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Huang, Joe Xi, Dorothy Mehrens, Rick Wiese, Sandy Lee, Sun W. Tam, Steve Daniel, James Gilmore, Michael Shi, and Deval Lashkari. "High-Throughput Genomic and Proteomic Analysis Using Microarray Technology." Clinical Chemistry 47, no. 10 (October 1, 2001): 1912–16. http://dx.doi.org/10.1093/clinchem/47.10.1912.
Повний текст джерелаАнотація:
Abstract Background: High-density microarrays are ideally suited for analyzing thousands of genes against a small number of samples. The next step in the discovery process is to take the resulting genes of interest and rapidly screen them against thousands of patient samples, tissues, or cell lines to further investigate their involvement in disease risk or the response to medication. Methods: We used a microarray technology platform for both single-nucleotide polymorphisms (SNPs) and protein expression. Each microarray contains up to 250 elements that can be customized for each application. Slides contained either a 16- or 96-microarray format (4000–24 000 elements per slide), allowing the corresponding number of samples to be rapidly processed in parallel. Results: Results for SNP genotyping and protein profiling agreed with results of restriction fragment length polymorphism (RFLP) analysis or ELISA, respectively. Genotyping analyses, using the microarray technology, on large sample sets over multiple polymorphisms in the NAT2 gene were in full agreement with traditional methodologies, such as sequencing and RFLP analysis. The multiplexed protein microarray had correlation coefficients of 0.82–0.99 (depending on analyte) compared with ELISAs. Conclusions: The integrated microarray technology platform is adaptable and versatile, while offering the high-throughput capabilities needed for drug development and discovery applications.
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Sansaloni, Carolina P., César D. Petroli, Jason Carling, Corey J. Hudson, Dorothy A. Steane, Alexander A. Myburg, Dario Grattapaglia, René E. Vaillancourt, and Andrzej Kilian. "A high-density Diversity Arrays Technology (DArT) microarray for genome-wide genotyping in Eucalyptus." Plant Methods 6, no. 1 (2010): 16. http://dx.doi.org/10.1186/1746-4811-6-16.
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Dacheux, Laurent, Nicolas Berthet, Gabriel Dissard, Edward C. Holmes, Olivier Delmas, Florence Larrous, Ghislaine Guigon, et al. "Application of Broad-Spectrum Resequencing Microarray for Genotyping Rhabdoviruses." Journal of Virology 84, no. 18 (July 7, 2010): 9557–74. http://dx.doi.org/10.1128/jvi.00771-10.
Повний текст джерелаАнотація:
ABSTRACT The rapid and accurate identification of pathogens is critical in the control of infectious disease. To this end, we analyzed the capacity for viral detection and identification of a newly described high-density resequencing microarray (RMA), termed PathogenID, which was designed for multiple pathogen detection using database similarity searching. We focused on one of the largest and most diverse viral families described to date, the family Rhabdoviridae. We demonstrate that this approach has the potential to identify both known and related viruses for which precise sequence information is unavailable. In particular, we demonstrate that a strategy based on consensus sequence determination for analysis of RMA output data enabled successful detection of viruses exhibiting up to 26% nucleotide divergence with the closest sequence tiled on the array. Using clinical specimens obtained from rabid patients and animals, this method also shows a high species level concordance with standard reference assays, indicating that it is amenable for the development of diagnostic assays. Finally, 12 animal rhabdoviruses which were currently unclassified, unassigned, or assigned as tentative species within the family Rhabdoviridae were successfully detected. These new data allowed an unprecedented phylogenetic analysis of 106 rhabdoviruses and further suggest that the principles and methodology developed here may be used for the broad-spectrum surveillance and the broader-scale investigation of biodiversity in the viral world.
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Desjardins, Christopher A., Jürgen Gadau, Jacqueline A. Lopez, Oliver Niehuis, Amanda R. Avery, David W. Loehlin, Stephen Richards, John K. Colbourne, and John H. Werren. "Fine-Scale Mapping of the Nasonia Genome to Chromosomes Using a High-Density Genotyping Microarray." G3: Genes|Genomes|Genetics 3, no. 2 (February 2013): 205–15. http://dx.doi.org/10.1534/g3.112.004739.
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Jasmine, F., H. Ahsan, I. L. Andrulis, E. M. John, J. Chang-Claude, and M. G. Kibriya. "Whole-Genome Amplification Enables Accurate Genotyping for Microarray-Based High-Density Single Nucleotide Polymorphism Array." Cancer Epidemiology Biomarkers & Prevention 17, no. 12 (December 1, 2008): 3499–508. http://dx.doi.org/10.1158/1055-9965.epi-08-0482.
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Hans, Aymeric, Delphine Gaudaire, Jean-Claude Manuguerra, Albertine Leon, Antoine Gessain, Claire Laugier, Nicolas Berthet, and Stephan Zientara. "Combination of an Unbiased Amplification Method and a Resequencing Microarray for Detecting and Genotyping Equine Arteritis Virus." Journal of Clinical Microbiology 53, no. 1 (October 22, 2014): 287–91. http://dx.doi.org/10.1128/jcm.01935-14.
Повний текст джерелаАнотація:
This study shows that an unbiased amplification method applied to equine arteritis virus RNA significantly improves the sensitivity of the real-time reverse transcription-quantitative PCR (RT-qPCR) recommended by the World Organization for Animal Health. Twelve viral RNAs amplified using this method were hybridized on a high-density resequencing microarray for effective viral characterization.
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Li, Honghua, Hui-Yun Wang, Danielle Greenawalt, Xiangfeng Cui, IrinaV Tereshchenko, Minjie Luo, Qifeng Yang, et al. "Identification of possible genetic alterations in the breast cancer cell line MCF-7 using high-density SNP genotyping microarray." Journal of Carcinogenesis 8, no. 1 (2009): 6. http://dx.doi.org/10.4103/1477-3163.50886.
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Vogler, Amy J., Dawn Birdsell, Lance B. Price, Jolene R. Bowers, Stephen M. Beckstrom-Sternberg, Raymond K. Auerbach, James S. Beckstrom-Sternberg, et al. "Phylogeography of Francisella tularensis: Global Expansion of a Highly Fit Clone." Journal of Bacteriology 191, no. 8 (February 27, 2009): 2474–84. http://dx.doi.org/10.1128/jb.01786-08.
