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Alkes Price

S Kayaniyil, M Hurry, J Wilson, P Wheatley-Price, B Melosky, J Rothenstein, V Cohen, C Koch, J Zhang, K Osenenko, G Liu
BACKGROUND: Crizotinib was the first agent approved for the treatment of anaplastic lymphoma kinase (ALK)-positive (+) non-small-cell lung cancer (nsclc), followed by ceritinib. However, patients eventually progress or develop resistance to crizotinib. With limited real-world data available, the objective of the present work was to evaluate treatment patterns and survival after crizotinib in patients with locally advanced or metastatic ALK+ nsclc in Canada. METHODS: In this retrospective study at 6 oncology centres across Canada, medical records of patients with locally advanced or metastatic ALK+ nsclc were reviewed...
December 2016: Current Oncology
Tristan J Hayeck, Po-Ru Loh, Samuela Pollack, Alexander Gusev, Nick Patterson, Noah A Zaitlen, Alkes L Price
Mixed models have become the tool of choice for genetic association studies; however, standard mixed model methods may be poorly calibrated or underpowered under family sampling bias and/or case-control ascertainment. Previously, we introduced a liability threshold-based mixed model association statistic (LTMLM) to address case-control ascertainment in unrelated samples. Here, we consider family-biased case-control ascertainment, where case and control subjects are ascertained non-randomly with respect to family relatedness...
January 5, 2017: American Journal of Human Genetics
Sara Lindström, Akweley Ablorh, Brad Chapman, Alexander Gusev, Gary Chen, Constance Turman, A Heather Eliassen, Alkes L Price, Brian E Henderson, Loic Le Marchand, Oliver Hofmann, Christopher A Haiman, Peter Kraft
BACKGROUND: Although genome-wide association studies (GWASs) have identified thousands of disease susceptibility regions, the underlying causal mechanism in these regions is not fully known. It is likely that the GWAS signal originates from one or many as yet unidentified causal variants. METHODS: Using next-generation sequencing, we characterized 12 breast cancer susceptibility regions identified by GWASs in 2288 breast cancer cases and 2323 controls across four populations of African American, European, Japanese, and Hispanic ancestry...
November 5, 2016: Breast Cancer Research: BCR
Kevin J Galinsky, Po-Ru Loh, Swapan Mallick, Nick J Patterson, Alkes L Price
Analyzing genetic differences between closely related populations can be a powerful way to detect recent adaptation. The very large sample size of the UK Biobank is ideal for using population differentiation to detect selection and enables an analysis of the UK population structure at fine resolution. In this study, analyses of 113,851 UK Biobank samples showed that population structure in the UK is dominated by five principal components (PCs) spanning six clusters: Northern Ireland, Scotland, northern England, southern England, and two Welsh clusters...
November 3, 2016: American Journal of Human Genetics
Po-Ru Loh, Petr Danecek, Pier Francesco Palamara, Christian Fuchsberger, Yakir A Reshef, Hilary K Finucane, Sebastian Schoenherr, Lukas Forer, Shane McCarthy, Goncalo R Abecasis, Richard Durbin, Alkes L Price
Haplotype phasing is a fundamental problem in medical and population genetics. Phasing is generally performed via statistical phasing in a genotyped cohort, an approach that can yield high accuracy in very large cohorts but attains lower accuracy in smaller cohorts. Here we instead explore the paradigm of reference-based phasing. We introduce a new phasing algorithm, Eagle2, that attains high accuracy across a broad range of cohort sizes by efficiently leveraging information from large external reference panels (such as the Haplotype Reference Consortium; HRC) using a new data structure based on the positional Burrows-Wheeler transform...
November 2016: Nature Genetics
Jie Zheng, A Mesut Erzurumluoglu, Benjamin L Elsworth, John P Kemp, Laurence Howe, Philip C Haycock, Gibran Hemani, Katherine Tansey, Charles Laurin, Beate St Pourcain, Nicole M Warrington, Hilary K Finucane, Alkes L Price, Brendan K Bulik-Sullivan, Verneri Anttila, Lavinia Paternoster, Tom R Gaunt, David M Evans, Benjamin M Neale
MOTIVATION: LD score regression is a reliable and efficient method of using genome-wide association study (GWAS) summary-level results data to estimate the SNP heritability of complex traits and diseases, partition this heritability into functional categories, and estimate the genetic correlation between different phenotypes. Because the method relies on summary level results data, LD score regression is computationally tractable even for very large sample sizes. However, publicly available GWAS summary-level data are typically stored in different databases and have different formats, making it difficult to apply LD score regression to estimate genetic correlations across many different traits simultaneously...
