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Handsaker, Robert

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Handsaker, Robert
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    Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics
    (Nature Publishing Group UK, 2018) Barbeira, Alvaro N.; Dickinson, Scott P.; Bonazzola, Rodrigo; Zheng, Jiamao; Wheeler, Heather E.; Torres, Jason M.; Torstenson, Eric S.; Shah, Kaanan P.; Garcia, Tzintzuni; Edwards, Todd L.; Stahl, Eli A.; Huckins, Laura M.; Aguet, François; Ardlie, Kristin G.; Cummings, Beryl; Gelfand, Ellen T.; Getz, Gad; Hadley, Kane; Handsaker, Robert; Huang, Katherine H.; Kashin, Seva; Karczewski, Konrad; Lek, Monkol; Li, Xiao; MacArthur, Daniel; Nedzel, Jared L.; Nguyen, Duyen T.; Noble, Michael S.; Segre, Ayellet; Trowbridge, Casandra A.; Tukiainen, Taru; Abell, Nathan S.; Balliu, Brunilda; Barshir, Ruth; Basha, Omer; Battle, Alexis; Bogu, Gireesh K.; Brown, Andrew; Brown, Christopher D.; Castel, Stephane E.; Chen, Lin S.; Chiang, Colby; Conrad, Donald F.; Damani, Farhan N.; Davis, Joe R.; Delaneau, Olivier; Dermitzakis, Emmanouil T.; Engelhardt, Barbara E.; Eskin, Eleazar; Ferreira, Pedro G.; Frésard, Laure; Gamazon, Eric R.; Garrido-Martín, Diego; Gewirtz, Ariel D. H.; Gliner, Genna; Gloudemans, Michael J.; Guigo, Roderic; Hall, Ira M.; Han, Buhm; He, Yuan; Hormozdiari, Farhad; Howald, Cedric; Jo, Brian; Kang, Eun Yong; Kim, Yungil; Kim-Hellmuth, Sarah; Lappalainen, Tuuli; Li, Gen; Li, Xin; Liu, Boxiang; Mangul, Serghei; McCarthy, Mark I.; McDowell, Ian C.; Mohammadi, Pejman; Monlong, Jean; Montgomery, Stephen B.; Muñoz-Aguirre, Manuel; Ndungu, Anne W.; Nobel, Andrew B.; Oliva, Meritxell; Ongen, Halit; Palowitch, John J.; Panousis, Nikolaos; Papasaikas, Panagiotis; Park, YoSon; Parsana, Princy; Payne, Anthony J.; Peterson, Christine B.; Quan, Jie; Reverter, Ferran; Sabatti, Chiara; Saha, Ashis; Sammeth, Michael; Scott, Alexandra J.; Shabalin, Andrey A.; Sodaei, Reza; Stephens, Matthew; Stranger, Barbara E.; Strober, Benjamin J.; Sul, Jae Hoon; Tsang, Emily K.; Urbut, Sarah; van de Bunt, Martijn; Wang, Gao; Wen, Xiaoquan; Wright, Fred A.; Xi, Hualin S.; Yeger-Lotem, Esti; Zappala, Zachary; Zaugg, Judith B.; Zhou, Yi-Hui; Akey, Joshua M.; Bates, Daniel; Chan, Joanne; Claussnitzer, Melina; Demanelis, Kathryn; Diegel, Morgan; Doherty, Jennifer A.; Feinberg, Andrew P.; Fernando, Marian S.; Halow, Jessica; Hansen, Kasper D.; Haugen, Eric; Hickey, Peter F.; Hou, Lei; Jasmine, Farzana; Jian, Ruiqi; Jiang, Lihua; Johnson, Audra; Kaul, Rajinder; Kellis, Manolis; Kibriya, Muhammad G.; Lee, Kristen; Li, Jin Billy; Li, Qin; Lin, Jessica; Lin, Shin; Linder, Sandra; Linke, Caroline; Liu, Yaping; Maurano, Matthew T.; Molinie, Benoit; Nelson, Jemma; Neri, Fidencio J.; Park, Yongjin; Pierce, Brandon L.; Rinaldi, Nicola J.; Rizzardi, Lindsay F.; Sandstrom, Richard; Skol, Andrew; Smith, Kevin S.; Snyder, Michael P.; Stamatoyannopoulos, John; Tang, Hua; Wang, Li; Wang, Meng; Van Wittenberghe, Nicholas; Wu, Fan; Zhang, Rui; Nierras, Concepcion R.; Branton, Philip A.; Carithers, Latarsha J.; Guan, Ping; Moore, Helen M.; Rao, Abhi; Vaught, Jimmie B.; Gould, Sarah E.; Lockart, Nicole C.; Martin, Casey; Struewing, Jeffery P.; Volpi, Simona; Addington, Anjene M.; Koester, Susan E.; Little, A. Roger; Brigham, Lori E.; Hasz, Richard; Hunter, Marcus; Johns, Christopher; Johnson, Mark; Kopen, Gene; Leinweber, William F.; Lonsdale, John T.; McDonald, Alisa; Mestichelli, Bernadette; Myer, Kevin; Roe, Brian; Salvatore, Michael; Shad, Saboor; Thomas, Jeffrey