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ABSTRACT Francisella tularensis contains several highly pathogenic subspecies, including Francisella tularensis subsp. holarctica, whose distribution is circumpolar in the northern hemisphere. The phylogeography of these subspecies and their subclades was examined using whole-genome single nucleotide polymorphism (SNP) analysis, high-density microarray SNP genotyping, and real-time-PCR-based canonical SNP (canSNP) assays. Almost 30,000 SNPs were identified among 13 whole genomes for phylogenetic analysis. We selected 1,655 SNPs to genotype 95 isolates on a high-density microarray platform. Finally, 23 clade- and subclade-specific canSNPs were identified and used to genotype 496 isolates to establish global geographic genetic patterns. We confirm previous findings concerning the four subspecies and two Francisella tularensis subsp. tularensis subpopulations and identify additional structure within these groups. We identify 11 subclades within F. tularensis subsp. holarctica, including a new, genetically distinct subclade that appears intermediate between Japanese F. tularensis subsp. holarctica isolates and the common F. tularensis subsp. holarctica isolates associated with the radiation event (the B radiation) wherein this subspecies spread throughout the northern hemisphere. Phylogenetic analyses suggest a North American origin for this B-radiation clade and multiple dispersal events between North America and Eurasia. These findings indicate a complex transmission history for F. tularensis subsp. holarctica.
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Ohlson, Erik W., and Michael P. Timko. "Mapping and Validation of Alectra vogelii Resistance in the Cowpea Landrace B301." Agronomy 12, no. 11 (October 27, 2022): 2654. http://dx.doi.org/10.3390/agronomy12112654.
Повний текст джерелаАнотація:
Cowpea is the most important food legume in West and Central Africa and a valuable economic commodity in the region. Among the major biotic constraints to cowpea production are root parasitic weeds of which Alectra vogelii (Benth.) is of increasing importance. The cowpea landrace B301 was previously identified as a source of Alectra resistance, but neither the genes nor genomic loci conferring this resistance have been mapped. Therefore, to map and identify genetic markers linked to Alectra resistance for use in the molecular improvement of cowpea, we developed an F2 population from a cross of the susceptible variety 524B with B301. The population was phenotyped for resistance to A. vogelii and genotyped with a cowpea high density single nucleotide polymorphism (SNP) microarray. Putative resistance loci were mapped in F2 populations by categorical trait–multiple interval mapping and validated by selective genotyping. Selective genotyping indicated that the resistance loci on Vu04 (Rav1) and Vu11 (Rav2) were significantly associated with resistance (p ≤ 0.01). Using marker assisted backcrossing, the two resistance loci were introgressed independently into the susceptible 524B genetic background. Phenotyping and genotyping of the segregating backcross families delineated Rav1 to a 10 cM on chromosome 4 and Rav2 to a 6.7 cM interval in chromosome 11. These two loci are desirable for breeding Alectra resistant cowpea varieties due to their simple inheritance and ability to independently confer complete immunity to the parasite.
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Björkholm, Britta, Annelie Lundin, Anna Sillén, Karen Guillemin, Nina Salama, Carlos Rubio, Jeffrey I. Gordon, Per Falk, and Lars Engstrand. "Comparison of Genetic Divergence and Fitness between Two Subclones of Helicobacter pylori." Infection and Immunity 69, no. 12 (December 1, 2001): 7832–38. http://dx.doi.org/10.1128/iai.69.12.7832-7838.2001.
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ABSTRACT Helicobacter pylori has a very plastic genome, reflecting its high rate of recombination and point mutation. This plasticity promotes divergence of the population by the development of subclones and presumably enhances adaptation to host niches. We have investigated the genotypic and phenotypic characteristics of two such subclones isolated from one patient as well as the genetic evolution of these isolates during experimental infection. Whole-genome genotyping of the isolates using DNA microarrays revealed that they were more similar to each other than to a panel of other genotyped strains recovered from different hosts. Nonetheless, they still showed significant differences. For example, one isolate (67:21) contained the entire Cag pathogenicity island (PAI), whereas the other (67:20) had excised the PAI. Phenotypic studies disclosed that both isolates expressed adhesins that recognized human histo-blood group Lewisb glycan receptors produced by gastric pit and surface mucus cells. In addition, both isolates were able to colonize, to equivalent density and with similar efficiency, germ-free transgenic mice genetically engineered to synthesize Lewisb glycans in their pit cells (12 to 14 mice/isolate). Remarkably, the Cag PAI-negative isolate was unable to colonize conventionally raised Lewisb transgenic mice harboring a normal gastric microflora, whereas the Cag PAI-positive isolate colonized 74% of the animals (39 to 40 mice/isolate). The genomic evolution of both isolates during the infection of conventionally raised and germ-free mice was monitored over the course of 3 months. The Cag PAI-positive isolate was also surveyed after a 10 month colonization of conventionally raised transgenic animals (n = 9 mice). Microarray analysis of the Cag PAI and sequence analysis of the cagA,recA, and 16S rRNA genes disclosed no changes in recovered isolates. Together, these results reveal that the H. pyloripopulation infecting one individual can undergo significant divergence, creating stable subclones with substantial genotypic and phenotypic differences.
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Blades, Matthew, Jamie Freyer, Jonas Donner, Rebecca Chodroff Foran, and Oliver P. Forman. "Large scale across-breed genome-wide association study reveals a variant in HMGA2 associated with inguinal cryptorchidism risk in dogs." PLOS ONE 17, no. 5 (May 26, 2022): e0267604. http://dx.doi.org/10.1371/journal.pone.0267604.
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Cryptorchidism is the most common congenital sex development disorder in dogs. Despite this, little progress has been made in understanding its genetic background. Extensive genetic testing of dogs through consumer and veterinary channels using a high-density SNP genotyping microarray coupled with links to clinical records presents the opportunity for a large-scale genome-wide association study to elucidate the molecular risk factors associated with cryptorchidism in dogs. Using an inter-breed genome-wide association study approach, a significant statistical association on canine chromosome 10 was identified, with the top SNP pinpointing a variant of HMGA2 previously associated with adult weight variance. In further analysis we show that incidence of cryptorchidism is skewed towards smaller dogs in concordance with the identified variant’s previous association with adult weight. This study represents the first putative variant to be associated with cryptorchidism in dogs.
