Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (OR=1.11, P=5.7×10−15), which persisted after excluding loci implicated in previous studies (OR=1.07, P=1.7 ×10−6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 ×10−11) and neurobehavioral phenotypes in mouse (OR = 1.18, P= 7.3 ×10−5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by non-allelic homologous recombination

Estimation of Genetic Correlation via Linkage Disequilibrium Score Regression and Genomic Restricted Maximum Likelihood

J. Lönnqvist on työryhmän Psychiat Genomics Consortium jäsen.Genetic correlation is a key population parameter that describes the shared genetic architecture of complex traits and diseases. It can be estimated by current state-of-art methods, i.e., linkage disequilibrium score regression (LDSC) and genomic restricted maximum likelihood (GREML). The massively reduced computing burden of LDSC compared to GREML makes it an attractive tool, although the accuracy (i.e., magnitude of standard errors) of LDSC estimates has not been thoroughly studied. In simulation, we show that the accuracy of GREML is generally higher than that of LDSC. When there is genetic heterogeneity between the actual sample and reference data from which LD scores are estimated, the accuracy of LDSC decreases further. In real data analyses estimating the genetic correlation between schizophrenia (SCZ) and body mass index, we show that GREML estimates based on similar to 150,000 individuals give a higher accuracy than LDSC estimates based on similar to 400,000 individuals (from combinedmeta-data). A GREML genomic partitioning analysis reveals that the genetic correlation between SCZ and height is significantly negative for regulatory regions, which whole genome or LDSC approach has less power to detect. We conclude that LDSC estimates should be carefully interpreted as there can be uncertainty about homogeneity among combined meta-datasets. We suggest that any interesting findings from massive LDSC analysis for a large number of complex traits should be followed up, where possible, with more detailed analyses with GREML methods, even if sample sizes are lesser.Peer reviewe

Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

While germline copy-number variants (CNVs) contribute to schizophrenia (SCZ) risk, the contribution of somatic CNVs (sCNVs)—present in some but not all cells—remains unknown. We identified sCNVs using blood-derived genotype arrays from 12,834 SCZ cases and 11,648 controls, filtering sCNVs at loci recurrently mutated in clonal blood disorders. Likely early-developmental sCNVs were more common in cases (0.91%) than controls (0.51%, p = 2.68e−4), with recurrent somatic deletions of exons 1–5 of the NRXN1 gene in five SCZ cases. Hi-C maps revealed ectopic, allele-specific loops forming between a potential cryptic promoter and non-coding cis-regulatory elements upon 5′ deletions in NRXN1. We also observed recurrent intragenic deletions of ABCB11, encoding a transporter implicated in anti-psychotic response, in five treatment-resistant SCZ cases and showed that ABCB11 is specifically enriched in neurons forming mesocortical and mesolimbic dopaminergic projections. Our results indicate potential roles of sCNVs in SCZ risk

Composição mineral do produto comercial da erva-mate (Ilex paraguariensis St. Hil.) Mineral composition of a commercial product from mate-herb (Ilex paraguariensis St. Hil.)

Com o objetivo de quantificar e avaliar a concentração mineral na matéria seca e na infusão de erva-mate tipo chimarrão, selecionaram-se três amostras comerciais, com ampla aceitação pelo consumidor, as quais foram amostradas com quatro repetições. Na industrialização da erva-mate tipo chimarrão, são utilizadas folhas, pecíolos e ramos finos, tendo uma composição aproximada de 30% ramos e 70% folhas, que são beneficiados para posterior comercialização. O preparo das amostras e as análises foram efetuadas no Laboratório de Nutrição Mineral de Plantas do Centro de Energia Nuclear na Agricultura (CENA/USP). Para determinação da composição mineral da matéria seca, as amostras foram moídas em moinho "tipo Willey", com posterior digestão e determinação dos teores de N, P, K, Ca, Mg, S, B, Cu, Fe, Mn, Ni, Zn, Al, Cd, Co, Cr, Na e Pb. Para determinação dos elementos na infusão, utilizaram-se 70g de erva-mate para um litro de água desionizada a 80ºC, simulando-se a temperatura para chimarrão, mantendo-se até esfriar e posteriormente coando-se. Os elementos analisados na infusão foram os determinados na matéria seca e, além destes, Mo, Ba, Si e Sr, exceto Co. As leituras das concentrações foram realizadas através da espectrometria de emissão atômica com plasma de argônio. Na matéria seca, os elementos que apresentaram maior destaque é a concentração são Mg e Mn. As maiores concentrações na infusão da erva-mate, em ordem decrescente, foram: K; Mg; S; Ca e P. Quanto à solubilidade do elemento, em relação a sua concentração na matéria seca foi a seguinte: B > S-SO4 > Zn > K > P > Mg =Mn > Cu > Cr, os demais apresentaram valores menores que 30%. A infusão da erva-mate apresenta altas concentrações de K, Mg e Mn (por ser um micronutriente), intermediárias de S, Ca e P, baixa de Al e zero de Cd e Pb.<br>The mineral composition of three commercial mate products and of the infusions thereof were evaluated, being four replicates used. In the industrial processing of 'chimarrão' mate-herb, leaves and twigs are employed, having an approximate proportion of 70% and 30% respectively. Both in the commercial mate products and their infusions N was determined by micro-Kjeldahl whereas P, K, Ca, Mg, S, B, Cu, Fe, Mn, Ni, Zn, Al, Cd, Co, Cr, Na, and Pb were analysed either by atomic absorption or by argon plasma. In the commercial product Mg and Mn were the main elements. In the infusions higher concentrations were in decreasing order: K, Mg, S, Ca and P. Solubility obeyed the order: B > S-SO4 > Zn > K > P > Mg =Mn > Cu > Cr. The remaining elements showed lower 30% soluble proportions. The infusion has high concentrations of K, Mg and Mn (a micronutrient), intermediate ones for S, Ca and P, low level of Al, and zero concentrations of Cd and Pb

Circulating Interleukin-1 and Tumor Necrosis Factor in Septic Shock and Experimental Endotoxin Fever

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