Objective: Individuals with schizophrenia and substance use disorders have a poor prognosis and increased psychiatric symptoms. The present study aimed to explore the association of 106 genes in individuals with schizophrenia and comorbid substance use through a next-generation sequencing (NGS) analysis and different in silico algorithms. Methods: We included 105 individuals diagnosed with schizophrenia and a family history of schizophrenia, of whom 49 (46.67%) presented comorbid substance use. Using NGS, we sequenced 106 genes previously associated with schizophrenia. Logistic regression models were used to assess differences in allele frequencies, and a generalized gene-set analysis was performed at the gene level. Functional annotations were performed using different algorithms and databases. Results: We identified a total of 3,109 variants, of which 25 were associated with schizophrenia and comorbid substance use and were located in regulatory and coding regions. We found low-frequency variants in COMT p.Ala72Ser, independently of p.Val158Met, that were associated with substance use. The endocannabinoid functional variant FAAH p.Pro129Thr was also associated with substance use. Conclusions: Genetic variants of genes related to dopaminergic and cannabinoid neurotransmitter systems were associated with comorbid substance use in schizophrenia. Nevertheless, more studies with larger sample sizes are needed to confirm our findings.

Pharmacogenomics (PGx), one of the several tools of precision medicine, has been slowly implemented in the clinic during the past decades. This process generally starts with direct and indirect genotype-phenotype associations of gene variants and drug efficacy, or adverse drug reactions, followed by replication and validation studies. Institutional efforts led by the PGx Research Network, The PGx Knowledge Base, and The Clinical Pharmacogenetics Implementation Consortium, mine all available data for further validation or research in additional populations. This data mining gives rise to a detailed classification of over 200 drug-gene pairs which, with enough documentation, may become part of a publishable guideline to aid clinicians in drug selection and dosing using genetics. The US Food and Drug Administration utilizes these guidelines to issue warnings and recommendations for specific drugs and their cautioning serves clinicians and pharmacists worldwide. Here, we aim to discuss the steps of this process and list existing actionable drug-gene pairs. Moreover, we describe the current status of PGx knowledge in populations from Mexico for actionable variants on the 19 genes listed by present PGx guidelines affecting 47 drugs. Our review collects current allele frequency information for these actionable variants, lists gaps of PGx information for relevant markers, and highlights the importance of continuing PGx research in Native and Mestizo populations. (REV INVEST CLIN. 2020;72(5):271-9)

Abstract Background Schizophrenia (SCZ) and dementia, often related, are two of the most common neuropsychiatric diseases; epidemiological studies have shown that SCZ patients present a 2-fold increased risk for dementia compared to non-schizophrenic individuals. We explored the presence of rare and novel damaging gene variants in patients diagnosed with late-onset dementia of Alzheimer’s type (DAT) or SCZ. Methods We included 7 DAT and 12 SCZ patients and performed high-depth targeted sequencing of 184 genes. Results We found novel and rare damaging variants in 18 genes in these Mexican patients. Carriers of these variants showed extreme phenotypes, including, treatment-resistant SCZ or cognitive decline. Furthermore, we found a variation on ABCC1 as a possible link between psychosis and cognitive impairment. Discussion As an exploratory analysis, we report some interesting variations that should be corroborated in larger sample size studies.

Fmoc-trinucleoside-diphosphate phosphoramidites are molecules assembled with three nucleosides, having application as mutagenic units during automated synthesis of oligonucleotides. These synthons afford substitution of wild-type codons by complete mutant codons in a specific region of the target gene, avoiding at the protein level, the bias toward certain kind of amino acids that is generated with conventional methods of mutagenesis. In the present work, three pathways of organic synthesis were explored for the preparation of such valuable compounds, setting as main goal the achievement of clean, one-pot internucleotidic reactions that enable the easy purification of the target compound by column chromatography. Syntheses were performed in liquid-phase and gram-scales through the phosphotriester method. The best pathway for the preparation of dinucleotides and trinucleotides made use of 2-chlorophenyl-O,O-bis(1-hydroxybenzotriazoly)phosphate as phosphorylating reagent.

Los Fmoc-trinucleósido-difosfato fosforamiditos (FTDFs)¹ son moléculas compuestas por tres nucleósidos, teniendo aplicación como unidades mutagénicas durante el ensamble automatizado de oligonucleótidos. El uso de estos sintones permite sustituir codones silvestres por codones mutantes completos en una región determinada del gen de interés, evitando a nivel de proteína, el sesgo hacia sólo cierto tipo de aminoácidos que se genera con los métodos de mutagénesis basados en mutaciones puntuales de nucleótidos y también la redundancia de codones que se obtiene con la preparación de oligonucleótidos degenerados. En el presente trabajo se exploraron varias rutas sintéticas para su preparación, teniendo como principal objetivo lograr reacciones de acoplamiento internucleotídico limpias que faciliten los procesos de purificación cromatográficos, utilizando insumos de fácil preparación. Las síntesis se realizaron en fase líquida, en escalas de gramos, evaluando metodologías de fosfatotriéster. El mejor resultado se obtuvo usando 2-clorofenil-O,O-bis(1-hidroxibenzotriazolil)fosfato como reactivo fosforilante y tres reacciones sin aislar.