Over 100 genetic loci harbor schizophrenia associated variants, yet how these variants confer liability is uncertain. The CommonMind Consortium sequenced RNA from dorsolateral prefrontal cortex of schizophrenia cases (N = 258) and control subjects (N = 279), creating a resource of gene expression and its genetic regulation. Using this resource, ~20% of schizophrenia loci have variants that could contribute to altered gene expression and liability. In five loci, only a single gene was involved: FURIN, TSNARE1, CNTN4, CLCN3, or SNAP91. Altering expression of FURIN, TSNARE1, or CNTN4 changes neurodevelopment in zebrafish; knockdown of FURIN in human neural progenitor cells yields abnormal migration. Of 693 genes showing significant case/control differential expression, their fold changes are ≤ 1.33, and an independent cohort yields similar results. Gene co-expression implicates a network relevant for schizophrenia. Our findings show schizophrenia is polygenic and highlight the utility of this resource for mechanistic interpretations of genetic liability for brain diseases.

73Over 100 genetic loci harbor schizophrenia associated variants, yet how these common 74 variants confer risk is uncertain. The CommonMind Consortium has sequenced dorsolateral 75 prefrontal cortex RNA from schizophrenia cases (n=258) and control subjects (n=279), creating 76 the largest publicly available resource to date of gene expression and its genetic regulation; ~5 77 times larger than the latest release of GTEx. Using this resource, we find that ~20% of the 78 schizophrenia risk loci have common variants that could explain regulation of brain gene 79 expression. In five loci, these variants modulate expression of a single gene: FURIN, TSNARE1, 80 CNTN4, CLCN3 or SNAP91. Experimentally altered expression of three of them, FURIN, 81 TSNARE1, and CNTN4, perturbs the proliferation and apoptotic index of neural progenitors and 82 leads to neuroanatomical deficits in zebrafish. Furthermore, shRNA mediated knock-down of 83 FURIN in neural progenitor cells derived from human induced pluripotent stem cells produces 84 abnormal neural migration. Although 4.2% of genes (N = 693) display significant differential 85 expression between cases and controls, 44% show some evidence for differential expression. 86All fold changes are ≤ 1.33, and an independent cohort yields similar differential expression for 87 these 693 genes (r = 0.58). These findings are consistent with schizophrenia being highly 88 polygenic, as has been reported in investigations of common and rare genetic variation. Co-89 expression analyses identify a gene module that shows enrichment for genetic associations and 90 is thus relevant for schizophrenia. Taken together, these results pave the way for mechanistic 91 interpretations of genetic liability for schizophrenia and other brain diseases. 4The human brain is complicated and not well understood. Seemingly straightforward 93 fundamental information such as which genes are expressed therein and what functions they 94 perform are only partially characterized. To overcome these obstacles, we established the 95 CommonMind Consortium (CMC; www.synpase.org/CMC), a public-private partnership to 96 generate functional genomic data in brain samples obtained from autopsies of cases with and 97 without severe psychiatric disorders. The CMC is the largest existing collection of collaborating 98 brain banks and includes over 1,150 samples. A wide spectrum of data is being generated on 99 these samples including regional gene expression, epigenomics (cell-type specific histone 100 modifications and open chromatin), whole genome sequencing, and somatic mosaicism. 101 102 Schizophrenia (SCZ), affecting roughly 0.7% of adults, is a severe psychiatric disorder 103 characterized by abnormalities in thought and cognition (1). Despite a century of evidence 104 establishing its genetic basis, only recently have specific genetic risk factors been conclusively 105identified, including rare copy number variants (2) and >100 common variants (3). However, 106 there is not a one-to-one Mendelian mapping between these SCZ ris...

