%0 Journal Article %J Nat Genet %D 2012 %T Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways. %A Stolk, Lisette %A Perry, John R B %A Chasman, Daniel I %A He, Chunyan %A Mangino, Massimo %A Sulem, Patrick %A Barbalic, Maja %A Broer, Linda %A Byrne, Enda M %A Ernst, Florian %A Esko, Tõnu %A Franceschini, Nora %A Gudbjartsson, Daniel F %A Hottenga, Jouke-Jan %A Kraft, Peter %A McArdle, Patrick F %A Porcu, Eleonora %A Shin, So-Youn %A Smith, Albert V %A van Wingerden, Sophie %A Zhai, Guangju %A Zhuang, Wei V %A Albrecht, Eva %A Alizadeh, Behrooz Z %A Aspelund, Thor %A Bandinelli, Stefania %A Lauc, Lovorka Barac %A Beckmann, Jacques S %A Boban, Mladen %A Boerwinkle, Eric %A Broekmans, Frank J %A Burri, Andrea %A Campbell, Harry %A Chanock, Stephen J %A Chen, Constance %A Cornelis, Marilyn C %A Corre, Tanguy %A Coviello, Andrea D %A D'Adamo, Pio %A Davies, Gail %A de Faire, Ulf %A de Geus, Eco J C %A Deary, Ian J %A Dedoussis, George V Z %A Deloukas, Panagiotis %A Ebrahim, Shah %A Eiriksdottir, Gudny %A Emilsson, Valur %A Eriksson, Johan G %A Fauser, Bart C J M %A Ferreli, Liana %A Ferrucci, Luigi %A Fischer, Krista %A Folsom, Aaron R %A Garcia, Melissa E %A Gasparini, Paolo %A Gieger, Christian %A Glazer, Nicole %A Grobbee, Diederick E %A Hall, Per %A Haller, Toomas %A Hankinson, Susan E %A Hass, Merli %A Hayward, Caroline %A Heath, Andrew C %A Hofman, Albert %A Ingelsson, Erik %A Janssens, A Cecile J W %A Johnson, Andrew D %A Karasik, David %A Kardia, Sharon L R %A Keyzer, Jules %A Kiel, Douglas P %A Kolcic, Ivana %A Kutalik, Zoltán %A Lahti, Jari %A Lai, Sandra %A Laisk, Triin %A Laven, Joop S E %A Lawlor, Debbie A %A Liu, Jianjun %A Lopez, Lorna M %A Louwers, Yvonne V %A Magnusson, Patrik K E %A Marongiu, Mara %A Martin, Nicholas G %A Klaric, Irena Martinovic %A Masciullo, Corrado %A McKnight, Barbara %A Medland, Sarah E %A Melzer, David %A Mooser, Vincent %A Navarro, Pau %A Newman, Anne B %A Nyholt, Dale R %A Onland-Moret, N Charlotte %A Palotie, Aarno %A Paré, Guillaume %A Parker, Alex N %A Pedersen, Nancy L %A Peeters, Petra H M %A Pistis, Giorgio %A Plump, Andrew S %A Polasek, Ozren %A Pop, Victor J M %A Psaty, Bruce M %A Räikkönen, Katri %A Rehnberg, Emil %A Rotter, Jerome I %A Rudan, Igor %A Sala, Cinzia %A Salumets, Andres %A Scuteri, Angelo %A Singleton, Andrew %A Smith, Jennifer A %A Snieder, Harold %A Soranzo, Nicole %A Stacey, Simon N %A Starr, John M %A Stathopoulou, Maria G %A Stirrups, Kathleen %A Stolk, Ronald P %A Styrkarsdottir, Unnur %A Sun, Yan V %A Tenesa, Albert %A Thorand, Barbara %A Toniolo, Daniela %A Tryggvadottir, Laufey %A Tsui, Kim %A Ulivi, Sheila %A van Dam, Rob M %A van der Schouw, Yvonne T %A van Gils, Carla H %A van Nierop, Peter %A Vink, Jacqueline M %A Visscher, Peter M %A Voorhuis, Marlies %A Waeber, Gérard %A Wallaschofski, Henri %A Wichmann, H Erich %A Widen, Elisabeth %A Wijnands-van Gent, Colette J M %A Willemsen, Gonneke %A Wilson, James F %A Wolffenbuttel, Bruce H R %A Wright, Alan F %A Yerges-Armstrong, Laura M %A Zemunik, Tatijana %A Zgaga, Lina %A Zillikens, M Carola %A Zygmunt, Marek %A Arnold, Alice M %A Boomsma, Dorret I %A Buring, Julie E %A Crisponi, Laura %A Demerath, Ellen W %A Gudnason, Vilmundur %A Harris, Tamara B %A Hu, Frank B %A Hunter, David J %A Launer, Lenore J %A Metspalu, Andres %A Montgomery, Grant W %A Oostra, Ben A %A Ridker, Paul M %A Sanna, Serena %A Schlessinger, David %A Spector, Tim D %A Stefansson, Kari %A Streeten, Elizabeth A %A Thorsteinsdottir, Unnur %A Uda, Manuela %A Uitterlinden, André G %A van Duijn, Cornelia M %A Völzke, Henry %A Murray, Anna %A Murabito, Joanne M %A Visser, Jenny A %A Lunetta, Kathryn L %K Age Factors %K DNA Helicases %K DNA Polymerase gamma %K DNA Primase %K DNA Repair %K DNA Repair Enzymes %K DNA-Directed DNA Polymerase %K European Continental Ancestry Group %K Exodeoxyribonucleases %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Immunity %K Menopause %K Polymorphism, Single Nucleotide %K Proteins %X

To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.

%B Nat Genet %V 44 %P 260-8 %8 2012 Jan 22 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/22267201?dopt=Abstract %R 10.1038/ng.1051 %0 Journal Article %J Biol Psychiatry %D 2013 %T A genome-wide association study of depressive symptoms. %A Hek, Karin %A Demirkan, Ayse %A Lahti, Jari %A Terracciano, Antonio %A Teumer, Alexander %A Cornelis, Marilyn C %A Amin, Najaf %A Bakshis, Erin %A Baumert, Jens %A Ding, Jingzhong %A Liu, Yongmei %A Marciante, Kristin %A Meirelles, Osorio %A Nalls, Michael A %A Sun, Yan V %A Vogelzangs, Nicole %A Yu, Lei %A Bandinelli, Stefania %A Benjamin, Emelia J %A Bennett, David A %A Boomsma, Dorret %A Cannas, Alessandra %A Coker, Laura H %A de Geus, Eco %A De Jager, Philip L %A Diez-Roux, Ana V %A Purcell, Shaun %A Hu, Frank B %A Rimma, Eric B %A Hunter, David J %A Jensen, Majken K %A Curhan, Gary %A Rice, Kenneth %A Penman, Alan D %A Rotter, Jerome I %A Sotoodehnia, Nona %A Emeny, Rebecca %A Eriksson, Johan G %A Evans, Denis A %A Ferrucci, Luigi %A Fornage, Myriam %A Gudnason, Vilmundur %A Hofman, Albert %A Illig, Thomas %A Kardia, Sharon %A Kelly-Hayes, Margaret %A Koenen, Karestan %A Kraft, Peter %A Kuningas, Maris %A Massaro, Joseph M %A Melzer, David %A Mulas, Antonella %A Mulder, Cornelis L %A Murray, Anna %A Oostra, Ben A %A Palotie, Aarno %A Penninx, Brenda %A Petersmann, Astrid %A Pilling, Luke C %A Psaty, Bruce %A Rawal, Rajesh %A Reiman, Eric M %A Schulz, Andrea %A Shulman, Joshua M %A Singleton, Andrew B %A Smith, Albert V %A Sutin, Angelina R %A Uitterlinden, André G %A Völzke, Henry %A Widen, Elisabeth %A Yaffe, Kristine %A Zonderman, Alan B %A Cucca, Francesco %A Harris, Tamara %A Ladwig, Karl-Heinz %A Llewellyn, David J %A Räikkönen, Katri %A Tanaka, Toshiko %A van Duijn, Cornelia M %A Grabe, Hans J %A Launer, Lenore J %A Lunetta, Kathryn L %A Mosley, Thomas H %A Newman, Anne B %A Tiemeier, Henning %A Murabito, Joanne %K Aged %K Aged, 80 and over %K Chromosomes, Human, Pair 5 %K Depression %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %X

BACKGROUND: Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms.

METHODS: In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p<1×10(-5)) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies.

RESULTS: The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05×10(-7)). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, p = 9.19×10(-3)). This 5q21 region reached genome-wide significance (p = 4.78×10(-8)) in the overall meta-analysis combining discovery and replication studies (n = 51,258).

CONCLUSIONS: The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms.

