medRxiv - Genetic and Genomic Medicine最新文献

{"title":"Fragile X Syndrome Carrier Screening Using a Nanopore Sequencing Assay","authors":"Zhongmin xia, Qiuxiao Deng, Ping Hu, Chunliu Gao, Yu Jiang, Yulin Zhou, Qiwei Guo","doi":"10.1101/2024.07.23.24310865","DOIUrl":"https://doi.org/10.1101/2024.07.23.24310865","url":null,"abstract":"Background: Fragile X syndrome (FXS) is the leading cause of monogenic autism spectrum disorder and inherited intellectual disabilities. Although the value of population-based FXS carrier screening has been acknowledged, appropriate screening methods are urgently required to establish and implement screening programs.\u0000Methods: We developed a nanopore sequencing-based assay that includes data analysis software to identify FXS carriers. Reference and clinical samples were used to evaluate the performance of our nanopore sequencing assay. Triplet-primed PCR and PacBio long-read sequencing were used for comparisons.\u0000Results: Nanopore sequencing identified reference carrier samples with a full range of premutation alleles in single-, 10-, and 100-plex assays, and identified AGG interruptions in an allele-specific manner. Nanopore sequencing revealed no size preference for amplicons containing different length CGG repeat regions. Finally, nanopore sequencing successfully identified three carriers among ten clinical samples for preliminary clinical validation. The observed variation in CGG repeat region size resulted from the base-calling process of nanopore sequencing.\u0000Conclusions: Our nanopore sequencing assay is rapid, high-capacity, inexpensive, and easy to perform, thus providing a promising tool and paving the way for population-based FXS carrier screening.","PeriodicalId":501375,"journal":{"name":"medRxiv - Genetic and Genomic Medicine","volume":"86 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141784951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polygenic Risk Score predicts QTc-prolongation and Short-Term Mortality in Patients using QT-prolonging Psychoactive Medications","authors":"Mays Altaraihi","doi":"10.1101/2024.07.24.24310940","DOIUrl":"https://doi.org/10.1101/2024.07.24.24310940","url":null,"abstract":"Background: There is a genetic component to the QT-interval. This study investigated whether a polygenic risk score for QTc (PRSQTc) could predict ∆QTc and short-term mortality in first-time users of QT-prolonging medications (QTPM) with a known risk of Torsade de Pointes. Methods:\u0000First-time users of psychoactive QTPM in the Copenhagen Hospital Biobank and the Danish Blood Donor Study from 2009-2021 were included. ∆QTc was calculated and all-cause 30-day mortality following initiation of treatment was explored. All models were adjusted for conventional QT-prolonging risk factors, and models investigating death were additionally adjusted for potential comorbidity confounders. Results:\u0000The PRSQTc could predict ∆QTc (2.88 milliseconds (ms) for every increase of standard deviation in PRSQTc (P <0.001)) following treatment initiation. Individuals in the top ≥80 % of PRSQTc had a higher risk of ∆QTc of ≥60 ms compared to individuals in <80 % PRSQTc (OR = 4.88 P = 0.019). Furthermore, the study has also shown that the shorter QTc before initiation of QTPM, the higher the risk of greater ∆QTc. A high PRSQTc could also predict short-term mortality following treatment initiation: Individuals in the top PRSQTc ≥90 % had an odds ratio of 1.84 (P-value = 0.002) for short-term mortality compared to individuals with PRSQTc <90 %. Individuals in the top PRSQTc ≥99 % had an odds ratio of 4.95 (P-value = 0.009) for short-term mortality compared to individuals in the <99 % PRSQTc\u0000It could be replicated that PRSQTc ≥90 % was a predictor of short-term mortality with OR 1.52 (P-value = 0.002) compared to PRSQTc <90 % in a bigger cohort (N=15.249). Conclusion: PRSQTc seems to be predictive of ∆QTc following initiation of treatment. PRSQTc proves to be a sufficient predictor of 30-day mortality after initiation of QT-prolonging psychoactive drugs with a known risk of Torsade de Pointes. If used in a clinical setting, PRSQT may help prevent sudden cardiac deaths associated with QTPM.","PeriodicalId":501375,"journal":{"name":"medRxiv - Genetic and Genomic Medicine","volume":"46 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141784953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"\"They don't know how to live with a child with these conditions, they can't understand...\": The lived experiences of parenting a child with a genetic neurodevelopmental disorder.","authors":"Karen J Low, Georgia Treneman-Evans, Sarah Wynn, GenROC Study Consortium, Jenny Ingram","doi":"10.1101/2024.07.24.24310802","DOIUrl":"https://doi.org/10.1101/2024.07.24.24310802","url":null,"abstract":"Background:\u0000A genetic neurodevelopmental diagnosis (GND) impacts all aspects of a child and family's life. GNDs are rare; most have limited natural history data. We aimed to understand parents' experiences around data acquisition about their child's GNDs which can help inform clinical practice. Design and participants:\u0000This analysis is part of the UK multicentre GenROC study. We conducted 17 semi-structured interviews with parents of children with GNDs (aged 0-15 years). Data were analysed following the principles of thematic analysis.