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The trans-ancestral genomic architecture of glycemic traits.

ABSTRACT: Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10^-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.

SUBMITTER: Chen J

PROVIDER: S-EPMC7610958 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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The trans-ancestral genomic architecture of glycemic traits.

Chen Ji J Spracklen Cassandra N CN Marenne Gaëlle G Varshney Arushi A Corbin Laura J LJ Luan Jian'an J Willems Sara M SM Wu Ying Y Zhang Xiaoshuai X Horikoshi Momoko M Boutin Thibaud S TS Mägi Reedik R Waage Johannes J Li-Gao Ruifang R Chan Kei Hang Katie KHK Yao Jie J Anasanti Mila D MD Chu Audrey Y AY Claringbould Annique A Heikkinen Jani J Hong Jaeyoung J Hottenga Jouke-Jan JJ Huo Shaofeng S Kaakinen Marika A MA Louie Tin T März Winfried W Moreno-Macias Hortensia H Ndungu Anne A Nelson Sarah C SC Nolte Ilja M IM North Kari E KE Raulerson Chelsea K CK Ray Debashree D Rohde Rebecca R Rybin Denis D Schurmann Claudia C Sim Xueling X Southam Lorraine L Stewart Isobel D ID Wang Carol A CA Wang Yujie Y Wu Peitao P Zhang Weihua W Ahluwalia Tarunveer S TS Appel Emil V R EVR Bielak Lawrence F LF Brody Jennifer A JA Burtt Noël P NP Cabrera Claudia P CP Cade Brian E BE Chai Jin Fang JF Chai Xiaoran X Chang Li-Ching LC Chen Chien-Hsiun CH Chen Brian H BH Chitrala Kumaraswamy Naidu KN Chiu Yen-Feng YF de Haan Hugoline G HG Delgado Graciela E GE Demirkan Ayse A Duan Qing Q Engmann Jorgen J Fatumo Segun A SA Gayán Javier J Giulianini Franco F Gong Jung Ho JH Gustafsson Stefan S Hai Yang Y Hartwig Fernando P FP He Jing J Heianza Yoriko Y Huang Tao T Huerta-Chagoya Alicia A Hwang Mi Yeong MY Jensen Richard A RA Kawaguchi Takahisa T Kentistou Katherine A KA Kim Young Jin YJ Kleber Marcus E ME Kooner Ishminder K IK Lai Shuiqing S Lange Leslie A LA Langefeld Carl D CD Lauzon Marie M Li Man M Ligthart Symen S Liu Jun J Loh Marie M Long Jirong J Lyssenko Valeriya V Mangino Massimo M Marzi Carola C Montasser May E ME Nag Abhishek A Nakatochi Masahiro M Noce Damia D Noordam Raymond R Pistis Giorgio G Preuss Michael M Raffield Laura L Rasmussen-Torvik Laura J LJ Rich Stephen S SS Robertson Neil R NR Rueedi Rico R Ryan Kathleen K Sanna Serena S Saxena Richa R Schraut Katharina E KE Sennblad Bengt B Setoh Kazuya K Smith Albert V AV Sparsø Thomas T Strawbridge Rona J RJ Takeuchi Fumihiko F Tan Jingyi J Trompet Stella S van den Akker Erik E van der Most Peter J PJ Verweij Niek N Vogel Mandy M Wang Heming H Wang Chaolong C Wang Nan N Warren Helen R HR Wen Wanqing W Wilsgaard Tom T Wong Andrew A Wood Andrew R AR Xie Tian T Zafarmand Mohammad Hadi MH Zhao Jing-Hua JH Zhao Wei W Amin Najaf N Arzumanyan Zorayr Z Astrup Arne A Bakker Stephan J L SJL Baldassarre Damiano D Beekman Marian M Bergman Richard N RN Bertoni Alain A Blüher Matthias M Bonnycastle Lori L LL Bornstein Stefan R SR Bowden Donald W DW Cai Qiuyin Q Campbell Archie A Campbell Harry H Chang Yi Cheng YC de Geus Eco J C EJC Dehghan Abbas A Du Shufa S Eiriksdottir Gudny G Farmaki Aliki Eleni AE Frånberg Mattias M Fuchsberger Christian C Gao Yutang Y Gjesing Anette P AP Goel Anuj A Han Sohee S Hartman Catharina A CA Herder Christian C Hicks Andrew A AA Hsieh Chang-Hsun CH Hsueh Willa A WA Ichihara Sahoko S Igase Michiya M Ikram M Arfan MA Johnson W Craig WC Jørgensen Marit E ME Joshi Peter K PK Kalyani Rita R RR Kandeel Fouad R FR Katsuya Tomohiro T Khor Chiea Chuen CC Kiess Wieland W Kolcic Ivana I Kuulasmaa Teemu T Kuusisto Johanna J Läll Kristi K Lam Kelvin K Lawlor Deborah A DA Lee Nanette R NR Lemaitre Rozenn N RN Li Honglan H Lin Shih-Yi SY Lindström Jaana J Linneberg Allan A Liu Jianjun J Lorenzo Carlos C Matsubara Tatsuaki T Matsuda Fumihiko F Mingrone Geltrude G Mooijaart Simon S Moon Sanghoon S