%0 Journal Article %J Nat Commun %D 2015 %T Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility. %A Wessel, Jennifer %A Chu, Audrey Y %A Willems, Sara M %A Wang, Shuai %A Yaghootkar, Hanieh %A Brody, Jennifer A %A Dauriz, Marco %A Hivert, Marie-France %A Raghavan, Sridharan %A Lipovich, Leonard %A Hidalgo, Bertha %A Fox, Keolu %A Huffman, Jennifer E %A An, Ping %A Lu, Yingchang %A Rasmussen-Torvik, Laura J %A Grarup, Niels %A Ehm, Margaret G %A Li, Li %A Baldridge, Abigail S %A Stančáková, Alena %A Abrol, Ravinder %A Besse, Céline %A Boland, Anne %A Bork-Jensen, Jette %A Fornage, Myriam %A Freitag, Daniel F %A Garcia, Melissa E %A Guo, Xiuqing %A Hara, Kazuo %A Isaacs, Aaron %A Jakobsdottir, Johanna %A Lange, Leslie A %A Layton, Jill C %A Li, Man %A Hua Zhao, Jing %A Meidtner, Karina %A Morrison, Alanna C %A Nalls, Mike A %A Peters, Marjolein J %A Sabater-Lleal, Maria %A Schurmann, Claudia %A Silveira, Angela %A Smith, Albert V %A Southam, Lorraine %A Stoiber, Marcus H %A Strawbridge, Rona J %A Taylor, Kent D %A Varga, Tibor V %A Allin, Kristine H %A Amin, Najaf %A Aponte, Jennifer L %A Aung, Tin %A Barbieri, Caterina %A Bihlmeyer, Nathan A %A Boehnke, Michael %A Bombieri, Cristina %A Bowden, Donald W %A Burns, Sean M %A Chen, Yuning %A Chen, Yii-DerI %A Cheng, Ching-Yu %A Correa, Adolfo %A Czajkowski, Jacek %A Dehghan, Abbas %A Ehret, Georg B %A Eiriksdottir, Gudny %A Escher, Stefan A %A Farmaki, Aliki-Eleni %A Frånberg, Mattias %A Gambaro, Giovanni %A Giulianini, Franco %A Goddard, William A %A Goel, Anuj %A Gottesman, Omri %A Grove, Megan L %A Gustafsson, Stefan %A Hai, Yang %A Hallmans, Göran %A Heo, Jiyoung %A Hoffmann, Per %A Ikram, Mohammad K %A Jensen, Richard A %A Jørgensen, Marit E %A Jørgensen, Torben %A Karaleftheri, Maria %A Khor, Chiea C %A Kirkpatrick, Andrea %A Kraja, Aldi T %A Kuusisto, Johanna %A Lange, Ethan M %A Lee, I T %A Lee, Wen-Jane %A Leong, Aaron %A Liao, Jiemin %A Liu, Chunyu %A Liu, Yongmei %A Lindgren, Cecilia M %A Linneberg, Allan %A Malerba, Giovanni %A Mamakou, Vasiliki %A Marouli, Eirini %A Maruthur, Nisa M %A Matchan, Angela %A McKean-Cowdin, Roberta %A McLeod, Olga %A Metcalf, Ginger A %A Mohlke, Karen L %A Muzny, Donna M %A Ntalla, Ioanna %A Palmer, Nicholette D %A Pasko, Dorota %A Peter, Andreas %A Rayner, Nigel W %A Renstrom, Frida %A Rice, Ken %A Sala, Cinzia F %A Sennblad, Bengt %A Serafetinidis, Ioannis %A Smith, Jennifer A %A Soranzo, Nicole %A Speliotes, Elizabeth