Genome-wide association study in a Swedish population yields support for greater CNV and MHC involvement in schizophrenia compared with bipolar disorder

Schizophrenia (SCZ) and bipolar disorder (BD) are highly heritable psychiatric disorders with overlapping susceptibility loci and symptomatology. We conducted a genome-wide association study (GWAS) of these disorders in a large Swedish sample. We report a new and independent case–control analysis of 1507 SCZ cases, 836 BD cases and 2093 controls. No single-nucleotide polymorphisms (SNPs) achieved significance in these new samples; however, combining new and previously reported SCZ samples (2111 SCZ and 2535 controls) revealed a genome-wide significant association in the major histocompatibility complex (MHC) region (rs886424, P = 4.54 × 10−8). Imputation using multiple reference panels and meta-analysis with the Psychiatric Genomics Consortium SCZ results underscored the broad, significant association in the MHC region in the full SCZ sample. We evaluated the role of copy number variants (CNVs) in these subjects. As in prior reports, deletions were enriched in SCZ, but not BD cases compared with controls. Singleton deletions were more frequent in both case groups compared with controls (SCZ: P = 0.003, BD: P = 0.013), whereas the largest CNVs (>500 kb) were significantly enriched only in SCZ cases (P = 0.0035). Two CNVs with previously reported SCZ associations were also overrepresented in this SCZ sample: 16p11.2 duplications (P = 0.0035) and 22q11 deletions (P = 0.03). These results reinforce prior reports of significant MHC and CNV associations in SCZ, but not BD

Copy number variation in schizophrenia in Sweden

Schizophrenia is a highly heritable neuropsychiatric disorder of complex genetic etiology. Previous genome-wide surveys have revealed a greater burden of large, rare CNVs in schizophrenia cases and identified multiple rare recurrent CNVs that increase risk of schizophrenia although with incomplete penetrance and pleiotropic effects. Identification of additional recurrent CNVs and biological pathways enriched for schizophrenia CNVs requires greater sample sizes. We conducted a genome-wide survey for CNVs associated with schizophrenia using a Swedish national sample (4,719 cases and 5,917 controls). High-confidence CNV calls were generated using genotyping array intensity data and their effect on risk of schizophrenia was measured. Our data confirm increased burden of large, rare CNVs in schizophrenia cases as well as significant associations for recurrent 16p11.2 duplications, 22q11.2 deletions and 3q29 deletions. We report a novel association for 17q12 duplications (odds ratio=4.16, P=0.018), previously associated with autism and mental retardation but not schizophrenia. Intriguingly, gene set association analyses implicate biological pathways previously associated with schizophrenia through common variation and exome sequencing (calcium channel signaling and binding partners of the fragile X mental retardation protein). We found significantly increased burden of the largest CNVs (>500Kb) in genes present in the post-synaptic density, in genomic regions implicated via schizophrenia genome-wide association studies, and in gene products localized to mitochondria and cytoplasm. Our findings suggest that multiple lines of genomic inquiry – genome-wide screens for CNVs, common variation, and exonic variation – are converging on similar sets of pathways and/or genes

The Role of Thioredoxin Reductases in Brain Development

The thioredoxin-dependent system is an essential regulator of cellular redox balance. Since oxidative stress has been linked with neurodegenerative disease, we studied the roles of thioredoxin reductases in brain using mice with nervous system (NS)-specific deletion of cytosolic (Txnrd1) and mitochondrial (Txnrd2) thioredoxin reductase. While NS-specific Txnrd2 null mice develop normally, mice lacking Txnrd1 in the NS were significantly smaller and displayed ataxia and tremor. A striking patterned cerebellar hypoplasia was observed. Proliferation of the external granular layer (EGL) was strongly reduced and fissure formation and laminar organisation of the cerebellar cortex was impaired in the rostral portion of the cerebellum. Purkinje cells were ectopically located and their dendrites stunted. The Bergmann glial network was disorganized and showed a pronounced reduction in fiber strength. Cerebellar hypoplasia did not result from increased apoptosis, but from decreased proliferation of granule cell precursors within the EGL. Of note, neuron-specific inactivation of Txnrd1 did not result in cerebellar hypoplasia, suggesting a vital role for Txnrd1 in Bergmann glia or neuronal precursor cells

Genome-wide Association Analysis Identifies 14 New Risk Loci for Schizophrenia

Schizophrenia is a heritable disorder with 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, 6,243 controls) followed by meta-analysis with prior schizophrenia GWAS (8,832 cases, 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls, and 581 trios). In total, 22 regions met genome-wide significance (14 novel and one previously implicated in bipolar disorder). The results strongly implicate calcium signaling in the etiology of schizophrenia, and include genome-wide significant results for CACNA1C and CACNB2 whose protein products interact. We estimate that ∼8,300 independent and predominantly common SNPs contribute to risk for schizophrenia and that these collectively account for most of its heritability. Common genetic variation plays an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this devastating disorder

Involvement of glutaredoxin-1 and thioredoxin-1 in -amyloid toxicity and Alzheimer's disease

