Showing papers by "Kimberly Chambert published in 2013"
••
TL;DR: Empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.
Abstract: Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.
2,058 citations
••
Harvard University1, Broad Institute2, Karolinska Institutet3, University of North Carolina at Chapel Hill4, Oslo University Hospital5, Icahn School of Medicine at Mount Sinai6, University of Queensland7, deCODE genetics8, Aarhus University Hospital9, Lundbeck10, Aarhus University11, Trinity College, Dublin12, Cardiff University13, VU University Amsterdam14, Radboud University Nijmegen15, Russian Academy16, Statens Serum Institut17, Virginia Commonwealth University18, King's College London19, Queen's University Belfast20, University of Belgrade21, Erasmus University Rotterdam22, Ludwig Maximilian University of Munich23, Martin Luther University of Halle-Wittenberg24, University of Iceland25, Tbilisi State Medical University26, National Institutes of Health27, University of Verona28, University College London29
TL;DR: The authors conducted a multi-stage genome-wide association study (GWAS) for schizophrenia and found that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia.
Abstract: Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-Analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder.
1,343 citations
••
TL;DR: Differential regulation of distinct ANK3 transcription start sites and coupling of specific 5′ ends with 3′ mRNA splicing events in postmortem human brain and human stem cell-derived neural progenitors and neurons are detected.
Abstract: Several genome-wide association studies (GWAS) for bipolar disorder (BD) have found a strong association of the Ankyrin3 (ANK3) gene. This association spans numerous linked single nucleotide polymorphisms (SNPs) in a ~250 kb genomic region overlapping ANK3. The associated region encompasses predicted regulatory elements as well as two of six validated alternative first exons, which encode distinct protein domains at the N-terminus of the protein also known as ankyrin-G (AnkG). Using RNA Ligase-Mediated Rapid Amplification of cDNA Ends (RLM-RACE) to identify novel transcripts in conjunction with a highly sensitive, exon-specific multiplexed mRNA expression assay, we detected differential regulation of distinct ANK3 transcription start sites (TSSs) and coupling of specific 5’ ends with 3’ mRNA splicing events in post-mortem human brain and human stem cell-derived neural progenitors and neurons. Furthermore, allelic variation at the BD–associated SNP rs1938526 correlated with a significant difference in cerebellar expression of a brain-specific ANK3 transcript. These findings suggest a brain-specific cis-regulatory transcriptional effect of ANK3 may be relevant to BD pathophysiology.
80 citations
••
TL;DR: This work mapped the locations of 70 scaffolds spanning 4 million base pairs of the human genome's unplaced euchromatic sequence, including more than a dozen protein-coding genes, and identified 8 new large interchromosomal segmental duplications.
Abstract: Tens of millions of base pairs of euchromatic human genome sequence, including many protein-coding genes, have no known location in the human genome. We describe an approach for localizing the human genome's missing pieces using the patterns of genome sequence variation created by population admixture. We mapped the locations of 70 scaffolds spanning 4 million base pairs of the human genome's unplaced euchromatic sequence, including more than a dozen protein-coding genes, and identified 8 new large interchromosomal segmental duplications. We find that most of these sequences are hidden in the genome's heterochromatin, particularly its pericentromeric regions. Many cryptic, pericentromeric genes are expressed at the RNA level and have been maintained intact for millions of years while their expression patterns diverged from those of paralogous genes elsewhere in the genome. We describe how knowledge of the locations of these sequences can inform disease association and genome biology studies.
72 citations
••
Cardiff University1, Hebrew University of Jerusalem2, Fujita Health University3, Broad Institute4, Harvard University5, Karolinska Institutet6, Trinity College, Dublin7, University of Bonn8, Rutgers University9, Heidelberg University10, German Center for Neurodegenerative Diseases11, Icahn School of Medicine at Mount Sinai12, University of Chicago13, National Institutes of Health14, Virginia Commonwealth University15, Queen's University Belfast16, University of California, San Diego17, Cold Spring Harbor Laboratory18, Stanford University19
TL;DR: A new locus is added to the list of copy number variations that increase the risk for development of schizophrenia: a deletion at distal 16p11.2, which does not overlap the proximal 16p 11.2 locus previously reported in schizophrenia and autism.
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.
Uncovering the genetic factors underlying schizophrenia (SZ) has proven difficult despite heritability estimates of up to 80%.1 Copy number variations (CNVs) at several loci show consistently replicated evidence for association with SZ.2- 3 These CNVs are individually very rare, are not fully penetrant, and are found cumulatively in approximately 2% of SZ cases; therefore, large samples were required to establish their association. Given their low baseline frequency, further CNV susceptibility loci likely have yet to be discovered.
In the present study, we report the identification of a CNV locus at distal 16p11.2 that increases the risk for SZ. Findings pointing to a possible association between this locus and SZ were obtained independently by 2 teams of investigators. During the process of obtaining replication data, the 2 groups became aware of each other's work and decided to combine results from their discovery and replication cohorts. Using high-resolution microarrays, one group (from New York and Israel) examined an SZ case-control cohort from the Ashkenazi Jewish (AJ) population, whereas the other group (from Cardiff, Wales) examined a cohort of parent-offspring trios from Bulgaria (BG). Because of the need for large-scale replication, we contacted research groups worldwide who were willing to share raw data from microarray-based CNV studies in cohorts of SZ cases and controls and obtained data from a total of approximately 34 000 individuals.
70 citations
••
TL;DR: The results suggest the utility of exome-focused arrays in surveying large genic CNVs in very large samples; and open the door for new opportunities such as conducting well-powered CNV assessment and comparisons between different diseases.
Abstract: Detecting large copy number variants using exome genotyping arrays in a large Swedish schizophrenia sample
27 citations
••
TL;DR: Copy number variants (CNVs) have been shown to play a role in schizophrenia and intellectual disability and need further investigation to determine their role in disease.
Abstract: Copy number variants (CNVs) have been shown to play a role in schizophrenia and intellectual disability. We compared the CNV burden in 66 patients with intellectual disability and no symptoms of psychosis (ID-only) with the burden in 64 patients with intellectual disability and schizophrenia (ID + SCZ). Samples were genotyped on three plates by the Broad Institute using the Affymetrix 6.0 array. For CNVs larger than 100 kb, there was no difference in the CNV burden of ID-only and ID + SCZ. In contrast, the number of duplications larger than 1 Mb was increased in ID + SCZ compared to ID-only. We detected seven large duplications and two large deletions at chromosome 15q11.2 (18.5-20.1 Mb) which were all present in patients with ID + SCZ. The involvement of this region in schizophrenia was confirmed in Scottish samples from the ISC study (N = 2,114; 1,130 cases and 984 controls). Finally, one of the patients with schizophrenia and low IQ carrying a duplication at 15q11.2, is a member of a previously described pedigree with multiple cases of mild intellectual disability, schizophrenia, hearing impairment, retinitis pigmentosa and cataracts. DNA samples were available for 11 members of this family and the duplication was present in all 10 affected individuals and was absent in an unaffected individual. Duplications at 15q11.2 (18.5-20.1 Mb) are highly prevalent in a severe group of patients characterized by intellectual disability and comorbid schizophrenia. It is also associated with a phenotype that includes schizophrenia, low IQ, hearing and visual impairments resembling the spectrum of symptoms described in "ciliopathies."
15 citations