Alzheimer disease (AD) is a devastating neurodegenerative disease with no cure. The pathogenesis of AD is believed to be driven primarily by amyloid-␤ (A␤), the principal component of senile plaques. A␤ is an ϳ4-kDa peptide generated via cleavage of the amyloid-␤ precursor protein (APP). Curcumin is a compound in the widely used culinary spice, turmeric, which possesses potent and broad biological activities, including anti-inflammatory and antioxidant activities, chemopreventative effects, and effects on protein trafficking. Recent in vivo studies indicate that curcumin is able to reduce A␤-related pathology in transgenic AD mouse models via unknown molecular mechanisms. Here, we investigated the effects of curcumin on A␤ levels and APP processing in various cell lines and mouse primary cortical neurons. We show for the first time that curcumin potently lowers A␤ levels by attenuating the maturation of APP in the secretory pathway. These data provide a mechanism of action for the ability of curcumin to attenuate amyloid-␤ pathology.

BackgroundTo date, nine Parkinson disease (PD) genome-wide association studies in North American, European and Asian populations have been published. The majority of studies have confirmed the association of the previously identified genetic risk factors, SNCA and MAPT, and two studies have identified three new PD susceptibility loci/genes (PARK16, BST1 and HLA-DRB5). In a recent meta-analysis of datasets from five of the published PD GWAS an additional 6 novel candidate genes (SYT11, ACMSD, STK39, MCCC1/LAMP3, GAK and CCDC62/HIP1R) were identified. Collectively the associations identified in these GWAS account for only a small proportion of the estimated total heritability of PD suggesting that an 'unknown' component of the genetic architecture of PD remains to be identified.MethodsWe applied a GWAS approach to a relatively homogeneous Ashkenazi Jewish (AJ) population from New York to search for both 'rare' and 'common' genetic variants that confer risk of PD by examining any SNPs with allele frequencies exceeding 2%. We have focused on a genetic isolate, the AJ population, as a discovery dataset since this cohort has a higher sharing of genetic background and historically experienced a significant bottleneck. We also conducted a replication study using two publicly available datasets from dbGaP. The joint analysis dataset had a combined sample size of 2,050 cases and 1,836 controls.ResultsWe identified the top 57 SNPs showing the strongest evidence of association in the AJ dataset (p < 9.9 × 10-5). Six SNPs located within gene regions had positive signals in at least one other independent dbGaP dataset: LOC100505836 (Chr3p24), LOC153328/SLC25A48 (Chr5q31.1), UNC13B (9p13.3), SLCO3A1(15q26.1), WNT3(17q21.3) and NSF (17q21.3). We also replicated published associations for the gene regions SNCA (Chr4q21; rs3775442, p = 0.037), PARK16 (Chr1q32.1; rs823114 (NUCKS1), p = 6.12 × 10-4), BST1 (Chr4p15; rs12502586, p = 0.027), STK39 (Chr2q24.3; rs3754775, p = 0.005), and LAMP3 (Chr3; rs12493050, p = 0.005) in addition to the two most common PD susceptibility genes in the AJ population LRRK2 (Chr12q12; rs34637584, p = 1.56 × 10-4) and GBA (Chr1q21; rs2990245, p = 0.015).ConclusionsWe have demonstrated the utility of the AJ dataset in PD candidate gene and SNP discovery both by replication in dbGaP datasets with a larger sample size and by replicating association of previously identified PD susceptibility genes. Our GWAS study has identified candidate gene regions for PD that are implicated in neuronal signalling and the dopamine pathway.

The availability of high-quality RNA-sequencing and genotyping data of post-mortem brain collections from consortia such as CommonMind Consortium (CMC) and the Accelerating Medicines Partnership for Alzheimer’s Disease (AMP-AD) Consortium enable the generation of a large-scale brain cis-eQTL meta-analysis. Here we generate cerebral cortical eQTL from 1433 samples available from four cohorts (identifying >4.1 million significant eQTL for >18,000 genes), as well as cerebellar eQTL from 261 samples (identifying 874,836 significant eQTL for >10,000 genes). We find substantially improved power in the meta-analysis over individual cohort analyses, particularly in comparison to the Genotype-Tissue Expression (GTEx) Project eQTL. Additionally, we observed differences in eQTL patterns between cerebral and cerebellar brain regions. We provide these brain eQTL as a resource for use by the research community. As a proof of principle for their utility, we apply a colocalization analysis to identify genes underlying the GWAS association peaks for schizophrenia and identify a potentially novel gene colocalization with lncRNA RP11-677M14.2 (posterior probability of colocalization 0.975).

