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Genome-wide association of copy number variants across six major psychiatric disorders reveals genotype-phenotype relationships of rare variants
Get PDFRare copy number variants (CNVs) have been strongly implicated in autism (ASD) and schizophrenia (SCZ), but well-powered genome-wide studies of rare variants have not been carried out across multiple major psychiatric disorders. Here we perform a genome-wide association of CNVs across schizophrenia (SCZ), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), post-traumatic stress disorder (PTSD), attention-deficit/hyperactivity disorder (ADHD) and in the combined cross-disorder cohort (XD) (N=537,466).CNV calling was performed using a consistent ensemble pipeline that enables the combining of datasets and disorders. CNV burden and CNV-GWAS were used to characterize genetic associations genome-wide. Associations were tested for deletion (DEL) and duplication (DUP) separately, controlling for ancestry, genotyping platform, and cohort.CNV burden analysis revealed that rare CNVs contribute to all 6 disorders but with effects that differ by disorder. Genome-wide association analyses of CNV across disorders found 36 significant associations at 21 independent loci. For all disorders, alleles span the full range of frequencies, but disorders differ in their distribution of effect sizes. Effects were strongest for ASD and were invariably positive. Rare variants in SCZ, BD, and MDD were a mixture of positive and negative effects. Effect sizes in MDD were comparatively weak. Many CNVs were associated with multiple disorders but not to the same extent. Some were predominantly associated with ASD (15q11-13 Dup), some were most strongly associated with SCZ (16p11Dup, 22q11Del), and other CNVs were weakly associated with several disorders but reached genome-wide significance only in the combined XD cohort (ASTN2, DLG2). Without exception, all associations occurred in genomic regions that are prone to high rates of structural mutation. 15 were hot spots for non-allelic homologous recombination (NAHR) and 6 were in common fragile sites (CFS) where chromosome breakage occurs within large neural genes (ASTN2, DLG2, DLGAP2/CSMD1, IMMP2L, NRXN1, SHANK3). Several large neural genes also intersect with topologically associating domain (TAD) boundaries, but associations were driven by protein coding deletions, and were not attributable to non-coding variants. An enrichment of CNV associations near TAD boundaries in this case may not be attributable to cis-regulatory effects of rare variants, but instead attributable to the intrinsic genomic instability of these regions that gives rise to deletions.Genome-wide analysis of rare CNVs across major psychiatric disorders identifies many risk loci including both positive and negative associations and novel gene associations. A comparative analysis highlights considerable genetic overlap between disorders but also distinguishable differences in allelic architecture and considerable phenotypic specificity to CNV associations
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Disparity between Maternal and Paternal Contributions to Inherited Risk for Autism
Get PDFThe genetic basis of autism is known to consist of de novo and inherited loss of function mutations in haploinsufficient genes. It is thought that inherited risk primarily derives from mothers, believed to be due to an increased tolerance for risk alleles. However, the distinct contributions of each parent to inherited risk for autism has not been explored in depth. We investigated paternal and maternal contributions to autism by analyzing the transmission of private deletions in coding and cis-regulatory (CRE-SVs) regions of functionally constrained genes in whole genomes of 10,015 individuals (2650 families). We then extended our transmission distortion analysis to encompass of loss of function single nucleotide variants (SNVs) and insertion/deletion (INDELs), as well as private potentially pathogenic missense mutations. Our goal is to untangle distinct modes of inheritance for autism risk, hypothesizing that fathers and mothers carry distinct risk contributions. We report that mothers and fathers over-transmit loss of function variants within functionally constrained coding regions. However, fathers but not mothers tended to over-transmit damaging CRE-SVs and missense variants to affected offspring. When we test the segregation of loss of function variants stratified by sex of the offspring, we find that most of the genetic risk to sons is derived from the father, which is not consistent with the previous female protective effect model. Our work demonstrates that inherited damaging variants comprise a significant component of missing heritability for autism with fathers contributing a substantial amount of risk
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The Effects of Structural Variation on 3D Chromatin Structure
Get PDFThree-dimensional spatial organization of chromosomes is defined by highly self-interacting regions 0.1-1 Mb in size termed Topological Associating Domains (TADs). Genetic factors that explain dynamic variation in TAD structure are not understood. We hypothesize that common structural variation (SV) in the human population; including deletions, insertions and inversions of >50 bp; can disrupt regulatory sequences and thereby influence TAD formation. To determine the effects of SVs on 3D chromatin organization, we performed chromosome conformation capture sequencing (Hi-C) of lymphoblastoid cell lines from 19 subjects for which SVs had been previously characterized in the 1000 genomes project. Large (>10kb) deletions had significant effects on long-range chromatin interactions. Deletions overall were associated with increased contacts that span the deleted region but had a modest effect on contacts in adjacent regions. Deletions at TAD boundaries were associated with diminished contacts in the adjacent domains, consistent with the structure of TADs being dependent on regulatory sequences at their boundaries. Large inversions in the population had a common signature characterized by a rearrangement of contacts that span its breakpoints. Our results suggest that common SVs in the population impact long range chromatin structure
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
The Effect of chr16p11.2 Microdeletions and Microduplications on Gene Expression in Autism Spectrum Disorders and Schizophrenia.
No full textThe number of rare variants found to be associated with multiple psychiatric disorders is growing. One such locus is a recurrent ~600kb copy number variant (CNV) at 16p11.2, occurring in approximately 1% of autism and 0.3% of schizophrenia cases, as compared to 0.01% of the general population. (Sebat 2007, Kumar 2007, Weiss 2008, McCarthy 2009). This mutation has been found at a higher frequency in autistics and schizophrenics, but is also found in patients with developmental delay without an autistic diagnosis, and is also rarely seen in healthy individuals. Head circumference is observed to be smaller in deletion cases versus duplication cases. (McCarthy 2009) We hypothesize that one or more of the 25 genes at this locus contribute to the neurodevelopmental phenotype observed in patients with psychiatric disorders. To determine how gene function is altered by this CNV, we analyzed genome wide expression data from Epstein Barr Virus (EBV) transformed Lymphoblast cell lines (LCL), of patients with autism or schizophrenia who have deletions of reciprocal duplications of 16p11.2. Using RNA expression profiling by Affymetrix Human Genome U133 Plus 2.0 chip, we examined differential dosage and trans gene expression in individuals with 1, 2, or 3 copies of the genomic region. (6, 19, 16 respectively) To avoid skewing of data due to limited sample size we customized the Significance Analysis of Microarrays (SAM) method to utilize all samples while accounting for sources of bias. Our data highlighted 7 genes located both within and outside of the mutation which expression correlates with genotype. Some of these genes play a role in development while others have been associated with psychiatric disorders. We have analyzed our list of 7 dysregulated genes to identify pathways and functions relevant to neurodevelopment, and psychiatric disorders. Data generated by this study will give insight into dosage sensitive genes within the risk variant, and may help pinpoint genes which are relevant to pathology of the psychiatric disorders associated with this region.Advisor(s): Jonathan Sebat. Committee Member(s): Marian Evinger; Turhan Canli; Lilia Iakoucheva; Joshua Dubnau.Stony Brook University Libraries. SBU Graduate School in Department of Genetics. Lawrence Martin (Dean of Graduate School)
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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