Human Heredity最新文献

{"title":"Identification of Influential Variants in Significant Aggregate Rare Variant Tests.","authors":"Rachel Z Blumhagen, David A Schwartz, Carl D Langefeld, Tasha E Fingerlin","doi":"10.1159/000513290","DOIUrl":"10.1159/000513290","url":null,"abstract":"<p><strong>Introduction: </strong>Studies that examine the role of rare variants in both simple and complex disease are increasingly common. Though the usual approach of testing rare variants in aggregate sets is more powerful than testing individual variants, it is of interest to identify the variants that are plausible drivers of the association. We present a novel method for prioritization of rare variants after a significant aggregate test by quantifying the influence of the variant on the aggregate test of association.</p><p><strong>Methods: </strong>In addition to providing a measure used to rank variants, we use outlier detection methods to present the computationally efficient Rare Variant Influential Filtering Tool (RIFT) to identify a subset of variants that influence the disease association. We evaluated several outlier detection methods that vary based on the underlying variance measure: interquartile range (Tukey fences), median absolute deviation, and SD. We performed 1,000 simulations for 50 regions of size 3 kb and compared the true and false positive rates. We compared RIFT using the Inner Tukey to 2 existing methods: adaptive combination of p values (ADA) and a Bayesian hierarchical model (BeviMed). Finally, we applied this method to data from our targeted resequencing study in idiopathic pulmonary fibrosis (IPF).</p><p><strong>Results: </strong>All outlier detection methods observed higher sensitivity to detect uncommon variants (0.001 < minor allele frequency, MAF > 0.03) compared to very rare variants (MAF <0.001). For uncommon variants, RIFT had a lower median false positive rate compared to the ADA. ADA and RIFT had significantly higher true positive rates than that observed for BeviMed. When applied to 2 regions found previously associated with IPF including 100 rare variants, we identified 6 polymorphisms with the greatest evidence for influencing the association with IPF.</p><p><strong>Discussion: </strong>In summary, RIFT has a high true positive rate while maintaining a low false positive rate for identifying polymorphisms influencing rare variant association tests. This work provides an approach to obtain greater resolution of the rare variant signals within significant aggregate sets; this information can provide an objective measure to prioritize variants for follow-up experimental studies and insight into the biological pathways involved.</p>","PeriodicalId":13226,"journal":{"name":"Human Heredity","volume":" ","pages":"1-13"},"PeriodicalIF":1.8,"publicationDate":"2021-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353006/pdf/nihms-1658543.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9764188","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":"Association of PNPLA3 I148M with Liver Disease Biomarkers in Latinos.","authors":"Jonathan D Roe,&nbsp;Luis A Garcia,&nbsp;Yann C Klimentidis,&nbsp;Dawn K Coletta","doi":"10.1159/000520734","DOIUrl":"https://doi.org/10.1159/000520734","url":null,"abstract":"<p><strong>Introduction: </strong>Liver disease accounts for approximately 2 million deaths per year worldwide. The majority of liver diseases are due to complications of cirrhosis, viral hepatitis, and hepatocellular carcinoma. Increased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) may indicate liver disease. Moreover, there are additional noninvasive liver fibrosis indices that help to estimate liver damage, including AST-to-ALT ratio, AST-to-platelet ratio index (APRI), fibrosis-4 (FIB-4) score, and nonalcoholic fatty liver disease (NAFLD) fibrosis score. The aims of the present study were to (1) perform an association analysis of the patatin-like phospholipase domain containing 3 (PNPLA3) I148M (rs738409) variant with ALT, AST, and various liver fibrosis indices, and (2) determine whether there are gender-related differences in these associations.</p><p><strong>Methods: </strong>We obtained demographic, anthropometric, and metabolic phenotypes from Latino adult participants (n = 503, 64% female, 36.4 ± 0.5 years) from the Arizona Insulin Resistance (AIR) registry. SNP genotyping of I148M was performed using the TaqMan allelic discrimination assay. We used linear regression for the association analyses of the genotypes with ALT, AST, and the various liver fibrosis indices. We included genotype, age, body mass index, and alcohol status in the linear regression model.