%B Biol Psychiatry %V 73 %P 667-78 %8 2013 Apr 01 %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/23290196?dopt=Abstract %R 10.1016/j.biopsych.2012.09.033 %0 Journal Article %J PLoS Genet %D 2013 %T A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function. %A Porcu, Eleonora %A Medici, Marco %A Pistis, Giorgio %A Volpato, Claudia B %A Wilson, Scott G %A Cappola, Anne R %A Bos, Steffan D %A Deelen, Joris %A den Heijer, Martin %A Freathy, Rachel M %A Lahti, Jari %A Liu, Chunyu %A Lopez, Lorna M %A Nolte, Ilja M %A O'Connell, Jeffrey R %A Tanaka, Toshiko %A Trompet, Stella %A Arnold, Alice %A Bandinelli, Stefania %A Beekman, Marian %A Böhringer, Stefan %A Brown, Suzanne J %A Buckley, Brendan M %A Camaschella, Clara %A de Craen, Anton J M %A Davies, Gail %A de Visser, Marieke C H %A Ford, Ian %A Forsen, Tom %A Frayling, Timothy M %A Fugazzola, Laura %A Gögele, Martin %A Hattersley, Andrew T %A Hermus, Ad R %A Hofman, Albert %A Houwing-Duistermaat, Jeanine J %A Jensen, Richard A %A Kajantie, Eero %A Kloppenburg, Margreet %A Lim, Ee M %A Masciullo, Corrado %A Mariotti, Stefano %A Minelli, Cosetta %A Mitchell, Braxton D %A Nagaraja, Ramaiah %A Netea-Maier, Romana T %A Palotie, Aarno %A Persani, Luca %A Piras, Maria G %A Psaty, Bruce M %A Räikkönen, Katri %A Richards, J Brent %A Rivadeneira, Fernando %A Sala, Cinzia %A Sabra, Mona M %A Sattar, Naveed %A Shields, Beverley M %A Soranzo, Nicole %A Starr, John M %A Stott, David J %A Sweep, Fred C G J %A Usala, Gianluca %A van der Klauw, Melanie M %A van Heemst, Diana %A van Mullem, Alies %A Vermeulen, Sita H %A Visser, W Edward %A Walsh, John P %A Westendorp, Rudi G J %A Widen, Elisabeth %A Zhai, Guangju %A Cucca, Francesco %A Deary, Ian J %A Eriksson, Johan G %A Ferrucci, Luigi %A Fox, Caroline S %A Jukema, J Wouter %A Kiemeney, Lambertus A %A Pramstaller, Peter P %A Schlessinger, David %A Shuldiner, Alan R %A Slagboom, Eline P %A Uitterlinden, André G %A Vaidya, Bijay %A Visser, Theo J %A Wolffenbuttel, Bruce H R %A Meulenbelt, Ingrid %A Rotter, Jerome I %A Spector, Tim D %A Hicks, Andrew A %A Toniolo, Daniela %A Sanna, Serena %A Peeters, Robin P %A Naitza, Silvia %K Female %K Genome-Wide Association Study %K Humans %K Hyperthyroidism %K Hypothyroidism %K Male %K Phenotype %K Polymorphism, Genetic %K Polymorphism, Single Nucleotide %K Sex Characteristics %K Signal Transduction %K Thyroid Gland %K Thyrotropin %K Thyroxine %X

Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.

%B PLoS Genet %V 9 %P e1003266 %8 2013 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/23408906?dopt=Abstract %R 10.1371/journal.pgen.1003266 %0 Journal Article %J Circulation %D 2013 %T Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease. %A Sabater-Lleal, Maria %A Huang, Jie %A Chasman, Daniel %A Naitza, Silvia %A Dehghan, Abbas %A Johnson, Andrew D %A Teumer, Alexander %A Reiner, Alex P %A Folkersen, Lasse %A Basu, Saonli %A Rudnicka, Alicja R %A Trompet, Stella %A Mälarstig, Anders %A Baumert, Jens %A Bis, Joshua C %A Guo, Xiuqing %A Hottenga, Jouke J %A Shin, So-Youn %A Lopez, Lorna M %A Lahti, Jari %A Tanaka, Toshiko %A Yanek, Lisa R %A Oudot-Mellakh, Tiphaine %A Wilson, James F %A Navarro, Pau %A Huffman, Jennifer E %A Zemunik, Tatijana %A Redline, Susan %A Mehra, Reena %A Pulanic, Drazen %A Rudan, Igor %A Wright, Alan F %A Kolcic, Ivana %A Polasek, Ozren %A Wild, Sarah H %A Campbell, Harry %A Curb, J David %A Wallace, Robert %A Liu, Simin %A Eaton, Charles B %A Becker, Diane M %A Becker, Lewis C %A Bandinelli, Stefania %A Räikkönen, Katri %A Widen, Elisabeth %A Palotie, Aarno %A Fornage, Myriam %A Green, David %A Gross, Myron %A Davies, Gail %A Harris, Sarah E %A Liewald, David C %A Starr, John M %A Williams, Frances M K %A Grant, Peter J %A Spector, Timothy D %A Strawbridge, Rona J %A Silveira, Angela %A Sennblad, Bengt %A Rivadeneira, Fernando %A Uitterlinden, André G %A Franco, Oscar H %A Hofman, Albert %A van Dongen, Jenny %A Willemsen, Gonneke %A Boomsma, Dorret I %A Yao, Jie %A Swords Jenny, Nancy %A Haritunians, Talin %A McKnight, Barbara %A Lumley, Thomas %A Taylor, Kent D %A Rotter, Jerome I %A Psaty, Bruce M %A Peters, Annette %A Gieger, Christian %A Illig, Thomas %A Grotevendt, Anne %A Homuth, Georg %A Völzke, Henry %A Kocher, Thomas %A Goel, Anuj %A Franzosi, Maria Grazia %A Seedorf, Udo %A Clarke, Robert %A Steri, Maristella %A Tarasov, Kirill V %A Sanna, Serena %A Schlessinger, David %A Stott, David J %A Sattar, Naveed %A Buckley, Brendan M %A Rumley, Ann %A Lowe, Gordon D %A McArdle, Wendy L %A Chen, Ming-Huei %A Tofler, Geoffrey H %A Song, Jaejoon %A Boerwinkle, Eric %A Folsom, Aaron R %A Rose, Lynda M %A Franco-Cereceda, Anders %A Teichert, Martina %A Ikram, M Arfan %A Mosley, Thomas H %A Bevan, Steve %A Dichgans, Martin %A Rothwell, Peter M %A Sudlow, Cathie L M %A Hopewell, Jemma C %A Chambers, John C %A Saleheen, Danish %A Kooner, Jaspal S %A Danesh, John %A Nelson, Christopher P %A Erdmann, Jeanette %A Reilly, Muredach P %A Kathiresan, Sekar %A Schunkert, Heribert %A Morange, Pierre-Emmanuel %A Ferrucci, Luigi %A Eriksson, Johan G %A Jacobs, David %A Deary, Ian J %A Soranzo, Nicole %A Witteman, Jacqueline C M %A de Geus, Eco J C %A Tracy, Russell P %A Hayward, Caroline %A Koenig, Wolfgang %A Cucca, Francesco %A Jukema, J Wouter %A Eriksson, Per %A Seshadri, Sudha %A Markus, Hugh S %A Watkins, Hugh %A Samani, Nilesh J %A Wallaschofski, Henri %A Smith, Nicholas L %A Tregouet, David %A Ridker, Paul M %A Tang, Weihong %A Strachan, David P %A Hamsten, Anders %A O'Donnell, Christopher J %K Adolescent %K Adult %K African Continental Ancestry Group %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Coronary Artery Disease %K European Continental Ancestry Group %K Female %K Fibrinogen %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Hispanic Americans %K Humans %K Male %K Middle Aged %K Myocardial Infarction %K Polymorphism, Single Nucleotide %K Risk Factors %K Stroke %K Venous Thromboembolism %K Young Adult %X

BACKGROUND: Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2%) of its variation.

METHODS AND RESULTS: We conducted a meta-analysis of 28 genome-wide association studies including >90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant (P<5×10(-8)) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism.

CONCLUSIONS: We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.