K %A Stahl, Eli A %A Stirrups, Kathleen %A Tentolouris, Nikos %A Thanopoulou, Anastasia %A Torres, Mina %A Traglia, Michela %A Tsafantakis, Emmanouil %A Javad, Sundas %A Yanek, Lisa R %A Zengini, Eleni %A Becker, Diane M %A Bis, Joshua C %A Brown, James B %A Cupples, L Adrienne %A Hansen, Torben %A Ingelsson, Erik %A Karter, Andrew J %A Lorenzo, Carlos %A Mathias, Rasika A %A Norris, Jill M %A Peloso, Gina M %A Sheu, Wayne H-H %A Toniolo, Daniela %A Vaidya, Dhananjay %A Varma, Rohit %A Wagenknecht, Lynne E %A Boeing, Heiner %A Bottinger, Erwin P %A Dedoussis, George %A Deloukas, Panos %A Ferrannini, Ele %A Franco, Oscar H %A Franks, Paul W %A Gibbs, Richard A %A Gudnason, Vilmundur %A Hamsten, Anders %A Harris, Tamara B %A Hattersley, Andrew T %A Hayward, Caroline %A Hofman, Albert %A Jansson, Jan-Håkan %A Langenberg, Claudia %A Launer, Lenore J %A Levy, Daniel %A Oostra, Ben A %A O'Donnell, Christopher J %A O'Rahilly, Stephen %A Padmanabhan, Sandosh %A Pankow, James S %A Polasek, Ozren %A Province, Michael A %A Rich, Stephen S %A Ridker, Paul M %A Rudan, Igor %A Schulze, Matthias B %A Smith, Blair H %A Uitterlinden, André G %A Walker, Mark %A Watkins, Hugh %A Wong, Tien Y %A Zeggini, Eleftheria %A Laakso, Markku %A Borecki, Ingrid B %A Chasman, Daniel I %A Pedersen, Oluf %A Psaty, Bruce M %A Tai, E Shyong %A van Duijn, Cornelia M %A Wareham, Nicholas J %A Waterworth, Dawn M %A Boerwinkle, Eric %A Kao, W H Linda %A Florez, Jose C %A Loos, Ruth J F %A Wilson, James G %A Frayling, Timothy M %A Siscovick, David S %A Dupuis, Josée %A Rotter, Jerome I %A Meigs, James B %A Scott, Robert A %A Goodarzi, Mark O %K African Continental Ancestry Group %K Blood Glucose %K Diabetes Mellitus, Type 2 %K European Continental Ancestry Group %K Exome %K Fasting %K Genetic Association Studies %K Genetic Loci %K Genetic Predisposition to Disease %K Genetic Variation %K Glucagon-Like Peptide-1 Receptor %K Glucose-6-Phosphatase %K Humans %K Insulin %K Mutation Rate %K Oligonucleotide Array Sequence Analysis %K Polymorphism, Single Nucleotide %X

Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol l(-1), P=3.4 × 10(-12)), T2D risk (OR[95%CI]=0.86[0.76-0.96], P=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose(-1), P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l(-1), P=4.3 × 10(-4)). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l(-1), P=1.3 × 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.

