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1. Distribution and medical impact of loss-of-function variants in the Finnish founder population.

Author

Elaine T Lim, Peter Würtz, Aki S Havulinna, Priit Palta, Taru Tukiainen, Karola Rehnström, Tõnu Esko, Reedik Mägi, Michael Inouye, Tuuli Lappalainen, Yingleong Chan, Rany M Salem, Monkol Lek, Jason Flannick, Xueling Sim, Alisa Manning, Claes Ladenvall, Suzannah Bumpstead, Eija Hämäläinen, Kristiina Aalto, Mikael Maksimow, Marko Salmi, Stefan Blankenberg, Diego Ardissino, Svati Shah, Benjamin Horne, Ruth McPherson, Gerald K Hovingh, Muredach P Reilly, Hugh Watkins, Anuj Goel, Martin Farrall, Domenico Girelli, Alex P Reiner, Nathan O Stitziel, Sekar Kathiresan, Stacey Gabriel, Jeffrey C Barrett, Terho Lehtimäki, Markku Laakso, Leif Groop, Jaakko Kaprio, Markus Perola, Mark I McCarthy, Michael Boehnke, David M Altshuler, Cecilia M Lindgren, Joel N Hirschhorn, Andres Metspalu, Nelson B Freimer, Tanja Zeller, Sirpa Jalkanen, Seppo Koskinen, Olli Raitakari, Richard Durbin, Daniel G MacArthur, Veikko Salomaa, Samuli Ripatti, Mark J Daly, Aarno Palotie, and Sequencing Initiative Suomi (SISu) Project

Subjects
Genetics, QH426-470
Abstract

Exome sequencing studies in complex diseases are challenged by the allelic heterogeneity, large number and modest effect sizes of associated variants on disease risk and the presence of large numbers of neutral variants, even in phenotypically relevant genes. Isolated populations with recent bottlenecks offer advantages for studying rare variants in complex diseases as they have deleterious variants that are present at higher frequencies as well as a substantial reduction in rare neutral variation. To explore the potential of the Finnish founder population for studying low-frequency (0.5-5%) variants in complex diseases, we compared exome sequence data on 3,000 Finns to the same number of non-Finnish Europeans and discovered that, despite having fewer variable sites overall, the average Finn has more low-frequency loss-of-function variants and complete gene knockouts. We then used several well-characterized Finnish population cohorts to study the phenotypic effects of 83 enriched loss-of-function variants across 60 phenotypes in 36,262 Finns. Using a deep set of quantitative traits collected on these cohorts, we show 5 associations (p

Published
2014
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2. Common genetic variants and modification of penetrance of BRCA2-associated breast cancer.

Author

Mia M Gaudet, Tomas Kirchhoff, Todd Green, Joseph Vijai, Joshua M Korn, Candace Guiducci, Ayellet V Segrè, Kate McGee, Lesley McGuffog, Christiana Kartsonaki, Jonathan Morrison, Sue Healey, Olga M Sinilnikova, Dominique Stoppa-Lyonnet, Sylvie Mazoyer, Marion Gauthier-Villars, Hagay Sobol, Michel Longy, Marc Frenay, GEMO Study Collaborators, Frans B L Hogervorst, Matti A Rookus, J Margriet Collée, Nicoline Hoogerbrugge, Kees E P van Roozendaal, HEBON Study Collaborators, Marion Piedmonte, Wendy Rubinstein, Stacy Nerenstone, Linda Van Le, Stephanie V Blank, Trinidad Caldés, Miguel de la Hoya, Heli Nevanlinna, Kristiina Aittomäki, Conxi Lazaro, Ignacio Blanco, Adalgeir Arason, Oskar T Johannsson, Rosa B Barkardottir, Peter Devilee, Olofunmilayo I Olopade, Susan L Neuhausen, Xianshu Wang, Zachary S Fredericksen, Paolo Peterlongo, Siranoush Manoukian, Monica Barile, Alessandra Viel, Paolo Radice, Catherine M Phelan, Steven Narod, Gad Rennert, Flavio Lejbkowicz, Anath Flugelman, Irene L Andrulis, Gord Glendon, Hilmi Ozcelik, OCGN, Amanda E Toland, Marco Montagna, Emma D'Andrea, Eitan Friedman, Yael Laitman, Ake Borg, Mary Beattie, Susan J Ramus, Susan M Domchek, Katherine L Nathanson, Tim Rebbeck, Amanda B Spurdle, Xiaoqing Chen, Helene Holland, kConFab, Esther M John, John L Hopper, Saundra S Buys, Mary B Daly, Melissa C Southey, Mary Beth Terry, Nadine Tung, Thomas V Overeem Hansen, Finn C Nielsen, Mark H Greene, Phuong L Mai, Ana Osorio, Mercedes Durán, Raquel Andres, Javier Benítez, Jeffrey N Weitzel, Judy Garber, Ute Hamann, EMBRACE, Susan Peock, Margaret Cook, Clare Oliver, Debra Frost, Radka Platte, D Gareth Evans, Fiona Lalloo, Ros Eeles, Louise Izatt, Lisa Walker, Jacqueline Eason, Julian Barwell, Andrew K Godwin, Rita K Schmutzler, Barbara Wappenschmidt, Stefanie Engert, Norbert Arnold, Dorothea Gadzicki, Michael Dean, Bert Gold, Robert J Klein, Fergus J Couch, Georgia Chenevix-Trench, Douglas F Easton, Mark J Daly, Antonis C Antoniou, David M Altshuler, and Kenneth Offit

