HGG Advances最新文献

{"title":"Unbiased causal inference with Mendelian randomization and covariate-adjusted GWAS data.","authors":"Peiyao Wang, Zhaotong Lin, Wei Pan","doi":"10.1016/j.xhgg.2025.100412","DOIUrl":"10.1016/j.xhgg.2025.100412","url":null,"abstract":"<p><p>Mendelian randomization (MR) facilitates causal inference with observational data using publicly available genome-wide association study (GWAS) results. In a GWAS, one or more heritable covariates may be adjusted for to estimate the direct effects of SNPs on a focal trait or to improve statistical power, which may introduce collider bias in SNP-trait association estimates, thus affecting downstream MR analyses. Numerical studies suggested that using covariate-adjusted GWAS summary data might introduce bias in univariable Mendelian randomization (UVMR), which can be mitigated by multivariable Mendelian randomization (MVMR). However, it remains unclear and even mysterious why/how MVMR works; a rigorous theory is needed to explain and substantiate the above empirical observation. In this paper, we derive some analytical results when multiple covariates are adjusted for in the GWAS of exposure and/or the GWAS of outcome, thus supporting and explaining the empirical results. Our analytical results offer insights to how bias arises in UVMR and how it is avoided in MVMR, regardless of whether collider bias is present. We also consider applying UVMR or MVMR methods after collider-bias correction. We conducted extensive simulations to demonstrate that with covariate-adjusted GWAS summary data, MVMR had an advantage over UVMR by producing nearly unbiased causal estimates; however, in some situations it is advantageous to apply UVMR after bias correction. In real data analyses of the GWAS data with body mass index (BMI) being adjusted for metabolomic principal components, we examined the causal effect of BMI on blood pressure, confirming the above points.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100412"},"PeriodicalIF":3.3,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11875156/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Context-specific eQTLs provide deeper insight into causal genes underlying shared genetic architecture of COVID-19 and idiopathic pulmonary fibrosis.","authors":"Trisha Dalapati, Liuyang Wang, Angela G Jones, Jonathan Cardwell, Iain R Konigsberg, Yohan Bossé, Don D Sin, Wim Timens, Ke Hao, Ivana Yang, Dennis C Ko","doi":"10.1016/j.xhgg.2025.100410","DOIUrl":"10.1016/j.xhgg.2025.100410","url":null,"abstract":"<p><p>Most genetic variants identified through genome-wide association studies (GWASs) are suspected to be regulatory in nature, but only a small fraction colocalize with expression quantitative trait loci (eQTLs, variants associated with expression of a gene). Therefore, it is hypothesized but largely untested that integration of disease GWAS with context-specific eQTLs will reveal the underlying genes driving disease associations. We used colocalization and transcriptomic analyses to identify shared genetic variants and likely causal genes associated with critically ill COVID-19 and idiopathic pulmonary fibrosis. We first identified five genome-wide significant variants associated with both diseases. Four of the variants did not demonstrate clear colocalization between GWAS and healthy lung eQTL signals. Instead, two of the four variants colocalized only in cell type- and disease-specific eQTL datasets. These analyses pointed to higher ATP11A expression from the C allele of rs12585036, in monocytes and in lung tissue from primarily smokers, which increased risk of idiopathic pulmonary fibrosis (IPF) and decreased risk of critically ill COVID-19. We also found lower DPP9 expression (and higher methylation at a specific CpG) from the G allele of rs12610495, acting in fibroblasts and in IPF lungs, and increased risk of IPF and critically ill COVID-19. We further found differential expression of the identified causal genes in diseased lungs when compared to non-diseased lungs, specifically in epithelial and immune cell types. These findings highlight the power of integrating GWASs, context-specific eQTLs, and transcriptomics of diseased tissue to harness human genetic variation to identify causal genes and where they function during multiple diseases.