Annals of Human Genetics最新文献

{"title":"Genetic architecture of adiposity measures among Asians: Findings from GWAS","authors":"Tripti Agarwal,&nbsp;Tanica Lyngdoh,&nbsp;Rajesh Khadgawat,&nbsp;Dorairaj Prabhakaran,&nbsp;Giriraj Ratan Chandak,&nbsp;Gagandeep Kaur Walia","doi":"10.1111/ahg.12526","DOIUrl":"10.1111/ahg.12526","url":null,"abstract":"<p>Adiposity has gradually become a global public threat over the years with drastic increase in the attributable deaths and disability adjusted life years (DALYs). Given an increased metabolic risk among Asians as compared to Europeans for any given body mass index (BMI) and considering the differences in genetic architecture between them, the present review aims to summarize the findings from genome-wide scans for various adiposity indices and related anthropometric measures from Asian populations. The search for related studies, published till February 2022, were made on PubMed and GWAS Catalog using search strategy built with relevant keywords joined by Boolean operators. It was recorded that out of a total of 47 identified studies, maximum studies are from Korean population (<i>n</i> = 14), followed by Chinese (<i>n</i> = 7), and Japanese (<i>n</i> = 6). Nearly 200 loci have been identified for BMI, 660 for height, 16 for weight, 28 for circumferences (waist and hip), 32 for ratios (waist hip ratio [WHR] and thoracic hip ratio [THR]), 5 for body fat, 16 for obesity, and 28 for adiposity-related blood markers among Asians. It was observed that though, most of the loci were unique for each trait, there were 3 loci in common to BMI and WHR. Apart from validation of variants identified in European setting, there were many novel loci discovered in Asian populations. Notably, 125 novel loci form Asian studies have been reported for BMI, 47 for height, 5 for waist circumference, and 2 for adiponectin level to the existing knowledge of the genetic framework of adiposity and related measures. It is necessary to examine more advanced adiposity measures, specifically of relevance to abdominal adiposity, a major risk factor for cardiometabolic disorders among Asians. Moreover, in spite of being one continent, there is diversity among different ethnicities across Asia in terms of lifestyle, climate, geography, genetic structure and consequently the phenotypic manifestations. Hence, it is also important to consider ethnic specific studies for identifying and validating reliable genetic variants of adiposity measures among Asians.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"87 6","pages":"255-273"},"PeriodicalIF":1.9,"publicationDate":"2023-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ahg.12526","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10164904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel heterozygous truncating variant in the AGO1 gene in an Iranian family with schizophrenia as an unreported symptom","authors":"Atefeh Mir,&nbsp;Erfan Khorram,&nbsp;Yongjun Song,&nbsp;Hane Lee,&nbsp;Mohammad Amin Tabatabaiefar","doi":"10.1111/ahg.12524","DOIUrl":"10.1111/ahg.12524","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <p>Intellectual disability (ID) and autism spectrum disorders (ASDs) are the most common developmental disorders in humans. Combined, they affect between 3% and 5% of the population. Although high-throughput genomic methods are rapidly increasing the pool of ASD genes, many cases remain idiopathic. <i>AGO1</i> is one of the less-known genes related to ID/ASD. This gene encodes a core member protein of the RNA-induced silencing complex, which suppresses mRNA expression through cleavage, degradation, and/or translational repression. Generally, patients with defects in the <i>AGO1</i> gene manifest varying degrees of ID, speech delay, and autistic behaviors. Herein, we used whole-exome sequencing (WES) to investigate an Iranian family with two affected members one of whom manifested ID and autism and the other showed borderline ID and schizophrenia. WES analysis identified a novel heterozygous truncating variant (NM_012199.5:c.1298G &gt; A, p.Trp433Ter) in the <i>AGO1</i> gene that co-segregated with the phenotypes using Sanger sequencing. Moreover, the structural analysis showed that due to this variant, two critical domains (Mid and PIWI) of the AGO1 protein have been lost, which has a detrimental effect on the protein's function and structure. To the best of our knowledge, schizophrenia has not been reported in patients with <i>AGO1</i> deficiency, which is a novel phenotypic finding that expands the <i>AGO1</i>-related behavioral disorders. Moreover, this study's findings determined that patients with the same variant in the <i>AGO1</i> gene may show heterogeneity in manifested phenotypes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"87 6","pages":"295-301"},"PeriodicalIF":1.9,"publicationDate":"2023-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10011777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel GALT variations and genetic spectrum in Turkish population with the correlation of genotype and phenotype","authors":"Irem Kalay,&nbsp;Cagri Gulec,&nbsp;Mehmet Cihan Balcı,&nbsp;Guven Toksoy,&nbsp;Gulden Gokcay,&nbsp;Seher Basaran,&nbsp;Mubeccel Demirkol,&nbsp;Zehra Oya Uyguner","doi":"10.1111/ahg.12523","DOIUrl":"10.1111/ahg.12523","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Classic galactosemia (OMIM#230400) is an autosomal recessive inborn error of carbohydrate metabolism caused by a deficiency of the galactose-1-phosphate-uridyl-transferase enzyme encoded by the <i>GALT</i> gene. Even though a galactose-restricted diet efficiently resolves the acute complications, it is insufficient to prevent long-term complications regarding speech defects, intellectual functioning, premature ovarian failure, cataract, hepatomegaly, dysarthria, ataxia, and tremor. Seventy-seven patients who were genetically diagnosed with classic galactosemia were included in this cohort. Identified novel variants were classified based on their predicted effect on the GALT function. Further, potential genotype–phenotype correlations were investigated via statistical analysis. In total, 18 different sequence variants were identified, including four novels (c.200delG/p.(Arg67Profs^*19), c.533T&gt;G/ p.(Met178Arg), c.708_709delGT/p.(Ser236Argfs^*30), c.467C&gt;A/p.(Ser156^*)). Jaundice was the most common short-term finding with 80% (61/77). Even with early diagnosis, intellectual disability is encountered with 36% (27/74) of the long-term complications. Patients with biallelic missense variants have a significantly higher prevalence of cataracts (OR: 17.9). Longitudinal observations showed attenuation of cataracts and hepatomegaly. This study has shown the <i>GALT</i> variation spectrum of the Turkish population with a 30-year retrospective cohort, submitting a significant contribution to the genotype/phenotype correlation in galactosemia. This study also highlights the cost-effective importance of Sanger sequencing in the diagnosis of single-gene metabolic diseases.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"87 6","pages":"285-294"},"PeriodicalIF":1.9,"publicationDate":"2023-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9977277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reassessing the association of MUC5B with survival in idiopathic pulmonary fibrosis","authors":"Siyang Cai,&nbsp;Richard J. Allen,&nbsp;Louise V. Wain,&nbsp;Frank Dudbridge","doi":"10.1111/ahg.12522","DOIUrl":"10.1111/ahg.12522","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <p>A variant in the mucin 5B gene (<i>MUC5B</i>) is strongly associated with the risk of idiopathic pulmonary fibrosis. However, the same variant is associated with increased survival time. Previous work suggested that this may be explained by index event bias, with the true effect being to decrease survival. Here, we reassessed this claim using more recent methods and datasets. We found that the statistical assumptions of the previous analysis did not hold, and instead, we applied recent methods of corrected weighted least squares, MR-RAPS and Slope-hunter to both the previous data and an updated consortium meta-analysis. However, these analyses did not yield robust evidence for increased or decreased survival. In simulations of a true effect of decreased survival, we did not observe any realistic scenario in which index event bias led to an observed effect of increased survival. We therefore regard as unsafe the claim that <i>MUC5B</i> has a true effect of decreased survival. Alternative explanations should be sought to explain the observed association with increased survival.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"87 5","pages":"248-253"},"PeriodicalIF":1.9,"publicationDate":"2023-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ahg.12522","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10053687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional characterization of a rare pathogenic variant c.875G > A, p.(Cys292Tyr) in COMP","authors":"Lan Yin,&nbsp;Yingchuan Zhu,&nbsp;Wenhao Jiang,&nbsp;Yue Song,&nbsp;Yilu Lu,&nbsp;Dachang Tao,&nbsp;Yunqiang Liu,&nbsp;Yongxin Ma","doi":"10.1111/ahg.12521","DOIUrl":"10.1111/ahg.12521","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The protein encoded by the cartilage oligomeric matrix protein (<i>COMP</i>) gene is a noncollagenous extracellular matrix (ECM) protein that is important for chondrocyte formation and growth. Variations in the <i>COMP</i> gene cause pseudoachondroplasia (PSACH), which is mainly characterized by short-limbed dwarfing in the clinic.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>To characterize the function of a rare pathogenic variant in the <i>COMP</i> gene (c.875G &gt; A, p.Cys292Tyr).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Materials &amp; Methods</h3>\u0000 \u0000 <p>We performed 3D structural analysis, in vitro expression analysis, and immunofluorescence to characterize the effects of the variant on protein structure, expression, and cellular localization respectively.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Variation modeling showed that the interactions between amino acids were changed after the variation, and there were 31 changes in the secondary structure of mutant COMP (MT-COMP). Western blot showed that the intracellular quantity of MT-COMP was higher than the wild-type COMP (WT-COMP). Cellular immunofluorescence results showed that WT-COMP was less abundant and homogenously distributed in cells, while the MT-COMP accumulated in the cytoplasm.