Subjects
Genetics, QH426-470
Abstract

The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (

Published
2010
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3. Genome-wide association studies in an isolated founder population from the Pacific Island of Kosrae.

Author

Jennifer K Lowe, Julian B Maller, Itsik Pe'er, Benjamin M Neale, Jacqueline Salit, Eimear E Kenny, Jessica L Shea, Ralph Burkhardt, J Gustav Smith, Weizhen Ji, Martha Noel, Jia Nee Foo, Maude L Blundell, Vita Skilling, Laura Garcia, Marcia L Sullivan, Heather E Lee, Anna Labek, Hope Ferdowsian, Steven B Auerbach, Richard P Lifton, Christopher Newton-Cheh, Jan L Breslow, Markus Stoffel, Mark J Daly, David M Altshuler, and Jeffrey M Friedman

Subjects
Genetics, QH426-470
Abstract

It has been argued that the limited genetic diversity and reduced allelic heterogeneity observed in isolated founder populations facilitates discovery of loci contributing to both Mendelian and complex disease. A strong founder effect, severe isolation, and substantial inbreeding have dramatically reduced genetic diversity in natives from the island of Kosrae, Federated States of Micronesia, who exhibit a high prevalence of obesity and other metabolic disorders. We hypothesized that genetic drift and possibly natural selection on Kosrae might have increased the frequency of previously rare genetic variants with relatively large effects, making these alleles readily detectable in genome-wide association analysis. However, mapping in large, inbred cohorts introduces analytic challenges, as extensive relatedness between subjects violates the assumptions of independence upon which traditional association test statistics are based. We performed genome-wide association analysis for 15 quantitative traits in 2,906 members of the Kosrae population, using novel approaches to manage the extreme relatedness in the sample. As positive controls, we observe association to known loci for plasma cholesterol, triglycerides, and C-reactive protein and to a compelling candidate loci for thyroid stimulating hormone and fasting plasma glucose. We show that our study is well powered to detect common alleles explaining >/=5% phenotypic variance. However, no such large effects were observed with genome-wide significance, arguing that even in such a severely inbred population, common alleles typically have modest effects. Finally, we show that a majority of common variants discovered in Caucasians have indistinguishable effect sizes on Kosrae, despite the major differences in population genetics and environment.

Published
2009
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4. Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol

