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Saurav Guha,
Elliott Rees,
Ariel Darvasi,
Dobril Ivanov,
Masashi Ikeda,
Sarah E Bergen,
Patrik K Magnusson,
Paul Cormican,
Derek Morris,
Michael Gill, [......],
Christina M Hultman,
Patrick F Sullivan, Jonathan Sebat,
Shane McCarthy,
Pablo V Gejman,
Douglas F Levinson,
Michael J Owen,
Michael C O'Donovan,
Todd Lencz,
George Kirov
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ABSTRACT: CONTEXT Large genomic copy number variations have been implicated as strong risk factors for schizophrenia. However, the rarity of these events has created challenges for the identification of further pathogenic loci, and extremely large samples are required to provide convincing replication. OBJECTIVE To detect novel copy number variations that increase the susceptibility to schizophrenia by using 2 ethnically homogeneous discovery cohorts and replication in large samples. DESIGN Genetic association study of microarray data. SETTING Samples of DNA were collected at 9 sites from different countries. PARTICIPANTS Two discovery cohorts consisted of 790 cases with schizophrenia and schizoaffective disorder and 1347 controls of Ashkenazi Jewish descent and 662 parent-offspring trios from Bulgaria, of which the offspring had schizophrenia or schizoaffective disorder. Replication data sets consisted of 12 398 cases and 17 945 controls. MAIN OUTCOME MEASURES Statistically increased rate of specific copy number variations in cases vs controls. RESULTS One novel locus was implicated: a deletion at distal 16p11.2, which does not overlap the proximal 16p11.2 locus previously reported in schizophrenia and autism. Deletions at this locus were found in 13 of 13 850 cases (0.094%) and 3 of 19 954 controls (0.015%) (odds ratio, 6.25 [95% CI, 1.78-21.93]; P = .001, Fisher exact test). CONCLUSIONS Deletions at distal 16p11.2 have been previously implicated in developmental delay and obesity. The region contains 9 genes, several of which are implicated in neurological diseases, regulation of body weight, and glucose homeostasis. A telomeric extension of the deletion, observed in about half the cases but no controls, potentially implicates an additional 8 genes. Our findings add a new locus to the list of copy number variations that increase the risk for development of schizophrenia.
JAMA psychiatry (Chicago, Ill.). 01/2013;
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Jacob J Michaelson,
Yujian Shi,
Madhusudan Gujral,
Hancheng Zheng,
Dheeraj Malhotra,
Xin Jin,
Minghan Jian,
Guangming Liu,
Douglas Greer,
Abhishek Bhandari, [......],
Therese Gadomski,
Balvindar Singh,
Kun Zhang,
Natacha Akshoomoff,
Christina Corsello,
Steven McCarroll,
Lilia M Iakoucheva,
Yingrui Li,
Jun Wang, Jonathan Sebat
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ABSTRACT: De novo mutation plays an important role in autism spectrum disorders (ASDs). Notably, pathogenic copy number variants (CNVs) are characterized by high mutation rates. We hypothesize that hypermutability is a property of ASD genes and may also include nucleotide-substitution hot spots. We investigated global patterns of germline mutation by whole-genome sequencing of monozygotic twins concordant for ASD and their parents. Mutation rates varied widely throughout the genome (by 100-fold) and could be explained by intrinsic characteristics of DNA sequence and chromatin structure. Dense clusters of mutations within individual genomes were attributable to compound mutation or gene conversion. Hypermutability was a characteristic of genes involved in ASD and other diseases. In addition, genes impacted by mutations in this study were associated with ASD in independent exome-sequencing data sets. Our findings suggest that regional hypermutation is a significant factor shaping patterns of genetic variation and disease risk in humans. PAPERFLICK:
Cell 12/2012; 151(7):1431-42. · 32.40 Impact Factor
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ABSTRACT: Human genetic variation is distributed nonrandomly across the genome, though the principles governing its distribution are only partially known. DNA replication creates opportunities for mutation, and the timing of DNA replication correlates with the density of SNPs across the human genome. To enable deeper investigation of how DNA replication timing relates to human mutation and variation, we generated a high-resolution map of the human genome's replication timing program and analyzed its relationship to point mutations, copy number variations, and the meiotic recombination hotspots utilized by males and females. DNA replication timing associated with point mutations far more strongly than predicted from earlier analyses and showed a stronger relationship to transversion than transition mutations. Structural mutations arising from recombination-based mechanisms and recombination hotspots used more extensively by females were enriched in early-replicating parts of the genome, though these relationships appeared to relate more strongly to the genomic distribution of causative sequence features. These results indicate differential and sex-specific relationship of DNA replication timing to different forms of mutation and recombination.