A.; Walters, Gary; Washington, Michael; Wheeler, Joseph; Bridge, Jason; Foster, Barbara A.; Gillard, Bryan M.; Karasik, Ellen; Kumar, Rachna; Miklos, Mark; Moser, Michael T.; Jewell, Scott D.; Montroy, Robert G.; Rohrer, Daniel C.; Valley, Dana R.; Davis, David A.; Mash, Deborah C.; Undale, Anita H.; Smith, Anna M.; Tabor, David E.; Roche, Nancy V.; McLean, Jeffrey A.; Vatanian, Negin; Robinson, Karna L.; Sobin, Leslie; Barcus, Mary E.; Valentino, Kimberly M.; Qi, Liqun; Hunter, Steven; Hariharan, Pushpa; Singh, Shilpi; Um, Ki Sung; Matose, Takunda; Tomaszewski, Maria M.; Barker, Laura K.; Mosavel, Maghboeba; Siminoff, Laura A.; Traino, Heather M.; Flicek, Paul; Juettemann, Thomas; Ruffier, Magali; Sheppard, Dan; Taylor, Kieron; Trevanion, Stephen J.; Zerbino, Daniel R.; Craft, Brian; Goldman, Mary; Haeussler, Maximilian; Kent, W. James; Lee, Christopher M.; Paten, Benedict; Rosenbloom, Kate R.; Vivian, John; Zhu, Jingchun; Nicolae, Dan L.; Cox, Nancy J.; Im, Hae Kyung
    Scalable, integrative methods to understand mechanisms that link genetic variants with phenotypes are needed. Here we derive a mathematical expression to compute PrediXcan (a gene mapping approach) results using summary data (S-PrediXcan) and show its accuracy and general robustness to misspecified reference sets. We apply this framework to 44 GTEx tissues and 100+ phenotypes from GWAS and meta-analysis studies, creating a growing public catalog of associations that seeks to capture the effects of gene expression variation on human phenotypes. Replication in an independent cohort is shown. Most of the associations are tissue specific, suggesting context specificity of the trait etiology. Colocalized significant associations in unexpected tissues underscore the need for an agnostic scanning of multiple contexts to improve our ability to detect causal regulatory mechanisms. Monogenic disease genes are enriched among significant associations for related traits, suggesting that smaller alterations of these genes may cause a spectrum of milder phenotypes.
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    A whole-genome sequence study identifies genetic risk factors for neuromyelitis optica
    (Nature Publishing Group UK, 2018) Estrada, Karol; Whelan, Christopher W.; Zhao, Fengmei; Bronson, Paola; Handsaker, Robert; Sun, Chao; Carulli, John P.; Harris, Tim; Ransohoff, Richard M.; McCarroll, Steven; Day-Williams, Aaron G.; Greenberg, Benjamin M.; MacArthur, Daniel
    Neuromyelitis optica (NMO) is a rare autoimmune disease that affects the optic nerve and spinal cord. Most NMO patients ( > 70%) are seropositive for circulating autoantibodies against aquaporin 4 (NMO-IgG+). Here, we meta-analyze whole-genome sequences from 86 NMO cases and 460 controls with genome-wide SNP array from 129 NMO cases and 784 controls to test for association with SNPs and copy number variation (total N = 215 NMO cases, 1244 controls). We identify two independent signals in the major histocompatibility complex (MHC) region associated with NMO-IgG+, one of which may be explained by structural variation in the complement component 4 genes. Mendelian Randomization analysis reveals a significant causal effect of known systemic lupus erythematosus (SLE), but not multiple sclerosis (MS), risk variants in NMO-IgG+. Our results suggest that genetic variants in the MHC region contribute to the etiology of NMO-IgG+ and that NMO-IgG+ is genetically more similar to SLE than MS.
