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An earlier age at onset (AAO) has been associated with greater genetic loadings in schizophrenia. This study aimed to identify modifier loci associated with an earlier AAO of schizophrenia. A genome-wide association analysis (GWAS) was conducted in 94 schizophrenia probands with the earliest AAO and 91 with the latest AAO. Candidate single nucleotide polymorphisms (SNPs) were then genotyped in the co-affected siblings and unrelated probands. Multi-SNP genetic risk scores (GRS) composed of the candidate loci were used to distinguish patients with an early or late AAO. The 14-SNP GRS could distinguish the co-affected siblings (n = 90) of the earliest probands from those (n = 91) of the latest probands. When 132 patients with an earlier AAO and 158 patients with a later AAO were included, a significant trend in the 14-SNP GRS was detected among those unrelated probands from 4 family groups with the earliest, earlier, later, and latest AAO. The overall effect of the 14 SNPs on an AAO in schizophrenia was verified using co-affected siblings of the GWAS probands and trend effect across unrelated patients. Preliminary network analysis of these loci revealed the involvement of PARK2, a gene intensively reported in Parkinson's disease and schizophrenia research.

Somatic mutations together with immunoediting drive extensive heterogeneity within non-small-cell lung cancer (NSCLC). Herein we examine heterogeneity of the T cell antigen receptor (TCR) repertoire. The number of TCR sequences selectively expanded in tumors varies within and between tumors and correlates with the number of nonsynonymous mutations. Expanded TCRs can be subdivided into TCRs found in all tumor regions (ubiquitous) and those present in a subset of regions (regional). The number of ubiquitous and regional TCRs correlates with the number of ubiquitous and regional nonsynonymous mutations, respectively. Expanded TCRs form part of clusters of TCRs of similar sequence, suggestive of a spatially constrained antigen-driven process. CD8.sup.+ tumor-infiltrating lymphocytes harboring ubiquitous TCRs display a dysfunctional tissue-resident phenotype. Ubiquitous TCRs are preferentially detected in the blood at the time of tumor resection as compared to routine follow-up. These findings highlight a noninvasive method to identify and track relevant tumor-reactive TCRs for use in adoptive T cell immunotherapy. A survey of T cell repertoire evolution in the tumors, healthy tissue and blood of patients with early-stage untreated lung cancer offers an opportunity to monitor and identify neoantigen-specific T cells for personalized immunotherapy., Author(s): Kroopa Joshi [sup.1] [sup.2] , Marc Robert de Massy [sup.1] , Mazlina Ismail [sup.3] , James L. Reading [sup.1] , Imran Uddin [sup.3] , Annemarie Woolston [sup.3] , Emine [...]

An amendment to this paper has been published and can be accessed via a link at the top of the paper., Author(s): Kroopa Joshi [sup.1] [sup.2] , Marc Robert de Massy [sup.1] , Mazlina Ismail [sup.3] , James L. Reading [sup.1] , Imran Uddin [sup.3] , Annemarie Woolston [sup.3] , Emine [...]

An earlier age at onset (AAO) has been associated with greater genetic loadings in schizophrenia. This study aimed to identify modifier loci associated with an earlier AAO of schizophrenia. A genome-wide association analysis (GWAS) was conducted in 94 schizophrenia probands with the earliest AAO and 91 with the latest AAO. Candidate single nucleotide polymorphisms (SNPs) were then genotyped in the co-affected siblings and unrelated probands. Multi-SNP genetic risk scores (GRS) composed of the candidate loci were used to distinguish patients with an early or late AAO. The 14-SNP GRS could distinguish the co-affected siblings (n = 90) of the earliest probands from those (n = 91) of the latest probands. When 132 patients with an earlier AAO and 158 patients with a later AAO were included, a significant trend in the 14-SNP GRS was detected among those unrelated probands from 4 family groups with the earliest, earlier, later, and latest AAO. The overall effect of the 14 SNPs on an AAO in schizophrenia was verified using co-affected siblings of the GWAS probands and trend effect across unrelated patients. Preliminary network analysis of these loci revealed the involvement of PARK2, a gene intensively reported in Parkinson’s disease and schizophrenia research.

The T cell receptor repertoire provides a window into the cellular adaptive immune response. In the context of cancer, determining the repertoire within a tumor can give important insights into the evolution of the T cell anti-cancer response, and has the potential to identify specific personalized biomarkers for tracking host responses during cancer therapy, including immunotherapy. We describe a protocol for amplifying, sequencing and analyzing T cell receptors which is economical, robust, sensitive and versatile. The key experimental step is the ligation of a single stranded oligonucleotide to the 3' end of the T cell receptor cDNA, which allows easy amplification of all possible rearrangements using only a single set of primers per locus, while simultaneously introducing a unique molecular identifier to label each starting cDNA molecule. After sequencing, this molecular identifier can be used to correct both sequence errors and the effects of differential PCR amplification efficiency, thus producing a more accurate measure of the true T cell receptor frequency within the sample. We describe a detailed protocol describing this method to create libraries of T cell receptors from in vitro T cell cultures, blood or tissue samples. We combine this with a computational pipeline, which incorporates sample multiplexing, T cell receptor annotation and error correction to provide accurate counts of individual T cell receptor sequences within samples. The integrated experimental and computational pipeline should be of value to researchers interested in documenting and understanding the T cell immune response to cancer, and in manipulating it for therapeutic purposes., (© 2019 Elsevier Inc. All rights reserved.)