%B Circulation %V 128 %P 1310-24 %8 2013 Sep 17 %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/23969696?dopt=Abstract %R 10.1161/CIRCULATIONAHA.113.002251 %0 Journal Article %J PLoS Genet %D 2014 %T Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease. %A Medici, Marco %A Porcu, Eleonora %A Pistis, Giorgio %A Teumer, Alexander %A Brown, Suzanne J %A Jensen, Richard A %A Rawal, Rajesh %A Roef, Greet L %A Plantinga, Theo S %A Vermeulen, Sita H %A Lahti, Jari %A Simmonds, Matthew J %A Husemoen, Lise Lotte N %A Freathy, Rachel M %A Shields, Beverley M %A Pietzner, Diana %A Nagy, Rebecca %A Broer, Linda %A Chaker, Layal %A Korevaar, Tim I M %A Plia, Maria Grazia %A Sala, Cinzia %A Völker, Uwe %A Richards, J Brent %A Sweep, Fred C %A Gieger, Christian %A Corre, Tanguy %A Kajantie, Eero %A Thuesen, Betina %A Taes, Youri E %A Visser, W Edward %A Hattersley, Andrew T %A Kratzsch, Jürgen %A Hamilton, Alexander %A Li, Wei %A Homuth, Georg %A Lobina, Monia %A Mariotti, Stefano %A Soranzo, Nicole %A Cocca, Massimiliano %A Nauck, Matthias %A Spielhagen, Christin %A Ross, Alec %A Arnold, Alice %A van de Bunt, Martijn %A Liyanarachchi, Sandya %A Heier, Margit %A Grabe, Hans Jörgen %A Masciullo, Corrado %A Galesloot, Tessel E %A Lim, Ee M %A Reischl, Eva %A Leedman, Peter J %A Lai, Sandra %A Delitala, Alessandro %A Bremner, Alexandra P %A Philips, David I W %A Beilby, John P %A Mulas, Antonella %A Vocale, Matteo %A Abecasis, Goncalo %A Forsen, Tom %A James, Alan %A Widen, Elisabeth %A Hui, Jennie %A Prokisch, Holger %A Rietzschel, Ernst E %A Palotie, Aarno %A Feddema, Peter %A Fletcher, Stephen J %A Schramm, Katharina %A Rotter, Jerome I %A Kluttig, Alexander %A Radke, Dörte %A Traglia, Michela %A Surdulescu, Gabriela L %A He, Huiling %A Franklyn, Jayne A %A Tiller, Daniel %A Vaidya, Bijay %A De Meyer, Tim %A Jørgensen, Torben %A Eriksson, Johan G %A O'Leary, Peter C %A Wichmann, Eric %A Hermus, Ad R %A Psaty, Bruce M %A Ittermann, Till %A Hofman, Albert %A Bosi, Emanuele %A Schlessinger, David %A Wallaschofski, Henri %A Pirastu, Nicola %A Aulchenko, Yurii S %A de la Chapelle, Albert %A Netea-Maier, Romana T %A Gough, Stephen C L %A Meyer Zu Schwabedissen, Henriette %A Frayling, Timothy M %A Kaufman, Jean-Marc %A Linneberg, Allan %A Räikkönen, Katri %A Smit, Johannes W A %A Kiemeney, Lambertus A %A Rivadeneira, Fernando %A Uitterlinden, André G %A Walsh, John P %A Meisinger, Christa %A den Heijer, Martin %A Visser, Theo J %A Spector, Timothy D %A Wilson, Scott G %A Völzke, Henry %A Cappola, Anne %A Toniolo, Daniela %A Sanna, Serena %A Naitza, Silvia %A Peeters, Robin P %K Autoantibodies %K Genetic Loci %K Genome-Wide Association Study %K Graves Disease %K Hashimoto Disease %K Humans %K Iodide Peroxidase %K Risk Factors %K Thyroiditis, Autoimmune %K Thyrotropin %X

Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5×10(-8)) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68-2.81, P = 8.1×10(-8)), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26-1.82, P = 2.9×10(-6)), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66-0.89, P = 6.5×10(-4)). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves' disease (OR: 1.37, 95% CI 1.22-1.54, P = 1.2×10(-7) and OR: 1.25, 95% CI 1.12-1.39, P = 6.2×10(-5)). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18-2.10, P = 1.9×10(-3)). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction.

%B PLoS Genet %V 10 %P e1004123 %8 2014 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24586183?dopt=Abstract %R 10.1371/journal.pgen.1004123 %0 Journal Article %J PLoS One %D 2014 %T No evidence for genome-wide interactions on plasma fibrinogen by smoking, alcohol consumption and body mass index: results from meta-analyses of 80,607 subjects. %A Baumert, Jens %A Huang, Jie %A McKnight, Barbara %A Sabater-Lleal, Maria %A Steri, Maristella %A Chu, Audrey Y %A Trompet, Stella %A Lopez, Lorna M %A Fornage, Myriam %A Teumer, Alexander %A Tang, Weihong %A Rudnicka, Alicja R %A Mälarstig, Anders %A Hottenga, Jouke-Jan %A Kavousi, Maryam %A Lahti, Jari %A Tanaka, Toshiko %A Hayward, Caroline %A Huffman, Jennifer E %A Morange, Pierre-Emmanuel %A Rose, Lynda M %A Basu, Saonli %A Rumley, Ann %A Stott, David J %A Buckley, Brendan M %A de Craen, Anton J M %A Sanna, Serena %A Masala, Marco %A Biffar, Reiner %A Homuth, Georg %A Silveira, Angela %A Sennblad, Bengt %A Goel, Anuj %A Watkins, Hugh %A Müller-Nurasyid, Martina %A Rückerl, Regina %A Taylor, Kent %A Chen, Ming-Huei %A de Geus, Eco J C %A Hofman, Albert %A Witteman, Jacqueline C M %A de Maat, Moniek P M %A Palotie, Aarno %A Davies, Gail %A Siscovick, David S %A Kolcic, Ivana %A Wild, Sarah H %A Song, Jaejoon %A McArdle, Wendy L %A Ford, Ian %A Sattar, Naveed %A Schlessinger, David %A Grotevendt, Anne %A Franzosi, Maria Grazia %A Illig, Thomas %A Waldenberger, Melanie %A Lumley, Thomas %A Tofler, Geoffrey H %A Willemsen, Gonneke %A Uitterlinden, André G %A Rivadeneira, Fernando %A Räikkönen, Katri %A Chasman, Daniel I %A Folsom, Aaron R %A Lowe, Gordon D %A Westendorp, Rudi G J %A Slagboom, P Eline %A Cucca, Francesco %A Wallaschofski, Henri %A Strawbridge, Rona J %A Seedorf, Udo %A Koenig, Wolfgang %A Bis, Joshua C %A Mukamal, Kenneth J %A van Dongen, Jenny %A Widen, Elisabeth %A Franco, Oscar H %A Starr, John M %A Liu, Kiang %A Ferrucci, Luigi %A Polasek, Ozren %A Wilson, James F %A Oudot-Mellakh, Tiphaine %A Campbell, Harry %A Navarro, Pau %A Bandinelli, Stefania %A Eriksson, Johan %A Boomsma, Dorret I %A Dehghan, Abbas %A Clarke, Robert %A Hamsten, Anders %A Boerwinkle, Eric %A Jukema, J Wouter %A Naitza, Silvia %A Ridker, Paul M %A Völzke, Henry %A Deary, Ian J %A Reiner, Alexander P %A Trégouët, David-Alexandre %A O'Donnell, Christopher J %A Strachan, David P %A Peters, Annette %A Smith, Nicholas L %K Alcohol Drinking %K Body Mass Index %K Fibrinogen %K Gene-Environment Interaction %K Genomics %K Humans %K Smoking %X

Plasma fibrinogen is an acute phase protein playing an important role in the blood coagulation cascade having strong associations with smoking, alcohol consumption and body mass index (BMI). Genome-wide association studies (GWAS) have identified a variety of gene regions associated with elevated plasma fibrinogen concentrations. However, little is yet known about how associations between environmental factors and fibrinogen might be modified by genetic variation. Therefore, we conducted large-scale meta-analyses of genome-wide interaction studies to identify possible interactions of genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentration. The present study included 80,607 subjects of European ancestry from 22 studies. Genome-wide interaction analyses were performed separately in each study for about 2.6 million single nucleotide polymorphisms (SNPs) across the 22 autosomal chromosomes. For each SNP and risk factor, we performed a linear regression under an additive genetic model including an interaction term between SNP and risk factor. Interaction estimates were meta-analysed using a fixed-effects model. No genome-wide significant interaction with smoking status, alcohol consumption or BMI was observed in the meta-analyses. The most suggestive interaction was found for smoking and rs10519203, located in the LOC123688 region on chromosome 15, with a p value of 6.2 × 10(-8). This large genome-wide interaction study including 80,607 participants found no strong evidence of interaction between genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentrations. Further studies are needed to yield deeper insight in the interplay between environmental factors and gene variants on the regulation of fibrinogen concentrations.

%B PLoS One %V 9 %P e111156 %8 2014 %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/25551457?dopt=Abstract %R 10.1371/journal.pone.0111156 %0 Journal Article %J Stroke %D 2014 %T Predicting stroke through genetic risk functions: the CHARGE Risk Score Project. %A Ibrahim-Verbaas, Carla A %A Fornage, Myriam %A Bis, Joshua C %A Choi, Seung Hoan %A Psaty, Bruce M %A Meigs, James B %A Rao, Madhu %A Nalls, Mike %A Fontes, João D %A O'Donnell, Christopher J %A Kathiresan, Sekar %A Ehret, Georg B %A Fox, Caroline S %A Malik, Rainer %A Dichgans, Martin %A Schmidt, Helena %A Lahti, Jari %A Heckbert, Susan R %A Lumley, Thomas %A Rice, Kenneth %A Rotter, Jerome I %A Taylor, Kent D %A Folsom, Aaron R %A Boerwinkle, Eric %A Rosamond, Wayne D %A Shahar, Eyal %A Gottesman, Rebecca F %A Koudstaal, Peter J %A Amin, Najaf %A Wieberdink, Renske G %A Dehghan, Abbas %A Hofman, Albert %A Uitterlinden, André G %A DeStefano, Anita L %A Debette, Stephanie %A Xue, Luting %A Beiser, Alexa %A Wolf, Philip A %A DeCarli, Charles %A Ikram, M Arfan %A Seshadri, Sudha %A Mosley, Thomas H %A Longstreth, W T %A van Duijn, Cornelia M %A Launer, Lenore J %K Age Factors %K Aged %K Aged, 80 and over %K Area Under Curve %K Case-Control Studies %K Cohort Studies %K European Continental Ancestry Group %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Regression Analysis %K Risk Factors %K ROC Curve %K Sex Factors %K Stroke %X

BACKGROUND AND PURPOSE: Beyond the Framingham Stroke Risk Score, prediction of future stroke may improve with a genetic risk score (GRS) based on single-nucleotide polymorphisms associated with stroke and its risk factors.