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Takita, Junko, Motohiro Kato, Fumihiko Nakamura, Yuyan Chen, Go Yamamoto, Yasuhito Nannya, Masashi Sanada, et al. "High-Resolution Analyses of Genetic and Epigenetic Aberrations in Infant Leukemia with MLL Rearrangement." Blood 110, no. 11 (November 16, 2007): 4238. http://dx.doi.org/10.1182/blood.v110.11.4238.4238.
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Abstract MLL rearrangement-positive leukemia is one of the most aggressive types of leukemia. It is diagnosed predominantly in infants and typically shows a multilineage phenotype. Since current chemotherapy fails in more than 50% of infantile leukemia with MLL rearrangement, a better understanding of biological features of the disease is importantly in order to develop more specific and successful treatment strategies. Thus, to explore both genetic and epigenetic lesions associated with MLL rearrangement-positive infantile leukemia, we performed genome-wide analyses of copy number alterations/allelic imbalances as well as methylation analysis using Affymetrix GeneChip SNP genotyping microarrays and promoter tiling array combined with methylated DNA immunoprecipitation (MeDIP). Combined with newly developed algorithm, CNAG/AsCNAR, SNP array analysis enables accurate copy number analysis at extremely high resolutions. In addition, by sensing subtle distortions in allele-specific signals caused by allelic imbalance using anonymous controls, sensitive detection of LOH is enabled with accurate determination of allele-specific copy numbers even in the face of up to 70–80% normal cell contamination. In total, 25 specimens from MLL rearrangement-positive leukemia were analyzed using high-density SNP-genotyping microarrays (Affymetrix GeneChip 100K/500K arrays). While unbalanced translocation involving chromosome 11q23 is the most frequent genetic alterations, uniparental disomy of 17q is also common genetic alterations in MLL rearrangement-positive leukemia. A number of other genetic changes were also identified but these were mostly found in a single case. On the other hand, epigenetic abnormalities have been implicated in MLL rearrangement-positive leukemia, because MLL is known to be involved in epigenetic regulations. In our assay, fragmented genomic DNA from leukemia specimens was immunoprecipitated with anti-methylcytosine antibody (MeDIP). The immunoprecipitated DNA was amplified by PCR and subjected to hybridization to the promoter tiling array, in which regulatory regions of more than 25,000 genes are tiled by 6.5 millions of oligonucleotide probes to enable sensitive detection of target sequences. This tiling array covers approximate 59% of CpG islands in the human genomes. In addition to the previously described genes, such as FHIT and HOX family, a number of tumor specific methylated sites were identified in the leukemic cells and which were subsequently verified by bisulfate sequencing. These results indicated that high-resolution analyses of genetic and epigenetic aberrations using microarray techniques are powerful and useful for detection of new findings in the pathogenesis of infant leukemia with MLL rearrangement.
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Kato-Maeda, Midori, Jeanne T. Rhee, Thomas R. Gingeras, Hugh Salamon, Jorg Drenkow, Nat Smittipat, and Peter M. Small. "Comparing Genomes within the Species Mycobacterium tuberculosis." Genome Research 11, no. 4 (April 1, 2001): 547–54. http://dx.doi.org/10.1101/gr166401.
Повний текст джерелаАнотація:
The study of genetic variability within natural populations of pathogens may provide insight into their evolution and pathogenesis. We used a Mycobacterium tuberculosis high-density oligonucleotide microarray to detect small-scale genomic deletions among 19 clinically and epidemiologically well-characterized isolates of M. tuberculosis. The pattern of deletions detected was identical within mycobacterial clones but differed between different clones, suggesting that this is a suitable genotyping system for epidemiologic studies. An analysis of genomic deletions among an extant population of pathogenic bacteria provided a novel perspective on genomic organization and evolution. Deletions are likely to contain ancestral genes whose functions are no longer essential for the organism's survival, whereas genes that are never deleted constitute the minimal mycobacterial genome. As the amount of genomic deletion increased, the likelihood that the bacteria will cause pulmonary cavitation decreased, suggesting that the accumulation of mutations tends to diminish their pathogenicity. Array-based comparative genomics is a promising approach to exploring molecular epidemiology, microbial evolution, and pathogenesis.
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Searles Quick, Veronica B., Belinda Wang, and Matthew W. State. "Leveraging large genomic datasets to illuminate the pathobiology of autism spectrum disorders." Neuropsychopharmacology 46, no. 1 (July 15, 2020): 55–69. http://dx.doi.org/10.1038/s41386-020-0768-y.
Повний текст джерелаАнотація:
Abstract“Big data” approaches in the form of large-scale human genomic studies have led to striking advances in autism spectrum disorder (ASD) genetics. Similar to many other psychiatric syndromes, advances in genotyping technology, allowing for inexpensive genome-wide assays, has confirmed the contribution of polygenic inheritance involving common alleles of small effect, a handful of which have now been definitively identified. However, the past decade of gene discovery in ASD has been most notable for the application, in large family-based cohorts, of high-density microarray studies of submicroscopic chromosomal structure as well as high-throughput DNA sequencing—leading to the identification of an increasingly long list of risk regions and genes disrupted by rare, de novo germline mutations of large effect. This genomic architecture offers particular advantages for the illumination of biological mechanisms but also presents distinctive challenges. While the tremendous locus heterogeneity and functional pleiotropy associated with the more than 100 identified ASD-risk genes and regions is daunting, a growing armamentarium of comprehensive, large, foundational -omics databases, across species and capturing developmental trajectories, are increasingly contributing to a deeper understanding of ASD pathology.
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Reverter, A., E. K. F. Chan, S. A. Lehnert, W. Barris, S. M. McWilliam, B. P. Dalrymple, and W. Barendse. "Dissection of beef quality phenotypes using a myogenin network-anchored systems biology approach." Australian Journal of Experimental Agriculture 48, no. 8 (2008): 1053. http://dx.doi.org/10.1071/ea08052.
