174 research outputs found
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)
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Genome-wide association of copy number variants across six major psychiatric disorders reveals genotype-phenotype relationships of rare variants
No full textRare 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
No full textThe 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
No full textThree-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
Major changes in our DNA lead to major changes in our thinking
No full textVariability in the human genome has far exceeded expectations. In the course of the past three years, we have learned that much of our naturally occurring genetic variation consists of large-scale differences in genome structure, including copy-number variants (CNVs) and balanced rearrangements such as inversions. Recent studies have begun to reveal that structural variants are an important contributor to disease risk; however, structural variants as a class may not conform well to expectations of current methods for gene mapping. New approaches are needed to understand the contribution of structural variants to disease
Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects
No full textOligogenic Effects of 16p11.2 Copy-Number Variation on Craniofacial Development
No full textFull author list omitted for brevity. For the full list of authors, see article.A copy-number variant (CNV) of 16p11.2 encompassing 30 genes is associated with developmental and psychiatric disorders, head size, and body mass. The genetic mechanisms that underlie these associations are not understood. To determine the influence of 16p11.2 genes on development, we investigated the effects of CNV on craniofacial structure in humans and model organisms. We show that deletion and duplication of 16p11.2 have "mirror" effects on specific craniofacial features that are conserved between human and rodent models of the CNV. By testing dosage effects of individual genes on the shape of the mandible in zebrafish, we identify seven genes with significant effects individually and find evidence for others when genes were tested in combination. The craniofacial phenotypes of 16p11.2 CNVs represent a model for studying the effects of genes on development, and our results suggest that the associated facial gestalts are attributable to the combined effects of multiple genes
Église abbatiale Notre-Dame
No full textExterior, Nave, N aisle, Bay 4, Portal (identified from desc. in CongArch, 1908, p. 294, where author, ELP or Sebat I think, refuses to argue that a reprise took place
CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics
No full textThe genetic bases of neuropsychiatric disorders are beginning to yield to scientific inquiry. Genome-wide studies of copy number variation (CNV) have given rise to a new understanding of disease etiology, bringing rare variants to the forefront. A proportion of risk for schizophrenia, bipolar disorder, and autism can be explained by rare mutations. Such alleles arise by de novo mutation in the individual or in recent ancestry. Alleles can have specific effects on behavioral and neuroanatomical traits; however, expressivity is variable, particularly for neuropsychiatric phenotypes. Knowledge from CNV studies reflects the nature of rare alleles in general and will serve as a guide as we move forward into a new era of whole-genome sequencing
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