%0 Journal Article %J J Am Soc Nephrol %D 2017 %T and Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function. %A Li, Man %A Li, Yong %A Weeks, Olivia %A Mijatovic, Vladan %A Teumer, Alexander %A Huffman, Jennifer E %A Tromp, Gerard %A Fuchsberger, Christian %A Gorski, Mathias %A Lyytikäinen, Leo-Pekka %A Nutile, Teresa %A Sedaghat, Sanaz %A Sorice, Rossella %A Tin, Adrienne %A Yang, Qiong %A Ahluwalia, Tarunveer S %A Arking, Dan E %A Bihlmeyer, Nathan A %A Böger, Carsten A %A Carroll, Robert J %A Chasman, Daniel I %A Cornelis, Marilyn C %A Dehghan, Abbas %A Faul, Jessica D %A Feitosa, Mary F %A Gambaro, Giovanni %A Gasparini, Paolo %A Giulianini, Franco %A Heid, Iris %A Huang, Jinyan %A Imboden, Medea %A Jackson, Anne U %A Jeff, Janina %A Jhun, Min A %A Katz, Ronit %A Kifley, Annette %A Kilpeläinen, Tuomas O %A Kumar, Ashish %A Laakso, Markku %A Li-Gao, Ruifang %A Lohman, Kurt %A Lu, Yingchang %A Mägi, Reedik %A Malerba, Giovanni %A Mihailov, Evelin %A Mohlke, Karen L %A Mook-Kanamori, Dennis O %A Robino, Antonietta %A Ruderfer, Douglas %A Salvi, Erika %A Schick, Ursula M %A Schulz, Christina-Alexandra %A Smith, Albert V %A Smith, Jennifer A %A Traglia, Michela %A Yerges-Armstrong, Laura M %A Zhao, Wei %A Goodarzi, Mark O %A Kraja, Aldi T %A Liu, Chunyu %A Wessel, Jennifer %A Boerwinkle, Eric %A Borecki, Ingrid B %A Bork-Jensen, Jette %A Bottinger, Erwin P %A Braga, Daniele %A Brandslund, Ivan %A Brody, Jennifer A %A Campbell, Archie %A Carey, David J %A Christensen, Cramer %A Coresh, Josef %A Crook, Errol %A Curhan, Gary C %A Cusi, Daniele %A de Boer, Ian H %A de Vries, Aiko P J %A Denny, Joshua C %A Devuyst, Olivier %A Dreisbach, Albert W %A Endlich, Karlhans %A Esko, Tõnu %A Franco, Oscar H %A Fulop, Tibor %A Gerhard, Glenn S %A Glümer, Charlotte %A Gottesman, Omri %A Grarup, Niels %A Gudnason, Vilmundur %A Hansen, Torben %A Harris, Tamara B %A Hayward, Caroline %A Hocking, Lynne %A Hofman, Albert %A Hu, Frank B %A Husemoen, Lise Lotte N %A Jackson, Rebecca D %A Jørgensen, Torben %A Jørgensen, Marit E %A Kähönen, Mika %A Kardia, Sharon L R %A König, Wolfgang %A Kooperberg, Charles %A Kriebel, Jennifer %A Launer, Lenore J %A Lauritzen, Torsten %A Lehtimäki, Terho %A Levy, Daniel %A Linksted, Pamela %A Linneberg, Allan %A Liu, Yongmei %A Loos, Ruth J F %A Lupo, Antonio %A Meisinger, Christine %A Melander, Olle %A Metspalu, Andres %A Mitchell, Paul %A Nauck, Matthias %A Nürnberg, Peter %A Orho-Melander, Marju %A Parsa, Afshin %A Pedersen, Oluf %A Peters, Annette %A Peters, Ulrike %A Polasek, Ozren %A Porteous, David %A Probst-Hensch, Nicole M %A Psaty, Bruce M %A Qi, Lu %A Raitakari, Olli T %A Reiner, Alex P %A Rettig, Rainer %A Ridker, Paul M %A Rivadeneira, Fernando %A Rossouw, Jacques E %A Schmidt, Frank %A Siscovick, David %A Soranzo, Nicole %A Strauch, Konstantin %A Toniolo, Daniela %A Turner, Stephen T %A Uitterlinden, André G %A Ulivi, Sheila %A Velayutham, Dinesh %A Völker, Uwe %A Völzke, Henry %A Waldenberger, Melanie %A Wang, Jie Jin %A Weir, David R %A Witte, Daniel %A Kuivaniemi, Helena %A Fox, Caroline S %A Franceschini, Nora %A Goessling, Wolfram %A Köttgen, Anna %A Chu, Audrey Y %K Animals %K Exome %K Genetic Loci %K Genome-Wide Association Study %K Glomerular Filtration Rate %K Humans %K Kidney %K Protein Tyrosine Phosphatases %K Proto-Oncogene Proteins %K Son of Sevenless Proteins %K Zebrafish %X

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (: 111,666; : 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (, , and ; <3.7×10), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, (=5.4×10 by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of and -knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.

