@article {360, title = {Genetic insights into biological mechanisms governing human ovarian ageing}, journal = {Nature}, volume = {596}, year = {2021}, pages = {393{\textendash}397}, abstract = {

Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1\% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

}, doi = {10.1038/s41586-021-03779-7}, author = {Ruth, Katherine S and Day, Felix R and Hussain, Jazib and Mart{\'\i}nez-Marchal, Ana and Aiken, Catherine E and Azad, Ajuna and Thompson, Deborah J and Knoblochova, Lucie and Abe, Hironori and Tarry-Adkins, Jane L and Gonzalez, Javier Martin and Fontanillas, Pierre and Claringbould, Annique and Bakker, Olivier B and Sulem, Patrick and Walters, Robin G and Terao, Chikashi and Turon, Sandra and Horikoshi, Momoko and Lin, Kuang and Onland-Moret, N Charlotte and Sankar, Aditya and Hertz, Emil Peter Thrane and Timshel, Pascal N and Shukla, Vallari and Borup, Rehannah and Olsen, Kristina W and Aguilera, Paula and Ferrer-Roda, M{\`o}nica and Huang, Yan and Stankovic, Stasa and Timmers, Paul R H J and Ahearn, Thomas U and Alizadeh, Behrooz Z and Naderi, Elnaz and Andrulis, Irene L and Arnold, Alice M and Aronson, Kristan J and Augustinsson, Annelie and Bandinelli, Stefania and Barbieri, Caterina M and Beaumont, Robin N and Becher, Heiko and Beckmann, Matthias W and Benonisdottir, Stefania and Bergmann, Sven and Bochud, Murielle and Boerwinkle, Eric and Bojesen, Stig E and Bolla, Manjeet K and Boomsma, Dorret I and Bowker, Nicholas and Brody, Jennifer A and Broer, Linda and Buring, Julie E and Campbell, Archie and Campbell, Harry and Castelao, Jose E and Catamo, Eulalia and Chanock, Stephen J and Chenevix-Trench, Georgia and Ciullo, Marina and Corre, Tanguy and Couch, Fergus J and Cox, Angela and Crisponi, Laura and Cross, Simon S and Cucca, Francesco and Czene, Kamila and Smith, George Davey and de Geus, Eco J C N and de Mutsert, Ren{\'e}e and De Vivo, Immaculata and Demerath, Ellen W and Dennis, Joe and Dunning, Alison M and Dwek, Miriam and Eriksson, Mikael and Esko, T{\~o}nu and Fasching, Peter A and Faul, Jessica D and Ferrucci, Luigi and Franceschini, Nora and Frayling, Timothy M and Gago-Dominguez, Manuela and Mezzavilla, Massimo and Garc{\'\i}a-Closas, Montserrat and Gieger, Christian and Giles, Graham G and Grallert, Harald and Gudbjartsson, Daniel F and Gudnason, Vilmundur and Gu{\'e}nel, Pascal and Haiman, Christopher A and H\aakansson, Niclas and Hall, Per and Hayward, Caroline and He, Chunyan and He, Wei and Heiss, Gerardo and H{\o}ffding, Miya K and Hopper, John L and Hottenga, Jouke J and Hu, Frank and Hunter, David and Ikram, Mohammad A and Jackson, Rebecca D and Joaquim, Micaella D R and John, Esther M and Joshi, Peter K and Karasik, David and Kardia, Sharon L R and Kartsonaki, Christiana and Karlsson, Robert and Kitahara, Cari M and Kolcic, Ivana and Kooperberg, Charles and Kraft, Peter and Kurian, Allison W and Kutalik, Zoltan and La Bianca, Martina and LaChance, Genevieve and Langenberg, Claudia and Launer, Lenore J and Laven, Joop S E and Lawlor, Deborah A and Le Marchand, Loic and Li, Jingmei and Lindblom, Annika and Lindstrom, Sara and Lindstrom, Tricia and Linet, Martha and Liu, Yongmei and Liu, Simin and Luan, Jian{\textquoteright}an and M{\"a}gi, Reedik and