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Highly Sensitive and Cost-Effective Polymeric-Sulfur-Based Mid-Wavelength Infrared Linear Polarizers with Tailored Fabry-Perot Resonance

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ADVANCED MATERIALS 2023年第7期35卷 2209377-2209377页

作者： Cho, Woongbi Hwang, Jehwan Lee, Sang Yeon Park, Jaeseo Han, Nara Lee, Chi Hwan Kang, Sang-Woo Urbas, Augustine Kim, Jun Oh Ku, Zahyun Wie, Jeong Jae Hanyang Univ Dept Organ & Nano Engn 222 Wangsimmni roSeongdong gu Seoul 04763 South Korea Purdue Univ Weldon Sch Biomed Engn W Lafayette IN 47907 USA Inha Univ Dept Polymer Sci & Engn 100 Inha roMichuhol gu Incheon 22212 South Korea Korea Res Inst Stand & Sci Adv Instrumentat Inst 267 Gajeong roYuseong gu Daejeon 34113 South Korea Univ Sci & Technol UST Precis Measurement 267 Gajeong roYuseong gu Daejeon 34113 South Korea Inha Univ Program Environm & Polymer Engn 100 Inha roMichuhol gu Incheon 22212 South Korea SUNY Coll Environm Sci & Forestry Dept Chem Engn Syracuse NY 13210 USA Purdue Univ Sch Mech Engn W Lafayette IN 47907 USA Purdue Univ Sch Mat Engn W Lafayette IN 47907 USA Purdue Univ Birck Nanotechnol Ctr W Lafayette IN 47907 USA Air Force Res Lab Wright Patterson AFB Mat & Mfg Directorate Dayton OH 45433 USA Hanyang Univ Human Tech Convergence Program 222 Wangsimmni roSeongdong gu Seoul 04763 South Korea Hanyang Univ Inst Nano Sci & Technol 222 Wangsimmni roSeongdong gu Seoul 04763 South Korea Hanyang Univ Dept Chem Engn 222 Wangsimmni roSeongdong gu Seoul 04763 South Korea SUNY Coll Environm Sci & Forestry Michael M Szwarc Polymer Res Inst Syracuse NY 13210 USA

Inverse-vulcanized polymeric sulfur has received considerable attention for application in waste-based infrared (IR) polarizers with high polarization sensitivities, owing to its high transmittance in the IR region and thermal processability. However, there have been few reports on highly sensitive polymeric sulfur-based polarizers by replication of pre-simulated dimensions to achieve a high transmission of the transverse magnetic field (T-TM) and extinction ratio (ER). Herein, a 400-nanometer-pitch mid-wavelength infrared bilayer linear polarizer with self-aligned metal gratings is introduced on polymeric sulfur gratings integrated with a spacer layer (SM-polarizer). The dimensions of the SM-polarizer can be closely replicated using pre-simulated dimensions via a systematic investigation of thermal nanoimprinting conditions. Spacer thickness is tailored from 40 to 5100 nm by adjusting the concentration of polymeric sulfur solution during spin-coating. A tailored spacer thickness can maximize T-TM in the broadband MWIR region by satisfying Fabry-Perot resonance. The SM-polarizer yields T-TM of 0.65, 0.59, and 0.43 and ER of 3.12 x 10(3), 5.19 x 10(3), and 5.81 x 10(3) at 4 mu m for spacer thicknesses of 90, 338, and 572 nm, respectively. This demonstration of a highly sensitive and cost-effective SM-polarizer opens up exciting avenues for infrared polarimetric imaging and for applications in polarization manipulation.

关键词： Fabry-Perot resonance inverse vulcanization linear polarizer mid-wavelength infrared polymeric sulfur

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Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish

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NATURE COMMUNICATIONS 2019年第1期10卷 1-15页

作者： Siekierska, Aleksandra Stamberger, Hannah Deconinck, Tine Oprescu, Stephanie N. Partoens, Michele Zhang, Yifan Sourbron, Jo Adriaenssens, Elias Mullen, Patrick Wiencek, Patrick Hardies, Katia Lee, Jeong-Soo Giong, Hoi-Khoanh Distelmaier, Felix Elpeleg, Orly Helbig, Katherine L. Hersh, Joseph Isikay, Sedat Jordan, Elizabeth Karaca, Ender Kecskes, Angela Lupski, James R. Kovacs-Nagy, Reka May, Patrick Narayanan, Vinodh Pendziwiat, Manuela Ramsey, Keri Rangasamy, Sampathkumar Shinde, Deepali N. Spiegel, Ronen Timmerman, Vincent von Spiczak, Sarah Helbig, Ingo Balak, Chris Belnap, Newell Claasen, Ana Courtright, Amanda de Both, Matt Huentelman, Matthew J. Naymik, Marcus Richholt, Ryan Siniard, Ashley L. Szelinger, Szabolcs Craig, David W. Schrauwen, Isabelle Afawi, Zaid Balling, Rudi Baulac, Stephanie Barisic, Nina Caglayan, Hande S. Craiu, Dana Guerrero-Lopez, Rosa Guerrini, Renzo Hjalgrim, Helle Jahn, Johanna Klein, Karl Martin Leguern, Eric Lemke, Johannes R. Lerche, Holger Marini, Carla Moller, Rikke S. Muhle, Hiltrud Rosenow, Felix Serratosa, Jose Suls, Arvid Stephani, Ulrich Sterbova, Katalin Striano, Pasquale Zara, Federico Weckhuysen, Sarah Francklyn, Christopher Antonellis, Anthony de Witte, Peter De Jonghe, Peter Katholieke Univ Leuven Dept Pharmaceut & Pharmacol Sci Lab Mol Biodiscovery B-3000 Louvain Belgium Univ Antwerp VIB Ctr Mol Neurol Neurogenet Grp B-2610 Antwerp Belgium Univ Antwerp Inst Born Bunge B-2610 Antwerp Belgium Antwerp Univ Hosp Dept Neurol B-2650 Antwerp Belgium Univ Michigan Dept Human Genet Ann Arbor MI 48109 USA Univ Antwerp Dept Biomed Sci Peripheral Neuropathy Res Grp B-2610 Antwerp Belgium Univ Vermont Dept Biochem Burlington VT 05405 USA Korea Res Inst Biosci & Biotechnol Dis Target Struct Res Ctr Daejeon 34141 South Korea Univ Sci & Technol KRIBB Sch Daejeon 34141 South Korea Korea Inst Sci & Technol Dementia DTC R&D Convergence Program Seoul 02792 South Korea Heinrich Heine Univ Dusseldorf Univ Childrens Hosp Dept Gen Pediat Neonatol & Pediat Cardiol D-40225 Dusseldorf Germany Hadassah Hebrew Univ Med Ctr Monique & Jacques Roboh Dept Genet Res IL-01120 Jerusalem Israel Childrens Hosp Philadelphia Div Neurol Philadelphia PA 19104 USA Univ Louisville Sch Med Dept Pediat 571S Floyd St Louisville KY 40202 USA Hasan Kalyoncu Univ Sch Hlth Sci Dept Physiotherapy & Rehabil TR-27410 Gaziantep Turkey Ohio State Univ Dept Internal Med Div Human Genet 460 W 12th Ave Columbus OH 43210 USA Baylor Coll Med Dept Mol & Human Genet Houston TX 77030 USA Baylor Coll Med Human Genome Sequencing Ctr Houston TX 77030 USA Baylor Coll Med Dept Pediat Houston TX 77030 USA Texas Childrens Hosp Houston TX 77030 USA Tech Univ Munich Inst Human Genet D-81675 Munich Germany Univ Luxembourg Luxembourg Ctr Syst Biomed Esch Alzette 4365 Luxembourg Luxembourg Translat Genom Res Inst Ctr Rare Childhood Disorders Phoenix AZ 85004 USA Christian Albrechts Univ Kiel Dept Neuropediat Campus Kiel D-24105 Kiel Germany Univ Hosp Schleswig Holstein Campus Kiel D-24105 Kiel Germany Ambry Genet Div Clin Genom Aliso Viejo CA 92656 USA Emek Med Ctr Pediat Dept B IL-1834111 Afula Israel Technion Rappaport Sch Med IL-3200003 Haifa Israel Northern G