%B J Am Soc Nephrol %V 28 %P 981-994 %8 2017 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27920155?dopt=Abstract %R 10.1681/ASN.2016020131 %0 Journal Article %J Nat Genet %D 2015 %T Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair. %A Day, Felix R %A Ruth, Katherine S %A Thompson, Deborah J %A Lunetta, Kathryn L %A Pervjakova, Natalia %A Chasman, Daniel I %A Stolk, Lisette %A Finucane, Hilary K %A Sulem, Patrick %A Bulik-Sullivan, Brendan %A Esko, Tõnu %A Johnson, Andrew D %A Elks, Cathy E %A Franceschini, Nora %A He, Chunyan %A Altmaier, Elisabeth %A Brody, Jennifer A %A Franke, Lude L %A Huffman, Jennifer E %A Keller, Margaux F %A McArdle, Patrick F %A Nutile, Teresa %A Porcu, Eleonora %A Robino, Antonietta %A Rose, Lynda M %A Schick, Ursula M %A Smith, Jennifer A %A Teumer, Alexander %A Traglia, Michela %A Vuckovic, Dragana %A Yao, Jie %A Zhao, Wei %A Albrecht, Eva %A Amin, Najaf %A Corre, Tanguy %A Hottenga, Jouke-Jan %A Mangino, Massimo %A Smith, Albert V %A Tanaka, Toshiko %A Abecasis, Goncalo R %A Andrulis, Irene L %A Anton-Culver, Hoda %A Antoniou, Antonis C %A Arndt, Volker %A Arnold, Alice M %A Barbieri, Caterina %A Beckmann, Matthias W %A Beeghly-Fadiel, Alicia %A Benitez, Javier %A Bernstein, Leslie %A Bielinski, Suzette J %A Blomqvist, Carl %A Boerwinkle, Eric %A Bogdanova, Natalia V %A Bojesen, Stig E %A Bolla, Manjeet K %A Borresen-Dale, Anne-Lise %A Boutin, Thibaud S %A Brauch, Hiltrud %A Brenner, Hermann %A Brüning, Thomas %A Burwinkel, Barbara %A Campbell, Archie %A Campbell, Harry %A Chanock, Stephen J %A Chapman, J Ross %A Chen, Yii-Der Ida %A Chenevix-Trench, Georgia %A Couch, Fergus J %A Coviello, Andrea D %A Cox, Angela %A Czene, Kamila %A Darabi, Hatef %A De Vivo, Immaculata %A Demerath, Ellen W %A Dennis, Joe %A Devilee, Peter %A Dörk, Thilo %A Dos-Santos-Silva, Isabel %A Dunning, Alison M %A Eicher, John D %A Fasching, Peter A %A Faul, Jessica D %A Figueroa, Jonine %A Flesch-Janys, Dieter %A Gandin, Ilaria %A Garcia, Melissa E %A García-Closas, Montserrat %A Giles, Graham G %A Girotto, Giorgia G %A Goldberg, Mark S %A González-Neira, Anna %A Goodarzi, Mark O %A Grove, Megan L %A Gudbjartsson, Daniel F %A Guenel, Pascal %A Guo, Xiuqing %A Haiman, Christopher A %A Hall, Per %A Hamann, Ute %A Henderson, Brian E %A Hocking, Lynne J %A Hofman, Albert %A Homuth, Georg %A Hooning, Maartje J %A Hopper, John L %A Hu, Frank B %A Huang, Jinyan %A Humphreys, Keith %A Hunter, David J %A Jakubowska, Anna %A Jones, Samuel E %A Kabisch, Maria %A Karasik, David %A Knight, Julia A %A Kolcic, Ivana %A Kooperberg, Charles %A Kosma, Veli-Matti %A Kriebel, Jennifer %A Kristensen, Vessela %A Lambrechts, Diether %A Langenberg, Claudia %A Li, Jingmei %A Li, Xin %A Lindström, Sara %A Liu, Yongmei %A Luan, Jian'an %A Lubinski, Jan %A Mägi, Reedik %A Mannermaa, Arto %A Manz, Judith %A Margolin, Sara %A Marten, Jonathan %A Martin, Nicholas G %A Masciullo, Corrado %A Meindl, Alfons %A Michailidou, Kyriaki %A Mihailov, Evelin %A Milani, Lili %A Milne, Roger L %A Müller-Nurasyid, Martina %A Nalls, Michael %A Neale, Benjamin M %A Nevanlinna, Heli %A Neven, Patrick %A Newman, Anne B %A Nordestgaard, Børge G %A Olson, Janet E %A Padmanabhan, Sandosh %A Peterlongo, Paolo %A Peters, Ulrike %A Petersmann, Astrid %A Peto, Julian %A Pharoah, Paul D P %A Pirastu, Nicola N %A Pirie, Ailith %A Pistis, Giorgio %A Polasek, Ozren %A Porteous, David %A Psaty, Bruce M %A Pylkäs, Katri %A Radice, Paolo %A Raffel, Leslie J %A Rivadeneira, Fernando %A Rudan, Igor %A Rudolph, Anja %A Ruggiero, Daniela %A Sala, Cinzia F %A Sanna, Serena %A Sawyer, Elinor J %A Schlessinger, David %A Schmidt, Marjanka K %A Schmidt, Frank %A Schmutzler, Rita K %A Schoemaker, Minouk J %A Scott, Robert A %A Seynaeve, Caroline M %A Simard, Jacques %A Sorice, Rossella %A Southey, Melissa C %A Stöckl, Doris %A Strauch, Konstantin %A Swerdlow, Anthony %A Taylor, Kent D %A Thorsteinsdottir, Unnur %A Toland, Amanda E %A Tomlinson, Ian %A Truong, Therese %A Tryggvadottir, Laufey %A Turner, Stephen T %A Vozzi, Diego %A Wang, Qin %A Wellons, Melissa %A Willemsen, Gonneke %A Wilson, James F %A Winqvist, Robert %A Wolffenbuttel, Bruce B H R %A Wright, Alan F %A Yannoukakos, Drakoulis %A Zemunik, Tatijana %A Zheng, Wei %A Zygmunt, Marek %A Bergmann, Sven %A Boomsma, Dorret I %A Buring, Julie E %A Ferrucci, Luigi %A Montgomery, Grant W %A Gudnason, Vilmundur %A Spector, Tim D %A van Duijn, Cornelia M %A Alizadeh, Behrooz Z %A Ciullo, Marina %A Crisponi, Laura %A Easton, Douglas F %A Gasparini, Paolo P %A Gieger, Christian %A Harris, Tamara B %A Hayward, Caroline %A Kardia, Sharon L R %A Kraft, Peter %A McKnight, Barbara %A Metspalu, Andres %A Morrison, Alanna C %A Reiner, Alex P %A Ridker, Paul M %A Rotter, Jerome I %A Toniolo, Daniela %A Uitterlinden, André G %A Ulivi, Sheila %A Völzke, Henry %A Wareham, Nicholas J %A Weir, David R %A Yerges-Armstrong, Laura M %A Price, Alkes L %A Stefansson, Kari %A Visser, Jenny A %A Ong, Ken K %A Chang-Claude, Jenny %A Murabito, Joanne M %A Perry, John R B %A Murray, Anna %X

Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ∼70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (∼6% increase in risk per year; P = 3 × 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

%B Nat Genet %V 47 %P 1294-303 %8 2015 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/26414677?dopt=Abstract %R 10.1038/ng.3412