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Item Amplification of Distant Estrogen Response Elements Deregulates Target Genes Associated with Tamoxifen Resistance in Breast Cancer(Elsevier, 2013) Hsu, Pei-Yin; Hsu, Hang-Kai; Lan, Xun; Juan, Liran; Yan, Pearlly S.; Labanowska, Jadwiga; Heerema, Nyla; Hsiao, Tzu-Hung; Chiu, Yu-Chiao; Chen, Yidong; Liu, Yunlong; Li, Lang; Li, Rong; Thompson, Ian M.; Nephew, Kenneth P.; Sharp, Zelton D.; Kirma, Nameer B.; Jin, Victor X.; Huang, Tim H.-M.; Medical and Molecular Genetics, School of MedicineA causal role of gene amplification in tumorigenesis is well known, whereas amplification of DNA regulatory elements as an oncogenic driver remains unclear. In this study, we integrated next-generation sequencing approaches to map distant estrogen response elements (DEREs) that remotely control the transcription of target genes through chromatin proximity. Two densely mapped DERE regions located on chromosomes 17q23 and 20q13 were frequently amplified in estrogen receptor-α-positive luminal breast cancer. These aberrantly amplified DEREs deregulated target gene expression potentially linked to cancer development and tamoxifen resistance. Progressive accumulation of DERE copies was observed in normal breast progenitor cells chronically exposed to estrogenic chemicals. These findings may extend to other DNA regulatory elements, the amplification of which can profoundly alter target transcriptome during tumorigenesis.Item Genetic and neurophysiological correlates of the age of onset of alcohol use disorders in adolescents and young adults(Springer, 2013) Chorlian, David B.; Rangaswamy, Madhavi; Manz, Niklas; Wang, Jen-Chyong; Dick, Danielle; Almasy, Laura; Bauer, Lance; Bucholz, Kathleen; Foroud, Tatiana; Hesselbrock, Victor; Kang, Sun J.; Kramer, John; Kuperman, Sam; Nurnberger, John, Jr.; Rice, John; Schuckit, Marc; Tischfield, Jay; Edenberg, Howard J.; Goate, Alison; Bierut, Laura; Porjesz, Bernice; Medical and Molecular Genetics, School of MedicineDiscrete time survival analysis was used to assess the age-specific association of event-related oscillations (EROs) and CHRM2 gene variants on the onset of regular alcohol use and alcohol dependence. The subjects were 2,938 adolescents and young adults ages 12-25. Results showed that the CHRM2 gene variants and ERO risk factors had hazards which varied considerably with age. The bulk of the significant age-specific associations occurred in those whose age of onset was under 16. These associations were concentrated in those subjects who at some time took an illicit drug. These results are consistent with studies which associate greater rates of alcohol dependence among those who begin drinking at an early age. The age specificity of the genetic and neurophysiological factors is consistent with recent studies of adolescent brain development, which locate an interval of heightened vulnerability to substance use disorders in the early to mid teens.Item The Luminal Progenitor Compartment of the Normal Human Mammary Gland Constitutes a Unique Site of Telomere Dysfunction(Elsevier, 2013-06-04) Kannan, Nagarajan; Huda, Nazmul; Tu, LiRen; Droumeva, Radina; Aubert, Geraldine; Chavez, Elizabeth; Brinkman, Ryan R.; Lansdorp, Peter; Emerman, Joanne; Abe, Satoshi; Eaves, Connie; Gilley, David; Medical and Molecular Genetics, School of MedicineTelomeres are essential for genomic integrity, but little is known about their regulation in the normal human mammary gland. We now demonstrate that a phenotypically defined cell population enriched in luminal progenitors (LPs) is characterized by unusually short telomeres independently of donor age. Furthermore, we find that multiple DNA damage response proteins colocalize with telomeres in >95% of LPs but in <5% of basal cells. Paradoxically, 25% of LPs are still capable of exhibiting robust clonogenic activity in vitro. This may be partially explained by the elevated telomerase activity that was also seen only in LPs. Interestingly, this potential telomere salvage mechanism declines with age. Our findings thus reveal marked differences in the telomere biology of different subsets of primitive normal human mammary cells. The chronically dysfunctional telomeres unique to LPs have potentially important implications for normal mammary tissue homeostasis as well as the