Genes In Neurodevelopmental Pathways Research Articles

Transgenerational impact of grand-paternal lifetime exposures to both folic acid deficiency and supplementation on genome-wide DNA methylation in male germ cells.

DNA methylation (DNAme) erasure and reacquisition occur during prenatal male germ cell development; some further remodeling takes place after birth during spermatogenesis. Environmental insults during germline epigenetic reprogramming may affect DNAme, presenting a potential mechanism for transmission of environmental exposures across multiple generations. We investigated how germ cell DNAme is impacted by lifetime exposures to diets containing either low or high, clinically relevant, levels of the methyl donor folic acid and whether resulting DNAme alterations were inherited in germ cells of male offspring of subsequent generations. Female mice were placed on a control (FCD), 7-fold folic acid deficient (7FD) or10-to20-fold supplemented (10FS and 20FS) diet before and during pregnancy. Resulting F1 litters were weaned on the respective diets. F2 and F3 males received control diets. Genome-wide DNAme at cytosines (within CpG sites) was assessed in F1 spermatogonia, and in F1, F2 and F3 sperm. In F1 germ cells, a greater number of differentially methylated cytosines (DMCs) were observed in spermatogonia as compared with F1 sperm for all folic acid diets. DMCs were lower in number in F2 versus F1 sperm, while an unexpected increase was found in F3 sperm. DMCs were predominantly hypomethylated, with genes in neurodevelopmental pathways commonly affected in F1, F2 and F3 male germ cells. While no DMCs were found to be significantly inherited inter- or transgenerationally, we observed over-representation of repetitive elements, particularly young longinterspersednuclearelements(LINEs). These results suggest that the prenatal window is the time most susceptible to folate-induced alterations in sperm DNAme in male germ cells. Altered methylation of specific sites in F1 germ cells was not present in later generations. However, the presence of DNAme perturbations in the sperm of males of the F2 and F3 generations suggests that epigenetic inheritance mechanisms other than DNAme may have been impacted by the folate diet exposure of F1 germ cells.

Association study of RELN polymorphisms with schizophrenia in Han Chinese population

Schizophrenia (SZ) is a common and complex psychiatric disorder with a strong genetic component. Previous research suggests that mutations altering genes in neurodevelopmental pathways contribute to SZ. Reelin gene (RELN) maps to chromosome 7q22.1, the encoded protein plays a pivotal role in guiding neuronal migration, lamination and connection during embryonic brain development. Several reports had indicated that reduced RELN expression is associated with human mental illnesses such as SZ, mood disorders and autism. In this study, case-control association analyses were performed in the Han Chinese population to determine if the RELN gene is a susceptibility gene for SZ. Thirty-seven single nucleotide polymorphisms (SNPs) were genotyped in 528 paranoid SZ patients and 528 control subjects. A significant association was found between rs12705169 and SZ (p=0.001). Moreover, the haplotypes constructed from five SNPs showed significant differences between cases and controls (p=0.041). When subjects were divided by gender, rs12705169 remained significant difference only in females (OR=0.24, 95%CI=0.14-0.40 for CC and OR=0.40, 95%CI=0.27-0.58 for AC), both in the allele and genotype (p=0.0001 for both). This study describes a positive association between RELN and SZ in the Han Chinese population, and provides genetic evidence to support the gender difference of SZ.

A putative cis-acting polymorphism in the NOS1 gene is associated with schizophrenia and NOS1 immunoreactivity in the postmortem brain

Schizophrenia is a devastating neurodevelopmental disorder whose genetic influences remain elusive. Recent genome-wide scans revealed that rare structural variants disrupted multiple genes in neurodevelopmental pathways, which strongly implicate nitric oxide (NO) signaling in schizophrenia. NO acts as a second messenger of N-methyl-D aspartate receptor activation, which further interacts with both dopaminergic and serotonergic pathways. NO is mainly synthesized by neuronal nitric oxide synthase (NOS1) in the brain, and its gene locus, 12q24.2, has attracted much attention as a major linkage region for schizophrenia. Genetic variations of NOS1 have also been associated with schizophrenia, and differential expression of NOS1 was observed in the postmortem brain of schizophrenic patients. Here, we explored the hypothesis that a putative cis-acting G-84A single nucleotide polymorphism (SNP; rs41279104) in the exon 1c promoter region of the NOS1 gene is associated with the levels of NOS1 immunoreactivity in postmortem prefrontal cortex specimens regardless of disease phenotype. Individuals with the A-allele of this SNP showed significantly lower levels of NOS1 immunoreactivity than did GG homozygotes ( p = 0.002). Furthermore, a case–control study using 720 individuals in a Japanese population revealed a significant association between the SNP and schizophrenia (genotypic p = 0.0013 and allelic p = 0.0011). Additionally, the average of onset age in schizophrenic patients with the A-allele was significantly earlier than GG homozygotes ( p = 0.018). When the analyses took gender into account, this significance was more significant for female. These findings provide further evidences that NOS1 is associated with a biological susceptibility gene to schizophrenia.

