundation (GRK 793). M.M.N. also received support from the Alfried Krupp von Bohlen und Halbach-Stiftung. The HNR cohort was established with the support of the Heinz Nixdorf Foundation. I.N. was supported by a Junior Scientist grant of the Interdiziplinäres Zentrum für Klinische Forschung Jena (IZKF).
Conflicts of interest
There are no conflicts of interest.
Degenhardt F, Priebe L, Herms S, Mattheisen M, Mühleisen TW, Meier S, et al. Association between copy number variants in 16p11.2 and major depressive disorder in a German case–control sample. Am J Med Genet B Neuropsychiatr Genet. 2012;159B:263–273
Knight HM, Pickard BS, Maclean A, Malloy MP, Soares DC, Mcrae AF, et al. A cytogenetic abnormality and rare coding variants identify ABCA13 as a candidate gene in schizophrenia, bipolar disorder, and depression. Am J Hum Genet. 2009;85:833–846
Pickard BS, Van Den Bossche MJ, Malloy MP, Johnstone M, Lenaerts AS, Nordin A, et al. Multiplex amplicon quantification screening the ABCA13 gene for copy number variation in schizophrenia and bipolar disorder. Psychiatr Genet. 2012 [Epub ahead of print]
Priebe L, Degenhardt FA, Herms S, Haenisch B, Mattheisen M, Nieratschker V, et al. Genome-wide survey implicates the influence of copy number variants (CNVs) in the development of early-onset bipolar disorder. Mol Psychiatry. 2012;17:421–432
Rietschel M, Mattheisen M, Degenhardt F, Kahn RS, Linszen DH, Os JV, et al. Association between genetic variation in a region on chromosome 11 and schizophrenia in large samples from Europe. Mol Psychiatry. 2011 [Epub ahead of print]