Nabika Toru T Nadkarni Girish N GN Nadler Jerry L JL Nelis Mari M Neville Matt J MJ Norris Jill M JM Ohyagi Yasumasa Y Peters Annette A Peyser Patricia A PA Polasek Ozren O Qi Qibin Q Raven Dennis D Reilly Dermot F DF Reiner Alex A Rivideneira Fernando F Roll Kathryn K Rudan Igor I Sabanayagam Charumathi C Sandow Kevin K Sattar Naveed N Schürmann Annette A Shi Jinxiu J Stringham Heather M HM Taylor Kent D KD Teslovich Tanya M TM Thuesen Betina B Timmers Paul R H J PRHJ Tremoli Elena E Tsai Michael Y MY Uitterlinden Andre A van Dam Rob M RM van Heemst Diana D van Hylckama Vlieg Astrid A van Vliet-Ostaptchouk Jana V JV Vangipurapu Jagadish J Vestergaard Henrik H Wang Tao T Willems van Dijk Ko K Zemunik Tatijana T Abecasis Gonçalo R GR Adair Linda S LS Aguilar-Salinas Carlos Alberto CA Alarcón-Riquelme Marta E ME An Ping P Aviles-Santa Larissa L Becker Diane M DM Beilin Lawrence J LJ Bergmann Sven S Bisgaard Hans H Black Corri C Boehnke Michael M Boerwinkle Eric E Böhm Bernhard O BO Bønnelykke Klaus K Boomsma D I DI Bottinger Erwin P EP Buchanan Thomas A TA Canouil Mickaël M Caulfield Mark J MJ Chambers John C JC Chasman Daniel I DI Chen Yii-Der Ida YI Cheng Ching-Yu CY Collins Francis S FS Correa Adolfo A Cucca Francesco F de Silva H Janaka HJ Dedoussis George G Elmståhl Sölve S Evans Michele K MK Ferrannini Ele E Ferrucci Luigi L Florez Jose C JC Franks Paul W PW Frayling Timothy M TM Froguel Philippe P Gigante Bruna B Goodarzi Mark O MO Gordon-Larsen Penny P Grallert Harald H Grarup Niels N Grimsgaard Sameline S Groop Leif L Gudnason Vilmundur V Guo Xiuqing X Hamsten Anders A Hansen Torben T Hayward Caroline C Heckbert Susan R SR Horta Bernardo L BL Huang Wei W Ingelsson Erik E James Pankow S PS Jarvelin Marjo-Ritta MR Jonas Jost B JB Jukema J Wouter JW Kaleebu Pontiano P Kaplan Robert R Kardia Sharon L R SLR Kato Norihiro N Keinanen-Kiukaanniemi Sirkka M SM Kim Bong-Jo BJ Kivimaki Mika M Koistinen Heikki A HA Kooner Jaspal S JS Körner Antje A Kovacs Peter P Kuh Diana D Kumari Meena M Kutalik Zoltan Z Laakso Markku M Lakka Timo A TA Launer Lenore J LJ Leander Karin K Li Huaixing H Lin Xu X Lind Lars L Lindgren Cecilia C Liu Simin S Loos Ruth J F RJF Magnusson Patrik K E PKE Mahajan Anubha A Metspalu Andres A Mook-Kanamori Dennis O DO Mori Trevor A TA Munroe Patricia B PB Njølstad Inger I O'Connell Jeffrey R JR Oldehinkel Albertine J AJ Ong Ken K KK Padmanabhan Sandosh S Palmer Colin N A CNA Palmer Nicholette D ND Pedersen Oluf O Pennell Craig E CE Porteous David J DJ Pramstaller Peter P PP Province Michael A MA Psaty Bruce M BM Qi Lu L Raffel Leslie J LJ Rauramaa Rainer R Redline Susan S Ridker Paul M PM Rosendaal Frits R FR Saaristo Timo E TE Sandhu Manjinder M Saramies Jouko J Schneiderman Neil N Schwarz Peter P Scott Laura J LJ Selvin Elizabeth E Sever Peter P Shu Xiao-Ou XO Slagboom P Eline PE Small Kerrin S KS Smith Blair H BH Snieder Harold H Sofer Tamar T Sørensen Thorkild I A TIA Spector Tim D TD Stanton Alice A Steves Claire J CJ Stumvoll Michael M Sun Liang L Tabara Yasuharu Y Tai E Shyong ES Timpson Nicholas J NJ Tönjes Anke A Tuomilehto Jaakko J Tusie Teresa T Uusitupa Matti M van der Harst Pim P van Duijn Cornelia C Vitart Veronique V Vollenweider Peter P Vrijkotte Tanja G M TGM Wagenknecht Lynne E LE Walker Mark M Wang Ya X YX Wareham Nick J NJ Watanabe Richard M RM Watkins Hugh H Wei Wen B WB Wickremasinghe Ananda R AR Willemsen Gonneke G Wilson James F JF Wong Tien-Yin TY Wu Jer-Yuarn JY Xiang Anny H AH Yanek Lisa R LR Yengo Loïc L Yokota Mitsuhiro M Zeggini Eleftheria E Zheng Wei W Zonderman Alan B AB Rotter Jerome I JI Gloyn Anna L AL McCarthy Mark I MI Dupuis Josée J Meigs James B JB Scott Robert A RA Prokopenko Inga I Leong Aaron A Liu Ching-Ti CT Parker Stephen C J SCJ Mohlke Karen L KL Langenberg Claudia C Wheeler Eleanor E Morris Andrew P AP Barroso Inês I