AUTISTIC TRAITS AND DEVELOPMENTAL MARKERS IN ADULT ONSET SCHIZOPHRENIA

genetic and imaging findings has pointed out the interest of core neurobiological processes common for subsets of these two heterogeneous clinical groups (3). There is no wonder that this remarkable heterogeneity is intimately related to the complexity of the genetic control of brain development and function. In this sense, there are numerous direct and indirect genetic data linking both disorders (4-6). Specifically, various candidate gene and linkage studies (based on genes implicated in brain development and functioning pathways such as DISC1, NRXN1, RELN or GAD1), highlighting the emerging evidence for biological links between both disorders (3). Moreover, more recently, genomic microduplications and deletions or copy number variants (CNVs) have been reported in both Autism and Psychosis (7-10). Accordingly, it is likely that genetic studies will increasingly implicate patterns of brain developmental disturbance, leading to define disorders in novel ways.The present Symposium aims to focus on: i) common clinical and biological traits between Autistic Spectrum Disorders and Psychotic Disorders and the use of autistic and neurocognitve traits in Schizophrenia as intermediate phenotypes to define a putatively more homogeneous subgroup, ii) the recently described common and rare genomic arrangements and their association not onlywith Autism and Psychosis risk but also with specific clinical and cognitive traits. 1. Fombonne E. Epidemiology of autistic disorder and other pervasive developmental disorders. J Clin Psychiatry. 2005;66 Suppl 10:3-8.2. Perala J, Suvisaari J, et al. Lifetime prevalence of psychotic and bipolar I disorders in a general population. ArchGen Psychiatry. 2007 Jan;64(1):19-28.3. Rapoport J, Chavez A, et al. Autism spectrum disorders and childhood-onset schizophrenia: clinical and biological contributions to a relation revisited. J Am Acad Child Adolesc Psychiatry. 2009 Jan;48(1):10-8.4. Chagnon YC. Shared susceptibility region on chromosome 15 between autism and catatonia. Int Rev Neurobiol. 2006;72:16578.5. Di Cristo G. Development of cortical GABAergic circuits and its implications for neurodevelopmental disorders. Clin Genet. 2007 Jul;72(1):1-8.6. Fatemi SH. Reelin glycoprotein in autism and schizophrenia. Int Rev Neurobiol. 2005;71:179-87.7. Sebat J, Lakshmi B, et al. Strong association of de novo copy number mutations with autism. Science. 2007 Apr 20;316(5823):445-9.8. Stefansson H, Rujescu D, Cichon S, Pietilainen OP, Ingason A, Steinberg S, et al. Large recurrent microdeletions associated with schizophrenia. Nature. 2008 Jul 30.9. Stone JL, O'Donovan MC, et al. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature. 2008 Jul 30.10. Walsh T, McClellan JM, et al. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science. 2008 Apr 25;320(5875):539-43.

A genome-wide investigation of SNPs and CNVs in schizophrenia.

We report a genome-wide assessment of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) in schizophrenia. We investigated SNPs using 871 patients and 863 controls, following up the top hits in four independent cohorts comprising 1,460 patients and 12,995 controls, all of European origin. We found no genome-wide significant associations, nor could we provide support for any previously reported candidate gene or genome-wide associations. We went on to examine CNVs using a subset of 1,013 cases and 1,084 controls of European ancestry, and a further set of 60 cases and 64 controls of African ancestry. We found that eight cases and zero controls carried deletions greater than 2 Mb, of which two, at 8p22 and 16p13.11-p12.4, are newly reported here. A further evaluation of 1,378 controls identified no deletions greater than 2 Mb, suggesting a high prior probability of disease involvement when such deletions are observed in cases. We also provide further evidence for some smaller, previously reported, schizophrenia-associated CNVs, such as those in NRXN1 and APBA2. We could not provide strong support for the hypothesis that schizophrenia patients have a significantly greater “load” of large (>100 kb), rare CNVs, nor could we find common CNVs that associate with schizophrenia. Finally, we did not provide support for the suggestion that schizophrenia-associated CNVs may preferentially disrupt genes in neurodevelopmental pathways. Collectively, these analyses provide the first integrated study of SNPs and CNVs in schizophrenia and support the emerging view that rare deleterious variants may be more important in schizophrenia predisposition than common polymorphisms. While our analyses do not suggest that implicated CNVs impinge on particular key pathways, we do support the contribution of specific genomic regions in schizophrenia, presumably due to recurrent mutation. On balance, these data suggest that very few schizophrenia patients share identical genomic causation, potentially complicating efforts to personalize treatment regimens.