September 22, 2016: Bioinformatics
Paul Wheatley-Price, Quincy Chu, Maria Bonomi, Jean Seely, Ashish Gupta, Glenwood Goss, John Hilton, Ronald Feld, Christopher W Lee, John R Goffin, Andrew Maksymiuk, Nevin Murray, Linda Hagerman, Penelope A Bradbury
There is no approved second line systemic therapy option for malignant pleural mesothelioma, but targeting angiogenesis is an area of investigation. PF-03446962 is a fully human antibody against activin-like kinase 1 (ALK-1), commonly expressed in tumour vasculature. We performed a multi-centre, open label, single arm, 2-stage phase 2 study of PF-03446962 in MPM patients with progressive disease after platinum-based chemotherapy. In total, 17 patients were enrolled, but no partial or complete responses were observed...
July 19, 2016: Journal of Thoracic Oncology
Brielin C Brown, Chun Jimmie Ye, Alkes L Price, Noah Zaitlen
The increasing number of genetic association studies conducted in multiple populations provides an unprecedented opportunity to study how the genetic architecture of complex phenotypes varies between populations, a problem important for both medical and population genetics. Here, we have developed a method for estimating the transethnic genetic correlation: the correlation of causal-variant effect sizes at SNPs common in populations. This methods takes advantage of the entire spectrum of SNP associations and uses only summary-level data from genome-wide association studies...
July 7, 2016: American Journal of Human Genetics
Po-Ru Loh, Pier Francesco Palamara, Alkes L Price
Recent work has leveraged the extensive genotyping of the Icelandic population to perform long-range phasing (LRP), enabling accurate imputation and association analysis of rare variants in target samples typed on genotyping arrays. Here we develop a fast and accurate LRP method, Eagle, that extends this paradigm to populations with much smaller proportions of genotyped samples by harnessing long (>4-cM) identical-by-descent (IBD) tracts shared among distantly related individuals. We applied Eagle to N ≈ 150,000 samples (0...
July 2016: Nature Genetics
Brielin C Brown, Alkes L Price, Nikolaos A Patsopoulos, Noah Zaitlen
There is mounting evidence that complex human phenotypes are highly polygenic, with many loci harboring multiple causal variants, yet most genetic association studies examine each SNP in isolation. While this has led to the discovery of thousands of disease associations, discovered variants account for only a small fraction of disease heritability. Alternative multi-SNP methods have been proposed, but issues such as multiple-testing correction, sensitivity to genotyping error, and optimization for the underlying genetic architectures remain...
July 2016: Genetics
Alexander Gusev, Huwenbo Shi, Gleb Kichaev, Mark Pomerantz, Fugen Li, Henry W Long, Sue A Ingles, Rick A Kittles, Sara S Strom, Benjamin A Rybicki, Barbara Nemesure, William B Isaacs, Wei Zheng, Curtis A Pettaway, Edward D Yeboah, Yao Tettey, Richard B Biritwum, Andrew A Adjei, Evelyn Tay, Ann Truelove, Shelley Niwa, Anand P Chokkalingam, Esther M John, Adam B Murphy, Lisa B Signorello, John Carpten, M Cristina Leske, Suh-Yuh Wu, Anslem J M Hennis, Christine Neslund-Dudas, Ann W Hsing, Lisa Chu, Phyllis J Goodman, Eric A Klein, John S Witte, Graham Casey, Sam Kaggwa, Michael B Cook, Daniel O Stram, William J Blot, Rosalind A Eeles, Douglas Easton, Zsofia Kote-Jarai, Ali Amin Al Olama, Sara Benlloch, Kenneth Muir, Graham G Giles, Melissa C Southey, Liesel M Fitzgerald, Henrik Gronberg, Fredrik Wiklund, Markus Aly, Brian E Henderson, Johanna Schleutker, Tiina Wahlfors, Teuvo L J Tammela, Børge G Nordestgaard, Tim J Key, Ruth C Travis, David E Neal, Jenny L Donovan, Freddie C Hamdy, Paul Pharoah, Nora Pashayan, Kay-Tee Khaw, Janet L Stanford, Stephen N Thibodeau, Shannon K McDonnell, Daniel J Schaid, Christiane Maier, Walther Vogel, Manuel Luedeke, Kathleen Herkommer, Adam S Kibel, Cezary Cybulski, Dominika Wokolorczyk, Wojciech Kluzniak, Lisa Cannon-Albright, Craig Teerlink, Hermann Brenner, Aida K Dieffenbach, Volker Arndt, Jong Y Park, Thomas A Sellers, Hui-Yi Lin, Chavdar Slavov, Radka Kaneva, Vanio Mitev, Jyotsna Batra, Amanda Spurdle, Judith A Clements, Manuel R Teixeira, Hardev Pandha, Agnieszka Michael, Paula Paulo, Sofia Maia, Andrzej Kierzek, David V Conti, Demetrius Albanes, Christine Berg, Sonja I Berndt, Daniele Campa, E David Crawford, W Ryan Diver, Susan M Gapstur, J Michael Gaziano, Edward Giovannucci, Robert Hoover, David J Hunter, Mattias Johansson, Peter Kraft, Loic Le Marchand, Sara Lindström, Carmen Navarro, Kim Overvad, Elio Riboli, Afshan Siddiq, Victoria L Stevens, Dimitrios Trichopoulos, Paolo Vineis, Meredith Yeager, Gosia Trynka, Soumya Raychaudhuri, Frederick R Schumacher, Alkes L Price, Matthew L Freedman, Christopher A Haiman, Bogdan Pasaniuc
Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines...