Author

Leslie A. Lange, Youna Hu, He Zhang, Chenyi Xue, Ellen M. Schmidt, Zheng-Zheng Tang, Chris Bizon, Ethan M. Lange, Joshua D. Smith, Emily H. Turner, Goo Jun, Hyun Min Kang, Gina Peloso, Paul Auer, Kuo-ping Li, Jason Flannick, Ji Zhang, Christian Fuchsberger, Kyle Gaulton, Cecilia Lindgren, Adam Locke, Alisa Manning, Xueling Sim, Manuel A. Rivas, Oddgeir L. Holmen, Omri Gottesman, Yingchang Lu, Douglas Ruderfer, Eli A. Stahl, Qing Duan, Yun Li, Peter Durda, Shuo Jiao, Aaron Isaacs, Albert Hofman, Joshua C. Bis, Adolfo Correa, Michael E. Griswold, Johanna Jakobsdottir, Albert V. Smith, Pamela J. Schreiner, Mary F. Feitosa, Qunyuan Zhang, Jennifer E. Huffman, Jacy Crosby, Christina L. Wassel, Ron Do, Nora Franceschini, Lisa W. Martin, Jennifer G. Robinson, Themistocles L. Assimes, David R. Crosslin, Elisabeth A. Rosenthal, Michael Tsai, Mark J. Rieder, Deborah N. Farlow, Aaron R. Folsom, Thomas Lumley, Ervin R. Fox, Christopher S. Carlson, Ulrike Peters, Rebecca D. Jackson, Cornelia M. van Duijn, André G. Uitterlinden, Daniel Levy, Jerome I. Rotter, Herman A. Taylor, Vilmundur Gudnason, David S. Siscovick, Myriam Fornage, Ingrid B. Borecki, Caroline Hayward, Igor Rudan, Y. Eugene Chen, Erwin P. Bottinger, Ruth J.F. Loos, Pål Sætrom, Kristian Hveem, Michael Boehnke, Leif Groop, Mark McCarthy, Thomas Meitinger, Christie M. Ballantyne, Stacey B. Gabriel, Christopher J. O’Donnell, Wendy S. Post, Kari E. North, Alexander P. Reiner, Eric Boerwinkle, Bruce M. Psaty, David Altshuler, Sekar Kathiresan, Dan-Yu Lin, Gail P. Jarvik, L. Adrienne Cupples, Charles Kooperberg, James G. Wilson, Deborah A. Nickerson, Goncalo R. Abecasis, Stephen S. Rich, Russell P. Tracy, Cristen J. Willer, David M. Altshuler, Gonçalo R. Abecasis, Hooman Allayee, Sharon Cresci, Mark J. Daly, Paul I.W. de Bakker, Mark A. DePristo, Peter Donnelly, Tim Fennell, Kiran Garimella, Stanley L. Hazen, Daniel M. Jordan, Adam Kiezun, Guillaume Lettre, Bingshan Li, Mingyao Li, Christopher H. Newton-Cheh, Sandosh Padmanabhan, Sara Pulit, Daniel J. Rader, David Reich, Muredach P. Reilly, Steve Schwartz, Laura Scott, John A. Spertus, Nathaniel O. Stitziel, Nina Stoletzki, Shamil R. Sunyaev, Benjamin F. Voight, Ermeg Akylbekova, Larry D. Atwood, Maja Barbalic, R. Graham Barr, Emelia J. Benjamin, Joshua Bis, Donald W. Bowden, Jennifer Brody, Matthew Budoff, Greg Burke, Sarah Buxbaum, Jeff Carr, Donna T. Chen, Ida Y. Chen, Wei-Min Chen, Pat Concannon, Ralph D’Agostino, Anita L. DeStefano, Albert Dreisbach, Josée Dupuis, J. Peter Durda, Jaclyn Ellis, Caroline S. Fox, Ervin Fox, Vincent Funari, Santhi K. Ganesh, Julius Gardin, David Goff, Ora Gordon, Wayne Grody, Myron Gross, Xiuqing Guo, Ira M. Hall, Nancy L. Heard-Costa, Susan R. Heckbert, Nicholas Heintz, David M. Herrington, DeMarc Hickson, Jie Huang, Shih-Jen Hwang, David R. Jacobs, Nancy S. Jenny, Andrew D. Johnson, Craig W. Johnson, Steven Kawut, Richard Kronmal, Raluca Kurz, Martin G. Larson, Mark Lawson, Cora E. Lewis, Dalin Li, Honghuang Lin, Chunyu Liu, Jiankang Liu, Kiang Liu, Xiaoming Liu, Yongmei Liu, William T. Longstreth, Cay Loria, Kathryn Lunetta, Aaron J. Mackey, Rachel Mackey, Ani Manichaikul, Taylor Maxwell, Barbara McKnight, James B. Meigs, Alanna C. Morrison, Solomon K. Musani, Josyf C. Mychaleckyj, Jennifer A. Nettleton, Kari North, Daniel O’Leary, Frank Ong, Walter Palmas, James S. Pankow, Nathan D. Pankratz, Shom Paul, Marco Perez, Sharina D. Person, Joseph Polak, Aaron R. Quinlan, Leslie J. Raffel, Vasan S. Ramachandran, Kenneth Rice, Jill P. Sanders, Pamela Schreiner, Sudha Seshadri, Steve Shea, Stephen