\u0000Results:\u0000Five main themes are reported: Impact on the family around a genetic diagnosis: Distress results from diagnosis wait, the act of receiving it, associated irreversibility (loss of hope) and family/reproductive implications. GNDs and Uncertainty: Lack of data and rareness causes uncertainty for the future. Relationships with health professionals: Positive where parents are empowered and feel part of the team; Negative-parents feel not heard/believed or lack of expertise/understanding. Parent mental health: GNDs can be a significant burden to family life. Need for advocating for services is a negative impact. Isolation through rareness is a factor - this can be helped by support networks which mostly consist of gene specific Facebook groups. Development of positive parent identities: including that of advocate, professional and educator. Conclusions\u0000GNDs represent a major challenge for families, clinicians and service providers. Distressed parents are struggling to cope with challenges and suffer poor mental health. Psychosocial support, better signposting, and health professional education may help. Patient contribution\u0000PPI group contributed to topic guide development and commented on findings.","PeriodicalId":501375,"journal":{"name":"medRxiv - Genetic and Genomic Medicine","volume":"82 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141771240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Instability of high polygenic risk classification and mitigation by integrative scoring","authors":"Anika Misra, Buu Truong, Sarah M. Urbut, Yang Sui, Akl C. Fahed, Jordan W. Smoller, Aniruddh Pradip Patel, Pradeep Natarajan","doi":"10.1101/2024.07.24.24310897","DOIUrl":"https://doi.org/10.1101/2024.07.24.24310897","url":null,"abstract":"Polygenic risk scores (PRS) continue to improve with novel methods and expanding genome-wide association studies. Healthcare and third-party laboratories are increasingly deploying PRS reports to patients. Although new PRS show improving strengths of association with traits, it is unknown how the classification of high polygenic risk changes across individual PRS for the same trait. Here, we determined classification of high genetic risk from all cataloged PRS for three complex traits. While each PRS for each trait demonstrated generally consistent population-level strengths of associations, classification of individuals in the top 10% of each PRS distribution varied widely. Using the PRSMix framework, which incorporates information across several PRS to improve prediction, we generated sequential add-one-in (AOI) PRSMix_AOI scores based on order of publication. PRSMix_AOIₙ led to improved PRS performance and more consistent high-risk classification compared with the PRSₙ. The PRSMix_AOI approach provides more stable and reliable classification of high-risk as new PRS continue to be generated toward PRS standardization.","PeriodicalId":501375,"journal":{"name":"medRxiv - Genetic and Genomic Medicine","volume":"350 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141771241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic ancestral patterns in CYP2D6 alleles: structural variants, rare variants, and clinical associations in 479,144 UK Biobank genomes","authors":"Xiao Jiang, Fengyuan Hu, Xueqing Zoe Zou, Ali Abbasi, Sri Vishnu Vardhan DEEVI, Santosh Atanur, Amanda O'Neill, Jen Harrow, Margarete Fabre, Quanli Wang, Slavé Petrovski, William Rae, Oliver Simon Burren, Katherine Smith","doi":"10.1101/2024.07.23.24310892","DOIUrl":"https://doi.org/10.1101/2024.07.23.24310892","url":null,"abstract":"Cytochrome P450 2D6 (CYP2D6) is involved in metabolising over 20% of clinical drugs, yet its genetic variation across ancestries is underexplored in large-scale whole-genome sequencing (WGS) datasets. We analysed WGS data from 479,144 UK Biobank participants, identifying 95 distinct CYP2D6 star alleles across five biogeographic groups. Of these, 48 alleles had currently unknown effects. These alleles were more prevalent in African, admixed American, and South Asian groups (~5%) compared to European and East Asian groups (~2%), affecting the ability to provide pharmacogenomics recommendations across ancestries. We identified 99,656 (20.8%) individuals carrying CYP2D6 structural variations and predicted the CYP2D6 ultra-rapid metaboliser phenotype to be most common in Africans (4.5%) and rarest in East Asians (0.32%). Less than half (45.7%) of rare protein-truncating variant carriers were categorised as poor or intermediate metabolisers, indicating an underrepresentation of rare functional variants in the current CYP2D6 star allele evaluation. Phenome-wide association studies confirmed links with narcotic allergies and found new associations with plasma BAFFR and BAFF proteins, offering insights for the BAFF-targeted clinical therapy. Collectively, this largest WGS