METHODS: The study includes 4 population-based cohorts with 2047 first incident strokes from 22,720 initially stroke-free European origin participants aged ≥55 years, who were followed for up to 20 years. GRSs were constructed with 324 single-nucleotide polymorphisms implicated in stroke and 9 risk factors. The association of the GRS to first incident stroke was tested using Cox regression; the GRS predictive properties were assessed with area under the curve statistics comparing the GRS with age and sex, Framingham Stroke Risk Score models, and reclassification statistics. These analyses were performed per cohort and in a meta-analysis of pooled data. Replication was sought in a case-control study of ischemic stroke.

RESULTS: In the meta-analysis, adding the GRS to the Framingham Stroke Risk Score, age and sex model resulted in a significant improvement in discrimination (all stroke: Δjoint area under the curve=0.016, P=2.3×10(-6); ischemic stroke: Δjoint area under the curve=0.021, P=3.7×10(-7)), although the overall area under the curve remained low. In all the studies, there was a highly significantly improved net reclassification index (P<10(-4)).

CONCLUSIONS: The single-nucleotide polymorphisms associated with stroke and its risk factors result only in a small improvement in prediction of future stroke compared with the classical epidemiological risk factors for stroke.

%B Stroke %V 45 %P 403-12 %8 2014 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24436238?dopt=Abstract %R 10.1161/STROKEAHA.113.003044 %0 Journal Article %J Am J Clin Nutr %D 2015 %T Consumption of meat is associated with higher fasting glucose and insulin concentrations regardless of glucose and insulin genetic risk scores: a meta-analysis of 50,345 Caucasians. %A Fretts, Amanda M %A Follis, Jack L %A Nettleton, Jennifer A %A Lemaitre, Rozenn N %A Ngwa, Julius S %A Wojczynski, Mary K %A Kalafati, Ioanna Panagiota %A Varga, Tibor V %A Frazier-Wood, Alexis C %A Houston, Denise K %A Lahti, Jari %A Ericson, Ulrika %A van den Hooven, Edith H %A Mikkilä, Vera %A Kiefte-de Jong, Jessica C %A Mozaffarian, Dariush %A Rice, Kenneth %A Renstrom, Frida %A North, Kari E %A McKeown, Nicola M %A Feitosa, Mary F %A Kanoni, Stavroula %A Smith, Caren E %A Garcia, Melissa E %A Tiainen, Anna-Maija %A Sonestedt, Emily %A Manichaikul, Ani %A van Rooij, Frank J A %A Dimitriou, Maria %A Raitakari, Olli %A Pankow, James S %A Djoussé, Luc %A Province, Michael A %A Hu, Frank B %A Lai, Chao-Qiang %A Keller, Margaux F %A Perälä, Mia-Maria %A Rotter, Jerome I %A Hofman, Albert %A Graff, Misa %A Kähönen, Mika %A Mukamal, Kenneth %A Johansson, Ingegerd %A Ordovas, Jose M %A Liu, Yongmei %A Männistö, Satu %A Uitterlinden, André G %A Deloukas, Panos %A Seppälä, Ilkka %A Psaty, Bruce M %A Cupples, L Adrienne %A Borecki, Ingrid B %A Franks, Paul W %A Arnett, Donna K %A Nalls, Mike A %A Eriksson, Johan G %A Orho-Melander, Marju %A Franco, Oscar H %A Lehtimäki, Terho %A Dedoussis, George V %A Meigs, James B %A Siscovick, David S %K Blood Glucose %K Cohort Studies %K Genetic Association Studies %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Hyperglycemia %K Hyperinsulinism %K Insulin %K Insulin Resistance %K Insulin-Secreting Cells %K Meat %K Meat Products %K Middle Aged %K Polymorphism, Single Nucleotide %K Risk Factors %X

BACKGROUND: Recent studies suggest that meat intake is associated with diabetes-related phenotypes. However, whether the associations of meat intake and glucose and insulin homeostasis are modified by genes related to glucose and insulin is unknown.

OBJECTIVE: We investigated the associations of meat intake and the interaction of meat with genotype on fasting glucose and insulin concentrations in Caucasians free of diabetes mellitus.

DESIGN: Fourteen studies that are part of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium participated in the analysis. Data were provided for up to 50,345 participants. Using linear regression within studies and a fixed-effects meta-analysis across studies, we examined 1) the associations of processed meat and unprocessed red meat intake with fasting glucose and insulin concentrations; and 2) the interactions of processed meat and unprocessed red meat with genetic risk score related to fasting glucose or insulin resistance on fasting glucose and insulin concentrations.

RESULTS: Processed meat was associated with higher fasting glucose, and unprocessed red meat was associated with both higher fasting glucose and fasting insulin concentrations after adjustment for potential confounders [not including body mass index (BMI)]. For every additional 50-g serving of processed meat per day, fasting glucose was 0.021 mmol/L (95% CI: 0.011, 0.030 mmol/L) higher. Every additional 100-g serving of unprocessed red meat per day was associated with a 0.037-mmol/L (95% CI: 0.023, 0.051-mmol/L) higher fasting glucose concentration and a 0.049-ln-pmol/L (95% CI: 0.035, 0.063-ln-pmol/L) higher fasting insulin concentration. After additional adjustment for BMI, observed associations were attenuated and no longer statistically significant. The association of processed meat and fasting insulin did not reach statistical significance after correction for multiple comparisons. Observed associations were not modified by genetic loci known to influence fasting glucose or insulin resistance.

CONCLUSION: The association of higher fasting glucose and insulin concentrations with meat consumption was not modified by an index of glucose- and insulin-related single-nucleotide polymorphisms. Six of the participating studies are registered at clinicaltrials.gov as NCT0000513 (Atherosclerosis Risk in Communities), NCT00149435 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetics of Lipid Lowering Drugs and Diet Network), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).

%B Am J Clin Nutr %V 102 %P 1266-78 %8 2015 Nov %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/26354543?dopt=Abstract %R 10.3945/ajcn.114.101238 %0 Journal Article %J Hum Mol Genet %D 2015 %T Gene × dietary pattern interactions in obesity: analysis of up to 68 317 adults of European ancestry. %A Nettleton, Jennifer A %A Follis, Jack L %A Ngwa, Julius S %A Smith, Caren E %A Ahmad, Shafqat %A Tanaka, Toshiko %A Wojczynski, Mary K %A Voortman, Trudy %A Lemaitre, Rozenn N %A Kristiansson, Kati %A Nuotio, Marja-Liisa %A Houston, Denise K %A Perälä, Mia-Maria %A Qi, Qibin %A Sonestedt, Emily %A Manichaikul, Ani %A Kanoni, Stavroula %A Ganna, Andrea %A Mikkilä, Vera %A North, Kari E %A Siscovick, David S %A Harald, Kennet %A McKeown, Nicola M %A Johansson, Ingegerd %A Rissanen, Harri %A Liu, Yongmei %A Lahti, Jari %A Hu, Frank B %A Bandinelli, Stefania %A Rukh, Gull %A Rich, Stephen %A Booij, Lisanne %A Dmitriou, Maria %A Ax, Erika %A Raitakari, Olli %A Mukamal, Kenneth %A Männistö, Satu %A Hallmans, Göran %A Jula, Antti %A Ericson, Ulrika %A Jacobs, David R %A van Rooij, Frank J A %A Deloukas, Panos %A Sjogren, Per %A Kähönen, Mika %A Djoussé, Luc %A Perola, Markus %A Barroso, Inês %A Hofman, Albert %A Stirrups, Kathleen %A Viikari, Jorma %A Uitterlinden, André G %A Kalafati, Ioanna P %A Franco, Oscar H %A Mozaffarian, Dariush %A Salomaa, Veikko %A Borecki, Ingrid B %A Knekt, Paul %A Kritchevsky, Stephen B %A Eriksson, Johan G %A Dedoussis, George V %A Qi, Lu %A Ferrucci, Luigi %A Orho-Melander, Marju %A Zillikens, M Carola %A Ingelsson, Erik %A Lehtimäki, Terho %A Renstrom, Frida %A Cupples, L Adrienne %A Loos, Ruth J F %A Franks, Paul W %K Adult %K Body Mass Index %K Case-Control Studies %K Diet, Western %K Epistasis, Genetic %K European Continental Ancestry Group %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Male %K Obesity %K Polymorphism, Single Nucleotide %X

Obesity is highly heritable. Genetic variants showing robust associations with obesity traits have been identified through genome-wide association studies. We investigated whether a composite score representing healthy diet modifies associations of these variants with obesity traits. Totally, 32 body mass index (BMI)- and 14 waist-hip ratio (WHR)-associated single nucleotide polymorphisms were genotyped, and genetic risk scores (GRS) were calculated in 18 cohorts of European ancestry (n = 68 317). Diet score was calculated based on self-reported intakes of whole grains, fish, fruits, vegetables, nuts/seeds (favorable) and red/processed meats, sweets, sugar-sweetened beverages and fried potatoes (unfavorable). Multivariable adjusted, linear regression within each cohort followed by inverse variance-weighted, fixed-effects meta-analysis was used to characterize: (a) associations of each GRS with BMI and BMI-adjusted WHR and (b) diet score modification of genetic associations with BMI and BMI-adjusted WHR. Nominally significant interactions (P = 0.006-0.04) were observed between the diet score and WHR-GRS (but not BMI-GRS), two WHR loci (GRB14 rs10195252; LYPLAL1 rs4846567) and two BMI loci (LRRN6C rs10968576; MTIF3 rs4771122), for the respective BMI-adjusted WHR or BMI outcomes. Although the magnitudes of these select interactions were small, our data indicated that associations between genetic predisposition and obesity traits were stronger with a healthier diet. Our findings generate interesting hypotheses; however, experimental and functional studies are needed to determine their clinical relevance.

