Identification of rare variants in KCTD13 at the schizophrenia risk locus 16p11.2.
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ABSTRACT:
SUBMITTER: Degenhardt F
PROVIDER: S-EPMC5087564 | biostudies-literature | 2016 Dec
REPOSITORIES: biostudies-literature
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Identification of rare variants in KCTD13 at the schizophrenia risk locus 16p11.2.
Degenhardt Franziska F Heinemann Barbara B Strohmaier Jana J Pfohl Marvin A MA Giegling Ina I Hofmann Andrea A Ludwig Kerstin U KU Witt Stephanie H SH Ludwig Michael M Forstner Andreas J AJ Albus Margot M Schwab Sibylle G SG Borrmann-Hassenbach Margitta M Lennertz Leonard L Wagner Michael M Hoffmann Per P Rujescu Dan D Maier Wolfgang W Cichon Sven S Rietschel Marcella M Nöthen Markus M MM
Psychiatric genetics 20161201 6
Duplications in 16p11.2 are a risk factor for schizophrenia (SCZ). Using genetically modified zebrafish, Golzio and colleagues identified KCTD13 within 16p11.2 as a major driver of the neuropsychiatric phenotype observed in humans. The aims of the present study were to explore the role of KCTD13 in the development of SCZ and to provide a more complete picture of the allelic architecture at this risk locus. The exons of KCTD13 were sequenced in 576 patients. The mutations c.6G>T and c.598G>A were ...[more]
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Project description:Background Chromosome 16p11.2 is one of the most significant loci in the genome-wide association study (GWAS) of schizophrenia. Despite several integrative analyses and functional genomics studies have been carried out to identify possible risk genes, their impacts in the pathogenesis of schizophrenia remain to be fully characterized. Methods We performed expression quantitative trait loci (eQTL) and summary-data-based Mendelian randomization (SMR) analyses to identify schizophrenia risk genes in the 16p11.2 GWAS locus. We constructed the murine model with dysregulated expression of risk gene in the medial prefrontal cortex (mPFC) using stereotaxic injection of Adeno-associated Virus (AAV), followed by behavioral assessments, dendritic spine analyses and RNA sequencing. Findings We identified significant associations between elevated INO80E mRNA expression in frontal cortex and risk of schizophrenia. The mice overexpressing Ino80e in mPFC (Ino80e-OE) exhibited schizophrenia-like behaviors, including increased anxiety behavior, anhedonia, and impaired prepulse inhibition (PPI) when compared with control group. The neuronal sparse labeling assay showed that the density of mushroom spines in the pyramidal neurons of mPFC was significantly decreased in Ino80e-OE mice compared with control mice, accompanied by a notable increase in the density of stubby spines. Transcriptomic analysis in the mPFC revealed significant alterations in the mRNA levels of schizophrenia-related genes and processes related to synapses upon overexpressing Ino80e . Interpretation Our results suggest that upregulation of the Ino80e gene in mPFC may induce schizophrenia-like behaviors in mice, further supporting the hypothesis that INO80E is an authentic risk gene.
2024-10-01 | GSE276239 | GEO
Project description: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.To detect novel copy number variations that increase the susceptibility to schizophrenia by using 2 ethnically homogeneous discovery cohorts and replication in large samples.Genetic association study of microarray data.Samples of DNA were collected at 9 sites from different countries.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.Statistically increased rate of specific copy number variations in cases vs controls.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).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.
| S-EPMC3750982 | biostudies-literature
Project description:BackgroundCommon variable immunodeficiency (CVID) is characterized clinically by inadequate quantity and quality of serum immunoglobulins with increased susceptibility to infections, resulting in significant morbidity and mortality. Only a few genes have been uncovered, and the genetic background of CVID remains elusive to date for the majority of patients.ObjectiveWe sought to seek novel associations of genes and genetic variants with CVID.MethodsWe performed association analyses in a discovery cohort of 164 patients with CVID and 19,542 healthy control subjects genotyped on the Immuno BeadChip from Illumina platform; replication of findings was examined in an independent cohort of 135 patients with CVID and 2,066 healthy control subjects, followed by meta-analysis.ResultsWe identified 11 single nucleotide polymorphisms (SNPs) at the 16p11.2 locus associated with CVID at a genome-wide significant level in the discovery cohort. The most significant SNP, rs929867 (P = 6.21 × 10(-9)), is in the gene fused-in-sarcoma (FUS), with 4 other SNPs mapping to integrin CD11b (ITGAM). Results were confirmed in our replication cohort. Conditional association analysis suggests a single association signal at the 16p11.2 locus. A strong trend of association was also seen for 38 SNPs (P < 5 × 10(-5)) in the MHC region, supporting that this is a genuine CVID locus. Interestingly, we found that 80% of patients with the rare ITGAM variants have reduced switched memory B-cell counts.ConclusionWe report a novel association of CVID with rare variants at the FUS/ITGAM (CD11b) locus on 16p11.2. The association signal is enriched for promoter/enhancer markers in the ITGAM gene. ITGAM encodes the integrin CD11b, a part of complement receptor 3, a novel candidate gene implicated here for the first time in the pathogenesis of CVID.