%B Nat Commun %V 6 %P 5897 %8 2015 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/25631608?dopt=Abstract %R 10.1038/ncomms6897 %0 Journal Article %J Proc Natl Acad Sci U S A %D 2016 %T KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference. %A Schumann, Gunter %A Liu, Chunyu %A O'Reilly, Paul %A Gao, He %A Song, Parkyong %A Xu, Bing %A Ruggeri, Barbara %A Amin, Najaf %A Jia, Tianye %A Preis, Sarah %A Segura Lepe, Marcelo %A Akira, Shizuo %A Barbieri, Caterina %A Baumeister, Sebastian %A Cauchi, Stephane %A Clarke, Toni-Kim %A Enroth, Stefan %A Fischer, Krista %A Hällfors, Jenni %A Harris, Sarah E %A Hieber, Saskia %A Hofer, Edith %A Hottenga, Jouke-Jan %A Johansson, Asa %A Joshi, Peter K %A Kaartinen, Niina %A Laitinen, Jaana %A Lemaitre, Rozenn %A Loukola, Anu %A Luan, Jian'an %A Lyytikäinen, Leo-Pekka %A Mangino, Massimo %A Manichaikul, Ani %A Mbarek, Hamdi %A Milaneschi, Yuri %A Moayyeri, Alireza %A Mukamal, Kenneth %A Nelson, Christopher %A Nettleton, Jennifer %A Partinen, Eemil %A Rawal, Rajesh %A Robino, Antonietta %A Rose, Lynda %A Sala, Cinzia %A Satoh, Takashi %A Schmidt, Reinhold %A Schraut, Katharina %A Scott, Robert %A Smith, Albert Vernon %A Starr, John M %A Teumer, Alexander %A Trompet, Stella %A Uitterlinden, André G %A Venturini, Cristina %A Vergnaud, Anne-Claire %A Verweij, Niek %A Vitart, Veronique %A Vuckovic, Dragana %A Wedenoja, Juho %A Yengo, Loic %A Yu, Bing %A Zhang, Weihua %A Zhao, Jing Hua %A Boomsma, Dorret I %A Chambers, John %A Chasman, Daniel I %A Daniela, Toniolo %A de Geus, Eco %A Deary, Ian %A Eriksson, Johan G %A Esko, Tõnu %A Eulenburg, Volker %A Franco, Oscar H %A Froguel, Philippe %A Gieger, Christian %A Grabe, Hans J %A Gudnason, Vilmundur %A Gyllensten, Ulf %A Harris, Tamara B %A Hartikainen, Anna-Liisa %A Heath, Andrew C %A Hocking, Lynne %A Hofman, Albert %A Huth, Cornelia %A Jarvelin, Marjo-Riitta %A Jukema, J Wouter %A Kaprio, Jaakko %A Kooner, Jaspal S %A Kutalik, Zoltán %A Lahti, Jari %A Langenberg, Claudia %A Lehtimäki, Terho %A Liu, Yongmei %A Madden, Pamela A F %A Martin, Nicholas %A Morrison, Alanna %A Penninx, Brenda %A Pirastu, Nicola %A Psaty, Bruce %A Raitakari, Olli %A Ridker, Paul %A Rose, Richard %A Rotter, Jerome I %A Samani, Nilesh J %A Schmidt, Helena %A Spector, Tim D %A Stott, David %A Strachan, David %A Tzoulaki, Ioanna %A van der Harst, Pim %A van Duijn, Cornelia M %A Marques-Vidal, Pedro %A Vollenweider, Peter %A Wareham, Nicholas J %A Whitfield, John B %A Wilson, James %A Wolffenbuttel, Bruce %A Bakalkin, Georgy %A Evangelou, Evangelos %A Liu, Yun %A Rice, Kenneth M %A Desrivières, Sylvane %A Kliewer, Steven A %A Mangelsdorf, David J %A Müller, Christian P %A Levy, Daniel %A Elliott, Paul %X

Excessive alcohol consumption is a major public health problem worldwide. Although drinking habits are known to be inherited, few genes have been identified that are robustly linked to alcohol drinking. We conducted a genome-wide association metaanalysis and replication study among >105,000 individuals of European ancestry and identified β-Klotho (KLB) as a locus associated with alcohol consumption (rs11940694; P = 9.2 × 10(-12)). β-Klotho is an obligate coreceptor for the hormone FGF21, which is secreted from the liver and implicated in macronutrient preference in humans. We show that brain-specific β-Klotho KO mice have an increased alcohol preference and that FGF21 inhibits alcohol drinking by acting on the brain. These data suggest that a liver-brain endocrine axis may play an important role in the regulation of alcohol drinking behavior and provide a unique pharmacologic target for reducing alcohol consumption.

