Accurately Assessing the Risk of Schizophrenia Conferred by Rare Copy-Number Variation Affecting Genes with Brain Function

University of Alabama at Birmingham, United States of America
PLoS Genetics (Impact Factor: 7.53). 09/2010; 6(9). DOI: 10.1371/journal.pgen.1001097
Source: PubMed


Investigators have linked rare copy number variation (CNVs) to neuropsychiatric diseases, such as schizophrenia. One hypothesis is that CNV events cause disease by affecting genes with specific brain functions. Under these circumstances, we expect that CNV events in cases should impact brain-function genes more frequently than those events in controls. Previous publications have applied "pathway" analyses to genes within neuropsychiatric case CNVs to show enrichment for brain-functions. While such analyses have been suggestive, they often have not rigorously compared the rates of CNVs impacting genes with brain function in cases to controls, and therefore do not address important confounders such as the large size of brain genes and overall differences in rates and sizes of CNVs. To demonstrate the potential impact of confounders, we genotyped rare CNV events in 2,415 unaffected controls with Affymetrix 6.0; we then applied standard pathway analyses using four sets of brain-function genes and observed an apparently highly significant enrichment for each set. The enrichment is simply driven by the large size of brain-function genes. Instead, we propose a case-control statistical test, cnv-enrichment-test, to compare the rate of CNVs impacting specific gene sets in cases versus controls. With simulations, we demonstrate that cnv-enrichment-test is robust to case-control differences in CNV size, CNV rate, and systematic differences in gene size. Finally, we apply cnv-enrichment-test to rare CNV events published by the International Schizophrenia Consortium (ISC). This approach reveals nominal evidence of case-association in neuronal-activity and the learning gene sets, but not the other two examined gene sets. The neuronal-activity genes have been associated in a separate set of schizophrenia cases and controls; however, testing in independent samples is necessary to definitively confirm this association. Our method is implemented in the PLINK software package.