| S-EPMC4461447 | biostudies-literature
Project description:Recent genetic data on schizophrenia (SCZ) have suggested that proteins of the postsynaptic density of excitatory synapses have a role in its etiology. Mutations in the three SHANK genes encoding for postsynaptic scaffolding proteins have been shown to represent risk factors for autism spectrum disorders and other neurodevelopmental disorders. To address if SHANK2 variants are associated with SCZ, we sequenced SHANK2 in 481 patients and 659 unaffected individuals. We identified a significant increase in the number of rare (minor allele frequency<1%) SHANK2 missense variants in SCZ individuals (6.9%) compared with controls (3.9%, P=0.039). Four out of fifteen non-synonymous variants identified in the SCZ cohort (S610Y, R958S, P1119T and A1731S) were selected for functional analysis. Overexpression and knockdown-rescue experiments were carried out in cultured primary hippocampal neurons with a major focus on the analysis of morphological changes. Furthermore, the effect on actin polymerization in fibroblast cell lines was investigated. All four variants revealed functional impairment to various degrees, as a consequence of alterations in spine volume and clustering at synapses and an overall loss of presynaptic contacts. The A1731S variant was identified in four unrelated SCZ patients (0.83%) but not in any of the sequenced controls and public databases (P=4.6 × 10(-5)). Patients with the A1731S variant share an early prodromal phase with an insidious onset of psychiatric symptoms. A1731S overexpression strongly decreased the SHANK2-Bassoon-positive synapse number and diminished the F/G-actin ratio. Our results strongly suggest a causative role of rare SHANK2 variants in SCZ and underline the contribution of SHANK2 gene mutations in a variety of neuropsychiatric disorders.
| S-EPMC4653611 | biostudies-literature
Project description:Anatomical structures and mechanisms linking genes to neuropsychiatric disorders are not deciphered. Reciprocal copy number variants at the 16p11.2 BP4-BP5 locus offer a unique opportunity to study the intermediate phenotypes in carriers at high risk for autism spectrum disorder (ASD) or schizophrenia (SZ). We investigated the variation in brain anatomy in 16p11.2 deletion and duplication carriers. Beyond gene dosage effects on global brain metrics, we show that the number of genomic copies negatively correlated to the gray matter volume and white matter tissue properties in cortico-subcortical regions implicated in reward, language and social cognition. Despite the near absence of ASD or SZ diagnoses in our 16p11.2 cohort, the pattern of brain anatomy changes in carriers spatially overlaps with the well-established structural abnormalities in ASD and SZ. Using measures of peripheral mRNA levels, we confirm our genomic copy number findings. This combined molecular, neuroimaging and clinical approach, applied to larger datasets, will help interpret the relative contributions of genes to neuropsychiatric conditions by measuring their effect on local brain anatomy.
| S-EPMC4320286 | biostudies-literature
Project description:Multiple lines of evidence corroborate impaired signaling pathways as relevant to the underpinnings of schizophrenia. There has been an interest in neurotrophins, since they are crucial mediators of neurodevelopment and in synaptic connectivity in the adult brain. Neurotrophins and their receptors demonstrate aberrant expression patterns in cortical areas for schizophrenia cases in comparison to control subjects. There is little known about the contribution of neurotrophin genes in psychiatric disorders. To begin to address this issue, we conducted high-coverage targeted exome capture in a subset of neurotrophin genes in 48 comprehensively characterized cases with schizophrenia-related psychosis. We herein report rare missense polymorphisms and novel missense mutations in neurotrophin receptor signaling pathway genes. Furthermore, we observed that several genes have a higher propensity to harbor missense coding variants than others. Based on this initial analysis we suggest that rare variants and missense mutations in neurotrophin genes might represent genetic contributions involved across psychiatric disorders.
| S-EPMC4591185 | biostudies-literature
Project description:BACKGROUND:Schizophrenia is a chronic and severe mental disorder, and it has been predicted to be highly polygenic. Common SNPs located in or near BNIP3L were found to be genome-wide significantly associated with schizophrenia in recent genome-wide association studies. The purpose of our study is to investigate potential causal variants in BNIP3L gene. RESULTS:We performed targeted sequencing for all exons and un-translated regions of BNIP3L gene among 1806 patients with schizophrenia and 998 healthy controls of Han Chinese origin. Three rare nonsynonymous mutations, BNIP3L (NM_004331): c.52A>G, c.167G>A and c.313A>T, were identified in schizophrenia cases, and two of them were newly reported. The frequencies of these rare nonsynonymous mutations were significantly different between schizophrenia cases and healthy controls. For the common variants, rs147389989 achieved significance in both allelic and genotypic distributions with schizophrenia. Rs1042992 and rs17310286 were significantly associated with schizophrenia in meta-analyses using PGC, CLOZUK, and our new datasets in this study. CONCLUSIONS:Our findings provided further evidence that BNIP3L gene is a susceptibility gene of schizophrenia and revealed functional and potential causal mutations in BNIP3L. However, more functional validations are suggested to better understand the role of BNIP3L in the etiology of schizophrenia.