Повний текст джерелаАнотація:
In order to uncover genes with transcriptional activity linked to various beef quality phenotypes of interest, we designed a systems biology approach. We focussed on traits representing the three major categories of growth and development, fat depots and meat quality phenotypes. We proceeded by linking bovine gene expression data derived from 147 microarray hybridisation experiments and high density marker data from 9260 single nucleotide polymorphisms (SNP) on 189 steers. The individuals in the genotyping study were unrelated to the samples used for expression profiling. The linkage was performed by anchoring these data to a gene network for myogenin (MYOG), a muscle-specific transcription factor essential for the development of skeletal muscle. This approach was able to identify and estimate the strength of the relationship between the statistical association of a SNP to a phenotype of interest with the transcriptional activity of genes in the network. The genes from the MYOG-centred network that were significantly associated with the largest number of meat quality traits were PDLIM3, CALM1 and CRYAB. Among our findings, a novel association between desmin and meat colour points to an alternative biochemical basis for meat colour differences involving costameric structures and their previously reported relationship with tenderness. These newly generated hypotheses can help formulate sound research to further illuminate the genetic architecture of beef quality phenotypes.
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Kim, Dong Hwan (Dennis), Boram Han, Kyusang Lee, TaeJin Ahn, Dae-soon Son, Insuk Sohn, Sin-Ho Jung, et al. "Pharmacogenomics-Based Drug Response Prediction Model for Acute Myeloid Leukemia with Normal Karyotype." Blood 116, no. 21 (November 19, 2010): 2698. http://dx.doi.org/10.1182/blood.v116.21.2698.2698.
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Abstract Abstract 2698 Introduction: AML is a heterogeneous disease characterized by various recurrent cytogenetic abnormalities, which provide the most important prognostic information. Although AML with normal karyotype (AML-NK) constitutes the largest subgroup representing 45–50% of adult AMLs, the prognosis of AML-NK is quite heterogeneous and their clinical outcomes are diverse. Several model capable of identifying non-responders prior to induction treatment has been proposed in AML-NK. While molecular-guided risk assessment (i.e. FLT3/ITD mutation or NPM1 mutation) and stratification are needed to confirm their prognostic significances, it is quite enthusiastic that genetic variations associated with ADMET (adsorption, desorption, metabolism, excretion, and transport) genes predict the responsiveness of anticancer drugs with better predictive power compared to other genomic variations based stratification. It is also expected SNP markers that reside within the loci of these genetic pathways may play an important role to classify responders and non-responders in AML-NK. Methods and materials: A high density SNP genotyping microarray designed by our group (custom PGX chip; Samsung Electronics Co., Suwon, Korea) was evaluated in 139 patients with AML-NK as a discovery set using both custom PGX chip and Affymetrix SNP array 6.0 (Affymetrix Inc., Santa Clara, CA USA). The DNA samples were obtained from the marrow samples at the time of diagnosis. The custom PGx chip included more extensive SNP markers of ADMET genes and cancer-related genes. Genotypes were determined by Birdseed v2 algorithm for Affymetrix SNP 6.0 and by BRLMM-p for custom PGx chip. Genotypes from 906,600 SNPs were obtained in Affymetrix SNP 6.0 chip while custom PGx chip provided genotype information of 90,647 SNPs. Between Affymetrix SNP 6.0 and custom PGx chip, 67,251 SNPs were shared. ADMET and cancer-related SNPs (n=23,396) were only available on custom PGx chip. The predictive model for the achievement of complete remission was developed using Max Test method with leave-one-out LDA cross validation (repeating 10,000 times of permutation test). The analysis compared the data of PGx chip with data from Affymetrix SNP 6.0 microarray. Results: Genotyping results from custom PGx chip was compared to results from Affymetrix SNP 6.0 showing 94.33% of concordance rate. Among the 164,578 SNP markers included in the original design, 90,647 of them were finally chosen to generate reliable genotype calls. Additional SNP markers including missing genotypes were again removed before the construction of prediction model. Finally, the total number of available SNP markers was reduced to 37,676 for the analysis and model contruction. Max Test provided p-values by performing permutation test. Significant SNP markers with p-values less than 0.01 were chosen to construct a prediction model using leave-one-out LDA (linear discriminate analysis) method. The numbers of SNP markers were narrowed down as p-values became more significant (No. of SNPs in p-value): n=329 in p <0.01; n=66 in p <0.001; n=7 in p<0.0001. The selection of SNP markers could be optimized and further narrowed down by extensive search. The accuracy of the model improved as more SNP markers were included in the model: the accuracy reaches 100% when N was 59. Followings are the example of the significant SNP markers included in the genetic predictive model for complete remission after induction therapy for AML-NK: CCDC93, LRP1B, LASS6, ATF2, and PDE11A on chr 2, PDE4D and PPP2R2B on chr 5, PARK2 on chr 6, PTPRD on chr 9, ABCC4 on chr 13, SLC25A21 on chr 14, ABCC1, PRKCB, ITGAX, and CNOT1 on chr 16, and other SNP markers. The biologic significances of these SNP markers are under investigation. Conclusion: The clinical relevance of the predictive model based on pharmacogenomic informations will be further clarified with external replication in the independent cohorts of AML. In patients with AML-NK which has diverse and heterogeneous clinical characteristics, the predictive model could identify non-responders who might benefit from alternative treatments prior to commencement of conventional induction therapy based on idarubicin plus cytarabine. In addition, it will also reduce the risk of adverse events in the non-responders and eventually improve overall survival in AML-NK. Disclosures: No relevant conflicts of interest to declare.
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Sanada, Masashi, Yasuhito Nannya, Kumi Nakazaki, Go Yamamoto, Lili Wang, Noriko Hosoya, Akira Hangaishi, Mineo Kurokawa, Shigeru Chiba, and Seishi Ogawa. "Genome-Wide Analysis of Copy Number Analysis of Myelodysplastic Syndromes Using High-Density SNP-Genotyping Microarrays." Blood 106, no. 11 (November 16, 2005): 3420. http://dx.doi.org/10.1182/blood.v106.11.3420.3420.
