Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.

/pdf/biological-insights-from-108-schizophrenia-associated-3rfvth8dm9.pdf

Biological insights from 108 schizophrenia-associated genetic loci

The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

/pdf/integrative-analysis-of-111-reference-human-epigenomes-4bavnjaon6.pdf

Integrative analysis of 111 reference human epigenomes

The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells.

CD4+ T cells, upon activation and expansion, develop into different T helper cell subsets with different cytokine profiles and distinct effector functions. Until recently, T cells were divided into Th1 or Th2 cells, depending on the cytokines they produce. A third subset of IL-17-producing effector T helper cells, called Th17 cells, has now been discovered and characterized. Here, we summarize the current information on the differentiation and effector functions of the Th17 lineage. Th17 cells produce IL-17, IL-17F, and IL-22, thereby inducing a massive tissue reaction owing to the broad distribution of the IL-17 and IL-22 receptors. Th17 cells also secrete IL-21 to communicate with the cells of the immune system. The differentiation factors (TGF-β plus IL-6 or IL-21), the growth and stabilization factor (IL-23), and the transcription factors (STAT3, RORγt, and RORα) involved in the development of Th17 cells have just been identified. The participation of TGF-β in the differentiation of Th17 cells places ...

IL-17 and Th17 Cells.

Understanding the functional consequences of genetic variation, and how it affects complex human disease and quantitative traits, remains a critical challenge for biomedicine. We present an analysi...

The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans

W1216 Disease Activity and pANCA Status Determine Early Response to Infliximab in Ulcerative Colitis

OBJECTIVES: Recent data suggest functional interactions between NOD2 and other receptors of the innate immune system modulating infl ammatory responses. Here we analyzed the role of Toll-like receptor 9 ( TLR-9 ) gene variants with respect to susceptibility to infl ammatory bowel disease (IBD) and tested for genetic interactions with NOD2 and other susceptibility genes for Crohn ' s disease (CD).

Response to Tsai et al.

Abstract Rising interest rates will impact municipal budgets in Germany by increasing the cost of loans and making it more difficult to finance necessary investments in infrastructure and transformation. While most municipalities should have sufficient leeway to deal with higher interest rates, highly indebted municipalities may be strongly affected by rising interest rates. In these municipalities, interest costs are increasing strongly, budgetary margins are narrower anyway, and these municipalities are more dependent on loans to finance their investments. Rising interest rates thus once again reveal the unresolved and fundamental challenges for the municipal financial system in Germany.

/pdf/kommunalfinanzen-in-zeiten-steigender-zinsen-3hb5xih0.pdf

Kommunalfinanzen in Zeiten steigender Zinsen

SIR, Thank you for commenting on our study published in AP&T (1). However, we disagree on the comments made by Szalai and Alarcón (2): (i) We never stated that the +1059G/C CRP polymorphism is associated with Crohn’s disease (CD 1 ). Instead, we pointed out in this article: ‘Our results demonstrate that the CRP +1059G/C polymorphism is not over-represented in CD patients compared with the normal population...’ (see page 1111 of Ref. ). In particular, none of the P-values comparing the genotypes in patients with CD with healthy controls demonstrated significance in our analysis (Table 3). Therefore, our conclusion was not – as claimed by Szalai and Alarcón – that this polymorphism is associated with CD, but that this polymorphism is associated with involvement of the terminal ileum and decreased serum CRP levels in patients with CD. This conclusion was not solely based on 5 CC homozygous patients but on all carriers of C alleles, which form the combined group of CC homozygous (n 1⁄4 5) and GC heterozygous carriers (n 1⁄4 17), compared with all wild-type carriers (n 1⁄4 219). (ii) All P-values given in Table 3 are >0.05 (and not <0.05 as assumed by Szalai and Alarcón) and therefore not significant, which is consistent with the result of the chi-squared test as performed by Szalai and Alarcón. (iii) Given our P-values in Table 2 and our explanations in the figure legend and the corresponding text in the Results and Discussion sections, it should have become clear that the conclusions drawn were not based on only five homozygous patients with the CC genotype but rather on the combined group of GC (n 1⁄4 17) and CC genotypes (n 1⁄4 5). Performing the analysis with the combined L1 phenotype (ileal involvement) and L3 phenotype (ileocolonic involvement), as suggested by Szalai and Alarcón, the prevalences were as follows: 58.4% among GG wild-type carriers (128/219), 88.2% among GC heterozygotes (15/17), and 80% among CC homozygotes (4/5). Analysing the resulting 3-by-2 Table (three genotypes vs. ileal involvement yes/no), as suggested by Szalai and Alarcón, yields a P-value below a 1⁄4 0.05, namely P 1⁄4 0.029 (Fisher’s exact test). Given that GG wild-type patients are by far the largest genotype group (90.9%) of all patients analysed, it is not unexpected that they also are the largest patient group with ileal involvement, as they are in all other phenotype categories: L1 (72.7%), L2 (97.9%), L3 (89.6%), L4 (95.7%). Nonetheless, GG wild-type patients are relatively underrepresented in the L1 group (ileal involvement only). In view of the exploratory, i.e. rather hypothesis-generating than confirmatory, character of our analyses, we agree with Szalai and Alarcón that large studies are necessary to confirm our results. This point was discussed in great detail in the Discussion section of our article (for details see page 1112/1113 of ref. ), which also included a power calculation. Depending on the prevalence of the CC genotype in different populations, between 1042 and 25000 patients would be necessary to demonstrate with 80% power an association of CC homozygosity with CD, which clearly can only be achieved in a large multicentre study, but also demonstrates that this polymorphism is not a major contributor to overall disease susceptibility for CD. S. BRAND* & A. CRISP IN *Department of Medicine II, University-Hospital Munich-Grosshadern, Munich, Germany; Department of Informatics, Biometry and Epidemiology, University of Munich, Munich, Germany E-mail: stephan.brand@med. uni-muenchen.de

Stephan Brand

Papers

W1216 Disease Activity and pANCA Status Determine Early Response to Infliximab in Ulcerative Colitis

Response to Tsai et al.

Kommunalfinanzen in Zeiten steigender Zinsen

C-reactive protein polymorphism and Crohn's disease: authors' reply