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100410"},"PeriodicalIF":3.3,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11872446/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143060892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Caution when using network partners for target identification in drug discovery.","authors":"Dandan Tan, Yiheng Chen, Yann Ilboudo, Kevin Y H Liang, Guillaume Butler-Laporte, J Brent Richards","doi":"10.1016/j.xhgg.2025.100409","DOIUrl":"10.1016/j.xhgg.2025.100409","url":null,"abstract":"<p><p>Identifying novel, high-yield drug targets is challenging and often results in a high failure rate. However, recent data indicate that leveraging human genetic evidence to identify and validate these targets significantly increases the likelihood of success in drug development. Two recent papers from Open Targets claimed that around half of US Food and Drug Administration-approved drugs had targets with direct human genetic evidence. By expanding target identification to include protein network partners-molecules in physical contact-the proportion of drug targets with genetic evidence support increased to two-thirds. However, the efficacy of using these network partners for target identification was not formally tested. To address this, we tested the approach on a list of robust positive control genes. We used the IntAct database to find physically interacting proteins of genes identified by exome-wide association studies (ExWASs), genome-wide association studies (GWASs) combined with a locus-to-gene mapping algorithm called the Effector Index, and Genetic Priority Score (GPS), which integrated eight genetic features with drug indications from the Open Targets and SIDER databases. We assessed how accurately including interacting genes with the ExWAS-, Effector Index-, and GPS-selected genes identified positive controls, focusing on precision, sensitivity, and specificity. Our results indicated that although molecular interactions led to higher sensitivity in identifying positive control genes, their practical application is limited by low precision. Expanding genetically identified targets to include network partners using IntAct did not increase the likelihood of identifying drug targets across the 412 tested traits, suggesting that such results should be interpreted with caution.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100409"},"PeriodicalIF":3.3,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11850190/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143042160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Missense variants at the p.Arg225 residue in ARHGEF40 identified in individuals with multiple congenital anomalies and developmental delay.","authors":"Melanie P Napier, Erin Ryan, Adi Reich, Joshua A Suhl, Diane Masser-Frye, Marilyn Jones, Celese Beaudreau, Nathaniel Robin, Dana Goodloe, Leandra Folk, Michelle M Morrow, Deanna Alexis Carere","doi":"10.1016/j.xhgg.2025.100408","DOIUrl":"10.1016/j.xhgg.2025.100408","url":null,"abstract":"<p><p>The ARHGEF40 gene, also known as SOLO, encodes a RhoA-targeting guanine nucleotide exchange factor (GEF) and is currently considered a candidate gene with a potential relationship to disease. Our laboratory has confirmed variants at position p.Arg225 of the ARHGEF40 protein in multiple unrelated individuals with a phenotype including dysmorphic features, congenital anomalies and neurodevelopmental abnormalities. Here, we provide genetic and phenotypic information for two individuals harboring de novo variants at p.Arg225 and sharing a highly similar phenotype. This report suggests a relationship between variants at this amino acid position and autosomal dominant disease, and further studies will be needed to characterize this disease-gene relationship and elucidate the disease mechanism.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100408"},"PeriodicalIF":3.3,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11850187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response to Karp-Tatham et al.","authors":"Astrid Marchal, Vanessa Sancho-Shimizu, Laurent Abel, Jean-Laurent Casanova, Aurélie Cobat, Alexandre Bolze","doi":"10.1016/j.xhgg.2025.100407","DOIUrl":"10.1016/j.xhgg.2025.100407","url":null,"abstract":"","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100407"},"PeriodicalIF":3.3,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11836477/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pitfalls in performing genome-wide association studies on ratio traits.","authors":"Zachary R McCaw, Rounak Dey, Hari Somineni, David Amar, Sumit Mukherjee, Kaitlin Sandor, Theofanis Karaletsos, Daphne Koller, Hugues Aschard, George Davey Smith, Daniel MacArthur, Colm O'Dushlaine, Thomas W Soare","doi":"10.1016/j.xhgg.2025.100406","DOIUrl":"10.1016/j.xhgg.2025.100406","url":null,"abstract":"<p><p>Genome-wide association studies (GWASs) are often performed on ratios composed of a numerator trait divided by a denominator trait. Examples include body mass index (BMI) and the waist-to-hip ratio, among many others. Explicitly or implicitly, the goal of forming the ratio is typically to adjust for an association between the numerator and denominator. While forming ratios may be clinically expedient, there are several important issues with performing GWAS on ratios. Forming a ratio does not \"adjust\" for the denominator in the sense of conditioning on it, and it is unclear whether associations with ratios are attributable to the numerator, the