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    An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge
    (BioMed Central, 2014) Brownstein, Catherine; Beggs, Alan; Homer, Nils; Merriman, Barry; Yu, Timothy W; Flannery, Katherine; DeChene, Elizabeth T; Towne, Meghan C; Savage, Sarah K; Price, Emily N; Holm, Ingrid; Luquette, Joe; Lyon, Elaine; Majzoub, Joseph; Neupert, Peter; McCallie Jr, David; Szolovits, Peter; Willard, Huntington F; Mendelsohn, Nancy J; Temme, Renee; Finkel, Richard S; Yum, Sabrina W; Medne, Livija; Sunyaev, Shamil; Adzhubey, Ivan; Cassa, Christopher; de Bakker, Paul IW; Duzkale, Hatice; Dworzyński, Piotr; Fairbrother, William; Francioli, Laurent; Funke, Birgit; Giovanni, Monica A; Handsaker, Robert; Lage, Kasper; Lebo, Matthew; Lek, Monkol; Leshchiner, Ignaty; MacArthur, Daniel; McLaughlin, Heather M; Murray, Michael F; Pers, Tune H; Polak, Paz P; Raychaudhuri, Soumya; Rehm, Heidi; Soemedi, Rachel; Stitziel, Nathan O; Vestecka, Sara; Supper, Jochen; Gugenmus, Claudia; Klocke, Bernward; Hahn, Alexander; Schubach, Max; Menzel, Mortiz; Biskup, Saskia; Freisinger, Peter; Deng, Mario; Braun, Martin; Perner, Sven; Smith, Richard JH; Andorf, Janeen L; Huang, Jian; Ryckman, Kelli; Sheffield, Val C; Stone, Edwin M; Bair, Thomas; Black-Ziegelbein, E Ann; Braun, Terry A; Darbro, Benjamin; DeLuca, Adam P; Kolbe, Diana L; Scheetz, Todd E; Shearer, Aiden E; Sompallae, Rama; Wang, Kai; Bassuk, Alexander G; Edens, Erik; Mathews, Katherine; Moore, Steven A; Shchelochkov, Oleg A; Trapane, Pamela; Bossler, Aaron; Campbell, Colleen A; Heusel, Jonathan W; Kwitek, Anne; Maga, Tara; Panzer, Karin; Wassink, Thomas; Van Daele, Douglas; Azaiez, Hela; Booth, Kevin; Meyer, Nic; Segal, Michael M; Williams, Marc S; Tromp, Gerard; White, Peter; Corsmeier, Donald; Fitzgerald-Butt, Sara; Herman, Gail; Lamb-Thrush, Devon; McBride, Kim L; Newsom, David; Pierson, Christopher R; Rakowsky, Alexander T; Maver, Aleš; Lovrečić, Luca; Palandačić, Anja; Peterlin, Borut; Torkamani, Ali; Wedell, Anna; Huss, Mikael; Alexeyenko, Andrey; Lindvall, Jessica M; Magnusson, Måns; Nilsson, Daniel; Stranneheim, Henrik; Taylan, Fulya; Gilissen, Christian; Hoischen, Alexander; van Bon, Bregje; Yntema, Helger; Nelen, Marcel; Zhang, Weidong; Sager, Jason; Zhang, Lu; Blair, Kathryn; Kural, Deniz; Cariaso, Michael; Lennon, Greg G; Javed, Asif; Agrawal, Saloni; Ng, Pauline C; Sandhu, Komal S; Krishna, Shuba; Veeramachaneni, Vamsi; Isakov, Ofer; Halperin, Eran; Friedman, Eitan; Shomron, Noam; Glusman, Gustavo; Roach, Jared C; Caballero, Juan; Cox, Hannah C; Mauldin, Denise; Ament, Seth A; Rowen, Lee; Richards, Daniel R; Lucas, F Anthony San; Gonzalez-Garay, Manuel L; Caskey, C Thomas; Bai, Yu; Huang, Ying; Fang, Fang; Zhang, Yan; Wang, Zhengyuan; Barrera, Jorge; Garcia-Lobo, Juan M; González-Lamuño, Domingo; Llorca, Javier; Rodriguez, Maria C; Varela, Ignacio; Reese, Martin G; De La Vega, Francisco M; Kiruluta, Edward; Cargill, Michele; Hart, Reece K; Sorenson, Jon M; Lyon, Gholson J; Stevenson, David A; Bray, Bruce E; Moore, Barry M; Eilbeck, Karen; Yandell, Mark; Zhao, Hongyu; Hou, Lin; Chen, Xiaowei; Yan, Xiting; Chen, Mengjie; Li, Cong; Yang, Can; Gunel, Murat; Li, Peining; Kong, Yong; Alexander, Austin C; Albertyn, Zayed I; Boycott, Kym M; Bulman, Dennis E; Gordon, Paul MK; Innes, A Micheil; Knoppers, Bartha M; Majewski, Jacek; Marshall, Christian R; Parboosingh, Jillian S; Sawyer, Sarah L; Samuels, Mark E; Schwartzentruber, Jeremy; Kohane, Isaac; Margulies, David
    Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups.
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    Using population admixture to help complete maps of the human genome
    (2013) Genovese, Giulio; Handsaker, Robert; Li, Heng; Altemose, Nicolas; Lindgren, Amelia M.; Chambert, Kimberly; Pasaniuc, Bogdan; Price, Alkes; Reich, David; Morton, Cynthia; Pollak, Martin; Wilson, James G.; McCarroll, Steven
    Tens of millions of base pairs of euchromatic human genome sequence, including many protein-coding genes, have no known location in the human genome. We describe an approach for localizing the human genome's missing pieces by utilizing the patterns of genome sequence variation created by population admixture. We mapped the locations of 70 scaffolds spanning four million base pairs of the human genome's unplaced euchromatic sequence, including more than a dozen protein-coding genes, and identified eight large novel inter-chromosomal segmental duplications. We find that most of these sequences are hidden in the genome's heterochromatin, particularly its pericentromeric regions. Many cryptic, pericentromeric genes are expressed in RNA and have been maintained intact for millions of years while their expression patterns diverged from those of paralogous genes elsewhere in the genome. We describe how knowledge of the locations of these sequences can inform disease association and genome biology studies.
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    Mutations causing medullary cystic kidney disease type 1 (MCKD1) lie in a large VNTR in MUC1 missed by massively parallel sequencing
    (2014) Kirby, Andrew; Gnirke, Andreas; Jaffe, David B.; Barešová, Veronika; Pochet, Nathalie; Blumenstiel, Brendan; Ye, Chun; Aird, Daniel; Stevens, Christine; Robinson, James T.; Cabili, Moran N.; Gat-Viks, Irit; Kelliher, Edward; Daza, Riza; DeFelice, Matthew; Hůlková, Helena; Sovová, Jana; Vylet’al, Petr; Antignac, Corinne; Guttman, Mitchell; Handsaker, Robert; Perrin, Danielle; Steelman, Scott; Sigurdsson, Snaevar; Scheinman, Steven J.; Sougnez, Carrie; Cibulskis, Kristian; Parkin, Melissa; Green, Todd; Rossin, Elizabeth; Zody, Michael C.; Xavier, Ramnik; Pollak, Martin; Alper, Seth; Lindblad-Toh, Kerstin; Gabriel, Stacey; Hart, P. Suzanne; Regev, Aviv; Nusbaum, Chad; Kmoch, Stanislav; Bleyer, Anthony J.; Lander, Eric; Daly, Mark
    While genetic lesions responsible for some Mendelian disorders can be rapidly discovered through massively parallel sequencing (MPS) of whole genomes or exomes, not all diseases readily yield to such efforts. We describe the illustrative case of the simple Mendelian disorder medullary cystic kidney disease type 1 (MCKD1), mapped more than a decade ago to a 2-Mb region on chromosome 1. Ultimately, only by cloning, capillary sequencing, and de novo assembly, we found that each of six MCKD1 families harbors an equivalent, but apparently independently arising, mutation in sequence dramatically underrepresented in MPS data: the insertion of a single C in one copy (but a different copy in each family) of the repeat unit comprising the extremely long (~1.5-5 kb), GC-rich (>80%), coding VNTR in the mucin 1 gene. The results provide a cautionary tale about the challenges in identifying genes responsible for Mendelian, let alone more complex, disorders through MPS.