The American Journal of Human Genetics 11/2012; · 10.60 Impact Factor
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ABSTRACT: Detecting genomic structural variants from high-throughput sequencing data is a complex and unresolved challenge. We have developed a statistical learning approach, based on Random Forests, that integrates prior knowledge about the characteristics of structural variants and leads to improved discovery in high-throughput sequencing data. The implementation of this technique, forestSV, offers high sensitivity and specificity coupled with the flexibility of a data-driven approach.
Nature Methods 07/2012; 9(8):819-21. · 19.28 Impact Factor
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ABSTRACT: The 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.
Cell 03/2012; 148(6):1223-41. · 32.40 Impact Factor
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Nature 01/2012; 485(7398):318-9. · 36.28 Impact Factor
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Dheeraj Malhotra,
Shane McCarthy,
Jacob J Michaelson,
Vladimir Vacic,
Katherine E Burdick,
Seungtai Yoon,
Sven Cichon,
Aiden Corvin,
Sydney Gary,
Elliot S Gershon, [......],
Deborah L Levy,
Vladimir Makarov,
Abhishek Bhandari,
Anil K Malhotra,
Francis J McMahon,
Markus M Nöthen,
James B Potash,
Marcella Rietschel,
Thomas G Schulze, Jonathan Sebat
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ABSTRACT: While it is known that rare copy-number variants (CNVs) contribute to risk for some neuropsychiatric disorders, the role of CNVs in bipolar disorder is unclear. Here, we reasoned that a contribution of CNVs to mood disorders might be most evident for de novo mutations. We performed a genome-wide analysis of de novo CNVs in a cohort of 788 trios. Diagnoses of offspring included bipolar disorder (n = 185), schizophrenia (n = 177), and healthy controls (n = 426). Frequencies of de novo CNVs were significantly higher in bipolar disorder as compared with controls (OR = 4.8 [1.4,16.0], p = 0.009). De novo CNVs were particularly enriched among cases with an age at onset younger than 18 (OR = 6.3 [1.7,22.6], p = 0.006). We also confirmed a significant enrichment of de novo CNVs in schizophrenia (OR = 5.0 [1.5,16.8], p = 0.007). Our results suggest that rare spontaneous mutations are an important contributor to risk for bipolar disorder and other major neuropsychiatric diseases.
Neuron 12/2011; 72(6):951-63. · 14.74 Impact Factor
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Kristen J Brennand,
Anthony Simone,
Jessica Jou,
Chelsea Gelboin-Burkhart,
Ngoc Tran,
Sarah Sangar,
Yan Li,
Yangling Mu,
Gong Chen,
Diana Yu,
Shane McCarthy, Jonathan Sebat,
Fred H Gage
Nature 10/2011; · 36.28 Impact Factor
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ABSTRACT: Accurate information on haplotypes and diplotypes (haplotype pairs) is required for population-genetic analyses; however, microarrays do not provide data on a haplotype or diplotype at a copy number variation (CNV) locus; they only provide data on the total number of copies over a diplotype or an unphased sequence genotype (e.g., AAB, unlike AB of single nucleotide polymorphism). Moreover, such copy numbers or genotypes are often incorrectly determined when microarray signal intensities derived from different copy numbers or genotypes are not clearly separated due to noise. Here we report an algorithm to infer CNV haplotypes and individuals' diplotypes at multiple loci from noisy microarray data, utilizing the probability that a signal intensity may be derived from different underlying copy numbers or genotypes. Performing simulation studies based on known diplotypes and an error model obtained from real microarray data, we demonstrate that this probabilistic approach succeeds in accurate inference (error rate: 1-2%) from noisy data, whereas previous deterministic approaches failed (error rate: 12-18%). Applying this algorithm to real microarray data, we estimated haplotype frequencies and diplotypes in 1486 CNV regions for 100 individuals. Our algorithm will facilitate accurate population-genetic analyses and powerful disease association studies of CNVs.
G3 (Bethesda, Md.). 06/2011; 1(1):35-42.