%B Hum Mol Genet %V 24 %P 4728-38 %8 2015 Aug 15 %G eng %N 16 %1 http://www.ncbi.nlm.nih.gov/pubmed/25994509?dopt=Abstract %R 10.1093/hmg/ddv186 %0 Journal Article %J Biol Psychiatry %D 2015 %T Genome-wide studies of verbal declarative memory in nondemented older people: the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. %A Debette, Stephanie %A Ibrahim Verbaas, Carla A %A Bressler, Jan %A Schuur, Maaike %A Smith, Albert %A Bis, Joshua C %A Davies, Gail %A Wolf, Christiane %A Gudnason, Vilmundur %A Chibnik, Lori B %A Yang, Qiong %A DeStefano, Anita L %A de Quervain, Dominique J F %A Srikanth, Velandai %A Lahti, Jari %A Grabe, Hans J %A Smith, Jennifer A %A Priebe, Lutz %A Yu, Lei %A Karbalai, Nazanin %A Hayward, Caroline %A Wilson, James F %A Campbell, Harry %A Petrovic, Katja %A Fornage, Myriam %A Chauhan, Ganesh %A Yeo, Robin %A Boxall, Ruth %A Becker, James %A Stegle, Oliver %A Mather, Karen A %A Chouraki, Vincent %A Sun, Qi %A Rose, Lynda M %A Resnick, Susan %A Oldmeadow, Christopher %A Kirin, Mirna %A Wright, Alan F %A Jonsdottir, Maria K %A Au, Rhoda %A Becker, Albert %A Amin, Najaf %A Nalls, Mike A %A Turner, Stephen T %A Kardia, Sharon L R %A Oostra, Ben %A Windham, Gwen %A Coker, Laura H %A Zhao, Wei %A Knopman, David S %A Heiss, Gerardo %A Griswold, Michael E %A Gottesman, Rebecca F %A Vitart, Veronique %A Hastie, Nicholas D %A Zgaga, Lina %A Rudan, Igor %A Polasek, Ozren %A Holliday, Elizabeth G %A Schofield, Peter %A Choi, Seung Hoan %A Tanaka, Toshiko %A An, Yang %A Perry, Rodney T %A Kennedy, Richard E %A Sale, Michèle M %A Wang, Jing %A Wadley, Virginia G %A Liewald, David C %A Ridker, Paul M %A Gow, Alan J %A Pattie, Alison %A Starr, John M %A Porteous, David %A Liu, Xuan %A Thomson, Russell %A Armstrong, Nicola J %A Eiriksdottir, Gudny %A Assareh, Arezoo A %A Kochan, Nicole A %A Widen, Elisabeth %A Palotie, Aarno %A Hsieh, Yi-Chen %A Eriksson, Johan G %A Vogler, Christian %A van Swieten, John C %A Shulman, Joshua M %A Beiser, Alexa %A Rotter, Jerome %A Schmidt, Carsten O %A Hoffmann, Wolfgang %A Nöthen, Markus M %A Ferrucci, Luigi %A Attia, John %A Uitterlinden, André G %A Amouyel, Philippe %A Dartigues, Jean-François %A Amieva, Hélène %A Räikkönen, Katri %A Garcia, Melissa %A Wolf, Philip A %A Hofman, Albert %A Longstreth, W T %A Psaty, Bruce M %A Boerwinkle, Eric %A DeJager, Philip L %A Sachdev, Perminder S %A Schmidt, Reinhold %A Breteler, Monique M B %A Teumer, Alexander %A Lopez, Oscar L %A Cichon, Sven %A Chasman, Daniel I %A Grodstein, Francine %A Müller-Myhsok, Bertram %A Tzourio, Christophe %A Papassotiropoulos, Andreas %A Bennett, David A %A Ikram, M Arfan %A Deary, Ian J %A van Duijn, Cornelia M %A Launer, Lenore %A Fitzpatrick, Annette L %A Seshadri, Sudha %A Mosley, Thomas H %K Aged %K Aged, 80 and over %K Aging %K Apolipoproteins E %K Claudin-5 %K Cohort Studies %K Female %K Genome-Wide Association Study %K Genotype %K Humans %K Male %K Memory Disorders %K Middle Aged %K Polymorphism, Single Nucleotide %K Proteins %K Proteoglycans %K Regression Analysis %K Sulfotransferases %K Verbal Learning %X

BACKGROUND: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting.

METHODS: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10(-6)) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults.

RESULTS: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10(-10)) and replication cohorts (p = 5.65 × 10(-8)). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10(-8), and rs6813517 [SPOCK3], p = 2.58 × 10(-8)) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism.

CONCLUSIONS: This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.

%B Biol Psychiatry %V 77 %P 749-63 %8 2015 Apr 15 %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/25648963?dopt=Abstract %R 10.1016/j.biopsych.2014.08.027 %0 Journal Article %J Am J Clin Nutr %D 2015 %T Habitual sleep duration is associated with BMI and macronutrient intake and may be modified by CLOCK genetic variants. %A Dashti, Hassan S %A Follis, Jack L %A Smith, Caren E %A Tanaka, Toshiko %A Cade, Brian E %A Gottlieb, Daniel J %A Hruby, Adela %A Jacques, Paul F %A Lamon-Fava, Stefania %A Richardson, Kris %A Saxena, Richa %A Scheer, Frank A J L %A Kovanen, Leena %A Bartz, Traci M %A Perälä, Mia-Maria %A Jonsson, Anna %A Frazier-Wood, Alexis C %A Kalafati, Ioanna-Panagiota %A Mikkilä, Vera %A Partonen, Timo %A Lemaitre, Rozenn N %A Lahti, Jari %A Hernandez, Dena G %A Toft, Ulla %A Johnson, W Craig %A Kanoni, Stavroula %A Raitakari, Olli T %A Perola, Markus %A Psaty, Bruce M %A Ferrucci, Luigi %A Grarup, Niels %A Highland, Heather M %A Rallidis, Loukianos %A Kähönen, Mika %A Havulinna, Aki S %A Siscovick, David S %A Räikkönen, Katri %A Jørgensen, Torben %A Rotter, Jerome I %A Deloukas, Panos %A Viikari, Jorma S A %A Mozaffarian, Dariush %A Linneberg, Allan %A Seppälä, Ilkka %A Hansen, Torben %A Salomaa, Veikko %A Gharib, Sina A %A Eriksson, Johan G %A Bandinelli, Stefania %A Pedersen, Oluf %A Rich, Stephen S %A Dedoussis, George %A Lehtimäki, Terho %A Ordovas, Jose M %K Adult %K Body Mass Index %K CLOCK Proteins %K Cohort Studies %K Cross-Sectional Studies %K Diet %K Dietary Proteins %K Energy Intake %K European Continental Ancestry Group %K Fatty Acids, Unsaturated %K Female %K Gene-Environment Interaction %K Genetic Predisposition to Disease %K Humans %K Male %K Middle Aged %K Obesity %K Polymorphism, Single Nucleotide %K Sleep %K Young Adult %X

BACKGROUND: Short sleep duration has been associated with greater risks of obesity, hypertension, diabetes, and cardiovascular disease. Also, common genetic variants in the human Circadian Locomotor Output Cycles Kaput (CLOCK) show associations with ghrelin and total energy intake.

OBJECTIVES: We examined associations between habitual sleep duration, body mass index (BMI), and macronutrient intake and assessed whether CLOCK variants modify these associations.

DESIGN: We conducted inverse-variance weighted, fixed-effect meta-analyses of results of adjusted associations of sleep duration and BMI and macronutrient intake as percentages of total energy as well as interactions with CLOCK variants from 9 cohort studies including up to 14,906 participants of European descent from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium.

RESULTS: We observed a significant association between sleep duration and lower BMI (β ± SE = 0.16 ± 0.04, P < 0.0001) in the overall sample; however, associations between sleep duration and relative macronutrient intake were evident in age- and sex-stratified analyses only. We observed a significant association between sleep duration and lower saturated fatty acid intake in younger (aged 20-64 y) adults (men: 0.11 ± 0.06%, P = 0.03; women: 0.10 ± 0.05%, P = 0.04) and with lower carbohydrate (-0.31 ± 0.12%, P < 0.01), higher total fat (0.18 ± 0.09%, P = 0.05), and higher PUFA (0.05 ± 0.02%, P = 0.02) intakes in older (aged 65-80 y) women. In addition, the following 2 nominally significant interactions were observed: between sleep duration and rs12649507 on PUFA intake and between sleep duration and rs6858749 on protein intake.

CONCLUSIONS: Our results indicate that longer habitual sleep duration is associated with lower BMI and age- and sex-specific favorable dietary behaviors. Differences in the relative intake of specific macronutrients associated with short sleep duration could, at least in part, explain previously reported associations between short sleep duration and chronic metabolic abnormalities. In addition, the influence of obesity-associated CLOCK variants on the association between sleep duration and macronutrient intake suggests that longer habitual sleep duration could ameliorate the genetic predisposition to obesity via a favorable dietary profile.