Magnusson, Patrik K E and Mangino, Massimo and Mannermaa, Arto and Marco, Brumat and Marten, Jonathan and Martin, Nicholas G and Mbarek, Hamdi and McKnight, Barbara and Medland, Sarah E and Meisinger, Christa and Meitinger, Thomas and Menni, Cristina and Metspalu, Andres and Milani, Lili and Milne, Roger L and Montgomery, Grant W and Mook-Kanamori, Dennis O and Mulas, Antonella and Mulligan, Anna M and Murray, Alison and Nalls, Mike A and Newman, Anne and Noordam, Raymond and Nutile, Teresa and Nyholt, Dale R and Olshan, Andrew F and Olsson, H\aakan and Painter, Jodie N and Patel, Alpa V and Pedersen, Nancy L and Perjakova, Natalia and Peters, Annette and Peters, Ulrike and Pharoah, Paul D P and Polasek, Ozren and Porcu, Eleonora and Psaty, Bruce M and Rahman, Iffat and Rennert, Gad and Rennert, Hedy S and Ridker, Paul M and Ring, Susan M and Robino, Antonietta and Rose, Lynda M and Rosendaal, Frits R and Rossouw, Jacques and Rudan, Igor and Rueedi, Rico and Ruggiero, Daniela and Sala, Cinzia F and Saloustros, Emmanouil and Sandler, Dale P and Sanna, Serena and Sawyer, Elinor J and Sarnowski, Chlo{\'e} and Schlessinger, David and Schmidt, Marjanka K and Schoemaker, Minouk J and Schraut, Katharina E and Scott, Christopher and Shekari, Saleh and Shrikhande, Amruta and Smith, Albert V and Smith, Blair H and Smith, Jennifer A and Sorice, Rossella and Southey, Melissa C and Spector, Tim D and Spinelli, John J and Stampfer, Meir and St{\"o}ckl, Doris and van Meurs, Joyce B J and Strauch, Konstantin and Styrkarsdottir, Unnur and Swerdlow, Anthony J and Tanaka, Toshiko and Teras, Lauren R and Teumer, Alexander and {\TH}orsteinsdottir, Unnur and Timpson, Nicholas J and Toniolo, Daniela and Traglia, Michela and Troester, Melissa A and Truong, Th{\'e}r{\`e}se and Tyrrell, Jessica and Uitterlinden, Andr{\'e} G and Ulivi, Sheila and Vachon, Celine M and Vitart, Veronique and V{\"o}lker, Uwe and Vollenweider, Peter and V{\"o}lzke, Henry and Wang, Qin and Wareham, Nicholas J and Weinberg, Clarice R and Weir, David R and Wilcox, Amber N and van Dijk, Ko Willems and Willemsen, Gonneke and Wilson, James F and Wolffenbuttel, Bruce H R and Wolk, Alicja and Wood, Andrew R and Zhao, Wei and Zygmunt, Marek and Biobank-based Integrative Omics Study (BIOS) Consortium and eQTLGen Consortium and Biobank Japan Project and China Kadoorie Biobank Collaborative Group and kConFab Investigators and Lifelines Cohort Study and InterAct consortium and 23andMe Research Team and Chen, Zhengming and Li, Liming and Franke, Lude and Burgess, Stephen and Deelen, Patrick and Pers, Tune H and Gr{\o}ndahl, Marie Louise and Andersen, Claus Yding and Pujol, Anna and Lopez-Contreras, Andres J and Daniel, Jeremy A and Stefansson, Kari and Chang-Claude, Jenny and van der Schouw, Yvonne T and Lunetta, Kathryn L and Chasman, Daniel I and Easton, Douglas F and Visser, Jenny A and Ozanne, Susan E and Namekawa, Satoshi H and Solc, Petr and Murabito, Joanne M and Ong, Ken K and Hoffmann, Eva R and Murray, Anna and Roig, Ignasi and Perry, John R B} } @article {355, title = {Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability}, journal = {Nature Communications}, volume = {12}, year = {2021}, pages = {24}, abstract = {

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.

