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Tandon, Arti

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Tandon

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Tandon, Arti
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    A multi-stage genome-wide association study of uterine fibroids in African Americans
    (Springer Berlin Heidelberg, 2017) Hellwege, Jacklyn N.; Jeff, Janina M.; Wise, Lauren A.; Gallagher, C. Scott; Wellons, Melissa; Hartmann, Katherine E.; Jones, Sarah F.; Torstenson, Eric S.; Dickinson, Scott; Ruiz-Narváez, Edward A.; Rohland, Nadin; Allen, Alexander; Reich, David; Tandon, Arti; Pasaniuc, Bogdan; Mancuso, Nicholas; Im, Hae Kyung; Hinds, David A.; Palmer, Julie R.; Rosenberg, Lynn; Denny, Joshua C.; Roden, Dan M.; Stewart, Elizabeth A.; Morton, Cynthia; Kenny, Eimear E.; Edwards, Todd L.; Velez Edwards, Digna R.
    Uterine fibroids are benign tumors of the uterus affecting up to 77% of women by menopause. They are the leading indication for hysterectomy, and account for $34 billion annually in the United States. Race/ethnicity and age are the strongest known risk factors. African American (AA) women have higher prevalence, earlier onset, and larger and more numerous fibroids than European American women. We conducted a multi-stage genome-wide association study (GWAS) of fibroid risk among AA women followed by in silico genetically predicted gene expression profiling of top hits. In Stage 1, cases and controls were confirmed by pelvic imaging, genotyped and imputed to 1000 Genomes. Stage 2 used self-reported fibroid and GWAS data from 23andMe, Inc. and the Black Women’s Health Study. Associations with fibroid risk were modeled using logistic regression adjusted for principal components, followed by meta-analysis of results. We observed a significant association among 3399 AA cases and 4764 AA controls at rs739187 (risk-allele frequency = 0.27) in CYTH4 (OR (95% confidence interval) = 1.23 (1.16–1.30), p value = 7.82 × 10−9). Evaluation of the genetic association results with MetaXcan identified lower predicted gene expression of CYTH4 in thyroid tissue as significantly associated with fibroid risk (p value = 5.86 × 10−8). In this first multi-stage GWAS for fibroids among AA women, we identified a novel risk locus for fibroids within CYTH4 that impacts gene expression in thyroid and has potential biological relevance for fibroids. Electronic supplementary material The online version of this article (doi:10.1007/s00439-017-1836-1) contains supplementary material, which is available to authorized users.
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    The complete genome sequence of a Neandertal from the Altai Mountains
    (2014) Prüfer, Kay; Racimo, Fernando; Patterson, Nick; Jay, Flora; Sankararaman, Sriram; Sawyer, Susanna; Heinze, Anja; Renaud, Gabriel; Sudmant, Peter H.; de Filippo, Cesare; Li, Heng; Mallick, Swapan; Dannemann, Michael; Fu, Qiaomei; Kircher, Martin; Kuhlwilm, Martin; Lachmann, Michael; Meyer, Matthias; Ongyerth, Matthias; Siebauer, Michael; Theunert, Christoph; Tandon, Arti; Moorjani, Priya; Pickrell, Joseph; Mullikin, James C.; Vohr, Samuel H.; Green, Richard E.; Hellmann, Ines; Johnson, Philip L. F.; Blanche, Hélène; Cann, Howard; Kitzman, Jacob O.; Shendure, Jay; Eichler, Evan E.; Lein, Ed S.; Bakken, Trygve E.; Golovanova, Liubov V.; Doronichev, Vladimir B.; Shunkov, Michael V.; Derevianko, Anatoli P.; Viola, Bence; Slatkin, Montgomery; Reich, David; Kelso, Janet; Pääbo, Svante
    We present a high-quality genome sequence of a Neandertal woman from Siberia. We show that her parents were related at the level of half siblings and that mating among close relatives was common among her recent ancestors. We also sequenced the genome of a Neandertal from the Caucasus to low coverage. An analysis of the relationships and population history of available archaic genomes and 25 present-day human genomes shows that several gene flow events occurred among Neandertals, Denisovans and early modern humans, possibly including gene flow into Denisovans from an unknown archaic group. Thus, interbreeding, albeit of low magnitude, occurred among many hominin groups in the Late Pleistocene. In addition, the high quality Neandertal genome allows us to establish a definitive list of substitutions that became fixed in modern humans after their separation from the ancestors of Neandertals and Denisovans.
