Meta-analysis of genome-wide association studies for cancer therapy-related cardiovascular dysfunction and functional mapping highlight an intergenic region close to TP63.

Cancer therapy-related cardiac dysfunction (CTRCD), which commonly includes left ventricular dysfunction and heart failure, is the main adverse effect of anticancer therapy. In recent years several candidate genes studies and genome-wide association studies have identified common genetic variants associated with CTRCD, but evidence remains limited and few genetic variants are robust. A genome-wide meta-analysis of CTRCD was performed with 852 oncology patients receiving cancer therapy. DNA samples were genotyped and imputed to perform a GWAS meta-analysis for case-control (N = 852 (380 cases and 472 controls) and extreme phenotypes (N = 618 (78 cases and 472 controls) looking for genetic variants that predispose to CTRCD. The results were validated in a replicate cohort of 1,191 oncology patients (245 cases and 946 controls). Functional mapping of the replicated loci was then performed. The meta-analysis showed 9 and 17 loci suggestively associated (P-value < 1 × 10-5) with CTRCD in case-control and extreme phenotypes analyses, respectively. The 3q28 locus (rs rs7652759, P = 5.64 × 10-6) in the case-control analysis was the strongest signal, with up to 64 SNPs above the suggestive significance threshold. The rs7652759, an intergenic variant between TPRG1 and TP63 genes, was the only variant validated in the replication cohort (P-value = 0.01). Functional mapping of this significant locus revealed up to 5 new genes potentially involved in the CTRCD. We identified the intergenic region near TP63 as a novel CTRCD susceptibility locus. In the future, the genotyping of these markers could be considered in new CTRCD risk scores to improve preventive strategies in cardio-oncology.

Psychiatric polygenic risk as a predictor of COVID-19 risk and severity: insight into the genetic overlap between schizophrenia and COVID-19.

Despite the high contagion and mortality rates that have accompanied the coronavirus disease-19 (COVID-19) pandemic, the clinical presentation of the syndrome varies greatly from one individual to another. Potential host factors that accompany greater risk from COVID-19 have been sought and schizophrenia (SCZ) patients seem to present more severe COVID-19 than control counterparts, with certain gene expression similarities between psychiatric and COVID-19 patients reported. We used summary statistics from the last SCZ, bipolar disorder (BD), and depression (DEP) meta-analyses available on the Psychiatric Genomics Consortium webpage to calculate polygenic risk scores (PRSs) for a target sample of 11,977 COVID-19 cases and 5943 subjects with unknown COVID-19 status. Linkage disequilibrium score (LDSC) regression analysis was performed when positive associations were obtained from the PRS analysis. The SCZ PRS was a significant predictor in the case/control, symptomatic/asymptomatic, and hospitalization/no hospitalization analyses in the total and female samples; and of symptomatic/asymptomatic status in men. No significant associations were found for the BD or DEP PRS or in the LDSC regression analysis. SNP-based genetic risk for SCZ, but not for BD or DEP, may be associated with higher risk of SARS-CoV-2 infection and COVID-19 severity, especially among women; however, predictive accuracy barely exceeded chance level. We believe that the inclusion of sexual loci and rare variations in the analysis of genomic overlap between SCZ and COVID-19 will help to elucidate the genetic commonalities between these conditions.

The genomics of visuospatial neurocognition in obsessive-compulsive disorder: A preliminary GWAS.

BACKGROUND: The study of Obsessive-Compulsive Disorder (OCD) genomics has primarily been tackled by Genome-wide association studies (GWAS), which have encountered troubles in identifying replicable single nucleotide polymorphisms (SNPs). Endophenotypes have emerged as a promising avenue of study in trying to elucidate the genomic bases of complex traits such as OCD. METHODS: We analyzed the association of SNPs across the whole genome with the construction of visuospatial information and executive performance through four neurocognitive variables assessed by the Rey-Osterrieth Complex Figure Test (ROCFT) in a sample of 133 OCD probands. Analyses were performed at SNP- and gene-level. RESULTS: No SNP reached genome-wide significance, although there was one SNP almost reaching significant association with copy organization (rs60360940; P = 9.98E-08). Suggestive signals were found for the four variables at both SNP- (P < 1E-05) and gene-levels (P < 1E-04). Most of the suggestive signals pointed to genes and genomic regions previously associated with neurological function and neuropsychological traits. LIMITATIONS: Our main limitations were the sample size, which was limited to identify associated signals at a genome-wide level, and the composition of the sample, more representative of rather severe OCD cases than a population-based OCD sample with a broad severity spectrum. CONCLUSIONS: Our results suggest that studying neurocognitive variables in GWAS would be more informative on the genetic basis of OCD than the classical case/control GWAS, facilitating the genetic characterization of OCD and its different clinical profiles, the development of individualized treatment approaches, and the improvement of prognosis and treatment response.