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Discussion</h3>\u0000 \u0000 <p>Herein, we report a variant of <i>COMP</i> in a Chinese family with PSACH. We have shown that the rare missense variant, <i>COMP</i> c.875G &gt; A, previously reported in ClinVar and identified in our patient, results in excessive accumulation of mutant protein in the cytoplasm, and is therefore pathogenic.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Through in silico and experimental analyses, we provide evidence that <i>COMP</i> c.875G &gt; A is the likely cause of PSACH in a Chinese family.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"87 5","pages":"241-247"},"PeriodicalIF":1.9,"publicationDate":"2023-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10046593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Uncovering cilia function in glial development","authors":"Rachel M. Bear,&nbsp;Tamara Caspary","doi":"10.1111/ahg.12519","DOIUrl":"10.1111/ahg.12519","url":null,"abstract":"<p>Primary cilia play critical roles in regulating signaling pathways that underlie several developmental processes. In the nervous system, cilia are known to regulate signals that guide neuron development. Cilia dysregulation is implicated in neurological diseases, and the underlying mechanisms remain poorly understood. Cilia research has predominantly focused on neurons and has overlooked the diverse population of glial cells in the brain. Glial cells play essential roles during neurodevelopment, and their dysfunction contributes to neurological disease; however, the relationship between cilia function and glial development is understudied. Here we review the state of the field and highlight the glial cell types where cilia are found and the ciliary functions that are linked to glial development. This work uncovers the importance of cilia in glial development and raises outstanding questions for the field. We are poised to make progress in understanding the function of glial cilia in human development and their contribution to neurological diseases.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"88 1","pages":"27-44"},"PeriodicalIF":1.9,"publicationDate":"2023-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ahg.12519","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9754660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pitfalls of predicting age-related traits by polygenic risk scores","authors":"Valentina Escott-Price,&nbsp;Karl Michael Schmidt","doi":"10.1111/ahg.12520","DOIUrl":"10.1111/ahg.12520","url":null,"abstract":"<p>Polygenic risk scores (PRS) are a method increasingly used to capture the combined effect of genome-wide significant variants and those which individually do not show genome-wide significant association but are likely to contribute to the risk of developing diseases. However, their practical use incurs complications and inconsistencies that so far limit their clinical applicability. The aims of the present review are to discuss the PRS for age-related diseases and to highlight pitfalls and limitations of PRS prediction accuracy due to ageing and mortality effects. We argue that the PRS is widely used but the individual's PRS values differ substantially depending on the number of genetic variants included, the discovery GWAS and the method employed to generate them. Moreover, for neurodegenerative disorders, although an individual's genetics do not change with age, the actual score depends on the age of the sample used in the discovery GWAS and is likely to reflect the individual's disease risk at this particular age. Improvement of PRS prediction accuracy for neurodegenerative disorders will come from two sides, both the precision of clinical diagnoses, and a careful attention to the age distribution in the underlying samples and validation of the prediction in longitudinal studies.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"87 5","pages":"203-209"},"PeriodicalIF":1.9,"publicationDate":"2023-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ahg.12520","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10053150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic polymorphism and variability in the Guangdong Hakka, Teochew, and Cantonese groups: A comprehensive analysis of 19 X-STRs","authors":"Cheng Xiao,&nbsp;Xingyi Yang,&nbsp;Zhonghao Yu,&nbsp;Weibin Wu,&nbsp;Yuan Wang,&nbsp;Quyi Xu,&nbsp;Ling Chen","doi":"10.1111/ahg.12518","DOIUrl":"10.1111/ahg.12518","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>X chromosomeshort tandem repeat (X-STR) loci are playing an increasingly important role inforensic work, identifying female traces in male contamination and explainingcomplex kinship analyses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this study, we analyzed thegenetic polymorphism of 19 X-STR loci in the Guangdong Hakka, Teochew and Cantonese groups, respectively, aswell as in the Guangdong Hakka, Teochew andCantonese pooled Han. The genetic diversity and forensic characteristics of the19 X-STRs and 7 linkage groups were investigated, respectively.