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    Leveraging population admixture to explain missing heritability of complex traits
    (2014) Zaitlen, Noah; Pasaniuc, Bogdan; Sankararaman, Sriram; Bhatia, Gaurav; Zhang, Jianqi; Gusev, Alexander; Young, Taylor; Tandon, Arti; Pollack, Samuela; Vilhjálmsson, Bjarni J; Assimes, Themistocles L.; Berndt, Sonja I.; Blot, William J.; Chanock, Stephen; Franceschini, Nora; Goodman, Phyllis G.; He, Jing; Hennis, Anselm JM; Hsing, Ann; Ingles, Sue A.; Isaacs, William; Kittles, Rick A.; Klein, Eric A.; Lange, Leslie A.; Nemesure, Barbara; Patterson, Nick; Reich, David; Rybicki, Benjamin A.; Stanford, Janet L.; Stevens, Victoria L; Strom, Sara S.; Whitsel, Eric A; Witte, John S.; Xu, Jianfeng; Haiman, Christopher; Wilson, James G.; Kooperberg, Charles; Stram, Daniel; Reiner, Alex P.; Tang, Hua; Price, Alkes
    Despite recent progress on estimating the heritability explained by genotyped SNPs (hg2), a large gap between hg2 and estimates of total narrow-sense heritability (h2) remains. Explanations for this gap include rare variants, or upward bias in family-based estimates of h2 due to shared environment or epistasis. We estimate h2 from unrelated individuals in admixed populations by first estimating the heritability explained by local ancestry (hγ2). We show that hγ2 = 2FSTCθ(1−θ)h2, where FSTC measures frequency differences between populations at causal loci and θ is the genome-wide ancestry proportion. Our approach is not susceptible to biases caused by epistasis or shared environment. We examined 21,497 African Americans from three cohorts, analyzing 13 phenotypes. For height and BMI, we obtained h2 estimates of 0.55 ± 0.09 and 0.23 ± 0.06, respectively, which are larger than estimates of hg2 in these and other data, but smaller than family-based estimates of h2.
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    The Simons Genome Diversity Project: 300 genomes from 142 diverse populations
    (Springer Nature, 2016) Mallick, Swapan; Li, Heng; Lipson, Mark; Mathieson, Iain; Gymrek, Melissa Ann; Racimo, Fernando; Zhao, Mengyao; Chennagiri, Niru; Nordenfelt, Susanne; Tandon, Arti; Skoglund, Pontus R; Lazaridis, Iosif; Sankararaman, Sriram; Fu, Qiaomei; Rohland-Pinello, Nadin; Renaud, Gabriel; Erlich, Yaniv; Willems, Thomas; Gallo, Carla; Spence, Jeffrey P.; Song, Yun; Poletti, Giovanni; Balloux, Francois; van Driem, George; de Knijff, Peter; Romero, Irene Gallego; Jha, Aashish R.; Behar, Doron M.; Bravi, Claudio M.; Capelli, Cristian; Hervig, Tor; Moreno-Estrada, Andres; Posukh, Olga L.; Balanovska, Elena; Balanovsky, Oleg; Karachanak-Yankova, Sena; Sahakyan, Hovhannes; Toncheva, Draga; Yepiskoposyan, Levon; Tyler-Smith, Chris; Xue, Yali; Abdullah, M. Syafiq; Ruiz-Linares, Andres; Beall, Cynthia M.; Di Rienzo, Anna; Jeong, Choongwon; Starikovskaya, Elena B.; Metspalu, Ene; Parik, Jüri; Villems, Richard; Henn, Brenna M.; Hodoglugil, Ugur; Mahley, Robert; Sajantila, Antti; Stamatoyannopoulos, George; Wee, Joseph T. S.; Khusainova, Rita; Khusnutdinova, Elza; Litvinov, Sergey; Ayodo, George; Comas, David; Hammer, Michael F.; Kivisild, Toomas; Klitz, William; Winkler, Cheryl A.; Labuda, Damian; Bamshad, Michael; Jorde, Lynn B.; Tishkoff, Sarah A.; Watkins, W. Scott; Metspalu, Mait; Dryomov, Stanislav; Sukernik, Rem; Singh, Lalji; Thangaraj, Kumarasamy; Pääbo, Svante; Kelso, Janet; Patterson, Nick; Reich, David
    We report the Simons Genome Diversity Project (SGDP) dataset: high quality genomes from 300 individuals from 142 diverse populations. These genomes include at least 5.8 million base pairs that are not present in the human reference genome. Our analysis reveals key features of the landscape of human genome variation, including that the rate of accumulation of mutations has accelerated by about 5% in non-Africans compared to Africans since divergence. We show that the ancestors of some pairs of present-day human populations were substantially separated by 100,000 years ago, well before the archaeologically attested onset of behavioral modernity. We also demonstrate that indigenous Australians, New Guineans and Andamanese do not derive substantial ancestry from an early dispersal of modern humans; instead, their modern human ancestry is consistent with coming from the same source as that in other non-Africans.
