RESEARCH ARTICLE Neuropsychiatric Genetics
Clinical and Parental Age Characteristics of Rare Copy Number Variant Burden in Patients with Schizophrenia Andrew K. Martin,1* Gail Robinson,2 David Reutens,3 and Bryan Mowry4 1
University of Queensland, Queensland Brain Institute, Queensland, Australia
2
University of Queensland, School of Psychology, Queensland, Australia University of Queensland, Centre for Advanced Imaging, Queensland, Australia
3 4
University of Queensland, Queensland Brain Institute, Queensland Centre for Mental Health Research, Queensland, Australia
Manuscript Received: 15 October 2014; Manuscript Accepted: 15 April 2015
Copy number variant (CNV) burden, especially for rare deletions, has been associated with risk for schizophrenia as well as phenotypic differences within cognitive and neuroimaging domains. The current study investigated clinical and parental age characteristics of rare CNV burden in patients with schizophrenia. Clinical data was collected for 629 patients with schizophrenia who formed part of a genomewide association study, which included CNV data. Parental age was available for 368 patients. Correlations were calculated between burden scores and positive, negative, and mood symptoms from the Lifetime Diagnostic Psychosis Scale as well as age at onset. Patients were grouped according to number of rare deletions, duplications, or total CNVs and MANOVAs used to investigate differences in clinical and parental age characteristics. Patients with the least number of CNVs had older fathers and larger parental age difference. Patients with no deletions had older mothers and those with five or more deletions had younger mothers. Total deletion, duplication, and CNV burden, as measured by number of base pairs, were not associated with clinical or parental age differences although total rare duplication burden had a negative correlation with positive symptoms that did not survive correction for multiple testing. Likewise, a positive correlation between age at onset and total CNV burden did not survive correction. Rare CNVs are associated with differences in parental age in patients with schizophrenia. No robust clinical differences were identified. However, duplication burden may have a small protective effect against positive symptoms and age at onset may be influenced by total CNV burden. No clinical differences were associated with deletion burden measures.
How to Cite this Article: Martin AK, Robinson G, Reutens D, Mowry B. 2015. Clinical and parental age characteristics of rare copy number variant burden in patients with schizophrenia. Am J Med Genet Part B 168B:374–382.
Ó 2015 Wiley Periodicals, Inc.
thought and behaviour, apathy, and inactivity. Heritability estimates are as high as 80% [Cardno and Gottesman, 2000] and several large studies have started to uncover the complex genetic architecture involved in schizophrenia risk (see [Mowry and Gratten, 2013] for review). One such genetic variant to emerge is the copy number variant (CNV). CNVs are alterations of genomic DNA resulting in either a deletion (fewer than the normal number of copies), or duplication (more than the normal number of copies). CNVs can be inherited or occur de novo and are responsible for significant genomic differences between individuals [Kidd et al., 2008]. They have been implicated in several neurodevelopmental disorders such as autism, intellectual disability, and schizophrenia [International Schizophrenia Consortium, 2008; Guilmatre et al., 2009; Sebat, Levy, & McCarthy, 2009; Szatkiewicz et al., 2014]. To date, at least 12 individual CNVs have shown robust association with schizophrenia risk [Rees et al., 2014] with the strongest association (Odds Ratio18) identified for deletions at the 22q11.2 locus, with carriers developing schizophrenia in approximately 30% of cases. In addition to specific CNVs, general CNV measures such as large (>500kb), rare (
Clinical and Parental Age Characteristics of Rare Copy Number Variant Burden in Patients with Schizophrenia Andrew K. Martin,1* Gail Robinson,2 David Reutens,3 and Bryan Mowry4 1
University of Queensland, Queensland Brain Institute, Queensland, Australia
2
University of Queensland, School of Psychology, Queensland, Australia University of Queensland, Centre for Advanced Imaging, Queensland, Australia
3 4
University of Queensland, Queensland Brain Institute, Queensland Centre for Mental Health Research, Queensland, Australia
Manuscript Received: 15 October 2014; Manuscript Accepted: 15 April 2015
Copy number variant (CNV) burden, especially for rare deletions, has been associated with risk for schizophrenia as well as phenotypic differences within cognitive and neuroimaging domains. The current study investigated clinical and parental age characteristics of rare CNV burden in patients with schizophrenia. Clinical data was collected for 629 patients with schizophrenia who formed part of a genomewide association study, which included CNV data. Parental age was available for 368 patients. Correlations were calculated between burden scores and positive, negative, and mood symptoms from the Lifetime Diagnostic Psychosis Scale as well as age at onset. Patients were grouped according to number of rare deletions, duplications, or total CNVs and MANOVAs used to investigate differences in clinical and parental age characteristics. Patients with the least number of CNVs had older fathers and larger parental age difference. Patients with no deletions had older mothers and those with five or more deletions had younger mothers. Total deletion, duplication, and CNV burden, as measured by number of base pairs, were not associated with clinical or parental age differences although total rare duplication burden had a negative correlation with positive symptoms that did not survive correction for multiple testing. Likewise, a positive correlation between age at onset and total CNV burden did not survive correction. Rare CNVs are associated with differences in parental age in patients with schizophrenia. No robust clinical differences were identified. However, duplication burden may have a small protective effect against positive symptoms and age at onset may be influenced by total CNV burden. No clinical differences were associated with deletion burden measures.
How to Cite this Article: Martin AK, Robinson G, Reutens D, Mowry B. 2015. Clinical and parental age characteristics of rare copy number variant burden in patients with schizophrenia. Am J Med Genet Part B 168B:374–382.
Ó 2015 Wiley Periodicals, Inc.
thought and behaviour, apathy, and inactivity. Heritability estimates are as high as 80% [Cardno and Gottesman, 2000] and several large studies have started to uncover the complex genetic architecture involved in schizophrenia risk (see [Mowry and Gratten, 2013] for review). One such genetic variant to emerge is the copy number variant (CNV). CNVs are alterations of genomic DNA resulting in either a deletion (fewer than the normal number of copies), or duplication (more than the normal number of copies). CNVs can be inherited or occur de novo and are responsible for significant genomic differences between individuals [Kidd et al., 2008]. They have been implicated in several neurodevelopmental disorders such as autism, intellectual disability, and schizophrenia [International Schizophrenia Consortium, 2008; Guilmatre et al., 2009; Sebat, Levy, & McCarthy, 2009; Szatkiewicz et al., 2014]. To date, at least 12 individual CNVs have shown robust association with schizophrenia risk [Rees et al., 2014] with the strongest association (Odds Ratio18) identified for deletions at the 22q11.2 locus, with carriers developing schizophrenia in approximately 30% of cases. In addition to specific CNVs, general CNV measures such as large (>500kb), rare (