Rare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia

Rare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia

Recurrent CNVs Disrupt Three Candidate Genes in Schizophrenia Patients

Schizophrenia is a severe psychiatric disease with complex etiology, affecting approximately 1% of the general population. Most genetics studies so far have focused on disease association with common genetic variation, such as single-nucleotide polymorphisms (SNPs), but it has recently become apparent that large-scale genomic copy-number variants (CNVs) are involved in disease development as well. To assess the role of rare CNVs in schizophrenia, we screened 54 patients with deficit schizophrenia using Affymetrix's GeneChip 250K SNP arrays. We identified 90 CNVs in total, 77 of which have been reported previously in unaffected control cohorts. Among the genes disrupted by the remaining rare CNVs are MYT1L, CTNND2, NRXN1, and ASTN2, genes that play an important role in neuronal functioning but--except for NRXN1--have not been associated with schizophrenia before. We studied the occurrence of CNVs at these four loci in an additional cohort of 752 patients and 706 normal controls from The Netherlands. We identified eight additional CNVs, of which the four that affect coding sequences were found only in the patient cohort. Our study supports a role for rare CNVs in schizophrenia susceptibility and identifies at least three candidate genes for this complex disorder.

Common vs rare variants and a case for neurodevelopment in schizophrenia

Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophreniaWalsh et al. (2008)Science 320 (5875): 539–543. Epub 27 March 2008

Gene Mutations and Cognitive Delay

We congratulate T. Walsh et al. for a beautifully designed and executed study (“Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia,” Reports, 25 April, p. 539). The demonstration that the frequency of gene deletions and duplications is elevated in schizophrenia as well as in autism and many forms of mental retardation must raise suspicions that such genomic variants are not really specific for a particular disease. Buried in the Supporting Online Material is the astonishing fact that 47% of the patients with poor cognitive function (IQ < 80) had these variants, compared with only 11% of the patients with normal IQ. Poor cognitive function is a common feature of these developmental disorders and is associated with similar anatomical anomalies across a range of disorders (1–3). Perhaps genomic deletions and duplications have a nonspecific effect—restricting the flexibility of coping responses during development, constraining neuroplasticity, and rendering cognitive function more dependent on intrinsic neurobiology.