Aminoacyl tRNA synthetases (ARSs) link specific amino acids with their cognate transfer RNAs in a critical early step of protein translation. Mutations in ARSs have emerged as a cause of recessive, often complex neurological disease traits. Here we report an allelic series consisting of seven novel and two previously reported biallelic variants in valyl-tRNA synthetase (VARS) in ten patients with a developmental encephalopathy with microcephaly, often associated with early-onset epilepsy. In silico, in vitro, and yeast complementation assays demonstrate that the underlying pathomechanism of these mutations is most likely a loss of protein function. Zebrafish modeling accurately recapitulated some of the key neurological disease traits. These results provide both genetic and biological insights into neurodevelopmental disease and pave the way for further in-depth research on ARS related recessive disorders and precision therapies.

关键词： Disease genetics Encephalopathy Epilepsy Neurodevelopmental disorders

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Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls

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NATURE 2019年第7759期570卷 71-+页

作者： Flannick, Jason Mercader, Josep M. Fuchsberger, Christian Udler, Miriam S. Mahajan, Anubha Wessel, Jennifer Teslovich, Tanya M. Caulkins, Lizz Koesterer, Ryan Barajas-Olmos, Francisco Blackwell, Thomas W. Boerwinkle, Eric Brody, Jennifer A. Centeno-Cruz, Federico Chen, Ling Chen, Siying Contreras-Cubas, Cecilia Cordova, Emilio Correa, Adolfo Cortes, Maria DeFronzo, Ralph A. Dolan, Lawrence Drews, Kimberly L. Elliott, Amanda Floyd, James S. Gabriel, Stacey Garay-Sevilla, Maria Eugenia Garcia-Ortiz, Humberto Gross, Myron Han, Sohee Heard-Costa, Nancy L. Jackson, Anne U. Jorgensen, Marit E. Kang, Hyun Min Kelsey, Megan Kim, Bong-Jo Koistinen, Heikki A. Kuusisto, Johanna Leader, Joseph B. Linneberg, Allan Liu, Ching-Ti Liu, Jianjun Lyssenko, Valeriya Manning, Alisa K. Marcketta, Anthony Malacara-Hernandez, Juan Manuel Martinez-Hernandez, Angelica Matsuo, Karen Mayer-Davis, Elizabeth Mendoza-Caamal, Elvia Mohlke, Karen L. Morrison, Alanna C. Ndungu, Anne Ng, Maggie C. Y. O'Dushlaine, Colm Payne, Anthony J. Pihoker, Catherine Post, Wendy S. Preuss, Michael Psaty, Bruce M. Vasan, Ramachandran S. Rayner, N. William Reiner, Alexander P. Revilla-Monsalve, Cristina Robertson, Neil R. Santoro, Nicola Schurmann, Claudia So, Wing Yee Soberon, Xavier Stringham, Heather M. Strom, Tim M. Tam, Claudia H. T. Thameem, Farook Tomlinson, Brian Torres, Jason M. Tracy, Russell P. van Dam, Rob M. Vujkovic, Marijana Wang, Shuai Welch, Ryan P. Witte, Daniel R. Wong, Tien-Yin Atzmon, Gil Barzilai, Nir Blangero, John Bonnycastle, Lori L. Bowden, Donald W. Chambers, John C. Chan, Edmund Cheng, Ching-Yu Cho, Yoon Shin Collins, Francis S. De Vries, Paul S. Duggirala, Ravindranath Glaser, Benjamin Gonzalez, Clicerio Elena Gonzalez, Ma Groop, Leif Kooner, Jaspal Singh Kwak, Soo Heon Laakso, Markku Lehman, Donna M. Nilsson, Peter Spector, Timothy D. Tai, E. Shyong Tuomi, Tiinamaija Tuomilehto, Jaakko Wilson, James G. Aguilar-Salinas, Carlos A. Bottinger, Erwin Burke, Brian Carey, David J. Chan, Juliana C. N. Dupuis, Josee Frossard, Philippe Heckbe Broad Inst Program Metab Cambridge MA 02142 USA Boston Childrens Hosp Div Genet & Genom Boston MA 02115 USA Harvard Med Sch Dept Pediat Boston MA 02115 USA Broad Inst Program Med & Populat Genet Cambridge MA 02142 USA Massachusetts Gen Hosp Ctr Genom Med Boston MA 02114 USA Massachusetts Gen Hosp Diabet Unit Diabet Res Ctr Boston MA 02114 USA Univ Michigan Dept Biostat Ann Arbor MI 48109 USA Eurac Res Inst Biomed Bolzano Italy Univ Michigan Ctr Stat Genet Ann Arbor MI 48109 USA Univ Oxford Nuffield Dept Med Wellcome Ctr Human Genet Oxford England Univ Oxford Radcliffe Dept Med Oxford Ctr Diabet Endocrinol & Metab Oxford England Indiana Univ Fairbanks Sch Publ Hlth Dept Epidemiol Indianapolis IN 46204 USA Indiana Univ Sch Med Dept Med Indianapolis IN USA Indiana Univ Diabet Translat Res Ctr Indianapolis IN 46204 USA Regeneron Pharmaceut Regeneron Genet Ctr Tarrytown NY USA Inst Nacl Med Genom Mexico City DF Mexico Univ Texas Hlth Sci Ctr Houston Sch Publ Hlth Dept Epidemiol Human Genet & Environm Sci Human Genet Ctr Houston TX 77030 USA Baylor Coll Med Human Genome Sequencing Ctr Houston TX 77030 USA Univ Washington Dept Med Cardiovasc Res Unit Seattle WA USA Univ Mississippi Med Ctr Dept Med Jackson MS 39216 USA Broad Inst MIT & Harvard Cambridge MA USA Univ Texas Hlth Sci Ctr San Antonio Dept Med San Antonio TX 78229 USA Cincinnati Childrens Hosp Med Ctr Cincinnati OH 45229 USA George Washington Univ Ctr Biostat Rockville MD USA Univ Washington Dept Med & Epidemiol Seattle WA 98195 USA Univ Chicago Dept Med 5841 S Maryland Ave Chicago IL 60637 USA Univ Chicago Dept Human Genet Chicago IL 60637 USA Univ Minnesota Dept Lab Med & Pathol Minneapolis MN 55455 USA Natl Inst Hlth Ctr Genome Sci Div Genome Res Cheongju Chungcheongbuk South Korea Boston Univ Sch Med Dept Neurol Boston MA 02118 USA NHLBI Framingham Heart Study Framingham MA USA Steno Diabet Ctr Copenhagen Gentofte Denmark Univ Southern Denmark Natl I

Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 x 10(-3)) and candidate genes from knockout mice (P = 5.2 x 10(-3)). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.

关键词： Genome-wide association studies Genomics Next-generation sequencing Protein sequencing

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Aqueous Zinc Ion Batteries: Controlling Vanadate Nanofiber Interlayer via Intercalation with Conducting Polymers: Cathode Material Design for Rechargeable Aqueous Zinc Ion Batteries (Adv. Funct. Mater. 26/2021)

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Advanced Functional Materials 2021年第26期31卷

作者： Jichang Kim Se Hun Lee Changyong Park Hyung-Seok Kim Jae-Ho Park Kyung Yoon Chung Heejoon Ahn Human-Tech Convergence Program Department of Organic and Nano Engineering Hanyang University 222 Wangsimni-ro Seongdong-gu Seoul 04763 Republic of Korea Institute of Nano Science and Technology Hanyang University 222 Wangsimni-ro Seongdong-gu Seoul 04763 Republic of Korea Center for Energy Storage Research Korea Institute of Science and Technology 5 Hwarang-ro 14-gil Seongbuk-gu Seoul 02792 Republic of Korea KHU-KIST Department of Converging Science and Technology Kyung Hee University Seoul 02447 Republic of Korea Department of Materials Science and Engineering Korea University 145 Anam-ro Seongbuk-gu Seoul 02841 Republic of Korea Division of Energy & Environment Technology KIST School Korea University of Science and Technology 5 Hwarang-ro 14-gil Seongbuk-gu Seoul 02792 Republic of Korea

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The genetic architecture of type 2 diabetes

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NATURE 2016年第7614期536卷 41-+页

作者： Fuchsberger, Christian Flannick, Jason Teslovich, Tanya M. Mahajan, Anubha Agarwala, Vineeta Gaulton, Kyle J. Ma, Clement Fontanillas, Pierre Moutsianas, Loukas McCarthy, Davis J. Rivas, Manuel A. Perry, John R. B. Sim, Xueling Blackwell, Thomas W. Robertson, Neil R. Rayner, N. William Cingolani, Pablo Locke, Adam E. Tajes, Juan Fernandez Highland, Heather M. Dupuis, Josee Chines, Peter S. Lindgren, Cecilia M. Hartl, Christopher Jackson, Anne U. Chen, Han Huyghe, Jeroen R. van de Bunt, Martijn Pearson, Richard D. Kumar, Ashish Mueller-Nurasyid, Martina Grarup, Niels Stringham, Heather M. Gamazon, Eric R. Lee, Jaehoon Chen, Yuhui Scott, Robert A. Below, Jennifer E. Chen, Peng Huang, Jinyan Go, Min Jin Stitzel, Michael L. Pasko, Dorota Parker, Stephen C. J. Varga, Tibor V. Green, Todd Beer, Nicola L. Day-Williams, Aaron G. Ferreira, Teresa Fingerlin, Tasha Horikoshi, Momoko Hu, Cheng Huh, Iksoo Ikram, Mohammad Kamran Kim, Bong-Jo Kim, Yongkang Kim, Young Jin Kwon, Min-Seok Lee, Juyoung Lee, Selyeong Lin, Keng-Han Maxwell, Taylor J. Nagai, Yoshihiko Wang, Xu Welch, Ryan P. Yoon, Joon Zhang, Weihua Barzilai, Nir Voight, Benjamin F. Han, Bok-Ghee Jenkinson, Christopher P. Kuulasmaa, Teemu Kuusisto, Johanna Manning, Alisa Ng, Maggie C. Y. Palmer, Nicholette D. Balkau, Beverley Stancakova, Alena Abboud, Hanna E. Boeing, Heiner Giedraitis, Vilmantas Prabhakaran, Dorairaj Gottesman, Omri Scott, James Carey, Jason Kwan, Phoenix Grant, George Smith, Joshua D. Neale, Benjamin M. Purcell, Shaun Butterworth, Adam S. Howson, Joanna M. M. Lee, Heung Man Lu, Yingchang Kwak, Soo-Heon Zhao, Wei Danesh, John Lam, Vincent K. L. Park, Kyong Soo Saleheen, Danish So, Wing Yee Tam, Claudia H. T. Afzal, Uzma Aguilar, David Arya, Rector Aung, Tin Chan, Edmund Navarro, Carmen Cheng, Ching-Yu Palli, Domenico Correa, Adolfo Curran, Joanne E. Rybin, Denis Farook, Vidya S. Fowler, Sharon P. Freedman, Barry I. Griswold, Michael Hale, Daniel Esten Hicks, Pamela J. Khor, Chiea-Chuen Kumar, Satish Lehne, Benjamin Thuillier, Dorothee Lim, Wei Yen Li Univ Michigan Dept Biostat Ann Arbor MI 48109 USA Med Univ Innsbruck Dept Med Genet Mol & Clin Pharmacol Div Genet Epidemiol Innsbruck Austria Univ Lubeck European Acad Bolzano Bozen EURAC Ctr Biomed Bolzano Italy Broad Inst Program Med & Populat Genet Cambridge MA USA Massachusetts Gen Hosp Dept Mol Biol Boston MA 02114 USA Univ Oxford Wellcome Trust Ctr Human Genet Nuffield Dept Med Oxford England MIT Harvard Mit Div Hlth Sci & Technol Cambridge MA 02139 USA Univ Oxford Dept Stat Oxford England Univ Exeter Sch Med Genet Complex Traits Exeter Devon England Univ Cambridge Inst Metab Sci MRC Epidemiol Unit Cambridge England Kings Coll London Dept Twin Res & Genet Epidemiol London England Univ Oxford Radcliffe Dept Med Oxford Ctr Diabet Endocrinol & Metab Oxford England Wellcome Trust Sanger Inst Dept Human Genet Hinxton Cambs England McGill Univ Sch Comp Sci Montreal PQ Canada McGill Univ Montreal PQ Canada Genome Quebec Innovat Ctr Montreal PQ Canada Univ Texas Hlth Sci Ctr Houston Univ Texas Grad Sch Biomed Sci Houston Human Genet Ctr Houston TX 77030 USA Boston Univ Sch Publ Hlth Dept Biostat Boston MA USA NHLBI Framingham Heart Study Framingham MA USA NHGRI Med Genom & Metab Genet Branch NIH Bethesda MD 20892 USA Harvard Sch Publ Hlth Dept Biostat Boston MA USA Univ Basel Swiss Trop & Publ Hlth Inst Chron Dis Epidemiol Basel Switzerland German Res Ctr Environm Hlth Helmholtz Zentrum Munchen Inst Genet Epidemiol Neuherberg Germany Univ Munich Univ Hosp Grosshadern Dept Med 1 Munich Germany Univ Munich Chair Genet Epidemiol Inst Med Informat Biometry & Epidemiol Munich Germany Munich Heart Alliance DZHK German Ctr Cardiovasc Res Munich Germany Univ Copenhagen Fac Hlth & Med Sci Novo Nordisk Fdn Ctr Basic Metab Res Copenhagen Denmark Univ Chicago Dept Med Med Genet Sect 5841 S Maryland Ave Chicago IL 60637 USA Seoul Natl Univ Dept Stat Seoul South Korea Univ Texas Hlth Sci Ctr Houston Sch Publ Hlth Human Ge

