Effect of Race and Ethnicity on Risk of Radiotherapy Toxicity and Implications for Radiogenomics

AimsPatient factors affect the risk of radiotherapy toxicity, but many are poorly defined. Studies have shown that race affects cancer incidence, survival, drug response, molecular pathways and epigenetics. Effects on radiosensitivity and radiotherapy toxicity are not well studied. The aim of the present study was to identify the effects of race and ethnicity on the risk of radiotherapy toxicity.Materials and methodsA systematic review was carried out of PubMed, Ovid Medline and Ovid Embase with no year limit. PRISMA 2020 guidelines were followed. Two independent assessors reviewed papers.ResultsOf 607 papers screened, 46 fulfilled the inclusion criteria. Papers were published between 1996 and 2021 and involved 30–28,354 individuals (median 433). Most involved patients with prostate (33%), breast (26%) and lung (9%) cancer. Both early and late toxicities were studied. Some studies reported a higher risk of toxicity in White men with prostate cancer compared with other races and ethnicities. For breast cancer patients, some reported an increased risk of toxicity in White women compared with other race and ethnic groups. In general, it was difficult to draw conclusions due to insufficient reporting and analysis of race and ethnicity in published literature.ConclusionsReporting of race and ethnicity in radiotherapy studies must be harmonised and improved and frameworks are needed to improve the quality of reporting. Further research is needed to understand how ancestral heritage might affect radiosensitivity and risk of radiotherapy toxicity.     

Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project

IntroductionLarge variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways.MethodsGenome Research at Fundacio ACE ([email protected]) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, [email protected] series were meta-analyzed with additional genome-wide association study data sets.ResultsWe classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444.DiscussionThe regulation of vasculature is a prominent causal component of probable AD. [email protected] meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series.     

gwasfilter：用于筛选全基因组关联研究的R脚本

目的 开发一套能高效准确地从GWAS Catalog公开数据库中筛选全基因组关联研究（GWAS）的R脚本。方法 参考既往研究制定GWAS的筛选原则。将人工在GWAS Catalog的筛选过程抽象为标准的算法，2名程序员共同撰写R脚本（gwasfilter.R）后，由他人多次对脚本进行测试。结果 采用gwasfilter.R筛选GWAS包含6个步骤。该脚本内置5个主要函数，可以同时根据“是否有验证人群”“样本量大小”和“研究人群种族”等条件对GWAS进行筛选。筛选单个性状时，程序用时不超过1秒。结论 gwasfilter.R操作简便，筛选过程高效而标准化，可灵活应用于GWAS筛选。脚本源代码网址：https：//github.com/lab319/gwas_filter。     

Genome‐wide analysis of adolescent psychotic‐like experiences shows genetic overlap with psychiatric disorders

This study aimed to test for overlap in genetic influences between psychotic‐like experience traits shown by adolescents in the community, and clinically‐recognized psychiatric disorders in adulthood, specifically schizophrenia, bipolar disorder, and major depression. The full spectra of psychotic‐like experience domains, both in terms of their severity and type (positive, cognitive, and negative), were assessed using self‐ and parent‐ratings in three European community samples aged 15–19 years (Final N incl. siblings = 6,297–10,098). A mega‐genome‐wide association study (mega‐GWAS) for each psychotic‐like experience domain was performed. Single nucleotide polymorphism (SNP)‐heritability of each psychotic‐like experience domain was estimated using genomic‐relatedness‐based restricted maximum‐likelihood (GREML) and linkage disequilibrium‐ (LD‐) score regression. Genetic overlap between specific psychotic‐like experience domains and schizophrenia, bipolar disorder, and major depression was assessed using polygenic risk score (PRS) and LD‐score regression. GREML returned SNP‐heritability estimates of 3–9% for psychotic‐like experience trait domains, with higher estimates for less skewed traits (Anhedonia, Cognitive Disorganization) than for more skewed traits (Paranoia and Hallucinations, Parent‐rated Negative Symptoms). Mega‐GWAS analysis identified one genome‐wide significant association for Anhedonia within IDO2 but which did not replicate in an independent sample. PRS analysis revealed that the schizophrenia PRS significantly predicted all adolescent psychotic‐like experience trait domains (Paranoia and Hallucinations only in non‐zero scorers). The major depression PRS significantly predicted Anhedonia and Parent‐rated Negative Symptoms in adolescence. Psychotic‐like experiences during adolescence in the community show additive genetic effects and partly share genetic influences with clinically‐recognized psychiatric disorders, specifically schizophrenia and major depression.     

Visit-to-visit lipid variability: Clinical significance,effects of lipid-lowering treatment,and (pharmaco) genetics

In recent years, visit-to-visit variability of serum lipids has been linked to both clinical outcomes and surrogate markers for vascular disease. In this article, we present an overview of the current evidence connecting this intraindividual variability to these outcome measures, discuss its interplay with lipid-lowering treatment, and describe the literature regarding genetic factors of possible interest. In addition, we undertook an explorative genome-wide association analysis on visit-to-visit variability of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol, examining additive effects in 2530 participants from the placebo arm of the PROspective Study of Pravastatin in the Elderly at Risk trial. While we identified suggestive associations (P < 1 × 10^?6) at 3 different loci (KIAA0391, amiloride-sensitive cation channel 1 neuronal [ACCN1], and Dickkopf WNT signaling pathway inhibitor 3 [DKK3]), previously published data from the genome-wide association study literature did not suggest plausible mechanistic pathways. Given the large degree of both clinical and methodological heterogeneity in the literature, additional research is needed to harmonize visit-to-visit variability parameters across studies and to definitively assess the possible role of (pharmaco)genetic factors.     

