Finding the missing heritability of complex diseases
Teri A. Manolio,Francis S. Collins,Nancy J. Cox,David Goldstein,Lucia A. Hindorff,David J. Hunter,Mark I. McCarthy,Erin M. Ramos,Lon R. Cardon,Aravinda Chakravarti,Judy H. Cho,Alan E. Guttmacher,Augustine Kong,Leonid Kruglyak,Leonid Kruglyak,Elaine R. Mardis,Charles N. Rotimi,Montgomery Slatkin,David Valle,Alice S. Whittemore,Michael Boehnke,Andrew G. Clark,Evan E. Eichler,Greg Gibson,Jonathan L. Haines,Trudy F. C. Mackay,Steven A. McCarroll,Peter M. Visscher +27 more
TL;DR: This paper examined potential sources of missing heritability and proposed research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.
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Abstract: Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, 'missing' heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.
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Citations
Association mapping in crop plants: opportunities and challenges.
TL;DR: The research area of association mapping (AM) is currently receiving major attention for genetic studies of quantitative traits in all major crops as mentioned in this paper, however, the level of success and utility of AM achieved for crop improvement is not comparable to that in the area of human health care for diagnosis of complex human diseases.
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Transgenerational epigenetic effects on brain functions.
TL;DR: This review examines epigenetic mechanisms in complex diseases and summarizes the most illustrative examples of transgenerational epigenetic inheritance in mammals and their relevance for brain function.
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A functional variant in the CFI gene confers a high risk of age-related macular degeneration.
Johannes P. H. van de Ven,Sara C. Nilsson,Perciliz L. Tan,Gabriëlle H.S. Buitendijk,Tina Ristau,Frida C. Mohlin,Sander B. Nabuurs,Frederieke E. Schoenmaker-Koller,Dzenita Smailhodzic,Peter A. Campochiaro,Donald J. Zack,Maheswara R Duvvari,Bjorn Bakker,Codrut C. Paun,Camiel J. F. Boon,André G. Uitterlinden,Sandra Liakopoulos,B. Jeroen Klevering,Sascha Fauser,Mohamed R. Daha,Nicholas Katsanis,Caroline C W Klaver,Anna M. Blom,Carel B. Hoyng,Anneke I. den Hollander +24 more
TL;DR: It is demonstrated that rare, highly penetrant mutations contribute to the genetic burden of AMD by showing that human CFI mRNA encoding Arg119 had reduced activity compared to wild-type mRNA encoding Gly119 in regulating vessel thickness and branching in the zebrafish retina.
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Sex differences in disease genetics: evidence, evolution, and detection
TL;DR: Although genetic variation that has sex-dependent effects on disease risk could be maintained by mutation-selection balance and genetic drift, recent evidence indicates that intra-locus sexual conflict could be a powerful influence on complex trait architecture, and maintain sex- dependent disease risk alleles in a population because they are beneficial to the opposite sex.
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Large-scale replication and heterogeneity in Parkinson disease genetic loci
Manu Sharma,John P. A. Ioannidis,Jan O. Aasly,Grazia Annesi,Alexis Brice,Christine Van Broeckhoven,Lars Bertram,Maria Bozi,David Crosiers,Carl E Clarke,Maurizio F. Facheris,Matthew J. Farrer,Gaëtan Garraux,Suzana Gispert,Georg Auburger,Carles Vilariño-Güell,Georgios M. Hadjigeorgiou,Andrew A. Hicks,Nobutaka Hattori,Beom S. Jeon,Suzanne Lesage,Christina M. Lill,Juei-Jueng Lin,Timothy Lynch,Peter Lichtner,Anthony E. Lang,Vincent Mok,Barbara Jasinska-Myga,George D. Mellick,Karen E. Morrison,Grzegorz Opala,Peter P. Pramstaller,Irene Pichler,Sung Sup Park,Aldo Quattrone,Ekaterina Rogaeva,Owen A. Ross,Leonidas Stefanis,Joanne D. Stockton,Wataru Satake,Peter A. Silburn,Jessie Theuns,Jessie Theuns,Eng-King Tan,Tatsushi Toda,Hiroyuki Tomiyama,Ryan J. Uitti,Karin Wirdefeldt,Zbigniew K. Wszolek,Georgia Xiromerisiou,Kuo Chu Yueh,Yi Zhao,Thomas Gasser,Demetrius M. Maraganore,Rejko Krüger +54 more
TL;DR: This study allows insight into the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity.