study of CYP2D6 to date highlights the importance of leveraging all genetic variations for pharmacogenomic insights affecting therapeutic safety and development.","PeriodicalId":501375,"journal":{"name":"medRxiv - Genetic and Genomic Medicine","volume":"63 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141771245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polygenic proxies of age-related plasma protein levels reveal TIMP2 role in cognitive performance","authors":"Federica Anastasi, Patricia Genius, Blanca Rodríguez-Fernández, Chengran Yang, Priyanka Gorijala, Jigyasha Timsina, Felipe Hernández-Villamizar, Luigi Lorenzini, Marta del Campo, Gonzalo Sánchez-Benavides, Carolina Minguillón, Arcadi Navarro, Carlos Cruchaga, Marc Suárez-Calvet, Natalia Vilor-Tejedor","doi":"10.1101/2024.07.23.24310854","DOIUrl":"https://doi.org/10.1101/2024.07.23.24310854","url":null,"abstract":"Several studies have identified blood proteins that influence brain aging performance in mice, yet translating these findings to humans remains challenging. Here we found that higher predicted plasma levels of Tissue Inhibitor of Metalloproteinases 2 TIMP2 were significantly associated with improved global cognition and memory performance in humans. We first identified 12 proteins with aging or rejuvenating effects on murine brains through a systematic review. Using protein quantitative trait loci data for these proteins, we computed polygenic scores as proxies for plasma protein levels and validated their prediction accuracy in two independent cohorts. Association models between genetic proxies and cognitive performance highlighted the significance of TIMP2, also when the models were stratified by sex, APOE-e4, and Abeta-42 status. This finding aligns with TIMP2s brain rejuvenating role in murine models, suggesting it as a promising therapeutic target for brain aging and age-related brain diseases in humans.","PeriodicalId":501375,"journal":{"name":"medRxiv - Genetic and Genomic Medicine","volume":"181 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141771242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Life without sex: Large-scale study links sexlessness to physical, cognitive, and personality traits, socioecological factors, and DNA","authors":"Abdel Abdellaoui, Laura W. Wesseldijk, Scott D. Gordon, Joelle A. Pasman, Dirk J.A. Smit, Renata Androvicov, Nicholas G. Martin, Fredrik Ullen, Miriam A. Mosing, Brendan Zietsch, Karin J.H. Verweij","doi":"10.1101/2024.07.24.24310943","DOIUrl":"https://doi.org/10.1101/2024.07.24.24310943","url":null,"abstract":"Romantic (typically sexual) relationships are important to personal, physical, mental, social, and economic wellbeing, and to human evolution. Yet little is known about factors contributing to long-term lack of intimate relationships. We investigated phenotypic and genetic correlates of never having had sex in ~400,000 UK residents aged 39 to 73 and ~13,500 Australian residents aged 18 to 89. The strongest associations revealed that sexless individuals were more educated, less likely to use alcohol and smoke, more nervous, lonelier, and unhappier. Sexlessness was more strongly associated with physical characteristics (e.g. upper body strength) in men than in women. Sexless men tended to live in regions with fewer women, and sexlessness was more prevalent in regions with more income inequality. Common genetic variants explained 17% and 14% of variation in sexlessness in men and women, with a genetic correlation between sexes of 0.56. Polygenic scores predicted a range of related outcomes in the Australian dataset. Our findings uncover multifaceted correlates of human intimacy of evolutionary significance.","PeriodicalId":501375,"journal":{"name":"medRxiv - Genetic and Genomic Medicine","volume":"37 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141771243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomics of chronic cough unravels neurological pathways","authors":"Kayesha Coley, Catherine John, Jonas Ghouse, David J Shepherd, Nick Shrine, Abril G Izquierdo, Stavroula Kanoni, Emma F Magavern, Richard Packer, Lorcan McGarvey, Jaclyn A Smith, Henning Bundgaard, Sisse R Ostrowski, Christian Erikstrup, Ole B V Pedersen, David A van Heel, Genes & Health Research Team, William Hennah, Mikko Marttila, Robert C Free, Edward J Hollox, Louise V Wain, Martin D Tobin, Chiara Batini","doi":"10.1101/2024.07.23.24310853","DOIUrl":"https://doi.org/10.1101/2024.07.23.24310853","url":null,"abstract":"<strong>Background</strong>\u0000Chronic cough is a symptom of common lung conditions, occurs as a side effect of ACE inhibitors (ACEis), or may be unexplained. Despite chronic cough representing a substantial health burden, its biological mechanisms remain unclear. We hypothesised shared genetic architecture between chronic dry cough and ACEi-induced cough and aimed to identify causal genes underlying both phenotypes. <strong>Methods</strong>\u0000We performed multi-ancestry genome-wide association studies (GWAS) of chronic dry cough and ACEi-induced cough, and a multi-trait GWAS of both phenotypes, utilising data