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The experiments showed that the genetic diversity (GD) and polymorphism information content (PIC) in the pooledGuangdong Han ranged from 0.5320 to 0.9234 and 0.4369 to 0.9171, respectively, and the cumulative power of discrimination for males (PDM), power of discrimination for females (PDF) and mean paternity exclusion chance (MEC) were higher than 0.9999999, indicating that the 19 X-STRs had high geneticpolymorphism and discriminatory power. Genetic differences among Chinese Hansubgroups and among different Chinese populations were investigated byphylogenetic reconstruction and principal component analysis (PCA), respectively. Genetic analyses based on neighbor-joining (NJ) tree and principal component analysis plot showed that Cantonese, Teochew and Hakka were closely genetically related, and different populations with closer linguistic components had more genetic affinity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This study adds to the forensic X-STR database and demonstrates the forensic efficiency of 19 X-STRs for the Hakka, Teochewand Cantonese populations in Guangdong, and the pooled Han of Hakka, Teochewand Cantonese people in Guangdong.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"87 5","pages":"232-240"},"PeriodicalIF":1.9,"publicationDate":"2023-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10112288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low-pass whole genome sequencing is a reliable and cost-effective approach for copy number variant analysis in the clinical setting","authors":"P. Mazzonetto, Darine Villela, S. S. da Costa, A. Krepischi, F. Milanezi, M. Migliavacca, P. Pierry, A. Bonaldi, Luiz Gustavo D Almeida, Camila Alves De Souza, J. E. Kroll, Marcelo G. Paula, R. Guarischi-Sousa, C. Scapulatempo-Neto, C. Rosenberg","doi":"10.1101/2023.05.26.23290606","DOIUrl":"https://doi.org/10.1101/2023.05.26.23290606","url":null,"abstract":"We evaluated the performance of low-pass whole genome sequencing (LP-WGS) to detect copy number variants (CNVs) in clinical cytogenetics. DNA samples with known CNVs detected by chromosomal microarray analyses (CMA) were selected for comparison; our panel included 44 DNA samples (12 prenatal and 32 postnatal), comprising a total of 55 chromosome imbalances. The selected cases were chosen to provide a wide range of clinically relevant CNVs, being the vast majority associated with intellectual disability or recognizable syndromes. The chromosome imbalances ranged in size from 75 kb to 90.3 Mb, including aneuploidies and two cases of mosaicism. All CNVs were successfully detected by LP-WGS, showing a high level of consistency and robust performance of the sequencing method. Notably, the size of chromosome imbalances detected by CMA and LP-WGS were compatible between the two different platforms, which indicates that the resolution and sensitivity of the LP-WGS approach are at least similar to those provided by CMA. Our data show the potential use of LP-WGS to detect CNVs in clinical diagnosis and confirm the method as an alternative for chromosome imbalances detection. The diagnostic effectiveness and feasibility of LP-WGS, in this technical validation study, were evidenced by a clinically representative dataset of CNVs that allowed a systematic assessment of the detection power and the accuracy of the sequencing approach. Further, since the software used in this study is commercially available, the method can be easily tested and implemented in a routine diagnostic setting.","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"1 1","pages":""},"PeriodicalIF":1.9,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47211406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of influential rare variants in aggregate testing using random forest importance measures","authors":"Rachel Z. Blumhagen,&nbsp;David A. Schwartz,&nbsp;Carl D. Langefeld,&nbsp;Tasha E. Fingerlin","doi":"10.1111/ahg.12509","DOIUrl":"10.1111/ahg.12509","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <p>Aggregate tests of rare variants are often employed to identify associated regions compared to sequentially testing each individual variant. When an aggregate test is significant, it is of interest to identify which rare variants are “driving” the association. We recently developed the rare variant influential filtering tool (RIFT) to identify influential rare variants and showed RIFT had higher true positive rates compared to other published methods. Here we use importance measures from the standard random forest (RF) and variable importance weighted RF (vi-RF) to identify influential variants. For very rare variants (minor allele frequency [MAF] &lt; 0.001), the vi-RF:Accuracy method had the highest median true positive rate (TPR = 0.24; interquartile range [IQR]: 0.13, 0.42) followed by the RF:Accuracy method (TPR = 0.16; IQR: 0.07, 0.33) and both were superior to RIFT (TPR = 0.05; IQR: 0.02, 0.15). Among uncommon variants (0.001 &lt; MAF &lt; 0.03), the RF methods had higher true positive rates than RIFT while observing comparable false positive rates. Finally, we applied the RF methods to a targeted resequencing study in idiopathic pulmonary fibrosis (IPF), in which the vi-RF approach identified eight and seven variants in <i>TERT</i> and <i>FAM13A</i>, respectively. In summary, the vi-RF provides an improved, objective approach to identifying influential variants following a significant aggregate test. We have expanded our previously developed R package RIFT to include the random forest methods.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"87 4","pages":"184-195"},"PeriodicalIF":1.9,"publicationDate":"2023-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ahg.12509","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9679285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}