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    Schizophrenia risk from complex variation of complement component 4
    (2016) Sekar, Aswin; Rosen, Allison; de Rivera, Heather; Bell, Avery; Hammond, Timothy; Kamitaki, Nolan; Tooley, Katherine; Presumey, Jessy; Baum, Matt; Van Doren, Vanessa; Genovese, Giulio; Rose, Samuel A.; Handsaker, Robert; Daly, Mark; Carroll, Michael C.; Stevens, Beth; McCarroll, Steven
    Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia’s strongest genetic association at a population level involves variation in the Major Histocompatibility Complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to recognize. We show here that schizophrenia’s association with the MHC locus arises in substantial part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles promoted widely varying levels of C4A and C4B expression and associated with schizophrenia in proportion to their tendency to promote greater expression of C4A in the brain. Human C4 protein localized at neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediated synapse elimination during postnatal development. These results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals affected with schizophrenia.
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    Recurring exon deletions in the haptoglobin (HP) gene associate with lower blood cholesterol levels
    (2016) Boettger, Linda M.; Salem, Rany M; Handsaker, Robert; Peloso, Gina; Kathiresan, Sekar; Hirschhorn, Joel; McCarroll, Steven
    Two exons of the human haptoglobin (HP) gene exhibit copy number variation that affects HP multimerization and underlies one of the first protein polymorphisms identified in humans. The evolutionary origins and medical significance of this polymorphism have been uncertain. Here we show that this variation has likely arisen from the recurring reversion of an ancient hominin-specific duplication of these exons. Though this polymorphism has been largely invisible to genome-wide genetic studies to date, we describe a way to analyze it by imputation from SNP haplotypes and find among 22,288 individuals that these HP exonic deletions associate with reduced LDL and total cholesterol levels. We show that these deletions, and a SNP that affects HP expression, are the likely drivers of the strong but complex association of cholesterol levels to SNPs near HP. Recurring exonic deletions in the haptoglobin gene likely enhance human health by lowering cholesterol levels in the blood.
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    Structural forms of the human amylase locus and their relationships to SNPs, haplotypes, and obesity
    (2016) Usher, Christina; Handsaker, Robert; Esko, Tõnu; Tuke, Marcus A; Weedon, Michael N; Hastie, Alex R; Cao, Han; Moon, Jennifer E; Kashin, Seva; Fuchsberger, Christian; Metspalu, Andres; Pato, Carlos N; Pato, Michele T; McCarthy, Mark I; Boehnke, Michael; Altshuler, David; Frayling, Timothy M; Hirschhorn, Joel; McCarroll, Steven
    Hundreds of genes reside in structurally complex, poorly understood regions of the human genome1-3. One such region contains the three amylase genes (AMY2B, AMY2A, and AMY1) responsible for digesting starch into sugar. The copy number of AMY1 is reported to be the genome’s largest influence on obesity4, though genome-wide association studies for obesity have found this locus unremarkable. Using whole genome sequence analysis3,5, droplet digital PCR6, and genome mapping7, we identified eight common structural haplotypes of the amylase locus that suggest its mutational history. We found that AMY1 copy number in individuals’ genomes is generally even (rather than odd) and partially correlates to nearby SNPs, which do not associate with BMI. We measured amylase gene copy number in 1,000 obese or lean Estonians and in two other cohorts totaling ~3,500 individuals. We had 99% power to detect the lower bound of the reported effects on BMI4, yet found no association.