</p><p><strong>Results: </strong>The variant I148M was in Hardy-Weinberg equilibrium, with genotype distribution: non-risk CC 118, heterozygous CG 246, and risk GG 139. The G allele was significantly associated with increased ALT and AST levels (p = 7.8 × 10-7 and p = 9.7 × 10-6, respectively). Moreover, we showed that the G allele was significantly associated with higher APRI (p = 3.7 × 10-7) and FIB-4 score (p = 4.1 × 10-3). When we analyzed the data by gender, we observed similar significant trends for ALT, AST, and APRI (all, p < 0.01). In females, the G allele was significantly associated with increased FIB-4 score (p = 6.9 × 10-3), which was not observed in the males (p > 0.05). There was no association of the I148M variant with AST/ALT ratio nor NAFLD risk score, whether analyzed in all adults or by gender.</p><p><strong>Discussion/conclusion: </strong>Our findings provide additional evidence of an association of PNPLA3 I148M with several liver disease biomarkers in male and female Latinos residing in the Southwest of the United States.</p>","PeriodicalId":13226,"journal":{"name":"Human Heredity","volume":"86 1-4","pages":"21-27"},"PeriodicalIF":1.8,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39600798","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":"PhosSNPs-Regulated Gene Network and Pathway Significant for Rheumatoid Arthritis.","authors":"Pei He,&nbsp;Fei Jiang,&nbsp;Wei Guo,&nbsp;Yu-Fan Guo,&nbsp;Shu-Feng Lei,&nbsp;Fei-Yan Deng","doi":"10.1159/000518608","DOIUrl":"https://doi.org/10.1159/000518608","url":null,"abstract":"<p><strong>Objectives: </strong>Peripheral blood mononuclear cells (PBMCs) are critical for immunity and participate in multiple human diseases, including rheumatoid arthritis (RA). PhosSNPs are nonsynonymous SNPs influencing protein phosphorylation, thus probably modulate cell signaling and gene expression. We aimed to identify phosSNPs-regulated gene network/pathway potentially significant for RA.</p><p><strong>Methods: </strong>We collected genome-wide phosSNP genotyping data and transcriptome-wide mRNA expression data from PBMCs of a Chinese sample. We discovered and verified with public datasets differentially expressed genes (DEGs) associated with RA, and replicated RA-associated SNPs in our study sample. We performed a targeted expression quantitative trait locus (eQTL) study on significant phosSNPs and DEGs.</p><p><strong>Results: </strong>We identified 29 nominally significant eQTL phosSNPs and 83 target genes, and constructed comprehensive regulatory/interaction networks, highlighting the vital effects of two eQTL phosSNPs (rs371513 and rs4824675, FDR <0.05) and four critical node genes (HSPA4, NDUFA2, MRPL15, and ATP5O). Besides, two node/key genes NDUFA2 and ATP5O, regulated by rs371513, were significantly enriched in mitochondrial oxidative phosphorylation pathway. Besides, four pairs of eQTL effects were replicated independently in whole blood and/or transformed fibroblasts.</p><p><strong>Conclusions: </strong>The findings delineated a potential role of protein phosphorylation and genetic variations in RA and warranted the significant roles of phosSNPs in regulating RA-associated genes expression in PBMCs. The results pointed out the relevance and significance of oxidative phosphorylation pathway to RA.</p>","PeriodicalId":13226,"journal":{"name":"Human Heredity","volume":"86 1-4","pages":"10-20"},"PeriodicalIF":1.8,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39476973","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":"Importance of Family History in the Era of Exome Analysis: A Report of a Family with Multiple Concurrent Genetic Diseases.","authors":"Karishma Mahtani,&nbsp;Diana Park,&nbsp;Jessica Abbott,&nbsp;Pavalan Panneer Selvam,&nbsp;Paldeep S Atwal","doi":"10.1159/000519356","DOIUrl":"https://doi.org/10.1159/000519356","url":null,"abstract":"<p><p>Multiple familial diseases in a single patient often present with overlapping symptomatology that confers difficulty in delineating a clinical diagnosis. Pedigree analysis has been a long-standing practice in the field of medical genetics to discover familial diseases. In recent years, whole exome sequencing (WES) has proven to be a useful tool for aiding physicians in diagnosing and understanding disease etiology. This report shows that pedigree analysis and WES are co-dependent processes in establishing diagnoses in a family with 4 different genetic disorders: Birt-Hogg-Dubé Syndrome, RRM2B-related mitochondrial disease, CDC73-related primary hyperparathyroidism, and familial prostate cancer.