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Kristen J Brennand,
Anthony Simone,
Jessica Jou,
Chelsea Gelboin-Burkhart,
Ngoc Tran,
Sarah Sangar,
Yan Li,
Yangling Mu,
Gong Chen,
Diana Yu,
Shane McCarthy, Jonathan Sebat,
Fred H Gage
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ABSTRACT: Schizophrenia (SCZD) is a debilitating neurological disorder with a world-wide prevalence of 1%; there is a strong genetic component, with an estimated heritability of 80-85%. Although post-mortem studies have revealed reduced brain volume, cell size, spine density and abnormal neural distribution in the prefrontal cortex and hippocampus of SCZD brain tissue and neuropharmacological studies have implicated dopaminergic, glutamatergic and GABAergic activity in SCZD, the cell types affected in SCZD and the molecular mechanisms underlying the disease state remain unclear. To elucidate the cellular and molecular defects of SCZD, we directly reprogrammed fibroblasts from SCZD patients into human induced pluripotent stem cells (hiPSCs) and subsequently differentiated these disorder-specific hiPSCs into neurons (Supplementary Fig. 1). SCZD hiPSC neurons showed diminished neuronal connectivity in conjunction with decreased neurite number, PSD95-protein levels and glutamate receptor expression. Gene expression profiles of SCZD hiPSC neurons identified altered expression of many components of the cyclic AMP and WNT signalling pathways. Key cellular and molecular elements of the SCZD phenotype were ameliorated following treatment of SCZD hiPSC neurons with the antipsychotic loxapine. To date, hiPSC neuronal pathology has only been demonstrated in diseases characterized by both the loss of function of a single gene product and rapid disease progression in early childhood. We now report hiPSC neuronal phenotypes and gene expression changes associated with SCZD, a complex genetic psychiatric disorder.
Nature 05/2011; 473(7346):221-5. · 36.28 Impact Factor
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Alex S Nord,
Wendy Roeb,
Diane E Dickel,
Tom Walsh,
Mary Kusenda,
Kristen Lewis O'Connor,
Dheeraj Malhotra,
Shane E McCarthy,
Sunday M Stray,
Susan M Taylor, Jonathan Sebat,
Bryan King,
Mary-Claire King,
Jon M McClellan
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ABSTRACT: Individuals with autism are more likely to carry rare inherited and de novo copy number variants (CNVs). However, further research is needed to establish which CNVs are causal and the mechanisms by which these CNVs influence autism. We examined genomic DNA of children with autism (N = 41) and healthy controls (N = 367) for rare CNVs using a high-resolution array comparative genomic hybridization platform. We show that individuals with autism are more likely to harbor rare CNVs as small as ∼ 10 kb, a threshold not previously detectable, and that CNVs in cases disproportionately affect genes involved in transcription, nervous system development, and receptor activity. We also show that a subset of genes that have known or suspected allele-specific or imprinting effects and are within rare-case CNVs may undergo loss of transcript expression. In particular, expression of CNTNAP2 and ZNF214 are decreased in probands compared with their unaffected transmitting parents. Furthermore, expression of PRODH and ARID1B, two genes affected by de novo CNVs, are decreased in probands compared with controls. These results suggest that for some genes affected by CNVs in autism, reduced transcript expression may be a mechanism of pathogenesis during neurodevelopment.
European journal of human genetics: EJHG 03/2011; 19(6):727-31. · 3.56 Impact Factor
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Ryan E Mills,
Klaudia Walter,
Chip Stewart,
Robert E Handsaker,
Ken Chen,
Can Alkan,
Alexej Abyzov,
Seungtai Chris Yoon,
Kai Ye,
R Keira Cheetham, [......], Jonathan Sebat,
Michael Snyder,
Jun Wang,
Kenny Ye,
Evan E Eichler,
Mark B Gerstein,
Matthew E Hurles,
Charles Lee,
Steven A McCarroll,
Jan O Korbel
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ABSTRACT: Genomic structural variants (SVs) are abundant in humans, differing from other forms of variation in extent, origin and functional impact. Despite progress in SV characterization, the nucleotide resolution architecture of most SVs remains unknown. We constructed a map of unbalanced SVs (that is, copy number variants) based on whole genome DNA sequencing data from 185 human genomes, integrating evidence from complementary SV discovery approaches with extensive experimental validations. Our map encompassed 22,025 deletions and 6,000 additional SVs, including insertions and tandem duplications. Most SVs (53%) were mapped to nucleotide resolution, which facilitated analysing their origin and functional impact. We examined numerous whole and partial gene deletions with a genotyping approach and observed a depletion of gene disruptions amongst high frequency deletions. Furthermore, we observed differences in the size spectra of SVs originating from distinct formation mechanisms, and constructed a map of SV hotspots formed by common mechanisms. Our analytical framework and SV map serves as a resource for sequencing-based association studies.