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Elizabeth H. Corder,Ann M. Saunders,Warren J. Strittmatter,Donald E. Schmechel,P. C. Gaskell,Gary W. Small,A. D. Roses,Jonathan L. Haines,Margaret A. Pericak-Vance +8 more
TL;DR: The APOE-epsilon 4 allele is associated with the common late onset familial and sporadic forms of Alzheimer9s disease (AD) in 42 families with late onset AD.
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Prediction of Total Genetic Value Using Genome-Wide Dense Marker Maps
TL;DR: It was concluded that selection on genetic values predicted from markers could substantially increase the rate of genetic gain in animals and plants, especially if combined with reproductive techniques to shorten the generation interval.
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The Future of Genetic Studies of Complex Human Diseases
TL;DR: The identification of the genetic basis of complex human diseases such as schizophrenia and diabetes has proven difficult as mentioned in this paper, and Risch and Merikangas proposed that they can best accomplish this goal by combining the power of the human genome project with association studies.
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A second generation human haplotype map of over 3.1 million SNPs
Kelly A. Frazer,Dennis G. Ballinger,David R. Cox,David A. Hinds,Laura L. Stuve,Richard A. Gibbs,John W. Belmont,Andrew Boudreau,Paul Hardenbol,Suzanne M. Leal,Shiran Pasternak,David A. Wheeler,Thomas D. Willis,Fuli Yu,Huanming Yang,Changqing Zeng,Gao Yang,H. B. Hu,Weitao Hu,Chaohua Li,Wei Lin,Siqi Liu,Hao Pan,Xiaoli Tang,Jian Wang,Wei Wang,Jun Yu,Bo Zhang,Qingrun Zhang,Hongbin Zhao,Hui Zhao,Jun Zhou,Stacey Gabriel,Rachel Barry,Brendan Blumenstiel,Amy L. Camargo,Matthew Defelice,Maura Faggart,Mary Goyette,Supriya Gupta,Jamie Moore,Huy Nguyen,Robert C. Onofrio,Melissa Parkin,Jessica Roy,Erich Stahl,Ellen Winchester,Liuda Ziaugra,David Altshuler,Yan Shen,Zhijian Yao,Wei Huang,Xun Chu,Yungang He,Li Jin,Yangfan Liu,Yayun Shen,Weiwei Sun,Haifeng Wang,Yi Wang,Ying Wang,Xiaoyan Xiong,Liang Xu,Mary M.Y. Waye,Stephen Kwok-Wing Tsui,Hong Xue,J. Tze Fei Wong,Luana Galver,Jian-Bing Fan,Kevin L. Gunderson,Sarah S. Murray,Arnold Oliphant,Mark S. Chee,Alexandre Montpetit,Fanny Chagnon,Vincent Ferretti,Martin Leboeuf,Jean François Olivier,Michael S. Phillips,Stéphanie Roumy,Clémentine Sallée,Andrei Verner,Thomas J. Hudson,Pui-Yan Kwok,Dongmei Cai,Daniel C. Koboldt,Raymond D. Miller,Ludmila Pawlikowska,Patricia Taillon-Miller,Ming Xiao,Lap-Chee Tsui,William Mak,Qiang Song You,Paul K.H. Tam,Yusuke Nakamura,Takahisa Kawaguchi,Takuya Kitamoto,Takashi Morizono,Atsushi Nagashima,Yozo Ohnishi,Akihiro Sekine,Toshihiro Tanaka,Tatsuhiko Tsunoda,Panos Deloukas,Christine P. Bird,Marcos Delgado,Emmanouil T. Dermitzakis,Rhian Gwilliam,Sarah E. Hunt,Jonathan J. Morrison,Don Powell,Barbara E. Stranger,Pamela