}, doi = {10.1038/s41467-020-19366-9}, author = {Lagou, Vasiliki and M{\"a}gi, Reedik and Hottenga, Jouke- Jan and Grallert, Harald and Perry, John R B and Bouatia-Naji, Nabila and Marullo, Letizia and Rybin, Denis and Jansen, Rick and Min, Josine L and Dimas, Antigone S and Ulrich, Anna and Zudina, Liudmila and G\aadin, Jesper R and Jiang, Longda and Faggian, Alessia and Bonnefond, Am{\'e}lie and Fadista, Joao and Stathopoulou, Maria G and Isaacs, Aaron and Willems, Sara M and Navarro, Pau and Tanaka, Toshiko and Jackson, Anne U and Montasser, May E and O{\textquoteright}Connell, Jeff R and Bielak, Lawrence F and Webster, Rebecca J and Saxena, Richa and Stafford, Jeanette M and Pourcain, Beate St and Timpson, Nicholas J and Salo, Perttu and Shin, So-Youn and Amin, Najaf and Smith, Albert V and Li, Guo and Verweij, Niek and Goel, Anuj and Ford, Ian and Johnson, Paul C D and Johnson, Toby and Kapur, Karen and Thorleifsson, Gudmar and Strawbridge, Rona J and Rasmussen-Torvik, Laura J and Esko, T{\~o}nu and Mihailov, Evelin and Fall, Tove and Fraser, Ross M and Mahajan, Anubha and Kanoni, Stavroula and Giedraitis, Vilmantas and Kleber, Marcus E and Silbernagel, G{\"u}nther and Meyer, Julia and M{\"u}ller-Nurasyid, Martina and Ganna, Andrea and Sarin, Antti-Pekka and Yengo, Loic and Shungin, Dmitry and Luan, Jian{\textquoteright}an and Horikoshi, Momoko and An, Ping and Sanna, Serena and Boettcher, Yvonne and Rayner, N William and Nolte, Ilja M and Zemunik, Tatijana and van Iperen, Erik and Kovacs, Peter and Hastie, Nicholas D and Wild, Sarah H and McLachlan, Stela and Campbell, Susan and Polasek, Ozren and Carlson, Olga and Egan, Josephine and Kiess, Wieland and Willemsen, Gonneke and Kuusisto, Johanna and Laakso, Markku and Dimitriou, Maria and Hicks, Andrew A and Rauramaa, Rainer and Bandinelli, Stefania and Thorand, Barbara and Liu, Yongmei and Miljkovic, Iva and Lind, Lars and Doney, Alex and Perola, Markus and Hingorani, Aroon and Kivimaki, Mika and Kumari, Meena and Bennett, Amanda J and Groves, Christopher J and Herder, Christian and Koistinen, Heikki A and Kinnunen, Leena and Faire, Ulf de and Bakker, Stephan J L and Uusitupa, Matti and Palmer, Colin N A and Jukema, J Wouter and Sattar, Naveed and Pouta, Anneli and Snieder, Harold and Boerwinkle, Eric and Pankow, James S and Magnusson, Patrik K and Krus, Ulrika and Scapoli, Chiara and de Geus, Eco J C N and Bl{\"u}her, Matthias and Wolffenbuttel, Bruce H R and Province, Michael A and Abecasis, Goncalo R and Meigs, James B and Hovingh, G Kees and Lindstr{\"o}m, Jaana and Wilson, James F and Wright, Alan F and Dedoussis, George V and Bornstein, Stefan R and Schwarz, Peter E H and T{\"o}njes, Anke and Winkelmann, Bernhard R and Boehm, Bernhard O and M{\"a}rz, Winfried and Metspalu, Andres and Price, Jackie F and Deloukas, Panos and K{\"o}rner, Antje and Lakka, Timo A and Keinanen-Kiukaanniemi, Sirkka M and Saaristo, Timo E and Bergman, Richard N and Tuomilehto, Jaakko and Wareham, Nicholas J and Langenberg, Claudia and M{\"a}nnist{\"o}, Satu and Franks, Paul W and Hayward, Caroline and Vitart, Veronique and Kaprio, Jaakko and Visvikis-Siest, Sophie and Balkau, Beverley and Altshuler, David and Rudan, Igor and Stumvoll, Michael and Campbell, Harry and van Duijn, Cornelia M and Gieger, Christian and