%B Proc Natl Acad Sci U S A %V 113 %P 14372-14377 %8 2016 Dec 13 %G eng %N 50 %R 10.1073/pnas.1611243113 %0 Journal Article %J Nat Commun %D 2018 %T Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation. %A Teumer, Alexander %A Chaker, Layal %A Groeneweg, Stefan %A Li, Yong %A Di Munno, Celia %A Barbieri, Caterina %A Schultheiss, Ulla T %A Traglia, Michela %A Ahluwalia, Tarunveer S %A Akiyama, Masato %A Appel, Emil Vincent R %A Arking, Dan E %A Arnold, Alice %A Astrup, Arne %A Beekman, Marian %A Beilby, John P %A Bekaert, Sofie %A Boerwinkle, Eric %A Brown, Suzanne J %A De Buyzere, Marc %A Campbell, Purdey J %A Ceresini, Graziano %A Cerqueira, Charlotte %A Cucca, Francesco %A Deary, Ian J %A Deelen, Joris %A Eckardt, Kai-Uwe %A Ekici, Arif B %A Eriksson, Johan G %A Ferrrucci, Luigi %A Fiers, Tom %A Fiorillo, Edoardo %A Ford, Ian %A Fox, Caroline S %A Fuchsberger, Christian %A Galesloot, Tessel E %A Gieger, Christian %A Gögele, Martin %A De Grandi, Alessandro %A Grarup, Niels %A Greiser, Karin Halina %A Haljas, Kadri %A Hansen, Torben %A Harris, Sarah E %A van Heemst, Diana %A den Heijer, Martin %A Hicks, Andrew A %A den Hollander, Wouter %A Homuth, Georg %A Hui, Jennie %A Ikram, M Arfan %A Ittermann, Till %A Jensen, Richard A %A Jing, Jiaojiao %A Jukema, J Wouter %A Kajantie, Eero %A Kamatani, Yoichiro %A Kasbohm, Elisa %A Kaufman, Jean-Marc %A Kiemeney, Lambertus A %A Kloppenburg, Margreet %A Kronenberg, Florian %A Kubo, Michiaki %A Lahti, Jari %A Lapauw, Bruno %A Li, Shuo %A Liewald, David C M %A Lim, Ee Mun %A Linneberg, Allan %A Marina, Michela %A Mascalzoni, Deborah %A Matsuda, Koichi %A Medenwald, Daniel %A Meisinger, Christa %A Meulenbelt, Ingrid %A De Meyer, Tim %A Meyer zu Schwabedissen, Henriette E %A Mikolajczyk, Rafael %A Moed, Matthijs %A Netea-Maier, Romana T %A Nolte, Ilja M %A Okada, Yukinori %A Pala, Mauro %A Pattaro, Cristian %A Pedersen, Oluf %A Petersmann, Astrid %A Porcu, Eleonora %A Postmus, Iris %A Pramstaller, Peter P %A Psaty, Bruce M %A Ramos, Yolande F M %A Rawal, Rajesh %A Redmond, Paul %A Richards, J Brent %A Rietzschel, Ernst R %A Rivadeneira, Fernando %A Roef, Greet %A Rotter, Jerome I %A Sala, Cinzia F %A Schlessinger, David %A Selvin, Elizabeth %A Slagboom, P Eline %A Soranzo, Nicole %A Sørensen, Thorkild I A %A Spector, Timothy D %A Starr, John M %A Stott, David J %A Taes, Youri %A Taliun, Daniel %A Tanaka, Toshiko %A Thuesen, Betina %A Tiller, Daniel %A Toniolo, Daniela %A Uitterlinden, André G %A Visser, W Edward %A Walsh, John P %A Wilson, Scott G %A Wolffenbuttel, Bruce H R %A Yang, Qiong %A Zheng, Hou-Feng %A Cappola, Anne %A Peeters, Robin P %A Naitza, Silvia %A Völzke, Henry %A Sanna, Serena %A Köttgen, Anna %A Visser, Theo J %A Medici, Marco %X

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.

%B Nat Commun %V 9 %P 4455 %8 2018 10 26 %G eng %N 1 %R 10.1038/s41467-018-06356-1