Whittaker,David R. Bentley,Mark J. Daly,Paul I.W. de Bakker,Jeffrey C. Barrett,Yves Chretien,Julian Maller,Steve McCarroll,Nick Patterson,Itsik Pe'er,Alkes L. Price,Shaun Purcell,Daniel J. Richter,Pardis C. Sabeti,Richa Saxena,Stephen F. Schaffner,Pak C. Sham,Patrick Varilly,Lincoln Stein,Lalitha Krishnan,Albert V. Smith,Marcela K. Tello-Ruiz,Gudmundur A. Thorisson,Aravinda Chakravarti,Peter E. Chen,David J. Cutler,Carl S. Kashuk,Shin Lin,Gonçalo R. Abecasis,Weihua Guan,Yun Li,Heather M. Munro,Zhaohui S. Qin,Daryl J. Thomas,Gilean McVean,Adam Auton,Leonardo Bottolo,Niall Cardin,Susana Eyheramendy,Colin Freeman,Jonathan Marchini,Simon Myers,Chris C. A. Spencer,Matthew Stephens,Peter Donnelly,Lon R. Cardon,Geraldine M. Clarke,David M. Evans,Andrew P. Morris,Bruce S. Weir,Todd A. Johnson,James C. Mullikin,Stephen T. Sherry,Michael Feolo,Andrew D. Skol,Houcan Zhang,Ichiro Matsuda,Yoshimitsu Fukushima,Darryl Macer,Eiko Suda,Charles N. Rotimi,Clement Adebamowo,Ike Ajayi,Toyin Aniagwu,Patricia A. Marshall,Chibuzor Nkwodimmah,Charmaine D.M. Royal,Mark Leppert,Missy Dixon,Andy Peiffer,Renzong Qiu,Alastair Kent,Kazuto Kato,Norio Niikawa,Isaac F. Adewole,Bartha Maria Knoppers,Morris W. Foster,Ellen Wright Clayton,Jessica Watkin,Donna M. Muzny,Lynne V. Nazareth,Erica Sodergren,George M. Weinstock,Imtaz Yakub,Bruce W. Birren,Richard K. Wilson,Lucinda Fulton,Jane Rogers,John Burton,Nigel P. Carter,C M Clee,Mark Griffiths,Matthew C. Jones,Kirsten McLay,Robert W. Plumb,Mark T. Ross,Sarah Sims,David Willey,Zhu Chen,Hua Han,Le Kang,Martin Godbout,John C. Wallenburg,Paul L'Archevêque,Guy Bellemare,Koji Saeki,Hongguang Wang,Daochang An,Hongbo Fu,Qing Li,Zhen Wang,Renwu Wang,Arthur L. Holden,Lisa D. Brooks,Jean E. McEwen,Mark S. Guyer,Vivian Ota Wang,Jane Peterson,Michael Shi,Jack Spiegel,Lawrence M. Sung,Lynn F. Zacharia,Francis S. Collins,Karen Kennedy,Ruth Jamieson,John Stewart +237 more
TL;DR: The Phase II HapMap is described, which characterizes over 3.1 million human single nucleotide polymorphisms genotyped in 270 individuals from four geographically diverse populations and includes 25–35% of common SNP variation in the populations surveyed, and increased differentiation at non-synonymous, compared to synonymous, SNPs is demonstrated.
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Potential etiologic and functional implications of genome-wide association loci for human diseases and traits
Lucia A. Hindorff,Praveen Sethupathy,Heather Junkins,Erin M. Ramos,Jayashri P. Mehta,Francis S. Collins,Teri A. Manolio +6 more
TL;DR: An online catalog of SNP-trait associations from published genome-wide association studies for use in investigating genomic characteristics of trait/disease-associated SNPs (TASs) is developed, well-suited to guide future investigations of the role of common variants in complex disease etiology.
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