Illig, Thomas and Ferrucci, Luigi and Pedersen, Nancy L and Pramstaller, Peter P and Boehnke, Michael and Frayling, Timothy M and Shuldiner, Alan R and Peyser, Patricia A and Kardia, Sharon L R and Palmer, Lyle J and Penninx, Brenda W and Meneton, Pierre and Harris, Tamara B and Navis, Gerjan and Harst, Pim van der and Smith, George Davey and Forouhi, Nita G and Loos, Ruth J F and Salomaa, Veikko and Soranzo, Nicole and Boomsma, Dorret I and Groop, Leif and Tuomi, Tiinamaija and Hofman, Albert and Munroe, Patricia B and Gudnason, Vilmundur and Siscovick, David S and Watkins, Hugh and Lecoeur, Cecile and Vollenweider, Peter and Franco-Cereceda, Anders and Eriksson, Per and Jarvelin, Marjo-Riitta and Stefansson, Kari and Hamsten, Anders and Nicholson, George and Karpe, Fredrik and Dermitzakis, Emmanouil T and Lindgren, Cecilia M and McCarthy, Mark I and Froguel, Philippe and Kaakinen, Marika A and Lyssenko, Valeriya and Watanabe, Richard M and Ingelsson, Erik and Florez, Jose C and Dupuis, Jos{\'e}e and Barroso, In{\^e}s and Morris, Andrew P and Prokopenko, Inga and Meta-Analyses of Glucose and Insulin-related Traits Consortium (MAGIC)} } @article {347, title = {The trans-ancestral genomic architecture of glycemic traits}, journal = {Nature Genetics}, volume = {53}, year = {2021}, pages = {840{\textendash}860}, 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 $\times$ 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.

}, doi = {10.1038/s41588-021-00852-9}, author = {Chen, Ji and Spracklen, Cassandra N and Marenne, Ga{\"e}lle and Varshney, Arushi and Corbin, Laura J and Luan, Jian{\textquoteright}an and Willems, Sara M and Wu, Ying and Zhang, Xiaoshuai and Horikoshi, Momoko and Boutin, Thibaud S and M{\"a}gi, Reedik and Waage, Johannes and Li-Gao, Ruifang and Chan, Kei Hang Katie and Yao, Jie and Anasanti, Mila D and Chu, Audrey Y and Claringbould, Annique and Heikkinen, Jani and Hong, Jaeyoung and Hottenga, Jouke-Jan and Huo, Shaofeng and Kaakinen, Marika A and Louie, Tin and M{\"a}rz, Winfried and Moreno-Macias, Hortensia and Ndungu, Anne and Nelson, Sarah C and Nolte, Ilja M and North, Kari E and Raulerson, Chelsea K and Ray, Debashree and Rohde, Rebecca and Rybin, Denis and Schurmann, Claudia and Sim, Xueling and Southam, Lorraine and Stewart, Isobel D and Wang, Carol A and Wang, Yujie and Wu, Peitao and Zhang, Weihua and Ahluwalia, Tarunveer S and Appel, Emil V R and Bielak, Lawrence F and Brody, Jennifer A and Burtt, No{\"e}l P and Cabrera, Claudia P and Cade, Brian E and Chai, Jin Fang and Chai, Xiaoran and Chang, Li-Ching and Chen, Chien-Hsiun and Chen, Brian H and Chitrala, Kumaraswamy Naidu and Chiu, Yen-Feng and de Haan, Hugoline G and Delgado, Graciela E and Demirkan, Ayse and Duan, Qing and Engmann, Jorgen and Fatumo, Segun A and Gay{\'a}n, Javier and Giulianini, Franco and Gong, Jung Ho and Gustafsson, Stefan and Hai, Yang and Hartwig, Fernando P and He, Jing and Heianza, Yoriko and Huang, Tao and Huerta-Chagoya, Alicia and Hwang, Mi Yeong and Jensen, Richard A and Kawaguchi, Takahisa and Kentistou, Katherine A and Kim, Young Jin and Kleber, Marcus E and Kooner, Ishminder K and Lai, Shuiqing and Lange, Leslie A and Langefeld, Carl D and Lauzon, Marie and Li, Man and Ligthart, Symen and Liu, Jun and Loh, Marie and Long, Jirong and