April 7, 2016: Nature Communications
Kevin J Galinsky, Gaurav Bhatia, Po-Ru Loh, Stoyan Georgiev, Sayan Mukherjee, Nick J Patterson, Alkes L Price
Searching for genetic variants with unusual differentiation between subpopulations is an established approach for identifying signals of natural selection. However, existing methods generally require discrete subpopulations. We introduce a method that infers selection using principal components (PCs) by identifying variants whose differentiation along top PCs is significantly greater than the null distribution of genetic drift. To enable the application of this method to large datasets, we developed the FastPCA software, which employs recent advances in random matrix theory to accurately approximate top PCs while reducing time and memory cost from quadratic to linear in the number of individuals, a computational improvement of many orders of magnitude...
March 3, 2016: American Journal of Human Genetics
Alexander Gusev, Arthur Ko, Huwenbo Shi, Gaurav Bhatia, Wonil Chung, Brenda W J H Penninx, Rick Jansen, Eco J C de Geus, Dorret I Boomsma, Fred A Wright, Patrick F Sullivan, Elina Nikkola, Marcus Alvarez, Mete Civelek, Aldons J Lusis, Terho Lehtimäki, Emma Raitoharju, Mika Kähönen, Ilkka Seppälä, Olli T Raitakari, Johanna Kuusisto, Markku Laakso, Alkes L Price, Päivi Pajukanta, Bogdan Pasaniuc
Many genetic variants influence complex traits by modulating gene expression, thus altering the abundance of one or multiple proteins. Here we introduce a powerful strategy that integrates gene expression measurements with summary association statistics from large-scale genome-wide association studies (GWAS) to identify genes whose cis-regulated expression is associated with complex traits. We leverage expression imputation from genetic data to perform a transcriptome-wide association study (TWAS) to identify significant expression-trait associations...
March 2016: Nature Genetics
Grace X Y Zheng, Billy T Lau, Michael Schnall-Levin, Mirna Jarosz, John M Bell, Christopher M Hindson, Sofia Kyriazopoulou-Panagiotopoulou, Donald A Masquelier, Landon Merrill, Jessica M Terry, Patrice A Mudivarti, Paul W Wyatt, Rajiv Bharadwaj, Anthony J Makarewicz, Yuan Li, Phillip Belgrader, Andrew D Price, Adam J Lowe, Patrick Marks, Gerard M Vurens, Paul Hardenbol, Luz Montesclaros, Melissa Luo, Lawrence Greenfield, Alexander Wong, David E Birch, Steven W Short, Keith P Bjornson, Pranav Patel, Erik S Hopmans, Christina Wood, Sukhvinder Kaur, Glenn K Lockwood, David Stafford, Joshua P Delaney, Indira Wu, Heather S Ordonez, Susan M Grimes, Stephanie Greer, Josephine Y Lee, Kamila Belhocine, Kristina M Giorda, William H Heaton, Geoffrey P McDermott, Zachary W Bent, Francesca Meschi, Nikola O Kondov, Ryan Wilson, Jorge A Bernate, Shawn Gauby, Alex Kindwall, Clara Bermejo, Adrian N Fehr, Adrian Chan, Serge Saxonov, Kevin D Ness, Benjamin J Hindson, Hanlee P Ji
Haplotyping of human chromosomes is a prerequisite for cataloguing the full repertoire of genetic variation. We present a microfluidics-based, linked-read sequencing technology that can phase and haplotype germline and cancer genomes using nanograms of input DNA. This high-throughput platform prepares barcoded libraries for short-read sequencing and computationally reconstructs long-range haplotype and structural variant information. We generate haplotype blocks in a nuclear trio that are concordant with expected inheritance patterns and phase a set of structural variants...