Sidney, Kevin Silverstein, Nicholas L. Smith, Nona Sotoodehnia, Asoke Srinivasan, Kent Taylor, Fridtjof Thomas, Michael Y. Tsai, Kelly A. Volcik, Chrstina L. Wassel, Karol Watson, Gina Wei, Wendy White, Kerri L. Wiggins, Jemma B. Wilk, O. Dale Williams, Gregory Wilson, Phillip Wolf, Neil A. Zakai, John Hardy, James F. Meschia, Michael Nalls, Andrew Singleton, Brad Worrall, Michael J. Bamshad, Kathleen C. Barnes, Ibrahim Abdulhamid, Frank Accurso, Ran Anbar, Terri Beaty, Abigail Bigham, Phillip Black, Eugene Bleecker, Kati Buckingham, Anne Marie Cairns, Daniel Caplan, Barbara Chatfield, Aaron Chidekel, Michael Cho, David C. Christiani, James D. Crapo, Julia Crouch, Denise Daley, Anthony Dang, Hong Dang, Alicia De Paula, Joan DeCelie-Germana, Allen DozorMitch Drumm, Maynard Dyson, Julia Emerson, Mary J. Emond, Thomas Ferkol, Robert Fink, Cassandra Foster, Deborah Froh, Li Gao, William Gershan, Ronald L. Gibson, Elizabeth Godwin, Magdalen Gondor, Hector Gutierrez, Nadia N. Hansel, Paul M. Hassoun, Peter Hiatt, John E. Hokanson, Michelle Howenstine, Laura K. Hummer, Jamshed Kanga, Yoonhee Kim, Michael R. Knowles, Michael Konstan, Thomas Lahiri, Nan Laird, Christoph Lange, Lin Lin, Xihong Lin, Tin L. Louie, David Lynch, Barry Make, Thomas R. Martin, Steve C. Mathai, Rasika A. Mathias, John McNamara, Sharon McNamara, Deborah Meyers, Susan Millard, Peter Mogayzel, Richard Moss, Tanda Murray, Dennis Nielson, Blakeslee Noyes, Wanda O’Neal, David Orenstein, Brian O’Sullivan, Rhonda Pace, Peter Pare, H. Worth Parker, Mary Ann Passero, Elizabeth Perkett, Adrienne Prestridge, Nicholas M. Rafaels, Bonnie Ramsey, Elizabeth Regan, Clement Ren, George Retsch-Bogart, Michael Rock, Antony Rosen, Margaret Rosenfeld, Ingo Ruczinski, Andrew Sanford, David Schaeffer, Cindy Sell, Daniel Sheehan, Edwin K. Silverman, Don Sin, Terry Spencer, Jackie Stonebraker, Holly K. Tabor, Laurie Varlotta, Candelaria I. Vergara, Robert Weiss, Fred Wigley, Robert A. Wise, Fred A. Wright, Mark M. Wurfel, Robert Zanni, Fei Zou, Phil Green, Jay Shendure, Joshua M. Akey, Carlos D. Bustamante, Evan E. Eichler, P. Keolu Fox, Wenqing Fu, Adam Gordon, Simon Gravel, Jill M. Johnsen, Mengyuan Kan, Eimear E. Kenny, Jeffrey M. Kidd, Fremiet Lara-Garduno, Suzanne M. Leal, Dajiang J. Liu, Sean McGee, Timothy D. O’Connor, Bryan Paeper, Peggy D. Robertson, Jeffrey C. Staples, Jacob A. Tennessen, Gao Wang, Qian Yi, Rebecca Jackson, Garnet Anderson, Hoda Anton-Culver, Paul L. Auer, Shirley Beresford, Henry Black, Robert Brunner, Robert Brzyski, Dale Burwen, Bette Caan, Cara L. Carty, Rowan Chlebowski, Steven Cummings, J. David Curb, Charles B. Eaton, Leslie Ford, Stephanie M. Fullerton, Margery Gass, Nancy Geller, Gerardo Heiss, Barbara V. Howard, Li Hsu, Carolyn M. Hutter, John Ioannidis, Karen C. Johnson, Lewis Kuller, Andrea LaCroix, Kamakshi Lakshminarayan, Dorothy Lane, Norman Lasser, Erin LeBlanc, Kuo-Ping Li, Marian Limacher, Benjamin A. Logsdon, Shari Ludlam, JoAnn E. Manson, Karen Margolis, Lisa Martin, Joan McGowan, Keri L. Monda, Jane Morley Kotchen, Lauren Nathan, Judith Ockene, Mary Jo O’Sullivan, Lawrence S. Phillips, Ross L. Prentice, John Robbins, Jacques E. Rossouw, Haleh Sangi-Haghpeykar, Gloria E. Sarto, Sally Shumaker, Michael S. Simon, Marcia L. Stefanick, Evan Stein, Hua Tang, Kira C. Taylor, Cynthia A. Thomson, Timothy A. Thornton, Linda Van Horn, Mara Vitolins, Jean Wactawski-Wende, Robert Wallace, Sylvia Wassertheil-Smoller, Donglin Zeng, Deborah Applebaum-Bowden, Michael Feolo, Weiniu Gan, Dina N. Paltoo, Phyliss Sholinsky, Anne Sturcke, Epidemiology, and Internal Medicine