Nature genetics 20210531 6

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-ana ...[more]

PMID: 34059833

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Project description:BackgroundRainbow trout is a significant fish farming species under temperate climates. Female reproduction traits play an important role in the economy of breeding companies with the sale of fertilized eggs. The objectives of this study are threefold: to estimate the genetic parameters of female reproduction traits, to determine the genetic architecture of these traits by the identification of quantitative trait loci (QTL), and to assess the expected efficiency of a pedigree-based selection (BLUP) or genomic selection for these traits.ResultsA pedigreed population of 1343 trout were genotyped for 57,000 SNP markers and phenotyped for seven traits at 2 years of age: spawning date, female body weight before and after spawning, the spawn weight and the egg number of the spawn, the egg average weight and average diameter. Genetic parameters were estimated in multi-trait linear animal models. Heritability estimates were moderate, varying from 0.27 to 0.44. The female body weight was not genetically correlated to any of the reproduction traits. Spawn weight showed strong and favourable genetic correlation with the number of eggs in the spawn and individual egg size traits, but the egg number was uncorrelated to the egg size traits. The genome-wide association studies showed that all traits were very polygenic since less than 10% of the genetic variance was explained by the cumulative effects of the QTLs: for any trait, only 2 to 4 QTLs were detected that explained in-between 1 and 3% of the genetic variance. Genomic selection based on a reference population of only one thousand individuals related to candidates would improve the efficiency of BLUP selection from 16 to 37% depending on traits.ConclusionsOur genetic parameter estimates made unlikely the hypothesis that selection for growth could induce any indirect improvement for female reproduction traits. It is thus important to consider direct selection for spawn weight for improving egg production traits in rainbow trout breeding programs. Due to the low proportion of genetic variance explained by the few QTLs detected for each reproduction traits, marker assisted selection cannot be effective. However genomic selection would allow significant gains of accuracy compared to pedigree-based selection.

Project description:BackgroundIn this study, we aimed to investigate the molecular basis of lactation as well as to identify the genetic factors that influence milk yield and composition in goats. To achieve these two goals, we have analyzed how the mRNA profile of the mammary gland changes in seven Murciano-Granadina goats at each of three different time points, i.e. 78 d (T1, early lactation), 216 d (T2, late lactation) and 285 d (T3, dry period) after parturition. Moreover, we have performed a genome-wide association study (GWAS) for seven dairy traits recorded in the 1st lactation of 822 Murciano-Granadina goats.ResultsThe expression profiles of the mammary gland in the early (T1) and late (T2) lactation were quite similar (42 differentially expressed genes), while strong transcriptomic differences (more than one thousand differentially expressed genes) were observed between the lactating (T1/T2) and non-lactating (T3) mammary glands. A large number of differentially expressed genes were involved in pathways related with the biosynthesis of amino acids, cholesterol, triglycerides and steroids as well as with glycerophospholipid metabolism, adipocytokine signaling, lipid binding, regulation of ion transmembrane transport, calcium ion binding, metalloendopeptidase activity and complement and coagulation cascades. With regard to the second goal of the study, the performance of the GWAS allowed us to detect 24 quantitative trait loci (QTLs), including three genome-wide significant associations: QTL1 (chromosome 2, 130.72-131.01 Mb) for lactose percentage, QTL6 (chromosome 6, 78.90-93.48 Mb) for protein percentage and QTL17 (chromosome 17, 11.20 Mb) for both protein and dry matter percentages. Interestingly, QTL6 shows positional coincidence with the casein genes, which encode 80% of milk proteins.ConclusionsThe abrogation of lactation involves dramatic changes in the expression of genes participating in a broad array of physiological processes such as protein, lipid and carbohydrate metabolism, calcium homeostasis, cell death and tissue remodeling, as well as immunity. We also conclude that genetic variation at the casein genes has a major impact on the milk protein content of Murciano-Granadina goats.

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The trans-ancestral genomic architecture of glycemic traits.

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The trans-ancestral genomic architecture of glycemic traits.

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