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    Amerind Ancestry, Socioeconomic Status and the Genetics of Type 2 Diabetes in a Colombian Population
    (Public Library of Science, 2012) Campbell, Desmond D.; Parra, Maria V.; Duque, Constanza; Gallego, Natalia; Franco, Liliana; Hünemeier, Tábita; Bortolini, Cátira; Villegas, Alberto; Bedoya, Gabriel; McCarthy, Mark I.; Ruiz-Linares, Andrés; Tandon, Arti; Price, Alkes; Reich, David
    The “thrifty genotype” hypothesis proposes that the high prevalence of type 2 diabetes (T2D) in Native Americans and admixed Latin Americans has a genetic basis and reflects an evolutionary adaptation to a past low calorie/high exercise lifestyle. However, identification of the gene variants underpinning this hypothesis remains elusive. Here we assessed the role of Native American ancestry, socioeconomic status (SES) and 21 candidate gene loci in susceptibility to T2D in a sample of 876 T2D cases and 399 controls from Antioquia (Colombia). Although mean Native American ancestry is significantly higher in T2D cases than in controls (32% v 29%), this difference is confounded by the correlation of ancestry with SES, which is a stronger predictor of disease status. Nominally significant association (P<0.05) was observed for markers in: TCF7L2, RBMS1, CDKAL1, ZNF239, KCNQ1 and TCF1 and a significant bias (P<0.05) towards OR>1 was observed for markers selected from previous T2D genome-wide association studies, consistent with a role for Old World variants in susceptibility to T2D in Latin Americans. No association was found to the only known Native American-specific gene variant previously associated with T2D in a Mexican sample (rs9282541 in ABCA1). An admixture mapping scan with 1,536 ancestry informative markers (AIMs) did not identify genome regions with significant deviation of ancestry in Antioquia. Exclusion analysis indicates that this scan rules out ∼95% of the genome as harboring loci with ancestry risk ratios >1.22 (at P < 0.05).
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    African Ancestry and Its Correlation to Type 2 Diabetes in African Americans: A Genetic Admixture Analysis in Three U.S. Population Cohorts
    (Public Library of Science, 2012) Cheng, Ching-Yu; Haiman, Christopher A.; Patterson, Nick; Elizabeth, Selvin; Akylbekova, Ermeg L.; Brancati, Frederick L.; Coresh, Josef; Boerwinkle, Eric; Taylor, Herman A.; Henderson, Brian E.; Wilson, James G.; Reich, David; Tandon, Arti; Altshuler, David; Kao, W. H. Linda
    The risk of type 2 diabetes is approximately 2-fold higher in African Americans than in European Americans even after adjusting for known environmental risk factors, including socioeconomic status (SES), suggesting that genetic factors may explain some of this population difference in disease risk. However, relatively few genetic studies have examined this hypothesis in a large sample of African Americans with and without diabetes. Therefore, we performed an admixture analysis using 2,189 ancestry-informative markers in 7,021 African Americans (2,373 with type 2 diabetes and 4,648 without) from the Atherosclerosis Risk in Communities Study, the Jackson Heart Study, and the Multiethnic Cohort to 1) determine the association of type 2 diabetes and its related quantitative traits with African ancestry controlling for measures of SES and 2) identify genetic loci for type 2 diabetes through a genome-wide admixture mapping scan. The median percentage of African ancestry of diabetic participants was slightly greater than that of non-diabetic participants (study-adjusted difference = 1.6%, \(P\)<0.001). The odds ratio for diabetes comparing participants in the highest vs. lowest tertile of African ancestry was 1.33 (95% confidence interval 1.13–1.55), after adjustment for age, sex, study, body mass index (BMI), and SES. Admixture scans identified two potential loci for diabetes at 12p13.31 (LOD = 4.0) and 13q14.3 (Z score = 4.5, \(P\) = 6.6×10\(^{−6}\)). In conclusion, genetic ancestry has a significant association with type 2 diabetes above and beyond its association with non-genetic risk factors for type 2 diabetes in African Americans, but no single gene with a major effect is sufficient to explain a large portion of the observed population difference in risk of diabetes. There undoubtedly is a complex interplay among specific genetic loci and non-genetic factors, which may both be associated with overall admixture, leading to the observed ethnic differences in diabetes risk.