Nature 02/2011; 470(7332):59-65. · 36.28 Impact Factor
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Vladimir Vacic,
Shane McCarthy,
Dheeraj Malhotra,
Fiona Murray,
Hsun-Hua Chou,
Aine Peoples,
Vladimir Makarov,
Seungtai Yoon,
Abhishek Bhandari,
Roser Corominas, [......],
Derek W Morris,
Michael Gill,
Aiden Corvin,
Paul A Insel,
Jon McClellan,
Mary-Claire King,
Maria Karayiorgou,
Deborah L Levy,
Lynn E DeLisi, Jonathan Sebat
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ABSTRACT: Rare copy number variants (CNVs) have a prominent role in the aetiology of schizophrenia and other neuropsychiatric disorders. Substantial risk for schizophrenia is conferred by large (>500-kilobase) CNVs at several loci, including microdeletions at 1q21.1 (ref. 2), 3q29 (ref. 3), 15q13.3 (ref. 2) and 22q11.2 (ref. 4) and microduplication at 16p11.2 (ref. 5). However, these CNVs collectively account for a small fraction (2-4%) of cases, and the relevant genes and neurobiological mechanisms are not well understood. Here we performed a large two-stage genome-wide scan of rare CNVs and report the significant association of copy number gains at chromosome 7q36.3 with schizophrenia. Microduplications with variable breakpoints occurred within a 362-kilobase region and were detected in 29 of 8,290 (0.35%) patients versus 2 of 7,431 (0.03%) controls in the combined sample. All duplications overlapped or were located within 89 kilobases upstream of the vasoactive intestinal peptide receptor gene VIPR2. VIPR2 transcription and cyclic-AMP signalling were significantly increased in cultured lymphocytes from patients with microduplications of 7q36.3. These findings implicate altered vasoactive intestinal peptide signalling in the pathogenesis of schizophrenia and indicate the VPAC2 receptor as a potential target for the development of new antipsychotic drugs.
Nature 02/2011; 471(7339):499-503. · 36.28 Impact Factor
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ABSTRACT: The reduced expression of the Sp4 gene in Sp4 hypomorphic mice resulted in subtle vacuolization in the hippocampus as well as deficits in sensorimotor gating and contextual memory, putative endophenotypes for schizophrenia and other psychiatric disorders. In this study, we examined both spatial learning/memory and hippocampal long-term potentiation (LTP) of Sp4 hypomorphic mice. Impaired spatial learning/memory and markedly reduced LTP were found. To corroborate the functional studies, the expression of N-methyl-D-aspartate (NMDA) glutamate receptors was investigated with both western blot and immunohistochemical analyses. The reduced expression of the Sp4 gene decreased the level of the NR1 subunit of NMDA receptors in Sp4 hypomorphic mice. In human, SP4 gene was found to be deleted sporadically in schizophrenia patients, corroborating evidence that polymorphisms of human SP4 gene are associated with schizophrenia and other psychiatric disorders. Impaired NMDA neurotransmission has been implicated in several human psychiatric disorders. As yet, it remains unclear how mutations of candidate susceptibility genes for these disorders may contribute to the disruption of NMDA neurotransmission. Sp4 hypomorphic mice could therefore serve as a genetic model to investigate impaired NMDA functions resulting from loss-of-function mutations of human SP4 gene in schizophrenia and/or other psychiatric disorders. Furthermore, aberrant expression of additional genes, besides NMDAR1, likely also contributes to the behavioral abnormalities in Sp4 hypomorphic mice. Thus, further investigation of the Sp4 pathway may provide novel insights in our understanding of a variety of neuropsychiatric disorders.