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.

关键词： Next-generation sequencing Rare variants Diabetes Genome-wide association studies

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Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes

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AMERICAN JOURNAL OF human GENETICS 2022年第1期109卷 81-96页

作者： Hindy, George Dornbos, Peter Chaffin, Mark D. Liu, Dajiang J. Wang, Minxian Selvaraj, Margaret Sunitha Zhang, David Park, Joseph Aguilar-Salinas, Carlos A. Antonacci-Fulton, Lucinda Ardissino, Diego Arnett, Donna K. Aslibekyan, Stella Atzmon, Gil Ballantyne, Christie M. Barajas-Olmos, Francisco Barzilai, Nir Becker, Lewis C. Bielak, Lawrence F. Bis, Joshua C. Blangero, John Boerwinkle, Eric Bonnycastle, Lori L. Bottinger, Erwin Bowden, Donald W. Bown, Matthew J. Brody, Jennifer A. Broome, Jai G. Burtt, Noel P. Cade, Brian E. Centeno-Cruz, Federico Chan, Edmund Chang, Yi-Cheng Chen, Yii-Der I. Cheng, Ching-Yu Choi, Won Jung Chowdhury, Rajiv Contreras-Cubas, Cecilia Cordova, Emilio J. Correa, Adolfo Cupples, L. Adrienne Curran, Joanne E. Danesh, John de Vries, Paul S. DeFronzo, Ralph A. Doddapaneni, Harsha Duggirala, Ravindranath Dutcher, Susan K. Ellinor, Patrick T. Emery, Leslie S. Florez, Jose C. Fornage, Myriam Freedman, Barry I. Fuster, Valentin Garay-Sevilla, Ma. Eugenia Garcia-Ortiz, Humberto Germer, Soren Gibbs, Richard A. Gieger, Christian Glaser, Benjamin Gonzalez, Clicerio Gonzalez-Villalpando, Maria Elena Graff, Mariaelisa Graham, Sarah E. Grarup, Niels Groop, Leif C. Guo, Xiuqing Gupta, Namrata Han, Sohee Hanis, Craig L. Hansen, Torben He, Jiang Heard-Costa, Nancy L. Hung, Yi-Jen Hwang, Mi Yeong Irvin, Marguerite R. Islas-Andrade, Sergio Jarvik, Gail P. Kang, Hyun Min Kardia, Sharon L. R. Kelly, Tanika Kenny, Eimear E. Khan, Alyna T. Kim, Bong-Jo Kim, Ryan W. Kim, Young Jin Koistinen, Heikki A. Kooperberg, Charles Kuusisto, Johanna Kwak, Soo Heon Laakso, Markku Lange, Leslie A. Lee, Jiwon Lee, Juyoung Lee, Seonwook Lehman, Donna M. Lemaitre, Rozenn N. Linneberg, Allan Liu, Jianjun Loos, Ruth J. F. Lubitz, Steven A. Lyssenko, Valeriya Ma, Ronald C. W. Martin, Lisa Warsinger Martinez-Hernandez, Angelica Mathias, Rasika A. McGarvey, Stephen T. McPherson, Ruth Meigs, James B. Meitinger, Thomas Melander, Olle Mendoza-Caamal, Elvia Metcalf, Ginger A. Mi, Xuenan Mohlke, Karen L. Montasser, May E. Moon, Jee-Yo Broad Inst Harvard & MIT Program Med & Populat Genet Cambridge MA 02142 USA Lund Univ Dept Clin Sci Malmo Sweden Qatar Univ Dept Populat Med QU Hlth Coll Med Doha Qatar Broad Inst Programs Metab & Med & Populat Genet Cambridge MA 02142 USA Harvard Med Sch Dept Pediat Boston MA 02115 USA Boston Childrens Hosp Div Genet & Genom Boston MA 02115 USA Massachusetts Gen Hosp Dept Med Ctr Genom Med Boston MA 02114 USA Massachusetts Gen Hosp Cardiovasc Res Ctr Boston MA 02114 USA Penn State Coll Med Dept Publ Hlth Sci Hershey PA 17033 USA Broad Inst Harvard & MIT Cardiovasc Dis Initiat Cambridge MA 02142 USA Univ Penn Dept Genet Perelman Sch Med Philadelphia PA 19104 USA Univ Penn Dept Med Perelman Sch Med Philadelphia PA 19104 USA Inst Nacl Ciencias Med & Nutr Salvador Zubiran Mexico City DF Mexico Washington Univ Dept Genet St Louis MO 63110 USA Washington Univ Sch Med McDonnell Genome Inst St Louis MO 63108 USA ASTC Assoc Studio Trombosi Cardiol Pavia Italy Azienda Osped Univ Parma Parma Italy Univ Parma Parma Italy Univ Kentucky Coll Publ Hlth Deans Off Lexington KY 40536 USA Univ Alabama Birmingham Dept Epidemiol Birmingham AL 35233 USA Albert Einstein Coll Med Dept Med Bronx NY 10461 USA Albert Einstein Coll Med Dept Genet Bronx NY 10461 USA Univ Haifa Fac Nat Sci Haifa Israel Houston Methodist Debakey Heart & Vasc Ctr Houston TX 77030 USA Baylor Coll Med Sect Cardiovasc Res Houston TX 77030 USA Inst Nacl Med Genom Mexico City DF Mexico Johns Hopkins Univ Sch Med Dept Med Baltimore MD 21287 USA Univ Michigan Sch Publ Hlth Dept Epidemiol Ann Arbor MI 49109 USA Univ Washington Dept Med Cardiovasc Hlth Res Unit Seattle WA 98101 USA Univ Texas Rio Grande Valley Sch Med Dept Human Genet Brownsville TX 78520 USA Univ Texas Rio Grande Valley Sch Med South Texas Diabet & Obes Inst Brownsville TX 78520 USA Univ Texas Hlth Sci Ctr Houston Sch Publ Hlth Ctr Human Genet Dept Epidemiol Human Genet & Environm Sci Houston TX 7

Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency 1%) predicted damaging coding variation by using sequence data from 170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels;some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants;three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.

关键词： exome sequencing association lipid cholesterol gene-based association

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Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes

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NATURE COMMUNICATIONS 2021年第1期12卷 1-15页

作者： Goodrich, Julia K. Singer-Berk, Moriel Son, Rachel Sveden, Abigail Wood, Jordan England, Eleina Cole, Joanne B. Weisburd, Ben Watts, Nick Caulkins, Lizz Dornbos, Peter Koesterer, Ryan Zappala, Zachary Zhang, Haichen Maloney, Kristin A. Dahl, Andy Aguilar-Salinas, Carlos A. Atzmon, Gil Barajas-Olmos, Francisco Barzilai, Nir Blangero, John Boerwinkle, Eric Bonnycastle, Lori L. Bottinger, Erwin Bowden, Donald W. Centeno-Cruz, Federico Chambers, John C. Chami, Nathalie Chan, Edmund Chan, Juliana Cheng, Ching-Yu Cho, Yoon Shin Contreras-Cubas, Cecilia Cordova, Emilio Correa, Adolfo DeFronzo, Ralph A. Duggirala, Ravindranath Dupuis, Josee Eugenia Garay-Sevilla, Ma Garcia-Ortiz, Humberto Gieger, Christian Glaser, Benjamin Gonzalez-Villalpando, Clicerio Elena Gonzalez, Ma Grarup, Niels Groop, Leif Gross, Myron Haiman, Christopher Han, Sohee Hanis, Craig L. Hansen, Torben Heard-Costa, Nancy L. Henderson, Brian E. Hernandez, Juan Manuel Malacara Hwang, Mi Yeong Islas-Andrade, Sergio Jorgensen, Marit E. Kang, Hyun Min Kim, Bong-Jo Kim, Young Jin Koistinen, Heikki A. Kooner, Jaspal Singh Kuusisto, Johanna Kwak, Soo-Heon Laakso, Markku Lange, Leslie Lee, Jong-Young Lee, Juyoung Lehman, Donna M. Linneberg, Allan Liu, Jianjun Loos, Ruth J. F. Lyssenko, Valeriya Ma, Ronald C. W. Martinez-Hernandez, Angelica Meigs, James B. Meitinger, Thomas Mendoza-Caamal, Elvia Mohlke, Karen L. Morris, Andrew D. Morrison, Alanna C. Ng, Maggie C. Y. Nilsson, Peter M. O'Donnell, Christopher J. Orozco, Lorena Palmer, Colin N. A. Park, Kyong Soo Post, Wendy S. Pedersen, Oluf Preuss, Michael Psaty, Bruce M. Reiner, Alexander P. Revilla-Monsalve, Cristina Rich, Stephen S. Rotter, Jerome I. Saleheen, Danish Schurmann, Claudia Sim, Xueling Sladek, Rob Small, Kerrin S. So, Wing Yee Spector, Timothy D. Strauch, Konstantin Strom, Tim M. Tai, E. Shyong Tam, Claudia H. T. Teo, Yik Ying Thameem, Farook Tomlinson, Brian Tracy, Russell P. Tuomi, Tiinamaija Tuomilehto, Jaakko Tusie-Luna, Teresa van Dam, Rob M. Vasan, Ramachandran S. Wilson, James G. Witte, Dani Broad Inst MIT & Harvard Program Med & Populat Genet Cambridge MA 02142 USA Univ Maryland Sch Med Baltimore MD 21201 USA Univ Calif Los Angeles Dept Neurol Los Angeles CA 90024 USA Inst Nacl Ciencias Med & Nutr Salvador Zubiran Mexico City DF Mexico Albert Einstein Coll Med Dept Med New York NY USA Univ Haifa Fac Nat Sci Haifa Israel Albert Einstein Coll Med Dept Genet New York NY USA Inst Nacl Med Genom Mexico City DF Mexico Univ Texas Rio Grande Valley Dept Human Genet Brownsville TX USA Univ Texas Rio Grande Valley South Texas Diabet & Obes Inst Brownsville TX USA Univ Texas Rio Grande Valley Dept Human Genet Edinburg TX USA Univ Texas Rio Grande Valley South Texas Diabet & Obes Inst Edinburg TX USA Univ Texas Hlth Sci Ctr Houston Sch Publ Hlth Human Genet Ctr Houston TX 77030 USA Baylor Coll Med Human Genome Sequencing Ctr Houston TX 77030 USA NHGRI Med Genom & Metab Genet Branch NIH Bethesda MD 20892 USA Icahn Sch Med Mt Sinai Charles Bronfman Inst Personalized Med New York NY 10029 USA Wake Forest Sch Med Ctr Diabet Res Winston Salem NC 27101 USA Wake Forest Sch Med Ctr Genom & Personalized Med Res Winston Salem NC 27101 USA Wake Forest Sch Med Dept Biochem Winston Salem NC 27101 USA Imperial Coll London Dept Epidemiol & Biostat London England Nanyang Technol Univ Lee Kong Chian Sch Med Singapore Singapore Ichan Sch Med Mt Sinai Mindich Child Hlth & Dev Inst New York NY USA Natl Univ Singapore Yong Loo Lin Sch Med Dept Med Singapore Singapore Natl Univ Hlth Syst Singapore Singapore Chinese Univ Hong Kong Dept Med & Therapeut Hong Kong Peoples R China Chinese Univ Hong Kong Chinese Univ Hong Kong Shanghai Jiao Tong Univ Jo Hong Kong Peoples R China Chinese Univ Hong Kong Hong Kong Inst Diabet & Obes Hong Kong Peoples R China Chinese Univ Hong Kong Li Ka Shing Inst Hlth Sci Hong Kong Peoples R China Singapore Natl Eye Ctr Singapore Eye Res Inst Singapore Singapore Natl Univ Singapore Yong Loo Lin Sch Med Dept Ophthalmol