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    Reconstructing Native American Population History
    (2013) Reich, David; Patterson, Nick; Campbell, Desmond; Tandon, Arti; Mazieres, Stéphane; Ray, Nicolas; Parra, Maria V.; Rojas, Winston; Duque, Constanza; Mesa, Natalia; García, Luis F.; Triana, Omar; Blair, Silvia; Maestre, Amanda; Dib, Juan C.; Bravi, Claudio M.; Bailliet, Graciela; Corach, Daniel; Hünemeier, Tábita; Bortolini, Maria-Cátira; Salzano, Francisco M.; Petzl-Erler, María Luiza; Acuña-Alonzo, Victor; Aguilar-Salinas, Carlos; Canizales-Quinteros, Samuel; Tusié-Luna, Teresa; Riba, Laura; Rodríguez-Cruz, Maricela; Lopez-Alarcón, Mardia; Coral-Vazquez, Ramón; Canto-Cetina, Thelma; Silva-Zolezzi, Irma; Fernandez-Lopez, Juan Carlos; Contreras, Alejandra V.; Jimenez-Sanchez, Gerardo; Gómez-Vázquez, María José; Molina, Julio; Carracedo, Ángel; Salas, Antonio; Gallo, Carla; Poletti, Giovanni; Witonsky, David B.; Alkorta-Aranburu, Gorka; Sukernik, Rem I.; Osipova, Ludmila; Fedorova, Sardana; Vasquez, René; Villena, Mercedes; Moreau, Claudia; Barrantes, Ramiro; Pauls, David; Excoffier, Laurent; Bedoya, Gabriel; Rothhammer, Francisco; Dugoujon, Jean Michel; Larrouy, Georges; Klitz, William; Labuda, Damian; Kidd, Judith; Kidd, Kenneth; Rienzo, Anna Di; Freimer, Nelson B.; Price, Alkes; Ruiz-Linares, Andrés
    The peopling of the Americas has been the subject of extensive genetic, archaeological and linguistic research; however, central questions remain unresolved1–5. One contentious issue is whether the settlement occurred via a single6–8 or multiple streams of migration from Siberia9–15. The pattern of dispersals within the Americas is also poorly understood. To address these questions at higher resolution than was previously possible, we assembled data from 52 Native American and 17 Siberian groups genotyped at 364,470 single nucleotide polymorphisms. We show that Native Americans descend from at least three streams of Asian gene flow. Most descend entirely from a single ancestral population that we call “First American”. However, speakers of Eskimo-Aleut languages from the Arctic inherit almost half their ancestry from a second stream of Asian gene flow, and the Na-Dene-speaking Chipewyan from Canada inherit roughly one-tenth of their ancestry from a third stream. We show that the initial peopling followed a southward expansion facilitated by the coast, with sequential population splits and little gene flow after divergence, especially in South America. A major exception is in Chibchan-speakers on both sides of the Panama Isthmus, who have ancestry from both North and South America.
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    A High-Density Admixture Scan in 1,670 African Americans with Hypertension
    (Public Library of Science, 2007) Patterson, Nick; McDonald, Gavin J; Haiman, Christopher A; Ardlie, Kristin; Henderson, Brian E; Henderson, Sean O; Leal, Suzanne M; Deo, Rahul Chandrakant; Tandon, Arti; Reich, David
    Hypertension (HTN) is a devastating disease with a higher incidence in African Americans than European Americans, inspiring searches for genetic variants that contribute to this difference. We report the results of a large-scale admixture scan for genes contributing HTN risk, in which we screened 1,670 African Americans with HTN and 387 control individuals for regions of the genome with elevated proportion of African or European ancestry. No loci were identified that were significantly associated with HTN. We also searched for evidence of an admixture signal at 40 candidate genes and eight previously reported linkage peaks, but none appears to contribute substantially to the differential HTN risk between African and European Americans. Finally, we observed nominal association at one of the loci detected in the admixture scan of Zhu et al. 2005 (p = 0.016 at 6q24.3 correcting for four hypotheses tested), although we caution that the significance is marginal and the estimated odds ratio of 1.19 per African allele is less than what would be expected from the original report; thus, further work is needed to follow up this locus.