Lyssenko, Valeriya and Mangino, Massimo and Marzi, Carola and Montasser, May E and Nag, Abhishek and Nakatochi, Masahiro and Noce, Damia and Noordam, Raymond and Pistis, Giorgio and Preuss, Michael and Raffield, Laura and Rasmussen-Torvik, Laura J and Rich, Stephen S and Robertson, Neil R and Rueedi, Rico and Ryan, Kathleen and Sanna, Serena and Saxena, Richa and Schraut, Katharina E and Sennblad, Bengt and Setoh, Kazuya and Smith, Albert V and Spars{\o}, Thomas and Strawbridge, Rona J and Takeuchi, Fumihiko and Tan, Jingyi and Trompet, Stella and van den Akker, Erik and van der Most, Peter J and Verweij, Niek and Vogel, Mandy and Wang, Heming and Wang, Chaolong and Wang, Nan and Warren, Helen R and Wen, Wanqing and Wilsgaard, Tom and Wong, Andrew and Wood, Andrew R and Xie, Tian and Zafarmand, Mohammad Hadi and Zhao, Jing-Hua and Zhao, Wei and Amin, Najaf and Arzumanyan, Zorayr and Astrup, Arne and Bakker, Stephan J L and Baldassarre, Damiano and Beekman, Marian and Bergman, Richard N and Bertoni, Alain and Bl{\"u}her, Matthias and Bonnycastle, Lori L and Bornstein, Stefan R and Bowden, Donald W and Cai, Qiuyin and Campbell, Archie and Campbell, Harry and Chang, Yi Cheng and de Geus, Eco J C and Dehghan, Abbas and Du, Shufa and Eiriksdottir, Gudny and Farmaki, Aliki Eleni and Fr\aanberg, Mattias and Fuchsberger, Christian and Gao, Yutang and Gjesing, Anette P and Goel, Anuj and Han, Sohee and Hartman, Catharina A and Herder, Christian and Hicks, Andrew A and Hsieh, Chang-Hsun and Hsueh, Willa A and Ichihara, Sahoko and Igase, Michiya and Ikram, M Arfan and Johnson, W Craig and J{\o}rgensen, Marit E and Joshi, Peter K and Kalyani, Rita R and Kandeel, Fouad R and Katsuya, Tomohiro and Khor, Chiea Chuen and Kiess, Wieland and Kolcic, Ivana and Kuulasmaa, Teemu and Kuusisto, Johanna and L{\"a}ll, Kristi and Lam, Kelvin and Lawlor, Deborah A and Lee, Nanette R and Lemaitre, Rozenn N and Li, Honglan and Lifelines Cohort Study and Lin, Shih-Yi and Lindstr{\"o}m, Jaana and Linneberg, Allan and Liu, Jianjun and Lorenzo, Carlos and Matsubara, Tatsuaki and Matsuda, Fumihiko and Mingrone, Geltrude and Mooijaart, Simon and Moon, Sanghoon and Nabika, Toru and Nadkarni, Girish N and Nadler, Jerry L and Nelis, Mari and Neville, Matt J and Norris, Jill M and Ohyagi, Yasumasa and Peters, Annette and Peyser, Patricia A and Polasek, Ozren and Qi, Qibin and Raven, Dennis and Reilly, Dermot F and Reiner, Alex and Rivideneira, Fernando and Roll, Kathryn and Rudan, Igor and Sabanayagam, Charumathi and Sandow, Kevin and Sattar, Naveed and Sch{\"u}rmann, Annette and Shi, Jinxiu and Stringham, Heather M and Taylor, Kent D and Teslovich, Tanya M and Thuesen, Betina and Timmers, Paul R H J and Tremoli, Elena and Tsai, Michael Y and Uitterlinden, Andre and van Dam, Rob M and van Heemst, Diana and van Hylckama Vlieg, Astrid and van Vliet-Ostaptchouk, Jana V and Vangipurapu, Jagadish and Vestergaard, Henrik and Wang, Tao and Willems van Dijk, Ko and Zemunik, Tatijana and Abecasis, Gon\c calo R and Adair, Linda S and Aguilar-Salinas, Carlos Alberto and Alarc{\'o}n-Riquelme, Marta E and An, Ping and Aviles-Santa, Larissa and Becker, Diane M and Beilin, Lawrence J and Bergmann, Sven and Bisgaard, Hans and Black, Corri and Boehnke, Michael and Boerwinkle, Eric and B{\"o}hm, Bernhard O and