development of certain breast cancers.Item Genetic analysis of quantitative phenotypes in AD and MCI: imaging, cognition and biomarkers(Springer, 2014) Shen, Li; Thompson, Paul M.; Potkin, Steven G.; Bertram, Lars; Farrer, Lindsay A.; Foroud, Tatiana M.; Green, Robert C.; Hu, Xiaolan; Huentelman, Matthew J.; Kim, Sungeun; Kauwe, John S. K.; Li, Qingqin; Liu, Enchi; Macciardi, Fabio; Moore, Jason H.; Munsie, Leanne; Nho, Kwangsik; Ramanan, Vijay K.; Risacher, Shannon L.; Stone, David J.; Swaminathan, Shanker; Toga, Arthur W.; Weiner, Michael W.; Saykin, Andrew J.; Alzheimer’s Disease Neuroimaging Initiative; Medical and Molecular Genetics, School of MedicineThe Genetics Core of the Alzheimer's Disease Neuroimaging Initiative (ADNI), formally established in 2009, aims to provide resources and facilitate research related to genetic predictors of multidimensional Alzheimer's disease (AD)-related phenotypes. Here, we provide a systematic review of genetic studies published between 2009 and 2012 where either ADNI APOE genotype or genome-wide association study (GWAS) data were used. We review and synthesize ADNI genetic associations with disease status or quantitative disease endophenotypes including structural and functional neuroimaging, fluid biomarker assays, and cognitive performance. We also discuss the diverse analytical strategies used in these studies, including univariate and multivariate analysis, meta-analysis, pathway analysis, and interaction and network analysis. Finally, we perform pathway and network enrichment analyses of these ADNI genetic associations to highlight key mechanisms that may drive disease onset and trajectory. Major ADNI findings included all the top 10 AD genes and several of these (e.g., APOE, BIN1, CLU, CR1, and PICALM) were corroborated by ADNI imaging, fluid and cognitive phenotypes. ADNI imaging genetics studies discovered novel findings (e.g., FRMD6) that were later replicated on different data sets. Several other genes (e.g., APOC1, FTO, GRIN2B, MAGI2, and TOMM40) were associated with multiple ADNI phenotypes, warranting further investigation on other data sets. The broad availability and wide scope of ADNI genetic and phenotypic data has advanced our understanding of the genetic basis of AD and has nominated novel targets for future studies employing next-generation sequencing and convergent multi-omics approaches, and for clinical drug and biomarker development.Item New aQTL SNPs for the CYP2D6 Identified by a Novel Mediation Analysis of Genome-Wide SNP Arrays, Gene Expression Arrays, and CYP2D6 Activity(Hindawi, 2013) Jiang, Guanglong; Chakraborty, Arindom; Wang, Zhiping; Boustani, Malaz; Liu, Yunlong; Skaar, Todd; Li, Lang; Medical and Molecular Genetics, School of MedicineBackground: The genome-wide association studies (GWAS) have been successful during the last few years. A key challenge is that the interpretation of the results is not straightforward, especially for transacting SNPs. Integration of transcriptome data into GWAS may provide clues elucidating the mechanisms by which a genetic variant leads to a disease. Methods: Here, we developed a novel mediation analysis approach to identify new expression quantitative trait loci (eQTL) driving CYP2D6 activity by combining genotype, gene expression, and enzyme activity data. Results: 389,573 and 1,214,416 SNP-transcript-CYP2D6 activity trios are found strongly associated (P < 10⁻⁵, FDR = 16.6% and 11.7%) for two different genotype platforms, namely, Affymetrix and Illumina, respectively. The majority of eQTLs are trans-SNPs. A single polymorphism leads to widespread downstream changes in the expression of distant genes by affecting major regulators or transcription factors (TFs), which would be visible as an eQTL hotspot and can lead to large and consistent biological effects. Overlapped eQTL hotspots with the mediators lead to the discovery of 64 TFs. Conclusions: Our mediation analysis is a powerful approach in identifying the trans-QTL-phenotype associations. It improves our understanding of the functional genetic variations for the liver metabolism mechanisms.Item Cis-Regulatory Variants Affect CHRNA5 mRNA Expression in Populations of African and European Ancestry(Public Library of Science, 2013-11-26) Wang, Jen-Chyong; Spiegel, Noah; Bertelsen, Sarah; Le, Nhung; McKenna, Nicholas; Budde, John