25 páginas, 10 figuras.Strong evidence indicates oxidative stress in the pathogenesis of Alzheimer's disease (AD). Amyloid (A) has been implicated in both oxidative stress mechanisms and in neuronal apoptosis. Glutaredoxin-1 (GRX1) and thioredoxin-1 (TRX1) are antioxidants that can inhibit apoptosis signal-regulating kinase (ASK1). We examined levels of GRX1 and TRX1 in AD brain as well as their effects on A neurotoxicity. We show an increase in GRX1 and a decrease in neuronal TRX1 in AD brains. Using SH-SY5Y cells, we demonstrate that A causes an oxidation of both GRX1 and TRX1, and nuclear export of Daxx, a protein downstream of ASK1. Atoxicity was inhibited by insulin-like growth factor-I (IGF-I) and by overexpressing GRX1 or TRX1. Thus, A neurotoxicity might be mediated by oxidation of GRX1 or TRX1 and subsequent activation of the ASK1 cascade. Deregulation of GRX1 and TRX1 antioxidant systems could be important events in AD pathogenesis.This research was supported by grants from the following Swedish foundations: Hjärnfonden (Swedish Brain Foundation), Gun och Bertil Stohnes Stiftelse, Karolinska Institutets Foundation for geriatric research, Loo and Hans Ostermans Foundation, Åke Wiberg Foundation, Svenska Lundbeck-stiftelsen, Demensförbundet, Alzheimer Foundation; Sweden, Lars Hiertas minnesstiftelse, Gamla Tjänarinnor foundation, Insamlingsstiftelsen för Alzheimer och demenforskning (SADF) and Swedish Brain Power project. AM-V was supported by Swedish Medical Research Council (Projects 03P-14096, 03X-14041, and 13X-10370). AJ was supported by a postdoctoral fellowship EX2003-0390 from the Spanish Ministerio de Educacion, Cultura y Deporte.Peer reviewe

Activity-regulated cytoskeleton-associated protein in rodent brain is down-regulated by high fat diet in vivo and by 27-hydroxycholesterol in vitro

Growing evidence strongly suggests that high fat diet (HFD) has an important role in some neurodegenerative disorders, including Alzheimer's disease (AD). To identify new cellular pathways linking hypercholesterolemia and neurodegeneration, we analyzed the effects of HFD on gene expression in mouse brain. Using cDNA microarrays and real time RT-PCR, we found that HFD has a mild, but significant effect on the expression of several genes. The altered genes include molecules linked to AD pathology and others of potential interest for neurodegeneration. We further investigated the effect of HFD on the activity-regulated cytoskeleton-associated protein (Arc). Expression of Arc was decreased in cerebral cortex and hippocampus of HFD-fed animals. From the known regulatory mechanisms of Arc expression, HFD reduced N-methyl-D-aspartate receptor (NMDAR) activity, as seen by decreases in tyrosine phosphorylation of NMDAR2A and levels of NMDAR1. Additionally, we demonstrated that 27-hydroxycholesterol, a cholesterol metabolite that enters the brain from the blood, decreases Arc levels as well as NMDAR and Src kinase activities in rat primary hippocampal neurons. Finally, we showed that Arc levels are decreased in the cortex of AD brains. We propose that one of the mechanisms, by which hypercholesterolemia contributes to neurodegenerative diseases, could be through Arc down-regulation caused by 27-hydroxycholesterol

Genome-wide association study in a Swedish population yields support for greater CNV and MHC involvement in schizophrenia compared with bipolar disorder

Schizophrenia (SCZ) and bipolar disorder (BD) are highly heritable psychiatric disorders with overlapping susceptibility loci and symptomatology. We conducted a genome-wide association study (GWAS) of these disorders in a large Swedish sample. We report a new and independent case-control analysis of 1507 SCZ cases, 836 BD cases and 2093 controls. No single-nucleotide polymorphisms (SNPs) achieved significance in these new samples; however, combining new and previously reported SCZ samples (2111 SCZ and 2535 controls) revealed a genome-wide significant association in the major histocompatibility complex (MHC) region (rs886424, P4.54 × 10 8). Imputation using multiple reference panels and meta-analysis with the Psychiatric Genomics Consortium SCZ results underscored the broad, significant association in the MHC region in the full SCZ sample. We evaluated the role of copy number variants (CNVs) in these subjects. As in prior reports, deletions were enriched in SCZ, but not BD cases compared with controls. Singleton deletions were more frequent in both case groups compared with controls (SCZ: P0.003, BD: P0.013), whereas the largest CNVs (500 kb) were significantly enriched only in SCZ cases (P0.0035). Two CNVs with previously reported SCZ associations were also overrepresented in this SCZ sample: 16p11.2 duplications (P0.0035) and 22q11 deletions (P0.03). These results reinforce prior reports of significant MHC and CNV associations in SCZ, but not BD

Biomarkers in the Assessment of Therapies for Familial Amyloidotic Polyneuropathy

The identification of specific biomarkers provides opportunities to develop early diagnostic parameters, monitor disease progression, and test drug efficiency in clinical trials. We previously demonstrated that in familial amyloidotic polyneuropathy (FAP) related to the abnormal extracellular tissue deposition of mutant transthyretin (TTR), inflammatory and apoptotic pathways are triggered in the presymptomatic stages of the disease, when nonfibrillar TTR deposits are present. In the present work, to better define biomarkers for future assessment of prophylactic and therapeutic drugs in the treatment of FAP, we extended the search for oxidative stress and apoptotic biomarkers to clinical samples and animal models presenting nonfibrillar and fibrillar TTR. We found that lipid peroxidation measured by hydroxynonenal, oxidative DNA damage measured by 8-hydroxy-2′-deoxyguanosine, and cellular redox homeostasis measured by glutaredoxin 1 were consistently increased in biopsy specimens from FAP patients and in tissues from transgenic mouse models presenting nonfibrillar TTR deposition. Death-receptor Fas, caspase-8, and Bax were also found to be increased, indicative of the involvement of death receptors in the observed apoptosis process. Removal of TTR deposition by an immunization protocol resulted in significant decreases of the selected markers we describe, corroborating the relationship between TTR deposition, oxidative stress, and apoptosis. Taken together, our results provide a robust biomarker profile for initial experimental animal studies and clinical trials to assess the application of the selected markers in therapies aimed at removal and/or inhibition of TTR polymerization