B{\o}nnelykke, Klaus and Boomsma, D I and Bottinger, Erwin P and Buchanan, Thomas A and Canouil, Micka{\"e}l and Caulfield, Mark J and Chambers, John C and Chasman, Daniel I and Chen, Yii-Der Ida and Cheng, Ching-Yu and Collins, Francis S and Correa, Adolfo and Cucca, Francesco and de Silva, H Janaka and Dedoussis, George and Elmst\aahl, S{\"o}lve and Evans, Michele K and Ferrannini, Ele and Ferrucci, Luigi and Florez, Jose C and Franks, Paul W and Frayling, Timothy M and Froguel, Philippe and Gigante, Bruna and Goodarzi, Mark O and Gordon-Larsen, Penny and Grallert, Harald and Grarup, Niels and Grimsgaard, Sameline and Groop, Leif and Gudnason, Vilmundur and Guo, Xiuqing and Hamsten, Anders and Hansen, Torben and Hayward, Caroline and Heckbert, Susan R and Horta, Bernardo L and Huang, Wei and Ingelsson, Erik and James, Pankow S and Jarvelin, Marjo-Ritta and Jonas, Jost B and Jukema, J Wouter and Kaleebu, Pontiano and Kaplan, Robert and Kardia, Sharon L R and Kato, Norihiro and Keinanen-Kiukaanniemi, Sirkka M and Kim, Bong-Jo and Kivimaki, Mika and Koistinen, Heikki A and Kooner, Jaspal S and K{\"o}rner, Antje and Kovacs, Peter and Kuh, Diana and Kumari, Meena and Kutalik, Zoltan and Laakso, Markku and Lakka, Timo A and Launer, Lenore J and Leander, Karin and Li, Huaixing and Lin, Xu and Lind, Lars and Lindgren, Cecilia and Liu, Simin and Loos, Ruth J F and Magnusson, Patrik K E and Mahajan, Anubha and Metspalu, Andres and Mook-Kanamori, Dennis O and Mori, Trevor A and Munroe, Patricia B and Nj{\o}lstad, Inger and O{\textquoteright}Connell, Jeffrey R and Oldehinkel, Albertine J and Ong, Ken K and Padmanabhan, Sandosh and Palmer, Colin N A and Palmer, Nicholette D and Pedersen, Oluf and Pennell, Craig E and Porteous, David J and Pramstaller, Peter P and Province, Michael A and Psaty, Bruce M and Qi, Lu and Raffel, Leslie J and Rauramaa, Rainer and Redline, Susan and Ridker, Paul M and Rosendaal, Frits R and Saaristo, Timo E and Sandhu, Manjinder and Saramies, Jouko and Schneiderman, Neil and Schwarz, Peter and Scott, Laura J and Selvin, Elizabeth and Sever, Peter and Shu, Xiao-Ou and Slagboom, P Eline and Small, Kerrin S and Smith, Blair H and Snieder, Harold and Sofer, Tamar and S{\o}rensen, Thorkild I A and Spector, Tim D and Stanton, Alice and Steves, Claire J and Stumvoll, Michael and Sun, Liang and Tabara, Yasuharu and Tai, E Shyong and Timpson, Nicholas J and T{\"o}njes, Anke and Tuomilehto, Jaakko and Tusie, Teresa and Uusitupa, Matti and van der Harst, Pim and van Duijn, Cornelia and Vitart, Veronique and Vollenweider, Peter and Vrijkotte, Tanja G M and Wagenknecht, Lynne E and Walker, Mark and Wang, Ya X and Wareham, Nick J and Watanabe, Richard M and Watkins, Hugh and Wei, Wen B and Wickremasinghe, Ananda R and Willemsen, Gonneke and Wilson, James F and Wong, Tien-Yin and Wu, Jer-Yuarn and Xiang, Anny H and Yanek, Lisa R and Yengo, Lo\"{\i}c and Yokota, Mitsuhiro and Zeggini, Eleftheria and Zheng, Wei and Zonderman, Alan B and Rotter, Jerome I and Gloyn, Anna L and McCarthy, Mark I and Dupuis, Jos{\'e}e and Meigs, James B and Scott, Robert A and Prokopenko, Inga and Leong, Aaron and Liu, Ching-Ti and Parker, Stephen C J and Mohlke, Karen L and Langenberg, Claudia and Wheeler, Eleanor and Morris, Andrew P and Barroso, In{\^e}s and Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC)} } @article {261, title = {DNA methylation age is associated with an altered hemostatic profile in a multi-ethnic meta-analysis}, journal = {Blood}, year = {2018}, abstract = {