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias. Penetrance of variants in monogenic disease and clinical utility of common polygenic variation has not been well explored on a large-scale. Here, the authors use exome sequencing data from 77,184 individuals to generate penetrance estimates and assess the utility of polygenic variation in risk prediction of monogenic variants.

关键词： Endocrine system and metabolic diseases Medical genomics Molecular medicine

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Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes

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human MOLECULAR GENETICS 2022年第19期31卷 3377-3391页

作者： Pervjakova, Natalia Moen, Gunn-Helen Borges, Maria-Carolina Ferreira, Teresa Cook, James P. Allard, Catherine Beaumont, Robin N. Canouil, Mickael Hatem, Gad Heiskala, Anni Joensuu, Anni Karhunen, Ville Kwak, Soo Heon Lin, Frederick T. J. Liu, Jun Rifas-Shiman, Sheryl Tam, Claudia H. Tam, Wing Hung Thorleifsson, Gudmar Andrew, Toby Auvinen, Juha Bhowmik, Bishwajit Bonnefond, Amelie Delahaye, Fabien Demirkan, Ayse Froguel, Philippe Haller-Kikkatalo, Kadri Hardardottir, Hildur Hummel, Sandra Hussain, Akhtar Kajantie, Eero Keikkala, Elina Khamis, Amna Lahti, Jari Lekva, Tove Mustaniemi, Sanna Sommer, Christine Tagoma, Aili Tzala, Evangelia Uibo, Raivo Vaarasmaki, Marja Villa, Pia M. Birkeland, Kare, I Bouchard, Luigi Duijn, Cornelia M. Finer, Sarah Groop, Leif Hamalainen, Esa Hayes, Geoffrey M. Hitman, Graham A. Jang, Hak C. Jarvelin, Marjo-Riitta Jenum, Anne Karen Laivuori, Hannele Ma, Ronald C. Melander, Olle Oken, Emily Park, Kyong Soo Perron, Patrice Prasad, Rashmi B. Qvigstad, Elisabeth Sebert, Sylvain Stefansson, Kari Steinthorsdottir, Valgerdur Tuomi, Tiinamaija Hivert, Marie-France Franks, Paul W. McCarthy, Mark, I Lindgren, Cecilia M. Freathy, Rachel M. Lawlor, Deborah A. Morris, Andrew P. Magi, Reedik Univ Tartu Estonian Genome Ctr Inst Genom EE-51010 Tartu Estonia Univ Oslo Fac Med Inst Clin Med Oslo Norway Univ Queensland Diamantina Inst Woolloongabba Qld 4102 Australia Norwegian Univ Sci & Technol KG Jebsen Ctr Genet Epidemiol Dept Publ Hlth & Nursing NTNU Trondheim Norway Univ Bristol Bristol Med Sch Populat Hlth Sci Bristol Avon England Univ Bristol MRC Integrat Epidemiol Unit Bristol Avon England Univ Oxford Li Ka Shing Ctr Hlth Hlth Informat & Discovery Big Data Inst Oxford England Univ Liverpool Dept Hlth Data Sci Liverpool Merseyside England Univ Sherbrooke Ctr Rech Ctr Hosp Univ Sherbrooke CRCHUS Sherbrooke PQ Canada Univ Exeter Coll Med & Hlth Inst Biomed & Clin Sci Exeter Devon England Inst Pasteur European Genom Inst Diabet Inserm U1283 CNRS UMR 8199 F-59000 Lille France Univ Lille Lille Univ Hosp F-59000 Lille France Lund Univ Skane Univ Hosp Lund Univ Diabet Ctr Dept Clin Sci SE-20502 Malmo Sweden Univ Oulu Fac Med Ctr Life Course Hlth Res Oulu Finland Finnish Inst Hlth & Welf Dept Publ Hlth Solut Helsinki Finland Univ Helsinki Fac Med Res Program Clin & Mol Metab Helsinki Finland Imperial Coll London Sch Publ Hlth Dept Epidemiol & Biostat St Marys Hosp London England Seoul Natl Univ Hosp Dept Internal Med Seoul South Korea Northwestern Univ Dept Med Div Endocrinol Metab & Mol Med Feinberg Sch Med Chicago IL 60611 USA Erasmus MC Dept Epidemiol Rotterdam Netherlands Univ Oxford Nuffield Dept Populat Hlth Oxford England Harvard Med Sch Dept Populat Med Boston MA 02115 USA Harvard Pilgrim Hlth Care Inst Boston MA USA Chinese Univ Hong Kong Dept Med & Therapeut Hong Kong Peoples R China Chinese Univ Hong Kong Dept Obstet & Gynaecol Hong Kong Peoples R China Amgen Inc DeCODE Genet Reykjavik Iceland Imperial Coll London Dept Metab Digest & Reprod London England Diabet Assoc Bangladesh Ctr Global Hlth Res Dhaka Bangladesh Univ Surrey Dept Clin & Expt Res Sect Stat Multiomics Guildford Surrey E

Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy Consortium assembled genome-wide association studies of diverse ancestry in a total of 5485 women with GDM and 347 856 without GDM. Through multi-ancestry meta-analysis, we identified five loci with genome-wide significant association (P < 5 x 10(-8)) with GDM, mapping to/near MTNR1B (P = 4.3 x 10(-54)), TCF7L2 (P = 4.0 x 10(-16)), CDKAL1 (P = 1.6 x 10(-4)), CDKN2A-CDKN2B (P = 4.1 x 10(-9)) and HKDC1 (P = 2.9 x 10(-8)). Multiple lines of evidence pointed to the shared pathophysiology of GDM and T2D: (i) four of the five GDM loci (not HKDC1) have been previously reported at genome-wide significance for T2D;(ii) significant enrichment for associations with GDM at previously reported T2D loci;(iii) strong genetic correlation between GDM and T2D and (iv) enrichment of GDM associations mapping to genomic annotations in diabetes-relevant tissues and transcription factor binding sites. Mendelian randomization analyses demonstrated significant causal association (5% false discovery rate) of higher body mass index on increased GDM risk. Our results provide support for the hypothesis that GDM and T2D are part of the same underlying pathology but that, as exemplified by the HKDC1 locus, there are genetic determinants of GDM that are specific to glucose regulation in pregnancy.