Alzheimer disease (AD) is a devastating neurodegenerative disease with complex and strong genetic inheritance. Four genes have been established to either cause familial early onset AD (APP, PSEN1, and PSEN2) or to increase susceptibility for late onset AD (APOE). To date ϳ80% of the late onset AD genetic variance remains elusive. Recently our genome-wide association screen identified four novel late onset AD candidate genes. Ataxin 1 (ATXN1) is one of these four AD candidate genes and has been indicated to be the disease gene for spinocerebellar ataxia type 1, which is also a neurodegenerative disease. Mounting evidence suggests that the excessive accumulation of A␤, the proteolytic product of ␤-amyloid precursor protein (APP), is the primary AD pathological event. In this study, we ask whether ATXN1 may lead to AD pathogenesis by affecting A␤ and APP processing utilizing RNA interference in a human neuronal cell model and mouse primary cortical neurons. We show that knock-down of ATXN1 significantly increases the levels of both A␤40 and A␤42. This effect could be rescued with concurrent overexpression of ATXN1. Moreover, overexpression of ATXN1 decreased A␤ levels. Regarding the underlying molecular mechanism, we show that the effect of ATXN1 expression on A␤ levels is modulated via ␤-secretase cleavage of APP. Taken together, ATXN1 functions as a genetic risk modifier that contributes to AD pathogenesis through a loss-offunction mechanism by regulating ␤-secretase cleavage of APP and A␤ levels. Alzheimer disease (AD)2 is a devastating neurodegenerative disorder that is clinically characterized by deterioration of memory and cognitive function, progressive impairment of daily living activities, and several neuropsychiatric symptoms (1). On the cellular and molecular levels, the pathophysiology of AD is characterized by two distinctive features: amyloid plaques comprised primarily of a small peptide named A␤ (2-4), and neurofibrillary tangles composed of hyperphosphorylated Tau. Although A␤42 and A␤40 are the two primary A␤ species, A␤42 is more prevalent than A␤40 in amyloid plaques. Considerable genetic, biochemical, and molecular biological evidence suggests that the excessive accumulation of A␤ is the primary pathological event leading to AD (2, 4, 5). A␤ is produced by a sequential proteolytic cleavage of a type I transmembrane protein, ␤-amyloid precursor protein (APP) (6). The initial cleavage of APP can occur through ␣-or ␤-secretase (or BACE1). ␣-Secretase cleavage produces sAPP␣ and the ␣-C-terminal fragment (C83); ␤-secretase cleavage produces sAPP␤ and the ␤-C-terminal fragment (C99). Following trophic factor deprivation, sAPP␤ can be further cleaved by an unidentified protease, to produce N-APP, which contains the N-terminal 286 amino acids of APP (7). C83 and C99 can be further cleaved by ␥-secretase to produce P3 or A␤.AD is a genetically complex disease and only four genes have been established to either cause early onset autosomal dominant AD with complete penetrance (APP, PSEN1, and PSEN2) or t...

The popularity of this outpatient technique with patients reflects ease of treatment, lower cost, lack of downtime and elimination of venous signs and symptoms. Patients accept that UGFS can be repeated readily if required for recurrence in this common chronic condition. The subclinical ultrasound evidence of recanalization or new vein incompetence needs to be considered in this light.

A disposable on-chip whole blood/plasma separator, which is able to separate plasma from whole human blood by capillary force through a bead-packed microchannel, has been designed, fabricated and characterized in this work. Various sizes of silica beads were slurry-packed through a microchannel using a bump structure which held beads in a defined region. The bead-packed microchannel induces a capillary force which allows plasma to move forward through the bead-packed column more rapidly than red blood cells (RBCs). The blood/plasma separator with bead-packed microchannel has successfully separated plasma from the whole blood without haemolysis of RBCs. The separation method developed in this work can be applied to various on-chip stationary filtrations of RBC for point-of-care clinical diagnostics.