Elevated epigenetic age is associated with an altered hemostatic factor profile and lower clotting time (aPTT).DNA methylation age is associated with mRNA levels of fibrinogen in multiple tissues. Many hemostatic factors are associated with age and age-related diseases, however much remains unknown about the biological mechanisms linking aging and hemostatic factors. DNA methylation is a novel means by which to assess epigenetic aging, which is a measure of age and the aging processes as determined by altered epigenetic states. We used a meta-analysis approach to examine the association between measures of epigenetic aging and hemostatic factors, as well as a clotting time measure. For fibrinogen, we used European and African-ancestry participants who were meta-analyzed separately and combined via a random effects meta-analysis. All other measures only included participants of European-ancestry. We found that 1-year higher extrinsic epigenetic age as compared to chronological age was associated with higher fibrinogen (0.004 g/L per year; 95\% CI: 0.001, 0.007; P = 0.01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL per year; 95\% CI: 0.07, 0.20; P = 6.6x10-5) concentrations as well as lower activated partial thromboplastin time, a measure of clotting time. We replicated PAI-1 associations using an independent cohort. To further elucidate potential functional mechanisms we associated epigenetic aging with expression levels of the PAI-1 protein encoding gene (SERPINE1) and the three fibrinogen subunit-encoding genes (FGA, FGG, and FGB), in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of FGG in both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a pro-coagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription.

}, issn = {0006-4971}, doi = {10.1182/blood-2018-02-831347}, url = {http://www.bloodjournal.org/content/early/2018/07/24/blood-2018-02-831347}, author = {Ward-Caviness, Cavin K. and Huffman, Jennifer E. and Evertt, Karl and Germain, Marine and van Dongen, Jenny and Hill, W. David and Jhun, Min A. and Brody, Jennifer A. and Ghanbari, Mohsen and Du, Lei and Roetker, Nicholas S. and de Vries, Paul S. and Waldenberger, Melanie and Gieger, Christian and Wolf, Petra and Prokisch, Holger and Koenig, Wolfgang and O{\textquoteright}Donnell, Christopher J. and Levy, Daniel and Liu, Chunyu and Truong, Vinh and Wells, Philip S. and Tr{\'e}gou{\"e}t, David-Alexandre and Tang, Weihong and Morrison, Alanna C. and Boerwinkle, Eric and Wiggins, Kerri L. and McKnight, Barbara and Guo, Xiuqing and Psaty, Bruce M. and Sotoodenia, Nona and Dorret I. Boomsma and Gonneke Willemsen and Lannie Ligthart and Deary, Ian J. and Zhao, Wei and Ware, Erin B. and Kardia, Sharon L.R. and Joyce B.J. Van Meurs and Uitterlinden, Andre G. and Franco, Oscar H. and Eriksson, Per and Franco-Cereceda, Anders and Pankow, James S. and Johnson, Andrew D. and Gagnon, France and Morange, Pierre-Emmanuel and de Geus, Eco J.C. and Starr, John M. and Smith, Jennifer A. and Dehghan, Abbas and Bj{\"o}rck, Hanna M. and Smith, Nicholas L. and Peters, Annette} }