%B Am J Clin Nutr %V 101 %P 135-43 %8 2015 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/25527757?dopt=Abstract %R 10.3945/ajcn.114.095026 %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 Hum Mol Genet %D 2016 %T A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration. %A de Vries, Paul S %A Chasman, Daniel I %A Sabater-Lleal, Maria %A Chen, Ming-Huei %A Huffman, Jennifer E %A Steri, Maristella %A Tang, Weihong %A Teumer, Alexander %A Marioni, Riccardo E %A Grossmann, Vera %A Hottenga, Jouke J %A Trompet, Stella %A Müller-Nurasyid, Martina %A Zhao, Jing Hua %A Brody, Jennifer A %A Kleber, Marcus E %A Guo, Xiuqing %A Wang, Jie Jin %A Auer, Paul L %A Attia, John R %A Yanek, Lisa R %A Ahluwalia, Tarunveer S %A Lahti, Jari %A Venturini, Cristina %A Tanaka, Toshiko %A Bielak, Lawrence F %A Joshi, Peter K %A Rocanin-Arjo, Ares %A Kolcic, Ivana %A Navarro, Pau %A Rose, Lynda M %A Oldmeadow, Christopher %A Riess, Helene %A Mazur, Johanna %A Basu, Saonli %A Goel, Anuj %A Yang, Qiong %A Ghanbari, Mohsen %A Willemsen, Gonneke %A Rumley, Ann %A Fiorillo, Edoardo %A de Craen, Anton J M %A Grotevendt, Anne %A Scott, Robert %A Taylor, Kent D %A Delgado, Graciela E %A Yao, Jie %A Kifley, Annette %A Kooperberg, Charles %A Qayyum, Rehan %A Lopez, Lorna M %A Berentzen, Tina L %A Räikkönen, Katri %A Mangino, Massimo %A Bandinelli, Stefania %A Peyser, Patricia A %A Wild, Sarah %A Trégouët, David-Alexandre %A Wright, Alan F %A Marten, Jonathan %A Zemunik, Tatijana %A Morrison, Alanna C %A Sennblad, Bengt %A Tofler, Geoffrey %A de Maat, Moniek P M %A de Geus, Eco J C %A Lowe, Gordon D %A Zoledziewska, Magdalena %A Sattar, Naveed %A Binder, Harald %A Völker, Uwe %A Waldenberger, Melanie %A Khaw, Kay-Tee %A McKnight, Barbara %A Huang, Jie %A Jenny, Nancy S %A Holliday, Elizabeth G %A Qi, Lihong %A Mcevoy, Mark G %A Becker, Diane M %A Starr, John M %A Sarin, Antti-Pekka %A Hysi, Pirro G %A Hernandez, Dena G %A Jhun, Min A %A Campbell, Harry %A Hamsten, Anders %A Rivadeneira, Fernando %A McArdle, Wendy L %A Slagboom, P Eline %A Zeller, Tanja %A Koenig, Wolfgang %A Psaty, Bruce M %A Haritunians, Talin %A Liu, Jingmin %A Palotie, Aarno %A Uitterlinden, André G %A Stott, David J %A Hofman, Albert %A Franco, Oscar H %A Polasek, Ozren %A Rudan, Igor %A Morange, Pierre-Emmanuel %A Wilson, James F %A Kardia, Sharon L R %A Ferrucci, Luigi %A Spector, Tim D %A Eriksson, Johan G %A Hansen, Torben %A Deary, Ian J %A Becker, Lewis C %A Scott, Rodney J %A Mitchell, Paul %A März, Winfried %A Wareham, Nick J %A Peters, Annette %A Greinacher, Andreas %A Wild, Philipp S %A Jukema, J Wouter %A Boomsma, Dorret I %A Hayward, Caroline %A Cucca, Francesco %A Tracy, Russell %A Watkins, Hugh %A Reiner, Alex P %A Folsom, Aaron R %A Ridker, Paul M %A O'Donnell, Christopher J %A Smith, Nicholas L %A Strachan, David P %A Dehghan, Abbas %X

Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.

%B Hum Mol Genet %V 25 %P 358-70 %8 2016 Jan 15 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26561523?dopt=Abstract %R 10.1093/hmg/ddv454 %0 Journal Article %J Nat Commun %D 2016 %T A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape. %A Ried, Janina S %A Jeff M, Janina %A Chu, Audrey Y %A Bragg-Gresham, Jennifer L %A van Dongen, Jenny %A Huffman, Jennifer E %A Ahluwalia, Tarunveer S %A Cadby, Gemma %A Eklund, Niina %A Eriksson, Joel %A Esko, Tõnu %A Feitosa, Mary F %A Goel, Anuj %A Gorski, Mathias %A Hayward, Caroline %A Heard-Costa, Nancy L %A Jackson, Anne U %A Jokinen, Eero %A Kanoni, Stavroula %A Kristiansson, Kati %A Kutalik, Zoltán %A Lahti, Jari %A Luan, Jian'an %A Mägi, Reedik %A Mahajan, Anubha %A Mangino, Massimo %A Medina-Gómez, Carolina %A Monda, Keri L %A Nolte, Ilja M %A Perusse, Louis %A Prokopenko, Inga %A Qi, Lu %A Rose, Lynda M %A Salvi, Erika %A Smith, Megan T %A Snieder, Harold %A Stančáková, Alena %A Ju Sung, Yun %A Tachmazidou, Ioanna %A Teumer, Alexander %A Thorleifsson, Gudmar %A van der Harst, Pim %A Walker, Ryan W %A Wang, Sophie R %A Wild, Sarah H %A Willems, Sara M %A Wong, Andrew %A Zhang, Weihua %A Albrecht, Eva %A Couto Alves, Alexessander %A Bakker, Stephan J L %A Barlassina, Cristina %A Bartz, Traci M %A Beilby, John %A Bellis, Claire %A Bergman, Richard N %A Bergmann, Sven %A Blangero, John %A Blüher, Matthias %A Boerwinkle, Eric %A Bonnycastle, Lori L %A Bornstein, Stefan R %A Bruinenberg, Marcel %A Campbell, Harry %A Chen, Yii-Der Ida %A Chiang, Charleston W K %A Chines, Peter S %A Collins, Francis S %A Cucca, Fracensco %A Cupples, L Adrienne %A D'Avila, Francesca %A de Geus, Eco J C %A Dedoussis, George %A Dimitriou, Maria %A Döring, Angela %A Eriksson, Johan G %A Farmaki, Aliki-Eleni %A Farrall, Martin %A Ferreira, Teresa %A Fischer, Krista %A Forouhi, Nita G %A Friedrich, Nele %A Gjesing, Anette Prior %A Glorioso, Nicola %A Graff, Mariaelisa %A Grallert, Harald %A Grarup, Niels %A Gräßler, Jürgen %A Grewal, Jagvir %A Hamsten, Anders %A Harder, Marie Neergaard %A Hartman, Catharina A %A Hassinen, Maija %A Hastie, Nicholas %A Hattersley, Andrew Tym %A Havulinna, Aki S %A Heliövaara, Markku %A Hillege, Hans %A Hofman, Albert %A Holmen, Oddgeir %A Homuth, Georg %A Hottenga, Jouke-Jan %A Hui, Jennie %A Husemoen, Lise Lotte %A Hysi, Pirro G %A Isaacs, Aaron %A Ittermann, Till %A Jalilzadeh, Shapour %A James, Alan L %A Jørgensen, Torben %A Jousilahti, Pekka %A Jula, Antti %A Marie Justesen, Johanne %A Justice, Anne E %A Kähönen, Mika %A Karaleftheri, Maria %A Tee Khaw, Kay %A Keinanen-Kiukaanniemi, Sirkka M %A Kinnunen, Leena %A Knekt, Paul B %A Koistinen, Heikki A %A Kolcic, Ivana %A Kooner, Ishminder K %A Koskinen, Seppo %A Kovacs, Peter %A Kyriakou, Theodosios %A Laitinen, Tomi %A Langenberg, Claudia %A Lewin, Alexandra M %A Lichtner, Peter %A Lindgren, Cecilia M %A Lindström, Jaana %A Linneberg, Allan %A Lorbeer, Roberto %A Lorentzon, Mattias %A Luben, Robert %A Lyssenko, Valeriya %A Männistö, Satu %A Manunta, Paolo %A Leach, Irene Mateo %A McArdle, Wendy L %A McKnight, Barbara %A Mohlke, Karen L %A Mihailov, Evelin %A Milani, Lili %A Mills, Rebecca %A Montasser, May E %A Morris, Andrew P %A Müller, Gabriele %A Musk, Arthur W %A Narisu, Narisu %A Ong, Ken K %A Oostra, Ben A %A Osmond, Clive %A Palotie, Aarno %A Pankow, James S %A Paternoster, Lavinia %A Penninx, Brenda W %A Pichler, Irene %A Pilia, Maria G %A Polasek, Ozren %A Pramstaller, Peter P %A Raitakari, Olli T %A Rankinen, Tuomo %A Rao, D C %A Rayner, Nigel W %A Ribel-Madsen, Rasmus %A Rice, Treva K %A Richards, Marcus %A Ridker, Paul M %A Rivadeneira, Fernando %A Ryan, Kathy A %A Sanna, Serena %A Sarzynski, Mark A %A Scholtens, Salome %A Scott, Robert A %A Sebert, Sylvain %A Southam, Lorraine %A Sparsø, Thomas Hempel %A Steinthorsdottir, Valgerdur %A Stirrups, Kathleen %A Stolk, Ronald P %A Strauch, Konstantin %A Stringham, Heather M %A Swertz, Morris A %A Swift, Amy J %A Tönjes, Anke %A Tsafantakis, Emmanouil %A van der Most, Peter J %A van Vliet-Ostaptchouk, Jana V %A Vandenput, Liesbeth %A Vartiainen, Erkki %A Venturini, Cristina %A Verweij, Niek %A Viikari, Jorma S %A Vitart, Veronique %A Vohl, Marie-Claude %A Vonk, Judith M %A Waeber, Gérard %A Widen, Elisabeth %A Willemsen, Gonneke %A Wilsgaard, Tom %A Winkler, Thomas W %A Wright, Alan F %A Yerges-Armstrong, Laura M %A Hua Zhao, Jing %A Zillikens, M Carola %A Boomsma, Dorret I %A Bouchard, Claude %A Chambers, John C %A Chasman, Daniel I %A Cusi, Daniele %A Gansevoort, Ron T %A Gieger, Christian %A Hansen, Torben %A Hicks, Andrew A %A Hu, Frank %A Hveem, Kristian %A Jarvelin, Marjo-Riitta %A Kajantie, Eero %A Kooner, Jaspal S %A Kuh, Diana %A Kuusisto, Johanna %A Laakso, Markku %A Lakka, Timo A %A Lehtimäki, Terho %A Metspalu, Andres %A Njølstad, Inger %A Ohlsson, Claes %A Oldehinkel, Albertine J %A Palmer, Lyle J %A Pedersen, Oluf %A Perola, Markus %A Peters, Annette %A Psaty, Bruce M %A Puolijoki, Hannu %A Rauramaa, Rainer %A Rudan, Igor %A Salomaa, Veikko %A Schwarz, Peter E H %A Shudiner, Alan R %A Smit, Jan H %A Sørensen, Thorkild I A %A Spector, Timothy D %A Stefansson, Kari %A Stumvoll, Michael %A Tremblay, Angelo %A Tuomilehto, Jaakko %A Uitterlinden, André G %A Uusitupa, Matti %A Völker, Uwe %A Vollenweider, Peter %A Wareham, Nicholas J %A Watkins, Hugh %A Wilson, James F %A Zeggini, Eleftheria %A Abecasis, Goncalo R %A Boehnke, Michael %A Borecki, Ingrid B %A Deloukas, Panos %A van Duijn, Cornelia M %A Fox, Caroline %A Groop, Leif C %A Heid, Iris M %A Hunter, David J %A Kaplan, Robert C %A McCarthy, Mark I %A North, Kari E %A O'Connell, Jeffrey R %A Schlessinger, David %A Thorsteinsdottir, Unnur %A Strachan, David P %A Frayling, Timothy %A Hirschhorn, Joel N %A Müller-Nurasyid, Martina %A Loos, Ruth J F %K Anthropometry %K Body Size %K Genome-Wide Association Study %K Genotype %K Humans %K Models, Genetic %K Principal Component Analysis %X