Subjects
Male, Genome-wide association study, 030204 cardiovascular system & hematology, Cohort Studies, 0302 clinical medicine, Gene Frequency, Receptors, Genotype, Dyslipidemias/blood, Receptors, LDL/genetics, Genetics(clinical), Exome, Genetics (clinical), Exome sequencing, Genetics, 0303 health sciences, Serine Endopeptidases, Single Nucleotide, Middle Aged, 3. Good health, Cholesterol, Phenotype, Genetic Code, Cholesterol, LDL/genetics, Female, lipids (amino acids, peptides, and proteins), Proprotein Convertases, Proprotein Convertase 9, Sequence Analysis, Adult, Apolipoproteins E/blood, LDL/genetics, Serine Endopeptidases/genetics, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Apolipoproteins E, SDG 3 - Good Health and Well-being, Humans, Polymorphism, Allele frequency, 030304 developmental biology, Genetic association, Aged, Dyslipidemias, PCSK9, DNA, Cholesterol, LDL, Lipase, Sequence Analysis, DNA, Receptors, LDL, Lipase/genetics, Proprotein Convertases/genetics, Follow-Up Studies, Genome-Wide Association Study
Abstract

Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or

Published
2014

5. Correction: Common Genetic Variants and Modification of Penetrance of -Associated Breast Cancer.

Author

Mia M. Gaudet, Tomas Kirchhoff, Todd Green, Joseph Vijai, Joshua M. Korn, Candace Guiducci, Ayellet V. Segrè, Kate McGee, Lesley McGuffog, Christiana Kartsonaki, Jonathan Morrison, Sue Healey, Olga M. Sinilnikova, Dominique Stoppa-Lyonnet, Sylvie Mazoyer, Marion Gauthier-Villars, Hagay Sobol, Michel Longy, Marc Frenay, GEMO Study Collaborators, Frans B. L. Hogervorst, Matti A. Rookus, J. Margriet Collée, Nicoline Hoogerbrugge, Kees E. P. van Roozendaal, Marion Piedmonte, Wendy Rubinstein, Stacy Nerenstone, Linda Van Le, Stephanie V. Blank, Trinidad Caldés, Miguel de la Hoya, Heli Nevanlinna, Kristiina Aittomäki, Conxi Lazaro, Ignacio Blanco, Adalgeir Arason, Oskar T. Johannsson, Rosa B. Barkardottir, Peter Devilee, Olofunmilayo I. Olopade, Susan L. Neuhausen, Xianshu Wang, Zachary S. Fredericksen, Paolo Peterlongo, Siranoush Manoukian, Monica Barile, Alessandra Viel, Paolo Radice, Catherine M. Phelan, Steven Narod, Gad Rennert, Flavio Lejbkowicz, Anath Flugelman, Irene L. Andrulis, Gord Glendon, Hilmi Ozcelik, Amanda E. Toland, Marco Montagna, Emma D'Andrea, Eitan Friedman, Yael Laitman, Ake Borg, Mary Beattie, Susan J. Ramus, Susan M. Domchek, Katherine L. Nathanson, Tim Rebbeck, Amanda B. Spurdle, Xiaoqing Chen, Helene Holland, Esther M. John, John L. Hopper, Saundra S. Buys, Mary B. Daly, Melissa C. Southey, Mary Beth Terry, Nadine Tung, Thomas V. Overeem Hansen, Finn C. Nielsen, Mark I. Greene, Phuong L. Mai, Ana Osorio, Mercedes Durán, Raquel Andres, Javier Benítez, Jeffrey N. Weitzel, Judy Garber, Ute Hamann, Susan Peock, Margaret Cook, Clare Oliver, Debra Frost, Radka Platte, D. Gareth Evans, Fiona Lalloo, Ros Eeles, Louise Izatt, Lisa Walker, Jacqueline Eason, Julian Barwell, Andrew K. Godwin, Rita K. Schmutzler, Barbara Wappenschmidt, Stefanie Engert, Norbert Arnold, Dorothea Gadzicki, Michael Dean, Bert Gold, Robert J. Klein, Fergus J. Couch, Georgia Chenevix-Trench, Douglas F. Easton, Mark J. Daly, Antonis C. Antoniou, David M. Altshuler, and Kenneth Offit

Subjects
Genetics, QH426-470
Published
2010
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