March 2016: Nature Biotechnology
Alkes L Price, Chris C A Spencer, Peter Donnelly
Susceptibility to common human diseases is influenced by both genetic and environmental factors. The explosive growth of genetic data, and the knowledge that it is generating, are transforming our biological understanding of these diseases. In this review, we describe the technological and analytical advances that have enabled genome-wide association studies to be successful in identifying a large number of genetic variants robustly associated with common disease. We examine the biological insights that these genetic associations are beginning to produce, from functional mechanisms involving individual genes to biological pathways linking associated genes, and the identification of functional annotations, some of which are cell-type-specific, enriched in disease associations...
December 22, 2015: Proceedings. Biological Sciences
Melissa Gymrek, Thomas Willems, Audrey Guilmatre, Haoyang Zeng, Barak Markus, Stoyan Georgiev, Mark J Daly, Alkes L Price, Jonathan K Pritchard, Andrew J Sharp, Yaniv Erlich
The contribution of repetitive elements to quantitative human traits is largely unknown. Here we report a genome-wide survey of the contribution of short tandem repeats (STRs), which constitute one of the most polymorphic and abundant repeat classes, to gene expression in humans. Our survey identified 2,060 significant expression STRs (eSTRs). These eSTRs were replicable in orthogonal populations and expression assays. We used variance partitioning to disentangle the contribution of eSTRs from that of linked SNPs and indels and found that eSTRs contribute 10-15% of the cis heritability mediated by all common variants...
January 2016: Nature Genetics
Akweley Mensah-Ablorh, Sara Lindstrom, Christopher A Haiman, Brian E Henderson, Loic Le Marchand, Seunngeun Lee, Daniel O Stram, A Heather Eliassen, Alkes Price, Peter Kraft
Several methods have been proposed to increase power in rare variant association testing by aggregating information from individual rare variants (MAF < 0.005). However, how to best combine rare variants across multiple ethnicities and the relative performance of designs using different ethnic sampling fractions remains unknown. In this study, we compare the performance of several statistical approaches for assessing rare variant associations across multiple ethnicities. We also explore how different ethnic sampling fractions perform, including single-ethnicity studies and studies that sample up to four ethnicities...
January 2016: Genetic Epidemiology
Pier Francesco Palamara, Laurent C Francioli, Peter R Wilton, Giulio Genovese, Alexander Gusev, Hilary K Finucane, Sriram Sankararaman, Shamil R Sunyaev, Paul I W de Bakker, John Wakeley, Itsik Pe'er, Alkes L Price
The rate at which human genomes mutate is a central biological parameter that has many implications for our ability to understand demographic and evolutionary phenomena. We present a method for inferring mutation and gene-conversion rates by using the number of sequence differences observed in identical-by-descent (IBD) segments together with a reconstructed model of recent population-size history. This approach is robust to, and can quantify, the presence of substantial genotyping error, as validated in coalescent simulations...
December 3, 2015: American Journal of Human Genetics
George Tucker, Po-Ru Loh, Iona M MacLeod, Ben J Hayes, Michael E Goddard, Bonnie Berger, Alkes L Price
Genetic prediction based on either identity by state (IBS) sharing or pedigree information has been investigated extensively with best linear unbiased prediction (BLUP) methods. Such methods were pioneered in plant and animal-breeding literature and have since been applied to predict human traits, with the aim of eventual clinical utility. However, methods to combine IBS sharing and pedigree information for genetic prediction in humans have not been explored. We introduce a two-variance-component model for genetic prediction: one component for IBS sharing and one for approximate pedigree structure, both estimated with genetic markers...
November 5, 2015: American Journal of Human Genetics
Po-Ru Loh, Gaurav Bhatia, Alexander Gusev, Hilary K Finucane, Brendan K Bulik-Sullivan, Samuela J Pollack, Teresa R de Candia, Sang Hong Lee, Naomi R Wray, Kenneth S Kendler, Michael C O'Donovan, Benjamin M Neale, Nick Patterson, Alkes L Price
Heritability analyses of genome-wide association study (GWAS) cohorts have yielded important insights into complex disease architecture, and increasing sample sizes hold the promise of further discoveries. Here we analyze the genetic architectures of schizophrenia in 49,806 samples from the PGC and nine complex diseases in 54,734 samples from the GERA cohort. For schizophrenia, we infer an overwhelmingly polygenic disease architecture in which ≥71% of 1-Mb genomic regions harbor ≥1 variant influencing schizophrenia risk...
December 2015: Nature Genetics
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