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Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility

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NATURE GENETICS 2014年第3期46卷 234-+页

作者： Mahajan, Anubha Go, Min Jin Zhang, Weihua Below, Jennifer E. Gaulton, Kyle J. Ferreira, Teresa Horikoshi, Momoko Johnson, Andrew D. Ng, Maggie C. Y. Prokopenko, Inga Saleheen, Danish Wang, Xu Zeggini, Eleftheria Abecasis, Goncalo R. Adair, Linda S. Almgren, Peter Atalay, Mustafa Aung, Tin Baldassarre, Damiano Balkau, Beverley Bao, Yuqian Barnett, Anthony H. Barroso, Ines Basit, Abdul Been, Latonya F. Beilby, John Bell, Graeme I. Benediktsson, Rafn Bergman, Richard N. Boehm, Bernhard O. Boerwinkle, Eric Bonnycastle, Lori L. Burtt, Noel Cai, Qiuyin Campbell, Harry Carey, Jason Cauchi, Stephane Caulfield, Mark Chan, Juliana C. N. Chang, Li-Ching Chang, Tien-Jyun Chang, Yi-Cheng Charpentier, Guillaume Chen, Chien-Hsiun Chen, Han Chen, Yuan-Tsong Chia, Kee-Seng Chidambaram, Manickam Chines, Peter S. Cho, Nam H. Cho, Young Min Chuang, Lee-Ming Collins, Francis S. Cornelis, Marilyn C. Couper, David J. Crenshaw, Andrew T. van Dam, Rob M. Danesh, John Das, Debashish de Faire, Ulf Dedoussis, George Deloukas, Panos Dimas, Antigone S. Dina, Christian Doney, Alex S. F. Donnelly, Peter J. Dorkhan, Mozhgan van Duijn, Cornelia Dupuis, Josee Edkins, Sarah Elliott, Paul Emilsson, Valur Erbel, Raimund Eriksson, Johan G. Escobedo, Jorge Esko, Tonu Eury, Elodie Florez, Jose C. Fontanillas, Pierre Forouhi, Nita G. Forsen, Tom Fox, Caroline Fraser, Ross M. Frayling, Timothy M. Froguel, Philippe Frossard, Philippe Gao, Yutang Gertow, Karl Gieger, Christian Gigante, Bruna Grallert, Harald Grant, George B. Groop, Leif C. Groves, Christopher J. Grundberg, Elin Guiducci, Candace Hamsten, Anders Han, Bok-Ghee Hara, Kazuo Hassanali, Neelam Hattersley, Andrew T. Hayward, Caroline Hedman, Asa K. Herder, Christian Hofman, Albert Holmen, Oddgeir L. Hovingh, Kees Hreidarsson, Astradur B. Hu, Cheng Hu, Frank B. Hui, Jennie Humphries, Steve E. Hunt, Sarah E. Hunter, David J. Hveem, Kristian Hydrie, Zafar I. Ikegami, Hiroshi Illig, Thomas Ingelsson, Erik Islam, Muhammed Isomaa, Bo Jackson, Anne U. Jafar, Tazeen James, Alan Jia, Weiping Joeckel, Karl- Univ Oxford Wellcome Trust Ctr Human Genet Oxford England Natl Inst Hlth Ctr Genome Sci Gangoe Myeon Yeonje Ri South Korea Univ London Imperial Coll Sci Technol & Med London England Univ Washington Dept Genome Sci Seattle WA 98195 USA Univ Oxford Oxford Ctr Diabet Endocrinol & Metab Oxford OX1 2JD England NHLBI Framingham Heart Study Framingham MA USA Wake Forest Sch Med Ctr Genom & Personalized Med Res Winston Salem NC USA Wake Forest Sch Med Ctr Diabet Res Winston Salem NC USA Univ London Imperial Coll Sci Technol & Med Hammersmith Hosp London England Univ Cambridge Dept Publ Hlth & Primary Care Cambridge England Ctr Noncommunicable Dis Pakistan Karachi Pakistan Natl Univ Singapore Dept Epidemiol & Publ Hlth Singapore 117548 Singapore Wellcome Trust Sanger Inst Cambridge England Univ Michigan Dept Biostat Ann Arbor MI 48109 USA Univ N Carolina Dept Nutr Chapel Hill NC USA Lund Univ Scania Univ Hosp Dept Clin Sci Malmo Ctr Diabet Malmo Sweden Univ Eastern Finland Inst Biomed Kuopio Finland Singapore Natl Eye Ctr Singapore Eye Res Inst Singapore Singapore Natl Univ Singapore Dept Ophthalmol Singapore 117548 Singapore IRCCS Ctr Cardiol Monzino Milan Italy Univ Milan Dept Pharmacol Sci Milan Italy INSERM Ctr Rech Epidemiol & Sante Populat CESP U1018 Villejuif France Univ Paris 11 UMRS 1018 Villejuif France Shanghai Jiao Tong Univ Affiliated Peoples Hosp 6 Dept Endocrinol & Metab Shanghai Key Lab Diabet MellitusShanghai Diabet Shanghai 200030 Peoples R China Univ Birmingham Coll Med & Dent Sci Birmingham W Midlands England Heart England Natl Hlth Serv NHS Fdn Trust Ctr Biomed Res Birmingham W Midlands England Univ Cambridge Addenbrookes Hosp Metab Res Labs Inst Metab Sci Cambridge CB2 2QQ England Addenbrookes Hosp Inst Metab Sci Cambridge Biomed Res Ctr Natl Inst Hlth Res Cambridge England Baqai Inst Diabetol & Endocrinol Karachi Pakistan Univ Oklahoma Hlth Sci Ctr Coll Med Dept PediatSect Genet Oklahoma City OK 731

To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.