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    • "CNVs that were concordant within MZ pairs were tested for association with AP (ADHD symptoms) and TP (schizoobsessive symptoms) using the gene-enrichment test in PLINK (Purcell et al., 2007, Raychaudhuri et al., 2010). The enrichment was tested for all genes, and gene-sets involved in generation of neurons (83 genes), neuron development (61 genes), neuronal differentiation (76 genes), and neuron apoptosis (17 genes). "
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    ABSTRACT: Monozygotic (MZ) twins are genetically identical at conception, making them informative subjects for studies on somatic mutations. Copy number variants (CNVs) are responsible for a substantial part of genetic variation, have relatively high mutation rates, and are likely to be involved in phenotypic variation. We conducted a genome-wide survey for post-twinning de novo CNVs in 1,097 MZ twin pairs. Comparisons between MZ twins were made by CNVs measured in DNA from blood or buccal epithelium with the Affymetrix 6.0 microarray and two calling algorithms. In addition, CNV concordance rates were compared between the different sources of DNA, and gene-enrichment association analyses were conducted for thought problems (TP) and attention problems (AP) using CNVs concordant within MZ pairs. We found a total of 153 putative post-twinning de novo CNVs >100 kb, of which the majority resided in 15q11.2. Based on the discordance of raw intensity signals a selection was made of 20 de novo CNVs for a qPCR validation experiments. Two out of 20 post-twinning de novo CNVs were validated with qPCR in the same twin pair. The 13-year-old MZ twin pair that showed two discordances in CN in 15q11.2 in their buccal DNA did not show large phenotypic differences. From the remaining 18 putative de novo CNVs, 17 were deletions or duplications that were concordant within MZ twin pairs. Concordance rates within twin pairs of CNV calls with CN � 2 were �80%. Buccal epithelium-derived DNA showed a slightly but significantly higher concordance rate, and blood-derived DNA showed significantly more concordant CNVs per twin pair. The gene-enrichment analyses on concordant CNVs showed no significant associations between CNVs overlapping with genes involved in neuronal processes and TP or AP after accounting for the source of DNA.
    Twin Research and Human Genetics 02/2015; 18(1):1-12. DOI:10.1017/thg.2014.86 · 2.30 Impact Factor
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    • "More recently, both communities have come to appreciate other sources of genetic variation. The role of copy number variation (CNV) in schizophrenia (Need et al., 2009; Stefansson et al., 2009; Raychaudhuri et al., 2010; Malhotra et al., 2011) and autism (Marshall et al., 2008; Bucan et al., 2009; Glessner et al., 2009; Pinto et al., 2010) has grown significantly and the fact that there is often significant overlap and balancing dosage effects between the two at the same CNV loci has been crucial to the development of the concept of a shared adaptive molecular etiology (Carroll and Owen, 2009; Crespi et al., 2010; Owen et al., 2011; Crespi and Crofts, 2012). Here, we focus on the molecular evolution of protein-coding genes associated with schizophrenia, autism, and other neuropsychiatric diseases compared across mammalian species and among disease classes, with a focus on the primate (chimpanzee, bonobo, gorilla, orangutan, gibbon, macaque, baboon, marmoset, and squirrel monkey) and human lineages. "
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    ABSTRACT: Many psychiatric diseases observed in humans have tenuous or absent analogs in other species. Most notable among these are schizophrenia and autism. One hypothesis has posited that these diseases have arisen as a consequence of human brain evolution, for example, that the same processes that led to advances in cognition, language, and executive function also resulted in novel diseases in humans when dysfunctional. Here, the molecular evolution of the protein-coding regions of genes associated with these and other psychiatric disorders are compared among species. Genes associated with psychiatric disorders are drawn from the literature and orthologous sequences are collected from eleven primate species (human, chimpanzee, bonobo, gorilla, orangutan, gibbon, macaque, baboon, marmoset, squirrel monkey, and galago) and 34 non-primate mammalian species. Evolutionary parameters, including dN/dS, are calculated for each gene and compared between disease classes and among species, focusing on humans and primates compared to other mammals, and on large-brained taxa (cetaceans, rhinoceros, walrus, bear, and elephant) compared to their small-brained sister species. Evidence of differential selection in humans to the exclusion of non-human primates was absent, however elevated dN/dS was detected in catarrhines as a whole, as well as in cetaceans, possibly as part of a more general trend. Although this may suggest that protein changes associated with schizophrenia and autism are not a cost of the higher brain function found in humans, it may also point to insufficiencies in the study of these diseases including incomplete or inaccurate gene association lists and/or a greater role of regulatory changes or copy number variation. Through this work a better understanding of the molecular evolution of the human brain, the pathophysiology of disease, and the genetic basis of human psychiatric disease is gained.
    Frontiers in Human Neuroscience 05/2014; 8:283. DOI:10.3389/fnhum.2014.00283 · 3.63 Impact Factor
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    • "First, the power of enrichment analyses based on CNVs is limited by their large size, which in many cases encompasses a large number of genes. Furthermore, in such analyses gene size may also be an important confounding factor, especially when dealing with disorders of the brain (Raychaudhuri et al., 2010). Another approach was to study genes with single base mutations; including mutations that lead to ASD associated genetic syndromes (Sakai et al., 2011; Ben-David and Shifman, 2012). "
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    ABSTRACT: Though extensively characterized clinically, the causes of autism spectrum disorder (ASD) remain a mystery. ASD is known to have a strong genetic basis, but it is genetically very heterogeneous. Recent studies have estimated that de novo disruptive mutations in hundreds of genes may contribute to ASD. However, it is unclear how it is possible for mutations in so many different genes to contribute to ASD. Recent findings suggest that many of the mutations disrupt genes involved in transcription regulation that are expressed prenatally in the developing brain. De novo disruptive mutations are also more frequent in girls with ASD, despite the fact that ASD is more prevalent in boys. In this paper, we hypothesize that loss of robustness may contribute to ASD. Loss of phenotypic robustness may be caused by mutations that disrupt capacitors that operate in the developing brain. This may lead to the release of cryptic genetic variation that contributes to ASD. Reduced robustness is consistent with the observed variability in expressivity and incomplete penetrance. It is also consistent with the hypothesis that the development of the female brain is more robust, and it may explain the higher rate and severity of disruptive de novo mutations in girls with ASD.
    Frontiers in Genetics 04/2014; 5:81. DOI:10.3389/fgene.2014.00081
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