denominator, or both. Here we demonstrate that associations arising in ratio GWAS can be entirely denominator driven, implying that at least some associations uncovered by ratio GWAS may be due solely to a putative adjustment variable. In a survey of 10 common ratio traits, we find that the ratio model disagrees with the adjusted model (performing GWAS on the numerator while conditioning on the denominator) at around 1/3 of loci. Using BMI as an example, we show that variants detected by only the ratio model are more strongly associated with the denominator (height), while variants detected by only the adjusted model are more strongly associated with the numerator (weight). Although the adjusted model provides effect sizes with a clearer interpretation, it is susceptible to collider bias. We propose and validate a simple method of correcting for the genetic component of collider bias via leave-one-chromosome-out polygenic scoring.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100406"},"PeriodicalIF":3.3,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11808723/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intersection of rare pathogenic variants from TCGA in the All of Us Research Program v6.","authors":"Blaine A Bates, Kylee E Bates, Spencer A Boris, Colin Wessman, David Stone, Justin Bryan, Mary F Davis, Matthew H Bailey","doi":"10.1016/j.xhgg.2025.100405","DOIUrl":"10.1016/j.xhgg.2025.100405","url":null,"abstract":"<p><p>Using rare cancer predisposition alleles derived from The Cancer Genome Atlas (TCGA) and high cancer prevalence (14% of participants) in All of Us (version 6), we assessed the impact of these rare alleles on cancer occurrence in six broad groups of genetic similarity provided by All of Us: African/African American (AFR), Admixed American/Latino (AMR), East Asian (EAS), European (EUR), Middle Eastern (MID), or South Asian (SAS). We observed that germline susceptibility to cancer consistently replicates in EUR-like participants but less so in other participants. We found that All of Us participants from the EUR (p = 1.8 × 10^-7), AFR (p = 0.018), and MID (p = 0.0083) genetic similarity groups who carry a rare pathogenic mutation are more likely to have cancer than those without a rare pathogenic mutation. With the advent of combining medical records and genetic mutations, we also performed a phenome-wide association study (PheWAS) to assess the effect of pathogenic variants on additional phenotypes. This analysis again showed several associations between predisposition variants and cancer in EUR-like participants, but fewer in those of the other genetic similarity groups. As All of Us grows to 1 million participants, our projections suggest sufficient power (>99%) to detect cancer-associated variants that are common, but limited power (∼28%) to detect rare mutations when using the entire cohort. This study provides preliminary insights into genetic predispositions to cancer across a diverse cohort and demonstrates the value of All of Us as a resource for cancer research.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100405"},"PeriodicalIF":3.3,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11830373/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Missense variants weakening a SOX9 phosphodegron linked to odontogenesis defects, scoliosis, and other skeletal features.","authors":"Imane Ettaki, Abdul Haseeb, Anirudha Karvande, Ghita Amalou, Asmae Saih, Imane AitRaise, Salsabil Hamdi, Lahcen Wakrim, Abdelhamid Barakat, Hassan Fellah, Mustapha El Alloussi, Véronique Lefebvre","doi":"10.1016/j.xhgg.2025.100404","DOIUrl":"10.1016/j.xhgg.2025.100404","url":null,"abstract":"<p><p>SOX9 encodes an SRY-related transcription factor critical for chondrogenesis and sex determination among other processes. Loss-of-function variants cause campomelic dysplasia and Pierre Robin sequence, while both gain- and loss-of-function variants cause disorders of sex development. SOX9 has also been linked to scoliosis and cancers, but variants are undetermined. It is highly expressed in tooth progenitor cells, but its odontogenic roles remain elusive, and tooth defects are unreported in SOX9-related conditions. Here, we performed whole-exome sequencing for nine unrelated children with tooth eruption delay and no known syndromes and identified a 7-year-old girl heterozygous for a SOX9 p.Thr239Pro variant and a 10-year-old boy heterozygous for presumably adjacent p.Thr239Pro and p.Thr240Pro variants. These variants were de novo and rare in control populations. Both cases had primary tooth eruption delay. Additionally, the boy had mesiodens blocking permanent central upper incisor eruption, severe scoliosis, and mild craniofacial and appendicular skeleton abnormalities. p.Thr239 and p.Thr240 occupy variable and obligatory positions, respectively, in a cell division control protein 4 (Cdc4)/FBXW7-targeted phosphodegron motif (CPD) fully conserved in SOX9 vertebrate orthologs and SOX8 and SOX10 paralogs, but functionally uncharacterized in vivo. Structural modeling predicted p.Thr240Pro and p.Thr239Pro/p.Thr240Pro but not p.Thr239Pro to strongly reduce SOX9/FBXW7 interaction. Accordingly, p.Thr240Pro and p.Thr239Pro/p.Thr240Pro but not p.Thr239Pro blocked FBXW7-induced SOX9 degradation in cultured cells. All variants increased SOX9-mediated reporter activation independently of protein stabilization, suggesting that CPD may also modulate the transactivation function of SOX9. Altogether, these findings concur that CPD has critical functions, that SOX9 decisively controls odontogenesis, and that gain-of-function variants may markedly perturb both this process and skeletogenesis.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100404"},"PeriodicalIF":3.3,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834033/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142967213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Togaram1 is expressed in the neural tube and its absence causes neural tube closure defects.","authors":"Yanyan Wang, Nadine Kraemer, Joanna Schneider, Olaf Ninnemann, Kai Weng, Michael Hildebrand, Joshua Reid, Na Li, Hao Hu, Shyamala Mani, Angela M Kaindl","doi":"10.1016/j.xhgg.2024.100363","DOIUrl":"10.1016/j.xhgg.2024.100363","url":null,"abstract":"<p><p>Neural tube closure defect pathomechanisms in human embryonic development are poorly understood. Here we identified spina bifida patients expressing novel variants of the TOGARAM gene family. TOGARAM1 has been associated with the ciliopathy Joubert syndrome, but its connection to spina bifida and role in neural development is unknown. We show that Togaram1 is expressed in the neural tube and Togaram1 knockout mice have abnormal cilia, reduced sonic hedgehog (Shh) signaling, abnormal neural tube patterning, and display neural tube closure defects. Neural stem cells from Togaram1 knockout embryos showed reduced cilia and defects in Shh signaling. Overexpression in IMCD3 and HEK293 cells of TOGARAM1 carrying the variant found in the spina bifida patient resulted in cilia defect along with reduced pericentriolar material one (PCM1), a critical constituent of centriolar satellites involved in transporting proteins toward the centrosome and primary cilia. Our results demonstrate the role of TOGARAM1 in regulating Shh signaling during early neural development that is critical for neural tube closure and elucidates potential mechanisms whereby the ciliopathy-associated gene TOGARAM1 gives rise to spina bifida aperta in humans.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100363"},"PeriodicalIF":3.3,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11541697/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142393898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Variants in the β-globin locus are associated with pneumonia in African American children.","authors":"Nadine L N Halligan, Sarah C Hanks, Karen Matsuo, Taylor Martins, Sebastian Zöllner, Michael W Quasney, Laura J Scott, Mary K Dahmer","doi":"10.1016/j.xhgg.2024.100374","DOIUrl":"10.1016/j.xhgg.2024.100374","url":null,"abstract":"<p><p>In African American adults, the strongest genetic predictor of pneumonia appears to be the A allele of rs334, a variant in the β-globin gene, which in homozygous form causes sickle cell disease (SCD). No comparable studies have been done in African American children. We performed genome-wide association analyses of 482 African American children with documented pneumonia and 2,048 African American control individuals using genotypes imputed from two reference panels: 1000 Genomes (1KG) (which contains rs334) and TOPMed (does not contain rs334). Using 1KG imputed genotypes, the most significant variant was rs334 (A allele; odds ratio [OR] = 2.76; 95% CI, 2.21-3.74; p = 5.9 × 10^-19); using TOPMed imputed genotypes the most significant variant was rs2226952, found in the β-globin locus control region (G allele; OR = 2.14; 95% CI, 1.78-2.57; p = 5.1 × 10^-16). After conditioning on rs334, the most strongly associated variant in the β-globin locus, rs33930165 (T allele, 1KG: OR = 4.09; 95% CI, 2.29-7.29; p = 1.7 × 10^-6; TOPMed: OR = 3.58; 95% CI, 2.18-5.90; p = 4.7 × 10^-7), which as a compound heterozygote with rs334 A allele, can cause SCD. To compare the power of different sample sets we developed a way to estimate the power of sample sets with different sample sizes, genotype arrays, and imputation platforms. Our results suggest that, in African American children, the strongest genetic determinants of pneumonia are those that increase the risk of SCD.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100374"},"PeriodicalIF":3.3,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11664401/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142509498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}