Повний текст джерелаАнотація:
Abstract Myelodysplastic syndromes (MDS) are clonal disorders of hematopoietic progenitors characterized by impaired blood cell production due to ineffective hematopoiesis and high propensity to acute myeloid leukemias. One of the prominent features of MDS is the high frequency of unbalanced chromosomal abnormalities that result in genetic imbalances and copy number alterations. Although the chromosomal segments involved in these abnormalities are thought to contain relevant genes to the pathogenesis of MDS, conventional analyses including FISH have failed to identify critical regions small enough to pinpoint their target genes. Affymetrix® GeneChip® 100K/500K mapping arrays were originally developed for large-scale genotyping of more than 100,000/500,000 SNPs in two separate arrays, but the quantitative nature of the preparative whole-genome amplification and array hybridization thereafter also allows for accurate copy number estimate of the genome using these platforms at the resolutions of 21.3 kb and 5.4 kb with 116,204 and 520,000 oligonucleotide probes, respectively. Here we developed robust algorithms (CNAG) for copy number detection using 100K and/or 500K arrays and analyzed 88 MDS samples on these platforms in order to identify relevant genes for development of MDS. With these huge numbers of uniformly distributed SNP probes, numerous copy number alterations were sensitively detected in cases with MDS with more numbers of abnormalities found in advanced diseases (RAEB and RAEB-t). In addition to large-scale alterations of various chromosomal segments previously reported in these syndromes, a number of small cryptic chromosomal abnormalities were identified that would escape conventional cytogenetic analysis or array CGH analysis. Minimum overlapping deletions in 5q, 7q, 12p, 13q, and 20q were precisely defined, although no pinpoint homozygous deletions were detected within these regions. A common 20q deletion spans a 400 kb segment harboring five transcriptomes and the common 12p deletion defines a 1.3 Mb region that contains the ETV6 gene. Other common overlapping abnormalities include deletions in 21q22, 17q13, and gains of 11q25. Genome-wide analysis of copy number changes using high-density oligonucleotide arrays provides valuable information about genetic abnormalities in MDS.
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Suzuki, Makoto, Motohiro Kato, Chen Yuyan, Junko Takita, Masashi Sanada, Yasuhito Nannya, Go Yamamoto, et al. "Whole-genome profiling of chromosomal aberrations in hepatoblastoma using high-density single-nucleotide polymorphism genotyping microarrays." Cancer Science 99, no. 3 (March 2008): 564–70. http://dx.doi.org/10.1111/j.1349-7006.2007.00710.x.
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Homer, Nils, Szabolcs Szelinger, Margot Redman, David Duggan, Waibhav Tembe, Jill Muehling, John V. Pearson, Dietrich A. Stephan, Stanley F. Nelson, and David W. Craig. "Resolving Individuals Contributing Trace Amounts of DNA to Highly Complex Mixtures Using High-Density SNP Genotyping Microarrays." PLoS Genetics 4, no. 8 (August 29, 2008): e1000167. http://dx.doi.org/10.1371/journal.pgen.1000167.
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Borneman, Anthony R., Eveline J. Bartowsky, Jane McCarthy, and Paul J. Chambers. "Genotypic diversity in Oenococcus oeni by high-density microarray comparative genome hybridization and whole genome sequencing." Applied Microbiology and Biotechnology 86, no. 2 (January 29, 2010): 681–91. http://dx.doi.org/10.1007/s00253-009-2425-6.
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Scionti, Francesca, Maria Di Martino, Licia Pensabene, Valentina Bruni, and Daniela Concolino. "The Cytoscan HD Array in the Diagnosis of Neurodevelopmental Disorders." High-Throughput 7, no. 3 (September 14, 2018): 28. http://dx.doi.org/10.3390/ht7030028.
Повний текст джерелаАнотація:
Submicroscopic chromosomal copy number variations (CNVs), such as deletions and duplications, account for about 15–20% of patients affected with developmental delay, intellectual disability, multiple congenital anomalies, and autism spectrum disorder. Most of CNVs are de novo or inherited rearrangements with clinical relevance, but there are also rare inherited imbalances with unknown significance that make difficult the clinical management and genetic counselling. Chromosomal microarrays analysis (CMA) are recognized as the first-line test for CNV detection and are now routinely used in the clinical diagnostic laboratory. The recent use of CMA platforms that combine classic copy number analysis with single-nucleotide polymorphism (SNP) genotyping has increased the diagnostic yields. Here we discuss the application of the Cytoscan high-density (HD) SNP-array for the detection of CNVs. We provide an overview of molecular analyses involved in identifying pathogenic CNVs and highlight important guidelines to establish pathogenicity of CNV.
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Kato, Motohiro, Kumi Nakazaki, Kengo Takeuchi, Go Yamamoto, Yasuhito Nannya, Masashi Sanada, Satsuki Muto, et al. "Genomic Profiling of Different Subtypes of B-Cell Non-Hodgkin’s Lymphoma Using High-Density Single Nucleotide Polymorphism (SNP) Microarrays." Blood 110, no. 11 (November 16, 2007): 3588. http://dx.doi.org/10.1182/blood.v110.11.3588.3588.
Повний текст джерелаАнотація:
Abstract B-cell non-Hodgkin’s lymphoma (B-NHL) is a constellation of mature B-cell neoplasms characterized by distinct pathological and molecular genetic features, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), MATL-type lymphoma (MALT-L). These B-NHLs undergo a wide variety of genetic alterations, including gains and losses of genetic materials, as well as abnormalities in allelic composition, and these alterations may collectively comprise unique genomic profiles specific to different subtypes of B-NHL, which are tightly linked to the pathogenesis of each B-NHL subtype. Recently, we have developed a robust method (CNAG/AsCNAR) to detect allelic imbalances and other copy number changes in cancer genomes using SNP-genotyping microarrays (Nannya et al. Cancer Res, 2005 and Yamamoto et al. Am J Hum Genet, 2007). Without depending on the availability of constitutive genomic DNA, it enables sensitive detection of allelic imbalances including loss of heterozygosity (LOH) as well as copy number (CN) alterations in the face of 70–80% of normal cell components. In the current study, we performed SNP-chip/CNAG/AsCNAR analysis of 171 B-NHL specimens, including 65 cases of DLBCL, 61 cases of FL, and 45 cases of MALT-L in order to comparatively investigate the unique genomic profiles of different B-NHL subtypes. A large number of gains and losses of chromosomal/genomic segments as well as allelic imbalances were identified. While individual genomic profiles are substantially variable among different cases, they collectively showed a characteristic genomic profile in each B-NHL subtypes; +1q, +2p and +18 are common to DLBCL and FL, while +3 and +11q were more frequently found in DLBCL and +11p was more characteristic to FL. MALT-L also showed +3 and +18, but rarely had +1q and +2p. CN neutral LOH due to mitotic recombination (uniparental disomy; UPD) events are frequently found in DLBCL (70%) and FL (54%), but less common in MALT-L. UPD most commonly involves 1p, 1q, 6p, 9p and 12q. In total, 29 loci of high-grade amplification were identified. Among these recurring amplifications were observed at 1q and 2p, which involves FCGR2B, and cRel genes, respectively. These amplifications were detected in both DLBCL and FL, but rare in MALT-L. Total 14 loci of homozygous deletion were also detected and differentially distributed among different B-NHL subtypes. In conclusion, SNP-chip with CNAG/AsCNAR analysis revealed characteristic genomic signatures of distinctive B-NHL subtypes, implicating their unique pathogenesis.