</p>","PeriodicalId":13226,"journal":{"name":"Human Heredity","volume":"86 1-4","pages":"28-33"},"PeriodicalIF":1.8,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39565958","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":"Meta-Analysis of Joint Test of SNP and SNP-Environment Interaction with Heterogeneity.","authors":"Qinqin Jin,&nbsp;Gang Shi","doi":"10.1159/000519098","DOIUrl":"https://doi.org/10.1159/000519098","url":null,"abstract":"<p><p>Many complex diseases are caused by single nucleotide polymorphisms (SNPs), environmental factors, and the interaction between SNPs and environment. Joint tests of the SNP and SNP-environment interaction effects (JMA) and meta-regression (MR) are commonly used to evaluate these SNP-environment interactions. However, these two methods do not consider genetic heterogeneity. We previously presented a random-effect MR, which provided higher power than the MR in datasets with high heterogeneity. However, this method requires group-level data, which sometimes are not available. Given this, we designed this study to evaluate the introduction of the random effects of SNP and SNP-environment interaction into the JMA, and then extended this to the random effect model. Likelihood ratio statistic is applied to test the JMA and the new method we proposed in this paper. We evaluated the null distributions of these tests, and the powers for this method. This method was verified by simulation and was shown to provide similar powers to the random effect meta-regression method (RMR). However, this method only requires study-level data which relaxed the condition of the RMR. Our study suggests that this method is more suitable for finding the association between SNP and diseases in the absence of group-level data.</p>","PeriodicalId":13226,"journal":{"name":"Human Heredity","volume":"86 1-4","pages":"1-9"},"PeriodicalIF":1.8,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39569837","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":"Exome-Wide Pan-Cancer Analysis of Germline Variants in 8,719 Individuals Finds Little Evidence of Rare Variant Associations.","authors":"Zoe Guan,&nbsp;Ronglai Shen,&nbsp;Colin B Begg","doi":"10.1159/000519355","DOIUrl":"https://doi.org/10.1159/000519355","url":null,"abstract":"<p><strong>Background: </strong>Many cancer types show considerable heritability, and extensive research has been done to identify germline susceptibility variants. Linkage studies have discovered many rare high-risk variants, and genome-wide association studies (GWAS) have discovered many common low-risk variants. However, it is believed that a considerable proportion of the heritability of cancer remains unexplained by known susceptibility variants. The \"rare variant hypothesis\" proposes that much of the missing heritability lies in rare variants that cannot reliably be detected by linkage analysis or GWAS. Until recently, high sequencing costs have precluded extensive surveys of rare variants, but technological advances have now made it possible to analyze rare variants on a much greater scale.</p><p><strong>Objectives: </strong>In this study, we investigated associations between rare variants and 14 cancer types.</p><p><strong>Methods: </strong>We ran association tests using whole-exome sequencing data from The Cancer Genome Atlas (TCGA) and validated the findings using data from the Pan-Cancer Analysis of Whole Genomes Consortium (PCAWG).</p><p><strong>Results: </strong>We identified four significant associations in TCGA, only one of which was replicated in PCAWG (BRCA1 and ovarian cancer).</p><p><strong>Conclusions: </strong>Our results provide little evidence in favor of the rare variant hypothesis. Much larger sample sizes may be needed to detect undiscovered rare cancer variants.</p>","PeriodicalId":13226,"journal":{"name":"Human Heredity","volume":"86 1-4","pages":"34-44"},"PeriodicalIF":1.8,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8889565/pdf/nihms-1780279.