| S-EPMC7212671 | biostudies-literature
Project description:Copy number variants (CNVs) are major contributors to genetic disorders. We have dissected a region of the 16p11.2 chromosome--which encompasses 29 genes--that confers susceptibility to neurocognitive defects when deleted or duplicated. Overexpression of each human transcript in zebrafish embryos identified KCTD13 as the sole message capable of inducing the microcephaly phenotype associated with the 16p11.2 duplication, whereas suppression of the same locus yielded the macrocephalic phenotype associated with the 16p11.2 deletion, capturing the mirror phenotypes of humans. Analyses of zebrafish and mouse embryos suggest that microcephaly is caused by decreased proliferation of neuronal progenitors with concomitant increase in apoptosis in the developing brain, whereas macrocephaly arises by increased proliferation and no changes in apoptosis. A role for KCTD13 dosage changes is consistent with autism in both a recently reported family with a reduced 16p11.2 deletion and a subject reported here with a complex 16p11.2 rearrangement involving de novo structural alteration of KCTD13. Our data suggest that KCTD13 is a major driver for the neurodevelopmental phenotypes associated with the 16p11.2 CNV, reinforce the idea that one or a small number of transcripts within a CNV can underpin clinical phenotypes, and offer an efficient route to identifying dosage-sensitive loci.
| S-EPMC3366115 | biostudies-literature
Project description:BackgroundGene copy number variants play an important role in the occurrence of neurodevelopmental disorders. Particularly, the deletion of the 16p11.2 locus is associated with autism spectrum disorder, intellectual disability, and several other features. Earlier studies highlighted the implication of Kctd13 genetic imbalance in 16p11.2 deletion through the regulation of the RHOA pathway.MethodsHere, we generated a new mouse model with a small deletion of two key exons in Kctd13. Then, we targeted the RHOA pathway to rescue the cognitive phenotypes of the Kctd13 and 16p11.2 deletion mouse models in a pure genetic background. We used a chronic administration of fasudil (HA1077), an inhibitor of the Rho-associated protein kinase, for six weeks in mouse models carrying a heterozygous inactivation of Kctd13, or the deletion of the entire 16p11.2 BP4-BP5 homologous region.ResultsWe found that the small Kctd13 heterozygous deletion induced a cognitive phenotype similar to the whole deletion of the 16p11.2 homologous region, in the Del/+?mice. We then showed that chronic fasudil treatment can restore object recognition memory in adult heterozygous mutant mice for Kctd13 and for 16p11.2 deletion. In addition, learning and memory improvement occurred in parallel to change in the RHOA pathway.LimitationsThe Kcdt13 mutant line does not recapitulate all the phenotypes found in the 16p11.2 Del/+?model. In particular, the locomotor activity was not altered at 12 and 18 weeks of age and the object location memory was not defective in 18-week old mutants. Similarly, the increase in locomotor activity was not modified by the treatment in the 16p11.2 Del/+?mouse model, suggesting that other loci were involved in such defects. Rescue was observed only after four weeks of treatment but no long-term experiment has been carried out so far. Finally, we did not check the social behaviour, which requires working in another hybrid genetic background.ConclusionThese findings confirm KCTD13 as one target gene causing cognitive deficits in 16p11.2 deletion patients, and the relevance of the RHOA pathway as a therapeutic path for 16p11.2 deletion. In addition, they reinforce the contribution of other gene(s) involved in cognitive defects found in the 16p11.2 models in older mice.
| S-EPMC7805198 | biostudies-literature
Project description:ObjectiveSchizophrenia is a chronic debilitating neurobiological disorder of aberrant synaptic connectivity and synaptogenesis. Postsynaptic density (PSD)-related proteins in N-methyl-D-aspartate receptor-postsynaptic signaling complexes are crucial to regulating the synaptic transmission and functions of various synaptic receptors. This study examined the role of PSD-related genes in susceptibility to schizophrenia.MethodsWe resequenced 18 genes encoding the disks large-associated protein (DLGAP), HOMER, neuroligin (NLGN), neurexin, and SH3 and multiple ankyrin repeat domains (SHANK) protein families in 98 schizophrenic patients with family psychiatric history using semiconductor sequencing. We analyzed the protein function of the identified rare schizophrenia-associated mutants via immunoblotting and immunocytochemistry.ResultsWe identified 50 missense heterozygous mutations in 98 schizophrenic patients with family psychiatric history, and in silico analysis revealed some as damaging or pathological to the protein function. Ten missense mutations were absent from the dbSNP database, the gnomAD (non-neuro) dataset, and 1,517 healthy controls from Taiwan BioBank. Immunoblotting revealed eight missense mutants with altered protein expressions in cultured cells compared with the wild type.ConclusionOur findings suggest that PSD-related genes, especially the NLGN, SHANK, and DLGAP families, harbor rare functional mutations that might alter protein expression in some patients with schizophrenia, supporting contributing rare coding variants into the genetic architecture of schizophrenia.
| S-EPMC7746813 | biostudies-literature