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Camos, Mireia, Jordi Esteve, Dolors Colomer, Pedro Jares, Maria Rozman, Neus Villamor, Dolors Costa, et al. "Gene Expression Signature of Acute Myeloid Leukemia (AML) with T(8;16)(P11;P13) and MYST3-CREBBP Rearrangement: A Microarray Study Validated by Multiple Real-Time PCR." Blood 106, no. 11 (November 16, 2005): 3009. http://dx.doi.org/10.1182/blood.v106.11.3009.3009.
Повний текст джерелаАнотація:
Abstract AML with t(8;16)(p11;p13) is an infrequent leukemia subtype with characteristic clinical-biological features. The t(8;16)(p11;p13) translocation leads to the fusion of MYST3 and CREBBP genes, probably resulting in a disturbed transcriptional program of a myelo-monocytic precursor. In this study, the genetic signature of MYST3-CREBBP AML was compared with other well-defined AML subtypes. Genotypic analyses using oligonucleotide U133A arrays (Affymetrix) were performed on RNA of 23 AML patients, including three MYST3-CREBBP cases, PML-RARa (n=3), RUNX1-CBF2T1 (n=3), CBFβ-MYH11 (n=3), t(9;11)/AF9-MLL (n=1), monocytic AML (FAB M4/M5), n=8, and two cases of AML with multilineage dysplasia. Forty-six genes differentially expressed in MYST3-CREBBP cases were analyzed by multiple real-time RT-PCR using low-density arrays in an additional series of 40 patients, which included 7 MYST3-CREBBP cases, 18 AML samples with well characterized rearrangements (PML-RARa, n=3; RUNX1-CBF2T1, n=3; CBFβ-MYH11, n=3, MLL-rearranged AML, n=9), and 15 patients with normal karyotype AML. After unsupervised analysis, MYST3-CREBBP cases clustered together, displaying a distinctive expression signature. The analysis by RT-PCR confirmed the gene expression pattern found in the high-density array study. Thus, overexpressed genes included oncogene RET, several homeobox (HOXA9, HOXA10), genes involved in apoptosis (DAP) and prolactin gene. In contrast, cyclinD2, STAT5A, STAT5B and WT1 were underexpressed. Interestingly, MYST3-CREBBP cases showed up-regulation of a subgroup of genes (HOXA9, MEIS1, AKR7A2, CHD3, FLT3 and APBA2) that were also found overexpressed in MLL-rearranged leukemias. In summary, this study showed the distinctive genetic signature of MYST3-CREBBP AML, which harbours some similarities with MLL-rearranged AML. In addition, the low-density array methodology validated the results of the microarray analysis and allowed to study a larger series of patients, including samples not suitable for microarray analysis.
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Poznyak, Anastasia V., Andrey V. Grechko, Reinhard Wetzker, and Alexander N. Orekhov. "In Search for Genes Related to Atherosclerosis and Dyslipidemia Using Animal Models." International Journal of Molecular Sciences 21, no. 6 (March 18, 2020): 2097. http://dx.doi.org/10.3390/ijms21062097.
Повний текст джерелаАнотація:
Atherosclerosis is a multifactorial chronic disease that affects large arteries and may lead to fatal consequences. According to current understanding, inflammation and lipid accumulation are the two key mechanisms of atherosclerosis development. Animal models based on genetically modified mice have been developed to investigate these aspects. One such model is low-density lipoprotein (LDL) receptor knockout (KO) mice (ldlr−/−), which are characterized by a moderate increase of plasma LDL cholesterol levels. Another widely used genetically modified mouse strain is apolipoprotein-E KO mice (apoE−/−) that lacks the primary lipoprotein required for the uptake of lipoproteins through the hepatic receptors, leading to even greater plasma cholesterol increase than in ldlr−/− mice. These and other animal models allowed for conducting genetic studies, such as genome-wide association studies, microarrays, and genotyping methods, which helped identifying more than 100 mutations that contribute to atherosclerosis development. However, translation of the results obtained in animal models for human situations was slow and challenging. At the same time, genetic studies conducted in humans were limited by low sample sizes and high heterogeneity in predictive subclinical phenotypes. In this review, we summarize the current knowledge on the use of KO mice for identification of genes implicated in atherosclerosis and provide a list of genes involved in atherosclerosis-associated inflammatory pathways and their brief characteristics. Moreover, we discuss the approaches for candidate gene search in animals and humans and discuss the progress made in the field of epigenetic studies that appear to be promising for identification of novel biomarkers and therapeutic targets.
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Przychodzen, Bartlomiej P., Andres Jerez, Hideki Makishima, Kathryn M. Guinta, and Peter Chomczynski. "Mass Screening for Non-Synonymous SNPs Using Custom Cancer Microarrays Directly Reveals Possible Pathogenic Predisposition Factors in AA." Blood 118, no. 21 (November 18, 2011): 1333. http://dx.doi.org/10.1182/blood.v118.21.1333.1333.