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.

%B Nat Commun %V 7 %P 13357 %8 2016 11 23 %G eng %R 10.1038/ncomms13357 %0 Journal Article %J Psychosom Med %D 2017 %T Bivariate Genome-Wide Association Study of Depressive Symptoms with Type 2 Diabetes and Quantitative Glycemic Traits. %A Haljas, Kadri %A Amare, Azmeraw T %A Alizadeh, Behrooz Z %A Hsu, Yi-Hsiang %A Mosley, Thomas %A Newman, Anne %A Murabito, Joanne %A Tiemeier, Henning %A Tanaka, Toshiko %A van Duijn, Cornelia %A Ding, Jingzhong %A Llewellyn, David J %A Bennett, David A %A Terracciano, Antonio %A Launer, Lenore %A Ladwig, Karl-Heinz %A Cornelis, Marylin C %A Teumer, Alexander %A Grabe, Hans %A Kardia, Sharon L R %A Ware, Erin B %A Smith, Jennifer A %A Snieder, Harold %A Eriksson, Johan G %A Groop, Leif %A Räikkönen, Katri %A Lahti, Jari %X

OBJECTIVE: Shared genetic background may explain phenotypic associations between depression and Type-2-Diabetes (T2D). We aimed to study, on a genome-wide level, if genetic correlation and pleiotropic loci exist between depressive symptoms and T2D or glycemic traits.

METHODS: We estimated SNP-based heritability and analyzed genetic correlation between depressive symptoms and T2D and glycemic traits with the LD Score Regression (LDSC) by combining summary statistics of previously conducted meta-analyses for depressive symptoms by CHARGE consortium (N = 51,258), T2D by Diagram consortium (N = 34,840 patients and 114,981 controls), fasting glucose, fasting insulin, HOMA-β, and HOMA-IR by MAGIC consortium (N = 58,074). Finally, we investigated pleiotropic loci using a bivariate GWAS approach with summary statistics from GWAS meta-analyses and reported loci with genome-wide significant bivariate association p-value (p < 5x10). Biological annotation and function of significant pleiotropic SNPs were assessed in several databases.

RESULTS: The SNP-based heritability ranged from 0.04 to 0.10 in each individual trait. In the LDSC analyses, depressive symptoms showed no significant genetic correlation with T2D or glycemic traits (p > 0.37). Yet, we identified pleiotropic genetic variations for depressive symptoms and T2D (in the IGF2BP2, CDKAL1, CDKN2B-AS, and PLEKHA1 genes), and fasting glucose (in the MADD, CDKN2B-AS, PEX16, and MTNR1B genes).

CONCLUSIONS: We found no significant overall genetic correlations between depressive symptoms, T2D or glycemic traits suggesting major differences in underlying biology of these traits. Yet, several potential pleiotropic loci were identified between depressive symptoms, T2D and fasting glucose suggesting that previously established phenotypic associations may be partly explained by genetic variation in these specific loci.

%B Psychosom Med %8 2017 Dec 27 %G eng %R 10.1097/PSY.0000000000000555 %0 Journal Article %J PLoS One %D 2017 %T Genome-wide association meta-analysis of fish and EPA+DHA consumption in 17 US and European cohorts. %A Mozaffarian, Dariush %A Dashti, Hassan S %A Wojczynski, Mary K %A Chu, Audrey Y %A Nettleton, Jennifer A %A Männistö, Satu %A Kristiansson, Kati %A Reedik, Mägi %A Lahti, Jari %A Houston, Denise K %A Cornelis, Marilyn C %A van Rooij, Frank J A %A Dimitriou, Maria %A Kanoni, Stavroula %A Mikkilä, Vera %A Steffen, Lyn M %A de Oliveira Otto, Marcia C %A Qi, Lu %A Psaty, Bruce %A Djoussé, Luc %A Rotter, Jerome I %A Harald, Kennet %A Perola, Markus %A Rissanen, Harri %A Jula, Antti %A Krista, Fischer %A Mihailov, Evelin %A Feitosa, Mary F %A Ngwa, Julius S %A Xue, Luting %A Jacques, Paul F %A Perälä, Mia-Maria %A Palotie, Aarno %A Liu, Yongmei %A Nalls, Nike A %A Ferrucci, Luigi %A Hernandez, Dena %A Manichaikul, Ani %A Tsai, Michael Y %A Kiefte-de Jong, Jessica C %A Hofman, Albert %A Uitterlinden, André G %A Rallidis, Loukianos %A Ridker, Paul M %A Rose, Lynda M %A Buring, Julie E %A Lehtimäki, Terho %A Kähönen, Mika %A Viikari, Jorma %A Lemaitre, Rozenn %A Salomaa, Veikko %A Knekt, Paul %A Metspalu, Andres %A Borecki, Ingrid B %A Cupples, L Adrienne %A Eriksson, Johan G %A Kritchevsky, Stephen B %A Bandinelli, Stefania %A Siscovick, David %A Franco, Oscar H %A Deloukas, Panos %A Dedoussis, George %A Chasman, Daniel I %A Raitakari, Olli %A Tanaka, Toshiko %K Adult %K Aged %K Cohort Studies %K Docosahexaenoic Acids %K Eicosapentaenoic Acid %K Europe %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Seafood %K United States %X

BACKGROUND: Regular fish and omega-3 consumption may have several health benefits and are recommended by major dietary guidelines. Yet, their intakes remain remarkably variable both within and across populations, which could partly owe to genetic influences.

OBJECTIVE: To identify common genetic variants that influence fish and dietary eicosapentaenoic acid plus docosahexaenoic acid (EPA+DHA) consumption.

DESIGN: We conducted genome-wide association (GWA) meta-analysis of fish (n = 86,467) and EPA+DHA (n = 62,265) consumption in 17 cohorts of European descent from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium Nutrition Working Group. Results from cohort-specific GWA analyses (additive model) for fish and EPA+DHA consumption were adjusted for age, sex, energy intake, and population stratification, and meta-analyzed separately using fixed-effect meta-analysis with inverse variance weights (METAL software). Additionally, heritability was estimated in 2 cohorts.