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39843210","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":"Contents Vol. 84, 2019","authors":"Mulin Li","doi":"10.1159/000512546","DOIUrl":"https://doi.org/10.1159/000512546","url":null,"abstract":"203 48th European Mathematical Genetics Meeting (EMGM) 2020 Lausanne, Switzerland, April 16–17, 2020 Guest Editors: Zoltan Kutalik; Matthew Robinson (Lausanne)","PeriodicalId":13226,"journal":{"name":"Human Heredity","volume":"84 1","pages":"I - IV"},"PeriodicalIF":1.8,"publicationDate":"2020-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000512546","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47953741","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":"Front & Back Matter","authors":"","doi":"10.1159/000512996","DOIUrl":"https://doi.org/10.1159/000512996","url":null,"abstract":"","PeriodicalId":13226,"journal":{"name":"Human Heredity","volume":" ","pages":""},"PeriodicalIF":1.8,"publicationDate":"2020-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45010251","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":"Front & Back Matter","authors":"","doi":"10.1159/000510011","DOIUrl":"https://doi.org/10.1159/000510011","url":null,"abstract":"203 48th European Mathematical Genetics Meeting (EMGM) 2020 Lausanne, Switzerland, April 16–17, 2020 Guest Editors: Zoltan Kutalik; Matthew Robinson (Lausanne) Cover illustration iStock.com Cytogenetic and Genome Research has been the leading forum for original reports and reviews in human and animal cytogenetics, including molecular, clinical and comparative cytogenetics. In recent years, most of the contributions have centered on genome research, including gene regulation and expression, cancer genetics, comparative genetics and human malformation syndromes. The journal publishes key papers on the insights into the mechanisms of chromosome aberrations in somatic, meiotic and malignant cells. Its scope includes studies on invertebrate and plant cytogenetics and genomics. Also featured are recent international reports on human and animal chromosome nomenclature. In addition to regular issues, the journal has been publishing since 2002 a series of topical issues on a broad variety of themes from cytogenetic and genome research. Cytogenetic and Genome Research Founded: 1962 Category: Basic Research Field of Interest: Genetics Listed in bibliographic services, including: PubMed/MEDLINE, Web of Science, Google Scholar, Scopus, Embase 2019: Volumes 157, 158, 159 4 issues per volume Language: English ISSN 1424–8581 e-ISSN 1424–859X More information at w w w.karger.com/cgr A leading journal on human, animal and plant genomes and chromosomes Impact Factor: 1.587 5-Year Impact Factor: 1.682 Editor-in-Chief M. Schmid, Würzburg Executive Editors L.A. Cannizzaro, New York, NY T. Haaf, Würzburg Managing Editors T. Gößwein, Würzburg M. Guttenbach, Würzburg K. Schmid, Würzburg Associate Editors R.D. Burnside, Research Triangle Park, NC A. Geurts Van Kessel, Nijmegen A. Houben, Gatersleben O. Riess, Tübingen J. Smith, Roslin Selected contributions • Two Cases with Ring Chromosome 13 at either End of the Phenotypic Spectrum: Çakmaklı, S.; Çankaya, T.; Gürsoy, S.; Koç, A.; Kırbıyık, Ö.; Kılıçarslan, Ö.A.; Özer, E.; Erçal, D.; Bozkaya, Ö.G. (Izmir) • Clinical, Hormonal, and Genetic Evaluation of Idiopathic Nonobstructive Azoospermia and Klinefelter Syndrome Patients: Kim, S.Y.; Lee, B.Y.; Oh, A.R.; Park, S.Y.; Lee, H.S.; Seo, J.T. (Seoul) • Prenatal Diagnosis of Trisomy 2p due to Terminal 2p Duplication including Interstitial Telomeric Sequences: Marlet, L.; Alix, E.; Till, M. (Bron); Raskin-Champion, F.; Attia, J.; Boggio, D. (Pierre-Bénite); Sanlaville, D.; Schluth-Bolard, C. (Bron) • The Relationship between the (In-)Stability of NORs and Their Chromosomal Location: The Example of Cercopithecidae and a Short Review of Other Primates: Gerbault-Seureau, M.; Cacheux, L.; Dutrillaux, B. (Paris) • Production and Molecular Cytogenetic Characterization of a Durum Wheat-Thinopyrum elongatum 7E Disomic Addition Line with Resistance to Fusarium Head Blight: Liu, H.; Dai, Y. (Yangzhou/Ottawa, ON); Chi, D. (Ottawa, ON); Huang, S. (Nanjing); Li, H.; Duan, Y. (Yangzhou); Cao,","PeriodicalId":13226,"journal":{"name":"Human Heredity","volume":" ","pages":""},"PeriodicalIF":1.8,"publicationDate":"2020-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46721003","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":"Publisher's Note","authors":"","doi":"10.1159/000509257","DOIUrl":"https://doi.org/10.1159/000509257","url":null,"abstract":"","PeriodicalId":13226,"journal":{"name":"Human Heredity","volume":"84 1","pages":"159 - 159"},"PeriodicalIF":1.8,"publicationDate":"2020-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000509257","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43143979","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}