Повний текст джерелаАнотація:
Abstract Abstract 1333 While immune mechanisms are involved in the pathogenesis of idiopathic aplastic anemia (AA), identification of heritable predisposition/susceptibility traits has been difficult due to the impact of exogenous factors and the low prevalence of AA. The seemingly sporadic and likely complex and heterogeneous traits leading to AA are not easily amenable to genetic studies. With the advent of whole genome scanning (WGS) technologies such as single nucleotide polymorphism arrays (SNP-A), large scale investigations in various disorders have been conducted. A systems level understanding of a particular disease may allow for the identification of candidate genetic variants as prognostic and diagnostic biomarkers. Previous studies utilized arrays with mostly tagging SNPs and thereby the identification of causative polymorphisms was only indirectly possible through the narrowing of LD intervals. We have applied a custom cancer chip (Illumina) containing 211,155 SNP probes designed for non-synonymous SNPs, allowing for a more direct discovery of pathogenic genes with the aim of identifying low prevalence genetic variants that contribute to the development, risk and therapy responsiveness in idiopathic AA. Our study involved 116 cases used for discovery and 120 cases to be used for confirmatory studies, as well as a cohort of 1964 controls to improve the power of detection. After exclusion of SNPs with a GenTrain score of <0.65 and those in violation of Hardy Weinberg equilibrium, 202,905 SNPs (96.0% of the initial set) were passed for further investigation. Single allele 2 statistics for all autosomal markers were performed; 853 SNPs with p<1×10-7 were selected. Subsequently, all 853 SNPs were screened for functional prediction (transcription factor binding site, affecting splicing, detrimental non-synonymous variant of proteins such as cytokines or cytokine receptors). An initial group of SNPs was expanded by all the SNPs being in linkage disequilibrium (>0.8) to a total of 7445 loci. Remarkably, informative LD blocks were identified, represented by multiple markers pointing to the presence of informative polymorphisms in the corresponding regions. A total of 3 SNPs were prioritized for final investigation based on the frequency differential between patients/controls. Of great interest was rs2544773 located in MYT1L represented directly by a singular marker. The frequency of the heterozygous variant among patients was 41.9% vs. 6.5% in controls and 15.0% vs. 0.4% for the minor homozygous variant (p<1×10–17). Our results suggest that carriers of at least one copy of the G allele (GA/AA) are at a higher risk of developing AA (OR 17.6). Another interesting variant identified was a non-synonymous SNP (rs13405539) located in DPYSL5 represented directly by a singular marker. This gene was recently associated with autoimmune myelopathy and cancer. Our analysis showed that minor allele has a protective potential and was present at a frequency in patients; occurring at a homozygous (AA) frequency of 1.8% vs. 16.4% in patients and controls, respectively and a heterozygous (GA) frequency of 14.6% vs. 49.2% in patients and controls respectively (p<1×10–20). Comparison of AA patients with healthy individuals has been a primary focus of GWAS. However, we have also compared subgroups defined by clinical criteria. We subdivided patients based on responsiveness to immunosuppressive therapy. CEBPZ was represented by rs3213746 through LD with rs12469082 (p<.0001). The heterozygous (CT) frequency observed amongst refractory patients was 12.4% vs. 1.4% and 8.2% vs. 0% for the minor homozygous (TT) variant, in refractory and responder, respectively. Odds ratio: Patients carrying at least one copy of the minor allele (CT/TT) are at much higher risk being a non-responder to immunosuppressive treatment (OR=26.3). Genotypic frequencies of patients that responded to immunosuppressive treatment were similar to the frequencies observed in healthy population. CEBPZ belongs to a family of CCAAT/enhancer proteins. It has been shown to interact with TP53 and therefore may play role in modulation of apoptosis. In sum, our study represents novel, whole genome approach using custom designed, high density cancer microarray that unravels new gene targets responsible for disease susceptibility as well as response to immunosuppressive therapy. Disclosures: No relevant conflicts of interest to declare.
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Spivak, Jerry L., Chunfa Jie, Donna M. Williams, and Alison R. Moliterno. "Gender Counts: Defining the Core Genetic Profile of Polycythemia Vera." Blood 104, no. 11 (November 16, 2004): 660. http://dx.doi.org/10.1182/blood.v104.11.660.660.
Повний текст джерелаАнотація:
Abstract Intra-abdominal venous thrombosis and exuberant extramedullary hematopoiesis leading to painful splenomegaly and hepatomegaly are two of the most serious consequences of polycythemia vera. Although polycythemia vera is slightly more common in men, both of these complications appear to be more common in women, in whom the disease also presents at an earlier age. We previously reported that polycythemia vera peripheral blood (pb) CD34+ cells could be distinguished from their immunophenotypically similar normal counterparts by gene expression profiling. We, therefore, hypothesized that phenotypic differences in disease behavior between men and women with polycythemia vera were a consequence of gender-based genotypic differences and have employed gene expression profiling to examine this issue. For this purpose, cRNA was prepared from the total RNA of pb CD34+ cells of eleven polycythemia vera patients and six normal controls purified by immunomagnetic bead chromatography. The cRNA was hybridized to an Affymetrix HU133 high-density oligonucleotide microarray chip representing 22,000 genes. Approximately 30–45 % of chip genes were recorded as present in the RNA samples. GC-RMA (Robust Multiarray Analysis) was used for normalization, to adjust for probe effects and for signal estimation. A parametric empirical Bayes statistical modeling method was used for differential gene expression analysis between the patients and controls. A posterior probability of >0.5 was taken to indicate significant differential gene expression. As previously reported, all polycythemia vera patients could be unequivocally distinguished from the controls, indicating that gene expression profiling can be employed as diagnostic test for polycythemia vera. With respect to gender, comparing male patients with male controls, 1106 genes were differentially expressed in the patient group; comparing female patients with female controls, 461 genes were differentially expressed in the patient group. Using unsupervised hierarchical clustering, the control patients segregated as a single group while the polycythemia vera patients segregated into two groups based on exuberant extramedullary hematopoiesis but this segregation was not gender-based despite the marked differences in gender-specific gene expression. Importantly, however, after eliminating gender-specific genes, only 93 genes were concordantly expressed in the male and female patients (59 up regulated and 34 down regulated). This small group appears to represent core genes in polycythemia vera whose behavior may be modified by gender-specific genes but the specific up regulation or repression of which is essential for disease expression. These data indicate that gender-specific effects on gene expression must be addressed in order to determine the basic genetic signature of a hematologic malignancy and they also define a core genetic profile in polycythemia vera.