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    Pathways Disrupted in Human ALS Motor Neurons Identified through Genetic Correction of Mutant SOD1
    (Elsevier BV, 2014) Kiskinis, Evangelos; Sandoe, Jackson L; Williams, Lauren; Boulting, Gabriella; Moccia, Robert; Wainger, Brian; Han, Steve Sang-woo; Peng, Theodore; Thams, Sebastian; Mikkilineni, Shravani; Mellin, Cassidy; Merkle, Florian; Davis-Dusenbery, Brandi N; Ziller, Michael; Oakley, Derek; Ichida, Justin; Di Costanzo, Stefania; Atwater, Nick; Maeder, M; Goodwin, Marcus; Nemesh, James; Handsaker, Robert; Paull, Daniel; Noggle, Scott; McCarroll, Steven; Joung, Keith; Woolf, Carl; Brown, Robert H; Eggan, Kevin
    Direct electrical recording and stimulation of neural activity using micro-fabricated silicon and metal micro-wire probes have contributed extensively to basic neuroscience and therapeutic applications; however, the dimensional and mechanical mismatch of these probes with the brain tissue limits their stability in chronic implants and decreases the neuron–device contact. Here, we demonstrate the realization of a three-dimensional macroporous nanoelectronic brain probe that combines ultra-flexibility and subcellular feature sizes to overcome these limitations. Built-in strains controlling the local geometry of the macroporous devices are designed to optimize the neuron/probe interface and to promote integration with the brain tissue while introducing minimal mechanical perturbation. The ultra-flexible probes were implanted frozen into rodent brains and used to record multiplexed local field potentials and single-unit action potentials from the somatosensory cortex. Significantly, histology analysis revealed filling-in of neural tissue through the macroporous network and attractive neuron–probe interactions, consistent with long-term biocompatibility of the device.
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    A high-quality human reference panel reveals the complexity and distribution of genomic structural variants
    (Nature Publishing Group, 2016) Hehir-Kwa, Jayne Y.; Marschall, Tobias; Kloosterman, Wigard P.; Francioli, Laurent; Baaijens, Jasmijn A.; Dijkstra, Louis J.; Abdellaoui, Abdel; Koval, Vyacheslav; Thung, Djie Tjwan; Wardenaar, René; Renkens, Ivo; Coe, Bradley P.; Deelen, Patrick; de Ligt, Joep; Lameijer, Eric-Wubbo; van Dijk, Freerk; Hormozdiari, Fereydoun; Bovenberg, Jasper A.; de Craen, Anton J. M.; Beekman, Marian; Hofman, Albert; Willemsen, Gonneke; Wolffenbuttel, Bruce; Platteel, Mathieu; Du, Yuanping; Chen, Ruoyan; Cao, Hongzhi; Cao, Rui; Sun, Yushen; Cao, Jeremy Sujie; Neerincx, Pieter B. T.; Dijkstra, Martijn; Byelas, George; Kanterakis, Alexandros; Bot, Jan; Vermaat, Martijn; Laros, Jeroen F. J.; den Dunnen, Johan T.; de Knijff, Peter; Karssen, Lennart C.; van Leeuwen, Elisa M.; Amin, Najaf; Rivadeneira, Fernando; Estrada, Karol; Hottenga, Jouke-Jan; Kattenberg, V. Mathijs; van Enckevort, David; Mei, Hailiang; Santcroos, Mark; van Schaik, Barbera D. C.; Handsaker, Robert; McCarroll, Steven; Ko, Arthur; Sudmant, Peter; Nijman, Isaac J.; Uitterlinden, André G.; van Duijn, Cornelia M.; Eichler, Evan E.; de Bakker, Paul I. W.; Swertz, Morris A.; Wijmenga, Cisca; van Ommen, Gert-Jan B.; Slagboom, P. Eline; Boomsma, Dorret I.; Schönhuth, Alexander; Ye, Kai; Guryev, Victor
    Structural variation (SV) represents a major source of differences between individual human genomes and has been linked to disease phenotypes. However, the majority of studies provide neither a global view of the full spectrum of these variants nor integrate them into reference panels of genetic variation. Here, we analyse whole genome sequencing data of 769 individuals from 250 Dutch families, and provide a haplotype-resolved map of 1.9 million genome variants across 9 different variant classes, including novel forms of complex indels, and retrotransposition-mediated insertions of mobile elements and processed RNAs. A large proportion are previously under reported variants sized between 21 and 100 bp. We detect 4 megabases of novel sequence, encoding 11 new transcripts. Finally, we show 191 known, trait-associated SNPs to be in strong linkage disequilibrium with SVs and demonstrate that our panel facilitates accurate imputation of SVs in unrelated individuals.