关键词： GENETICS of disease susceptibility NON-insulin-dependent diabetes GENEALOGY GENOMES META-analysis CARBOHYDRATE intolerance

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A genomic mutational constraint map using variation in 76,156 human genomes

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NATURE 2024年第7993期625卷 92-100页

作者： Chen, Siwei Francioli, Laurent C. Goodrich, Julia K. Collins, Ryan L. Kanai, Masahiro Wang, Qingbo Alfoldi, Jessica Watts, Nicholas A. Vittal, Christopher Gauthier, Laura D. Poterba, Timothy Wilson, Michael W. Tarasova, Yekaterina Phu, William Grant, Riley Yohannes, Mary T. Koenig, Zan Farjoun, Yossi Banks, Eric Donnelly, Stacey Gabriel, Stacey Gupta, Namrata Ferriera, Steven Tolonen, Charlotte Novod, Sam Bergelson, Louis Roazen, David Ruano-Rubio, Valentin Covarrubias, Miguel Llanwarne, Christopher Petrillo, Nikelle Wade, Gordon Jeandet, Thibault Munshi, Ruchi Tibbetts, Kathleen O'Donnell-Luria, Anne Solomonson, Matthew Seed, Cotton Martin, Alicia R. Talkowski, Michael E. Rehm, Heidi L. Daly, Mark J. Tiao, Grace Neale, Benjamin M. MacArthur, Daniel G. Karczewski, Konrad J. Abreu, Maria Aguilar Salinas, Carlos A. Ahmad, Tariq Albert, Christine M. Alfoldi, Jessica Ardissino, Diego Armean, Irina M. Atkinson, Elizabeth G. Atzmon, Gil Banks, Eric Barnard, John Baxter, Samantha M. Beaugerie, Laurent Benjamin, Emelia J. Benjamin, David Bergelson, Louis Boehnke, Michael Bonnycastle, Lori L. Bottinger, Erwin P. Bowden, Donald W. Bown, Matthew J. Brand, Harrison Brant, Steven Brookings, Ted Bryant, Sam Calvo, Sarah E. Campos, Hannia Chambers, John C. Chan, Juliana C. Chao, Katherine R. Chapman, Sinead Chasman, Daniel I. Chen, Siwei Chisholm, Rex Cho, Judy Chowdhury, Rajiv Chung, Mina K. Chung, Wendy K. Cibulskis, Kristian Cohen, Bruce Collins, Ryan L. Connolly, Kristen M. Correa, Adolfo Covarrubias, Miguel Cummings, Beryl B. Dabelea, Dana Danesh, John Darbar, Dawood Darnowsky, Phil Denny, Joshua Donnelly, Stacey Duggirala, Ravindranath Dupuis, Josee Ellinor, Patrick T. Elosua, Roberto Emery, James England, Eleina Erdmann, Jeanette Esko, Tonu Evangelista, Emily Farjoun, Yossi Fatkin, Diane Ferriera, Steven Florez, Jose Francioli, Laurent C. Franke, Andre Fu, Jack Farkkila, Martti Gabriel, Stacey Garimella, Kiran Gauthier, Laura D. Gentry, Jeff Getz, Gad Glahn, David C. Glaser, Benjamin Glatt, Stephen J. Goldstein, David Go Broad Inst MIT & Harvard Program Med & Populat Genet Cambridge MA 02142 USA Massachusetts Gen Hosp Analyt & Translat Genet Unit Boston MA 02114 USA Massachusetts Gen Hosp Ctr Genom Med Boston MA 02114 USA Harvard Med Sch Div Med Sci Boston MA 02115 USA Osaka Univ Grad Sch Med Dept Stat Genet Suita Osaka Japan Broad Inst MIT & Harvard Data Sci Platform Cambridge MA 02142 USA Broad Inst MIT & Harvard Stanley Ctr Psychiat Res Cambridge MA 02142 USA Boston Childrens Hosp Div Genet & Genom Boston MA USA Lady Davis Inst Richards Lab Montreal PQ Canada Broad Inst MIT & Harvard Cambridge MA 02142 USA Broad Inst MIT & Harvard Broad Genom Cambridge MA 02142 USA Inst Mol Med Finland FIMM Helsinki Finland Garvan Inst Med Res Ctr Populat Genom Sydney NSW Australia UNSW Sydney Sydney NSW Australia Murdoch Childrens Res Inst Ctr Populat Genom Melbourne Vic Australia Univ Miami Miller Sch Med Gastroenterol Miami FL 33136 USA Inst Nacl Ciencias Med & Nutr Salvador Zubiran Unidad Invest Enfermedades Metabol Mexico City DF Mexico Peninsula Coll Med & Dent Exeter Devon England Brigham & Womens Hosp Div Prevent Med 75 Francis St Boston MA 02115 USA Brigham & Womens Hosp Div Cardiovasc Med 75 Francis St Boston MA 02115 USA Harvard Med Sch Boston MA 02115 USA Univ Hosp Dept Cardiol Parma Italy Baylor Coll Med Dept Mol & Human Genet Houston TX 77030 USA Univ Haifa Dept Biol Fac Nat Sci Haifa Israel Albert Einstein Coll Med Dept Med Bronx NY 10467 USA Albert Einstein Coll Med Dept Genet Bronx NY 10467 USA Cleveland Clin Dept Quantitat Hlth Sci Lerner Res Inst Cleveland OH 44106 USA Sorbonne Univ St Antoine Hosp AP HP Gastroenterol Dept Paris France NHLBI Framingham Heart Study Framingham MA USA Boston Univ Framingham MA USA Boston Univ Sch Med Chobanian & Avedisian Sch Med Boston MA 02118 USA Boston Univ Sch Publ Hlth Dept Epidemiol Boston MA USA Univ Michigan Dept Biostat Ann Arbor MI 48109 USA Univ Michigan Ctr Stat Genet Ann

The depletion of disruptive variation caused by purifying natural selection (constraint) has been widely used to investigate protein-coding genes underlying human disorders1-4, but attempts to assess constraint for non-protein-coding regions have proved more difficult. Here we aggregate, process and release a dataset of 76,156 human genomes from the Genome Aggregation Database (gnomAD)-the largest public open-access human genome allele frequency reference dataset-and use it to build a genomic constraint map for the whole genome (genomic non-coding constraint of haploinsufficient variation (Gnocchi)). We present a refined mutational model that incorporates local sequence context and regional genomic features to detect depletions of variation. As expected, the average constraint for protein-coding sequences is stronger than that for non-coding regions. Within the non-coding genome, constrained regions are enriched for known regulatory elements and variants that are implicated in complex human diseases and traits, facilitating the triangulation of biological annotation, disease association and natural selection to non-coding DNA analysis. More constrained regulatory elements tend to regulate more constrained protein-coding genes, which in turn suggests that non-coding constraint can aid the identification of constrained genes that are as yet unrecognized by current gene constraint metrics. We demonstrate that this genome-wide constraint map improves the identification and interpretation of functional human genetic variation. A genomic constraint map for the human genome constructed using data from 76,156 human genomes from the Genome Aggregation Database shows that non-coding constrained regions are enriched for regulatory elements and variants associated with complex diseases and traits.

关键词： Computational biology and bioinformatics DNA sequencing Evolutionary genetics Genetic variation Genotype

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