Disruption of Normal Gene Sequence May Lead to Schizophrenia

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessDisruption of Normal Gene Sequence May Lead to SchizophreniaJun YanJun YanSearch for more papers by this authorPublished Online:2 May 2008https://doi.org/10.1176/pn.43.9.0022aChunks of DNA fragments that are scattered throughout chromosomes and sometimes mess up functional gene sequences may in part explain the development of schizophrenia and other neuropsychiatric disorders, according to new research produced independently by two groups of researchers.Two studies in different patient populations were combined into one paper and published online in Science on March 27.A group of National Institute of Mental Health (NIMH) researchers, led by Anjene Addington, Ph.D., and Judith Rapoport, M.D., found that 28 percent of patients with childhood-onset schizophrenia (COS) carried certain rare structural variants that disrupted normal genes. Similarly, researchers from Cold Spring Harbor Laboratory and the University of Washington, led by Jonathan Sebat, Ph.D., and Jon McClellan, M.D., found that 15 percent of patients with the classic type of schizophrenia carried rare structural variants in their genomes. Among patients with classic schizophrenia, 20 percent of those with an onset before age 18 carried rare structural variants. In contrast, only 5 percent of healthy, unrelated controls had these variants.Structural variations or mutations refer to chunks of repeated or missing DNA sequences (that is, microduplications and microdeletions, respectively) throughout a chromosome. Such variations may arise from mistakes during replication or chromosome misalignment during the development of sperm or eggs. Some of these mutations, also known as copy number variations, are common to all or most people. Certain rare variations have been linked to diseases.The researchers systematically scanned and compared the genomes of schizophrenia patients and of healthy controls, and of COS patients and their healthy parents to identify rare structural variations that were more frequent in patients with the disorder.The genes disrupted by rare structural variants associated with schizophrenia were concentrated in brain-development pathways. For example, one of the genes disrupted, SLC1A3, codes for a glutamate transporter protein found in many synapses in the brain. Transcription from these genes may be defective, or the protein produced may be dysfunctional because of the random deletion or duplication of DNA sections.'Smoking Gun' Remains ElusiveTo further complicate the picture, “virtually every rare structural mutation detected in our [study] was different,” the authors wrote. Scientists have been searching for a few common genetic mutations in patients with schizophrenia with a focus on common mutations within the suspect genes themselves, but so far have been unable to find “the smoking gun.” Many genes seem to be involved in the disease but none has a large association.The new findings “suggest a new model for finding new genes and mechanisms,” Rapoport, a senior investigator and child psychiatrist at NIMH, told Psychiatric News. Each specific mutation was rare by itself, and many were confined to one family or a single patient. In other words, patients with the same clinical diagnoses have different mutations that affect different genes on different chromosomes. Collectively, however, they are associated with a substantial proportion of schizophrenia patients.“It means that there are different ways to disrupt the same neurological pathway and that there are different pathways to schizophrenia,” commented Rapoport. She noted that the COS patients studied by her group had a higher likelihood of carrying these rare structural mutations than did the classic schizophrenia cohort, probably because the COS patients are a more homogeneous group. COS is a rare and severe form of the disease with an onset before age 13.Mutations Came From Healthy ParentsMost of the rare mutations identified in the COS patients were inherited from their healthy parents, which adds to the mystery. “[The mutations] are risk factors, but they are neither necessary nor sufficient for developing schizophrenia,” she said. Structural mutations may also occur spontaneously.This type of genetic variations throughout chromosomes may be a lot more important to disease pathology than previously expected. In a study published in the April 20, 2007, Science, Jonathan Sebat and colleagues linked the same type of structural mutations to autism spectrum disorders. The number of genes disrupted by these mutations and the signaling pathways affected by these disrupted genes may be staggering.In the current study, a particular microdeletion and a microduplication identified in several COS patients in the study had previously been linked to autism, mental retardation, and bipolar disorder. All this evidence seems to suggest that one psychiatric disorder in different patients may originate from a variety of genetic mutations in a complex web of pathways during brain development, and different disorders may share some of the same mutations and pathways. “Anyone in the [schizophrenia genetics] research knows that the reality is exponentially more complicated than what we already know,” Rapoport said.An abstract of “Rare Structural Variants Disrupt Multiple Genes in Neuro-developmental Pathways in Schizophrenia” is posted at<www.sciencemag.org/cgi/content/abstract/1155174>.▪ ISSUES NewArchived

Genetics of Schizophrenia

Although complex disorders such as schizophrenia have a heritable component, identifying the genetic components associated has been very difficult. Walsh et al. found that multiple, individually rare, structural mutations (genomic microdeletions and -duplications) occurred more frequently in 150 individuals with schizophrenia than in controls. The enrichment was more than threefold among schizophrenia cases generally and more than fourfold among schizophrenia cases with onset by age 18. The genes disrupted by the genomic breakpoints of mutations in the schizophrenia patients were not random but were disproportionately members of pathways controlling neuronal signaling and brain development. T. Walsh, J. M. McClellan, S. E. McCarthy, A. M. Addington, S. B. Pierce, G. M. Cooper, A. S. Nord, M. Kusenda, D. Malhotra, A. Bhandari, S. M. Stray, C. F. Rippey, P. Roccanova, V. Makarov, B. Lakshmi, R. L. Findling, L. Sikich, T. Stromberg, B. Merriman, N. Gogtay, P. Butler, K. Eckstrand, L. Noory, P. Gochman, R. Long, Z. Chen, S. Davis, C. Baker, E. E. Eichler, P. S. Meltzer, S. F. Nelson, A. B. Singleton, M. K. Lee, J. L. Rapoport, M.-C. King, J. Sebat, Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320 , 539-543 (2008). [Abstract] [Full Text]

Rare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia

Schizophrenia is a devastating neurodevelopmental disorder whose genetic influences remain elusive. We hypothesize that individually rare structural variants contribute to the illness. Microdeletions and microduplications >100 kilobases were identified by microarray comparative genomic hybridization of genomic DNA from 150 individuals with schizophrenia and 268 ancestry-matched controls. All variants were validated by high-resolution platforms. Novel deletions and duplications of genes were present in 5% of controls versus 15% of cases and 20% of young-onset cases, both highly significant differences. The association was independently replicated in patients with childhood-onset schizophrenia as compared with their parents. Mutations in cases disrupted genes disproportionately from signaling networks controlling neurodevelopment, including neuregulin and glutamate pathways. These results suggest that multiple, individually rare mutations altering genes in neurodevelopmental pathways contribute to schizophrenia.