Human Molecular Genetics 10/2010; 19(19):3797-805. · 7.64 Impact Factor
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Tom Walsh,
Sarah B Pierce,
Danielle R Lenz,
Zippora Brownstein,
Orit Dagan-Rosenfeld,
Hashem Shahin,
Wendy Roeb,
Shane McCarthy,
Alex S Nord,
Carlos R Gordon,
Ziva Ben-Neriah, Jonathan Sebat,
Moien Kanaan,
Ming K Lee,
Moshe Frydman,
Mary-Claire King,
Karen B Avraham
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ABSTRACT: Age-related hearing loss is due to death over time, primarily by apoptosis, of hair cells in the inner ear. Studies of mutant genes responsible for inherited progressive hearing loss have suggested possible mechanisms for hair cell death, but critical connections between these mutations and the causes of progressive hearing loss have been elusive. In an Israeli kindred, dominant, adult-onset, progressive nonsyndromic hearing loss DFNA51 is due to a tandem inverted genomic duplication of 270 kb that includes the entire wild-type gene encoding the tight junction protein TJP2 (ZO-2). In the mammalian inner ear, TJP2 is expressed mainly in tight junctions, and also in the cytoplasm and nuclei. TJP2 expression normally decreases with age from embryonic development to adulthood. In cells of affected family members, TJP2 transcript and protein are overexpressed, leading to decreased phosphorylation of GSK-3beta and to altered expression of genes that regulate apoptosis. These results suggest that TJP2- and GSK-3beta-mediated increased susceptibility to apoptosis of cells of the inner ear is the mechanism for adult-onset hearing loss in this kindred and may serve as one model for age-related hearing loss in the general population.
The American Journal of Human Genetics 07/2010; 87(1):101-9. · 10.60 Impact Factor
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Santhosh Girirajan,
Jill A Rosenfeld,
Gregory M Cooper,
Francesca Antonacci,
Priscillia Siswara,
Andy Itsara,
Laura Vives,
Tom Walsh,
Shane E McCarthy,
Carl Baker, [......],
Eric Haan,
Kathryn L Friend,
Marco Fichera,
Corrado Romano,
Jozef Gécz,
Lynn E DeLisi, Jonathan Sebat,
Mary-Claire King,
Lisa G Shaffer,
Evan E Eichler
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ABSTRACT: We report the identification of a recurrent, 520-kb 16p12.1 microdeletion associated with childhood developmental delay. The microdeletion was detected in 20 of 11,873 cases compared with 2 of 8,540 controls (P = 0.0009, OR = 7.2) and replicated in a second series of 22 of 9,254 cases compared with 6 of 6,299 controls (P = 0.028, OR = 2.5). Most deletions were inherited, with carrier parents likely to manifest neuropsychiatric phenotypes compared to non-carrier parents (P = 0.037, OR = 6). Probands were more likely to carry an additional large copy-number variant when compared to matched controls (10 of 42 cases, P = 5.7 x 10(-5), OR = 6.6). The clinical features of individuals with two mutations were distinct from and/or more severe than those of individuals carrying only the co-occurring mutation. Our data support a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity indicates that this two-hit model might be more generally applicable to neuropsychiatric disease.
Nature Genetics 02/2010; 42(3):203-9. · 35.53 Impact Factor
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Shane E McCarthy,
Vladimir Makarov,
George Kirov,
Anjene M Addington,
Jon McClellan,
Seungtai Yoon,
Diana O Perkins,
Diane E Dickel,
Mary Kusenda,
Olga Krastoshevsky, [......],
Michael C O'Donovan,
Tamim H Shaikh,
Ezra Susser,
Lynn E Delisi,
Patrick F Sullivan,
Curtis K Deutsch,
Judith Rapoport,
Deborah L Levy,
Mary-Claire King, Jonathan Sebat
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ABSTRACT: Recurrent microdeletions and microduplications of a 600-kb genomic region of chromosome 16p11.2 have been implicated in childhood-onset developmental disorders. We report the association of 16p11.2 microduplications with schizophrenia in two large cohorts. The microduplication was detected in 12/1,906 (0.63%) cases and 1/3,971 (0.03%) controls (P = 1.2 x 10(-5), OR = 25.8) from the initial cohort, and in 9/2,645 (0.34%) cases and 1/2,420 (0.04%) controls (P = 0.022, OR = 8.3) of the replication cohort. The 16p11.2 microduplication was associated with a 14.5-fold increased risk of schizophrenia (95% CI (3.3, 62)) in the combined sample. A meta-analysis of datasets for multiple psychiatric disorders showed a significant association of the microduplication with schizophrenia (P = 4.8 x 10(-7)), bipolar disorder (P = 0.017) and autism (P = 1.9 x 10(-7)). In contrast, the reciprocal microdeletion was associated only with autism and developmental disorders (P = 2.3 x 10(-13)). Head circumference was larger in patients with the microdeletion than in patients with the microduplication (P = 0.0007).