P.; Harari, Oscar; Kapoor, Manav; Brooks, Andrew; Hancock, Dana; Tischfield, Jay; Foroud, Tatiana; Bierut, Laura J.; Steinbach, Joe Henry; Edenberg, Howard J.; Traynor, Bryan J.; Goate, Alison M.; Medical and Molecular Genetics, School of MedicineVariants within the gene cluster encoding α3, α5, and β4 nicotinic receptor subunits are major risk factors for substance dependence. The strongest impact on risk is associated with variation in the CHRNA5 gene, where at least two mechanisms are at work: amino acid variation and altered mRNA expression levels. The risk allele of the non-synonymous variant (rs16969968; D398N) primarily occurs on the haplotype containing the low mRNA expression allele. In populations of European ancestry, there are approximately 50 highly correlated variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster and the adjacent PSMA4 gene region that are associated with CHRNA5 mRNA levels. It is not clear which of these variants contribute to the changes in CHRNA5 transcript level. Because populations of African ancestry have reduced linkage disequilibrium among variants spanning this gene cluster, eQTL mapping in subjects of African ancestry could potentially aid in defining the functional variants that affect CHRNA5 mRNA levels. We performed quantitative allele specific gene expression using frontal cortices derived from 49 subjects of African ancestry and 111 subjects of European ancestry. This method measures allele-specific transcript levels in the same individual, which eliminates other biological variation that occurs when comparing expression levels between different samples. This analysis confirmed that substance dependence associated variants have a direct cis-regulatory effect on CHRNA5 transcript levels in human frontal cortices of African and European ancestry and identified 10 highly correlated variants, located in a 9 kb region, that are potential functional variants modifying CHRNA5 mRNA expression levels.Item Platelet-targeted gene therapy with human factor VIII establishes haemostasis in dogs with haemophilia A(Springer Nature, 2013) Du, Lily M.; Nurden, Paquita; Nurden, Alan T.; Nichols, Timothy C.; Bellinger, Dwight A.; Jensen, Eric S.; Haberichter, Sandra L.; Merricks, Elizabeth; Raymer, Robin A.; Fang, Juan; Koukouritaki, Sevasti B.; Jacobi, Paula M.; Hawkins, Troy B.; Cornetta, Kenneth; Shi, Qizhen; Wilcox, David A.; Medical and Molecular Genetics, School of MedicineIt is essential to improve therapies for controlling excessive bleeding in patients with haemorrhagic disorders. As activated blood platelets mediate the primary response to vascular injury, we hypothesize that storage of coagulation Factor VIII within platelets may provide a locally inducible treatment to maintain haemostasis for haemophilia A. Here we show that haematopoietic stem cell gene therapy can prevent the occurrence of severe bleeding episodes in dogs with haemophilia A for at least 2.5 years after transplantation. We employ a clinically relevant strategy based on a lentiviral vector encoding the ITGA2B gene promoter, which drives platelet-specific expression of human FVIII permitting storage and release of FVIII from activated platelets. One animal receives a hybrid molecule of FVIII fused to the von Willebrand Factor propeptide-D2 domain that traffics FVIII more effectively into α-granules. The absence of inhibitory antibodies to platelet-derived FVIII indicates that this approach may have benefit in patients who reject FVIII replacement therapies. Thus, platelet FVIII may provide effective long-term control of bleeding in patients with haemophilia A.Item Assessment of Gait Mechanics and Muscle Strength in Hypermobile Ehlers Danlos Syndrome(Elsevier, 2024) Ball, Lindsey N.; Jacobs, Mariana V.; McLouth, Christopher J.; Clasey, Jody; Francomano, Clair; Sheppard, Mary B.; Samaan, Michael A.; Medical and Molecular Genetics, School of MedicineBackground: Hypermobile Ehlers Danlos Syndrome, a heritable connective tissue disorder, is associated with muscle dysfunction, joint subluxations and pain. The impact of hypermobile Ehlers Danlos Syndrome on musculoskeletal mechanics is understudied. Therefore, the aim of this study was to assess the effects of hypermobile Ehlers Danlos Syndrome on lower extremity gait mechanics and muscle strength. Methods: Eleven people with hypermobile Ehlers Danlos Syndrome and 11 asymptomatic controls underwent a 3D gait analysis and isometric hip and knee muscle strength assessment. Joint subluxations were self-reported by the hypermobile Ehlers Danlos syndrome group. Independent t-tests and Mann Whitney U tests were used to analyze joint mechanics, muscle strength, and patient report outcomes (p < 0.05). Findings: Both groups exhibited similar walking speeds as well as similar hip, knee, and ankle joint kinematics. The hypermobile Ehlers Danlos Syndrome group walked with a lower peak hip extensor moment (hypermobile Ehlers Danlos Syndrome: -0.52 ± 0.28 Nmˑkg-1, Control: -0.83 ± 0.26 Nmˑkg-1, p = 0.01) yet similar knee and ankle joint moments. The hypermobile Ehlers Danlos Syndrome group exhibited a 40% deficit in peak hip extensor strength (hypermobile Ehlers Danlos Syndrome:1.07 ± 0.53 Nmˑkg-1, Control: 1.77 ± 0.79 Nmˑkg-1, p = 0.04). Approximately 73%, 55% and 45% of the hypermobile Ehlers Danlos Syndrome cohort self-reported hip, knee/patella and ankle joint subluxations, respectively, at least once a week. Interpretation: Patients with hypermobile Ehlers Danlos Syndrome ambulated with altered hip extensor moments and exhibit hip extensor weakness. Future work should investigate the underlying mechanisms of hip extensor weakness and corresponding effects on joint health in people with hypermobile Ehlers Danlos Syndrome.Item A Developmentally-Informative Genome-wide Association Study of Alcohol Use Frequency(Springer, 2024) Thomas, Nathaniel S.; Gillespie, Nathan A.; Chan, Grace; Edenberg, Howard J.; Kamarajan, Chella; I-Chun Kuo, Sally; Miller, Alex P.; Nurnberger, John I., Jr.; Tischfield, Jay; Dick, Danielle M.; Salvatore, Jessica E.; Medical and Molecular Genetics, School of MedicineContemporary genome-wide association study (GWAS) methods typically do not account for variability in genetic effects throughout development. We applied genomic structural equation modeling to combine developmentally-informative phenotype data and GWAS to create polygenic scores (PGS) for alcohol use frequency that are specific to developmental stage. Longitudinal cohort studies targeted for gene-identification analyses include the Collaborative Study on the Genetics of Alcoholism (adolescence n = 1,118, early adulthood n = 2,762, adulthood n = 5,255), the National Longitudinal Study of Adolescent to Adult Health (adolescence n = 3,089, early adulthood n = 3,993, adulthood n = 5,149), and the Avon Longitudinal Study of Parents and Children (ALSPAC; adolescence n = 5,382, early adulthood n = 3,613). PGS validation analyses were conducted in the COGA sample using an alternate version of the discovery analysis with COGA removed. Results suggest that genetic liability for alcohol use frequency in adolescence may be distinct from genetic liability for alcohol use frequency later in developmental periods. The age-specific PGS predicts an increase of 4 drinking days per year per PGS standard deviation when modeled separately from the common factor PGS in adulthood. The current work was underpowered at all steps of the analysis plan. Though small sample sizes and low statistical power limit the substantive conclusions that can be drawn regarding these research questions, this work provides a foundation for future genetic studies of developmental variability in the genetic underpinnings of alcohol use behaviors and genetically-informed, age-matched phenotype prediction.Item Harnessing diversity to study Alzheimer's disease: A new iPSC resource from the NIH CARD and ADNI(Elsevier, 2024) Screven, Laurel A.; Pantazis, Caroline B.; Andersh, Katherine M.; Hong, Samantha; Vitale, Dan; Lara, Erika; Ku, Ray Yueh; Heutink, Peter; Meyer, Jason; Faber, Kelley; Nho, Kwangsik; Saykin, Andrew J.; Foroud, Tatiana M.; Nalls, Mike A.; Blauwendraat, Cornelis; Singleton, Andrew; Narayan, Priyanka S.; Medical and Molecular Genetics, School of MedicineThe iDA Project (iPSCs to Study Diversity in Alzheimer's and Alzheimer's Disease-related Dementias) is generating 200 induced pluripotent stem cell lines from Alzheimer's Disease Neuroimaging Initiative participants. These lines are sex balanced, include common APOE genotypes, span disease stages, and are ancestrally diverse. Cell lines and characterization data will be shared openly.