from five cohort studies. Chronic dry cough was defined by questionnaire responses, and ACEi-induced cough by treatment switches or clinical diagnosis in electronic health records. We mapped putative causal genes and performed phenome-wide association studies (PheWAS) of associated variants and genetic risk scores (GRS) for these phenotypes to identify pleotropic effects. <strong>Findings</strong>\u0000We found seven novel genetic association signals reaching <em>p</em>-value &lt;5×10^-8 in the multi-trait or single-trait analyses of chronic dry cough and ACEi-induced cough. The novel variants mapped to 10 novel genes, and we mapped an additional three novel genes to known risk variants, many of which implicating neurological functions (<em>CTNNA1</em>, <em>KCNA10</em>, <em>MAPKAP1</em>, <em>OR4C12</em>, <em>OR4C13</em>, <em>SIL1</em>). The GRS-PheWAS highlighted associations with increased risk of several conditions reported as comorbidities of chronic cough, including fibromyalgia pain, and with spirometry measurements. <strong>Interpretation</strong>\u0000Our findings advance the understanding of neuronal dysfunction underlying cough hypersensitivity in chronic dry cough and ACEi-induced cough at the population-level, and the identification of comorbidities associated with genetic predisposition to cough could inform drug target discovery. <strong>Funding</strong>\u0000Medical Research Council, Wellcome Trust, National Institute for Health and Care Research, Orion Pharma.","PeriodicalId":501375,"journal":{"name":"medRxiv - Genetic and Genomic Medicine","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141784954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Specialized Reference Panel with Structural Variants Integration for Improving Genotype Imputation in Alzheimer's Disease and Related Dementias (ADRD)","authors":"Po-Liang Cheng, Hui Wang, Beth A Dombroski, John J Farrell, Iris Horng, Tingting Chung, Giuseppe Tosto, Brian W Kunkle, William S Bush, Badri Vardarajan, Gerard D Schellenberg, Wan-Ping Lee","doi":"10.1101/2024.07.22.24310827","DOIUrl":"https://doi.org/10.1101/2024.07.22.24310827","url":null,"abstract":"We developed an imputation panel for Alzheimer's disease (AD) and related dementias (ADRD) using whole-genome sequencing (WGS) data from the Alzheimer's Disease Sequencing Project (ADSP). Recognizing the significant associations between structural variants (SVs) and AD, and their underrepresentation in existing public reference panels, our panel uniquely integrates single nucleotide variants (SNVs), short insertions and deletions (indels), and SVs. This panel enhances the imputation of disease susceptibility, including rare AD-associated SNVs, indels, and SVs, onto genotype array data, offering a cost-effective alternative to whole-genome sequencing while significantly augmenting statistical power. Notably, we discovered 10 rare indels nominal significant related to AD that are absent in the TOPMed-r2 panel and identified three suggestive significant (p-value &lt; 1E-05) AD-associated SVs in the genes EXOC3L2 and DMPK, were identified. These findings provide new insights into AD genetics and underscore the critical role of imputation panels in advancing our understanding of complex diseases like ADRD.","PeriodicalId":501375,"journal":{"name":"medRxiv - Genetic and Genomic Medicine","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141771244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptome-Wide Root Causal Inference","authors":"Eric V Strobl, Eric R Gamazon","doi":"10.1101/2024.07.22.24310837","DOIUrl":"https://doi.org/10.1101/2024.07.22.24310837","url":null,"abstract":"Root causal genes correspond to the first gene expression levels perturbed during pathogenesis by genetic or non-genetic factors. Targeting root causal genes has the potential to alleviate disease entirely by eliminating pathology near its onset. No existing algorithm discovers root causal genes from observational data alone. We therefore propose the Transcriptome-Wide Root Causal Inference (TWRCI) algorithm that identifies root causal genes and their causal graph using a combination of genetic variant and unperturbed bulk RNA sequencing data. TWRCI uses a novel competitive regression procedure to annotate cis and trans-genetic variants to the gene expression levels they directly cause. The algorithm simultaneously recovers a causal ordering of the expression levels to pinpoint the underlying causal graph and estimate root causal effects. TWRCI outperforms alternative approaches across a diverse group of metrics by directly targeting root causal genes while accounting for distal relations, linkage disequilibrium, patient heterogeneity and widespread pleiotropy. We demonstrate the algorithm by uncovering the root causal mechanisms of two complex diseases, which we confirm by replication using independent genome-wide summary statistics.","PeriodicalId":501375,"journal":{"name":"medRxiv - Genetic and Genomic Medicine","volume":"26 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141771360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}