Common variants in DLG1 locus are associated with non‐syndromic cleft lip with or without cleft palate

Non‐syndromic cleft lip with or without cleft palate (nsCL/P) is a common craniofacial anomaly with a complex and heterogeneous aetiology. Knowledge regarding specific genetic factors underlying this birth defect is still not well understood. Therefore, we conducted an independent replication analysis for the top‐associated variants located within the DLG1 locus at chromosome 3q29, which was identified as a novel cleft‐susceptibility locus in our genome‐wide association study (GWAS). Mega‐analysis of the pooled individual data from the GWAS and replication study confirmed that common DLG1 variants are associated with the risk of nsCL/P. Two single nucleotide polymorphisms (SNPs), rs338217 and rs7649443, were statistically significant even at the genome‐wide level (P_trend = 9.70E?10 and P_trend = 8.96E?09, respectively). Three other SNPs, rs9826379, rs6805920 and rs6583202, reached a suggestive genome‐wide significance threshold (P_trend < 1.00E?05). The location of the strongest individual SNP in the intronic sequence of the gene encoding DLG1 antisense RNA suggests that the true causal variant implicated in the risk of nsCL/P may affect the DLG1 gene expression level rather than structure of the encoded protein. In conclusion, we identified a novel cleft‐susceptibility locus at chromosome 3q29 with a DLG1 as a novel candidate gene for this common craniofacial anomaly.     

Performance of polygenic risk scores for cancer prediction in a racially diverse academic biobank

PurposeGenome-wide association studies have identified hundreds of single nucleotide variations (formerly single nucleotide polymorphisms) associated with several cancers, but the predictive ability of polygenic risk scores (PRSs) is unclear, especially among non-Whites.MethodsPRSs were derived from genome-wide significant single-nucleotide variations for 15 cancers in 20,079 individuals in an academic biobank. We evaluated the improvement in discriminatory accuracy by including cancer-specific PRS in patients of genetically-determined African and European ancestry.ResultsAmong the individuals of European genetic ancestry, PRSs for breast, colon, melanoma, and prostate were significantly associated with their respective cancers. Among the individuals of African genetic ancestry, PRSs for breast, colon, prostate, and thyroid were significantly associated with their respective cancers. The area under the curve of the model consisting of age, sex, and principal components was 0.621 to 0.710, and it increased by 1% to 4% with the inclusion of PRS in individuals of European genetic ancestry. In individuals of African genetic ancestry, area under the curve was overall higher in the model without the PRS (0.723-0.810) but increased by <1% with the inclusion of PRS for most cancers.ConclusionPRS moderately increased the ability to discriminate the cancer status in individuals of European but not African ancestry. Further large-scale studies are needed to identify ancestry-specific genetic factors in non-White populations to incorporate PRS into cancer risk assessment.     

A genome-wide association study of suicide severity scores in bipolar disorder

BackgroundSuicide claims one million lives worldwide annually, making it a serious public health concern. The risk for suicidal behaviour can be partly explained by genetic factors, as suggested by twin and family studies (reviewed in (Zai et al. 2012)). Recently, genome-wide association studies (GWASs) of suicide attempt on large samples of bipolar disorder (BD) patients from multiple sites have identified a number of novel candidate genes. GWASs of suicide behaviour severity, from suicidal ideation to serious suicide attempt, have not been reported for BD.MethodsWe conducted a GWAS of suicide behaviour severity in three independent BD samples:212 small nuclear families with BD probands from Toronto, Canada, 428 BD cases from Toronto, and 483 BD cases from the UK. We carried out imputation with 1000 Genome Project data as reference using IMPUTE2. Quality control and data analysis was conducted using PLINK and R. We conducted the quantitative analyses of suicide behaviour severity in the three samples separately, and derived an overall significance by a meta-analysis using the METAL software.ResultsWe did not find genome-wide significant association of any tested markers in any of the BD samples, but we found a number of suggestive associations, including regions on chromosomes 8 and 10 (p < 1e-5).ConclusionsOur GWAS findings suggest that likely many gene variants of small effects contribute collectively to the risk for suicidal behaviour severity in BD. Larger independent replications are required to strengthen the findings from the GWAS presented here.     

HIV/AIDS的遗传背景及全基因组关联研究

宿主遗传背景是人类免疫缺陷病毒(HIV)感染机体后个体间表型差异的主要影响因素之一.它不仅影响HIV易感性,而且影响获得性免疫缺陷综合征(AIDS)进程.全基因组关联研究(GWAS)是一种在全基因组范围内检测与疾病相关基因的技术方法.目前,共有22项与HIV/AIDS相关的GWAS,发现了多个与HIV感染及AIDS进程相关的易感基因和位点.这些结果对研究宿主遗传背景在HIV感染中的作用、AIDS进程的预测及疫苗的研发都有重要意义.本文将对HIV/AIDS的遗传背景及其相关的GWAS作一综述.