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    Genetic Differences between the Determinants of Lipid Profile Phenotypes in African and European Americans: The Jackson Heart Study
    (Public Library of Science, 2009) Deo, Rahul Chandrakant; Reich, David; Tandon, Arti; Akylbekova, Ermeg; Patterson, Nick; Waliszewska, Alicja; Kathiresan, Sekar; Sarpong, Daniel; Taylor, Herman A., Jr.; Wilson, James G.
    Genome-wide association analysis in populations of European descent has recently found more than a hundred genetic variants affecting risk for common disease. An open question, however, is how relevant the variants discovered in Europeans are to other populations. To address this problem for cardiovascular phenotypes, we studied a cohort of 4,464 African Americans from the Jackson Heart Study (JHS), in whom we genotyped both a panel of 12 recently discovered genetic variants known to predict lipid profile levels in Europeans and a panel of up to 1,447 ancestry informative markers allowing us to determine the African ancestry proportion of each individual at each position in the genome. Focusing on lipid profiles—HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C), and triglycerides (TG)—we identified the lipoprotein lipase (LPL) locus as harboring variants that account for interethnic variation in HDL-C and TG. In particular, we identified a novel common variant within LPL that is strongly associated with TG (p = 2.7×10−6) and explains nearly 1% of the variability in this phenotype, the most of any variant in African Americans to date. Strikingly, the extensively studied “gain-of-function” S447X mutation at LPL, which has been hypothesized to be the major determinant of the LPL-TG genetic association and is in trials for human gene therapy, has a significantly diminished strength of biological effect when it is found on a background of African rather than European ancestry. These results suggest that there are other, yet undiscovered variants at the locus that are truly causal (and are in linkage disequilibrium with S447X) or that work synergistically with S447X to modulate TG levels. Finally, we find systematically lower effect sizes for the 12 risk variants discovered in European populations on the African local ancestry background in JHS, highlighting the need for caution in the use of genetic variants for risk assessment across different populations.
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    Admixture Mapping Scans Identify a Locus Affecting Retinal Vascular Caliber in Hypertensive African Americans: The Atherosclerosis Risk in Communities (ARIC) Study
    (Public Library of Science, 2010) Cheng, Ching-Yu; Wong, Tien Y.; Klein, Ronald; Klein, Barbara E. K.; Patterson, Nick; Li, Man; Boerwinkle, Eric; Sharrett, A. Richey; Reich, David; Tandon, Arti; Kao, W. H. Linda
    Retinal vascular caliber provides information about the structure and health of the microvascular system and is associated with cardiovascular and cerebrovascular diseases. Compared to European Americans, African Americans tend to have wider retinal arteriolar and venular caliber, even after controlling for cardiovascular risk factors. This has suggested the hypothesis that differences in genetic background may contribute to racial/ethnic differences in retinal vascular caliber. Using 1,365 ancestry-informative SNPs, we estimated the percentage of African ancestry (PAA) and conducted genome-wide admixture mapping scans in 1,737 African Americans from the Atherosclerosis Risk in Communities (ARIC) study. Central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE) representing summary measures of retinal arteriolar and venular caliber, respectively, were measured from retinal photographs. PAA was significantly correlated with CRVE (ρ = 0.071, P = 0.003), but not CRAE (ρ = 0.032, P = 0.182). Using admixture mapping, we did not detect significant admixture association with either CRAE (genome-wide score = −0.73) or CRVE (genome-wide score = −0.69). An a priori subgroup analysis among hypertensive individuals detected a genome-wide significant association of CRVE with greater African ancestry at chromosome 6p21.1 (genome-wide score = 2.31, locus-specific LOD = 5.47). Each additional copy of an African ancestral allele at the 6p21.1 peak was associated with an average increase in CRVE of 6.14 µm in the hypertensives, but had no significant effects in the non-hypertensives (P for heterogeneity <0.001). Further mapping in the 6p21.1 region may uncover novel genetic variants affecting retinal vascular caliber and further insights into the interaction between genetic effects of the microvascular system and hypertension.