Nature Genetics 11/2009; 41(11):1223-7. · 35.53 Impact Factor
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ABSTRACT: Recent studies have established an important role for rare genomic deletions and duplications in the etiology of schizophrenia. This research suggests that the genetic architecture of neuropsychiatric disorders includes a constellation of rare mutations in many different genes. Mutations that confer substantial risk for schizophrenia have been identified at several loci, most of which have also been implicated in other neurodevelopmental disorders, including autism. Genetic heterogeneity is a characteristic of schizophrenia; conversely, phenotypic heterogeneity is a characteristic of all schizophrenia-associated mutations. Both kinds of heterogeneity probably reflect the complexity of neurodevelopment. Research strategies must account for both genetic and clinical heterogeneity to identify the genes and pathways crucial for the development of neuropsychiatric disorders.
Trends in Genetics 10/2009; 25(12):528-35. · 10.06 Impact Factor
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Karolina Aberg,
Daniel E Adkins,
József Bukszár,
Bradley T Webb,
Stanley N Caroff,
Del D Miller, Jonathan Sebat,
Scott Stroup,
Ayman H Fanous,
Vladimir I Vladimirov,
Joseph L McClay,
Jeffrey A Lieberman,
Patrick F Sullivan,
Edwin J C G van den Oord
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ABSTRACT: Understanding individual differences in the development of extrapyramidal side effects (EPS) as a response to antipsychotic therapy is essential to individualize treatment.
We performed genomewide association studies to search for genetic susceptibility to EPS. Our sample consisted of 738 schizophrenia patients, genotyped for 492K single nucleotide polymorphisms (SNPs). We studied three quantitative measures of antipsychotic adverse drug reactions-the Simpson-Angus Scale (SAS) for Parkinsonism, the Barnes Akathisia Rating Scale, and the Abnormal Involuntary Movement Scale (AIMS)-as well as a clinical diagnosis of probable tardive dyskinesia.
Two SNPs for SAS, rs17022444 and rs2126709 with p = 1.2 x 10(-10) and p = 3.8 x 10(-7), respectively, and one for AIMS, rs7669317 with p = 7.7 x 10(-8), reached genomewide significance (Q value < .1). rs17022444 and rs7669317 were located in intergenic regions and rs2126709 was located in ZNF202 on 11q24. Fourteen additional signals were potentially interesting (Q value < .5). The ZNF202 is a transcriptional repressor controlling, among other genes, PLP1, which is the major protein in myelin. Mutations in PLP1 cause Pelizaeus-Merzbacher disease, which has Parkinsonism as an occurring symptom. Altered mRNA expression of PLP1 is associated with schizophrenia.
Although our findings require replication and validation, this study demonstrates the potential of genomewide association studies to discover genes and pathways that mediate adverse effects of antipsychotics.
Biological psychiatry 10/2009; 67(3):279-82. · 8.93 Impact Factor
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ABSTRACT: Methods for the direct detection of copy number variation (CNV) genome-wide have become effective instruments for identifying genetic risk factors for disease. The application of next-generation sequencing platforms to genetic studies promises to improve sensitivity to detect CNVs as well as inversions, indels, and SNPs. New computational approaches are needed to systematically detect these variants from genome sequence data. Existing sequence-based approaches for CNV detection are primarily based on paired-end read mapping (PEM) as reported previously by Tuzun et al. and Korbel et al. Due to limitations of the PEM approach, some classes of CNVs are difficult to ascertain, including large insertions and variants located within complex genomic regions. To overcome these limitations, we developed a method for CNV detection using read depth of coverage. Event-wise testing (EWT) is a method based on significance testing. In contrast to standard segmentation algorithms that typically operate by performing likelihood evaluation for every point in the genome, EWT works on intervals of data points, rapidly searching for specific classes of events. Overall false-positive rate is controlled by testing the significance of each possible event and adjusting for multiple testing. Deletions and duplications detected in an individual genome by EWT are examined across multiple genomes to identify polymorphism between individuals. We estimated error rates using simulations based on real data, and we applied EWT to the analysis of chromosome 1 from paired-end shotgun sequence data (30x) on five individuals. Our results suggest that analysis of read depth is an effective approach for the detection of CNVs, and it captures structural variants that are refractory to established PEM-based methods.
Genome Research 09/2009; 19(9):1586-92. · 13.61 Impact Factor