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Huang, Meng, Muyi Liu, Hongmin Li, Jonathan King, Amy Smuts, Bruce Budowle, and Jianye Ge. "A machine learning approach for missing persons cases with high genotyping errors." Frontiers in Genetics 13 (October 3, 2022). http://dx.doi.org/10.3389/fgene.2022.971242.
Повний текст джерелаАнотація:
Estimating the relationships between individuals is one of the fundamental challenges in many fields. In particular, relationship.ip estimation could provide valuable information for missing persons cases. The recently developed investigative genetic genealogy approach uses high-density single nucleotide polymorphisms (SNPs) to determine close and more distant relationships, in which hundreds of thousands to tens of millions of SNPs are generated either by microarray genotyping or whole-genome sequencing. The current studies usually assume the SNP profiles were generated with minimum errors. However, in the missing person cases, the DNA samples can be highly degraded, and the SNP profiles generated from these samples usually contain lots of errors. In this study, a machine learning approach was developed for estimating the relationships with high error SNP profiles. In this approach, a hierarchical classification strategy was employed first to classify the relationships by degree and then the relationship types within each degree separately. As for each classification, feature selection was implemented to gain better performance. Both simulated and real data sets with various genotyping error rates were utilized in evaluating this approach, and the accuracies of this approach were higher than individual measures; namely, this approach was more accurate and robust than the individual measures for SNP profiles with genotyping errors. In addition, the highest accuracy could be obtained by providing the same genotyping error rates in train and test sets, and thus estimating genotyping errors of the SNP profiles is critical to obtaining high accuracy of relationship estimation.
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Nguyen, Dat Thanh, Trang T. H. Tran, Mai Hoang Tran, Khai Tran, Duy Pham, Nguyen Thuy Duong, Quan Nguyen, and Nam S. Vo. "A comprehensive evaluation of polygenic score and genotype imputation performances of human SNP arrays in diverse populations." Scientific Reports 12, no. 1 (October 20, 2022). http://dx.doi.org/10.1038/s41598-022-22215-y.
Повний текст джерелаАнотація:
AbstractRegardless of the overwhelming use of next-generation sequencing technologies, microarray-based genotyping combined with the imputation of untyped variants remains a cost-effective means to interrogate genetic variations across the human genome. This technology is widely used in genome-wide association studies (GWAS) at bio-bank scales, and more recently, in polygenic score (PGS) analysis to predict and stratify disease risk. Over the last decade, human genotyping arrays have undergone a tremendous growth in both number and content making a comprehensive evaluation of their performances became more important. Here, we performed a comprehensive performance assessment for 23 available human genotyping arrays in 6 ancestry groups using diverse public and in-house datasets. The analyses focus on performance estimation of derived imputation (in terms of accuracy and coverage) and PGS (in terms of concordance to PGS estimated from whole-genome sequencing data) in three different traits and diseases. We found that the arrays with a higher number of SNPs are not necessarily the ones with higher imputation performance, but the arrays that are well-optimized for the targeted population could provide very good imputation performance. In addition, PGS estimated by imputed SNP array data is highly correlated to PGS estimated by whole-genome sequencing data in most cases. When optimal arrays are used, the correlations of PGS between two types of data are higher than 0.97, but interestingly, arrays with high density can result in lower PGS performance. Our results suggest the importance of properly selecting a suitable genotyping array for PGS applications. Finally, we developed a web tool that provides interactive analyses of tag SNP contents and imputation performance based on population and genomic regions of interest. This study would act as a practical guide for researchers to design their genotyping arrays-based studies. The tool is available at: https://genome.vinbigdata.org/tools/saa/.
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Erickson, Stephen W., Stewart L. MacLeod, and Charlotte A. Hobbs. "Cheek swabs, SNP chips, and CNVs: Assessing the quality of copy number variant calls generated with subject-collected mail-in buccal brush DNA samples on a high-density genotyping microarray." BMC Medical Genetics 13, no. 1 (June 26, 2012). http://dx.doi.org/10.1186/1471-2350-13-51.
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Belloy, Michael E., Sarah J. Eger, Yann Le Guen, Vincent Damotte, Shahzad Ahmad, M. Arfan Ikram, Alfredo Ramirez, et al. "Challenges at the APOE locus: a robust quality control approach for accurate APOE genotyping." Alzheimer's Research & Therapy 14, no. 1 (February 4, 2022). http://dx.doi.org/10.1186/s13195-022-00962-4.
Повний текст джерелаАнотація:
Abstract Background Genetic variants within the APOE locus may modulate Alzheimer’s disease (AD) risk independently or in conjunction with APOE*2/3/4 genotypes. Identifying such variants and mechanisms would importantly advance our understanding of APOE pathophysiology and provide critical guidance for AD therapies aimed at APOE. The APOE locus however remains relatively poorly understood in AD, owing to multiple challenges that include its complex linkage structure and uncertainty in APOE*2/3/4 genotype quality. Here, we present a novel APOE*2/3/4 filtering approach and showcase its relevance on AD risk association analyses for the rs439401 variant, which is located 1801 base pairs downstream of APOE and has been associated with a potential regulatory effect on APOE. Methods We used thirty-two AD-related cohorts, with genetic data from various high-density single-nucleotide polymorphism microarrays, whole-genome sequencing, and whole-exome sequencing. Study participants were filtered to be ages 60 and older, non-Hispanic, of European ancestry, and diagnosed as cognitively normal or AD (n = 65,701). Primary analyses investigated AD risk in APOE*4/4 carriers. Additional supporting analyses were performed in APOE*3/4 and 3/3 strata. Outcomes were compared under two different APOE*2/3/4 filtering approaches. Results Using more conventional APOE*2/3/4 filtering criteria (approach 1), we showed that, when in-phase with APOE*4, rs439401 was variably associated with protective effects on AD case-control status. However, when applying a novel filter that increases the certainty of the APOE*2/3/4 genotypes by applying more stringent criteria for concordance between the provided APOE genotype and imputed APOE genotype (approach 2), we observed that all significant effects were lost. Conclusions We showed that careful consideration of APOE genotype and appropriate sample filtering were crucial to robustly interrogate the role of the APOE locus on AD risk. Our study presents a novel APOE filtering approach and provides important guidelines for research into the APOE locus, as well as for elucidating genetic interaction effects with APOE*2/3/4.