RESULTS: Heritability estimates for fish and EPA+DHA consumption ranged from 0.13-0.24 and 0.12-0.22, respectively. A significant GWA for fish intake was observed for rs9502823 on chromosome 6: each copy of the minor allele (FreqA = 0.015) was associated with 0.029 servings/day (~1 serving/month) lower fish consumption (P = 1.96x10-8). No significant association was observed for EPA+DHA, although rs7206790 in the obesity-associated FTO gene was among top hits (P = 8.18x10-7). Post-hoc calculations demonstrated 95% statistical power to detect a genetic variant associated with effect size of 0.05% for fish and 0.08% for EPA+DHA.

CONCLUSIONS: These novel findings suggest that non-genetic personal and environmental factors are principal determinants of the remarkable variation in fish consumption, representing modifiable targets for increasing intakes among all individuals. Genes underlying the signal at rs72838923 and mechanisms for the association warrant further investigation.

%B PLoS One %V 12 %P e0186456 %8 2017 %G eng %N 12 %R 10.1371/journal.pone.0186456 %0 Journal Article %J Nat Commun %D 2017 %T Large meta-analysis of genome-wide association studies identifies five loci for lean body mass. %A Zillikens, M Carola %A Demissie, Serkalem %A Hsu, Yi-Hsiang %A Yerges-Armstrong, Laura M %A Chou, Wen-Chi %A Stolk, Lisette %A Livshits, Gregory %A Broer, Linda %A Johnson, Toby %A Koller, Daniel L %A Kutalik, Zoltán %A Luan, Jian'an %A Malkin, Ida %A Ried, Janina S %A Smith, Albert V %A Thorleifsson, Gudmar %A Vandenput, Liesbeth %A Hua Zhao, Jing %A Zhang, Weihua %A Aghdassi, Ali %A Åkesson, Kristina %A Amin, Najaf %A Baier, Leslie J %A Barroso, Inês %A Bennett, David A %A Bertram, Lars %A Biffar, Rainer %A Bochud, Murielle %A Boehnke, Michael %A Borecki, Ingrid B %A Buchman, Aron S %A Byberg, Liisa %A Campbell, Harry %A Campos Obanda, Natalia %A Cauley, Jane A %A Cawthon, Peggy M %A Cederberg, Henna %A Chen, Zhao %A Cho, Nam H %A Jin Choi, Hyung %A Claussnitzer, Melina %A Collins, Francis %A Cummings, Steven R %A De Jager, Philip L %A Demuth, Ilja %A Dhonukshe-Rutten, Rosalie A M %A Diatchenko, Luda %A Eiriksdottir, Gudny %A Enneman, Anke W %A Erdos, Mike %A Eriksson, Johan G %A Eriksson, Joel %A Estrada, Karol %A Evans, Daniel S %A Feitosa, Mary F %A Fu, Mao %A Garcia, Melissa %A Gieger, Christian %A Girke, Thomas %A Glazer, Nicole L %A Grallert, Harald %A Grewal, Jagvir %A Han, Bok-Ghee %A Hanson, Robert L %A Hayward, Caroline %A Hofman, Albert %A Hoffman, Eric P %A Homuth, Georg %A Hsueh, Wen-Chi %A Hubal, Monica J %A Hubbard, Alan %A Huffman, Kim M %A Husted, Lise B %A Illig, Thomas %A Ingelsson, Erik %A Ittermann, Till %A Jansson, John-Olov %A Jordan, Joanne M %A Jula, Antti %A Karlsson, Magnus %A Khaw, Kay-Tee %A Kilpeläinen, Tuomas O %A Klopp, Norman %A Kloth, Jacqueline S L %A Koistinen, Heikki A %A Kraus, William E %A Kritchevsky, Stephen %A Kuulasmaa, Teemu %A Kuusisto, Johanna %A Laakso, Markku %A Lahti, Jari %A Lang, Thomas %A Langdahl, Bente L %A Launer, Lenore J %A Lee, Jong-Young %A Lerch, Markus M %A Lewis, Joshua R %A Lind, Lars %A Lindgren, Cecilia %A Liu, Yongmei %A Liu, Tian %A Liu, Youfang %A Ljunggren, Osten %A Lorentzon, Mattias %A Luben, Robert N %A Maixner, William %A McGuigan, Fiona E %A Medina-Gómez, Carolina %A Meitinger, Thomas %A Melhus, Håkan %A Mellström, Dan %A Melov, Simon %A Michaëlsson, Karl %A Mitchell, Braxton D %A Morris, Andrew P %A Mosekilde, Leif %A Newman, Anne %A Nielson, Carrie M %A O'Connell, Jeffrey R %A Oostra, Ben A %A Orwoll, Eric S %A Palotie, Aarno %A Parker, Stephen C J %A Peacock, Munro %A Perola, Markus %A Peters, Annette %A Polasek, Ozren %A Prince, Richard L %A Räikkönen, Katri %A Ralston, Stuart H %A Ripatti, Samuli %A Robbins, John A %A Rotter, Jerome I %A Rudan, Igor %A Salomaa, Veikko %A Satterfield, Suzanne %A Schadt, Eric E %A Schipf, Sabine %A Scott, Laura %A Sehmi, Joban %A Shen, Jian %A Soo Shin, Chan %A Sigurdsson, Gunnar %A Smith, Shad %A Soranzo, Nicole %A Stančáková, Alena %A Steinhagen-Thiessen, Elisabeth %A Streeten, Elizabeth A %A Styrkarsdottir, Unnur %A Swart, Karin M A %A Tan, Sian-Tsung %A Tarnopolsky, Mark A %A Thompson, Patricia %A Thomson, Cynthia A %A Thorsteinsdottir, Unnur %A Tikkanen, Emmi %A Tranah, Gregory J %A Tuomilehto, Jaakko %A van Schoor, Natasja M %A Verma, Arjun %A Vollenweider, Peter %A Völzke, Henry %A Wactawski-Wende, Jean %A Walker, Mark %A Weedon, Michael N %A Welch, Ryan %A Wichmann, H-Erich %A Widen, Elisabeth %A Williams, Frances M K %A Wilson, James F %A Wright, Nicole C %A Xie, Weijia %A Yu, Lei %A Zhou, Yanhua %A Chambers, John C %A Döring, Angela %A van Duijn, Cornelia M %A Econs, Michael J %A Gudnason, Vilmundur %A Kooner, Jaspal S %A Psaty, Bruce M %A Spector, Timothy D %A Stefansson, Kari %A Rivadeneira, Fernando %A Uitterlinden, André G %A Wareham, Nicholas J %A Ossowski, Vicky %A Waterworth, Dawn %A Loos, Ruth J F %A Karasik, David %A Harris, Tamara B %A Ohlsson, Claes %A Kiel, Douglas P %X

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 × 10-8) or suggestively genome wide (p < 2.3 × 10-6). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.Lean body mass is a highly heritable trait and is associated with various health conditions. Here, Kiel and colleagues perform a meta-analysis of genome-wide association studies for whole body lean body mass and find five novel genetic loci to be significantly associated.

%B Nat Commun %V 8 %P 80 %8 2017 Jul 19 %G eng %N 1 %R 10.1038/s41467-017-00031-7 %0 Journal Article %J Cell Rep %D 2017 %T Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets. %A Lam, Max %A Trampush, Joey W %A Yu, Jin %A Knowles, Emma %A Davies, Gail %A Liewald, David C %A Starr, John M %A Djurovic, Srdjan %A Melle, Ingrid %A Sundet, Kjetil %A Christoforou, Andrea %A Reinvang, Ivar %A DeRosse, Pamela %A Lundervold, Astri J %A Steen, Vidar M %A Espeseth, Thomas %A Räikkönen, Katri %A Widen, Elisabeth %A Palotie, Aarno %A Eriksson, Johan G %A Giegling, Ina %A Konte, Bettina %A Roussos, Panos %A Giakoumaki, Stella %A Burdick, Katherine E %A Payton, Antony %A Ollier, William %A Chiba-Falek, Ornit %A Attix, Deborah K %A Need, Anna C %A Cirulli, Elizabeth T %A Voineskos, Aristotle N %A Stefanis, Nikos C %A Avramopoulos, Dimitrios %A Hatzimanolis, Alex %A Arking, Dan E %A Smyrnis, Nikolaos %A Bilder, Robert M %A Freimer, Nelson A %A Cannon, Tyrone D %A London, Edythe %A Poldrack, Russell A %A Sabb, Fred W %A Congdon, Eliza %A Conley, Emily Drabant %A Scult, Matthew A %A Dickinson, Dwight %A Straub, Richard E %A Donohoe, Gary %A Morris, Derek %A Corvin, Aiden %A Gill, Michael %A Hariri, Ahmad R %A Weinberger, Daniel R %A Pendleton, Neil %A Bitsios, Panos %A Rujescu, Dan %A Lahti, Jari %A Le Hellard, Stephanie %A Keller, Matthew C %A Andreassen, Ole A %A Deary, Ian J %A Glahn, David C %A Malhotra, Anil K %A Lencz, Todd %X

Here, we present a large (n = 107,207) genome-wide association study (GWAS) of general cognitive ability ("g"), further enhanced by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with general cognitive ability. Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis implicated the biological processes of neurogenesis and synaptic regulation, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker, and LY97241, a potassium channel inhibitor. Transcriptome-wide and epigenome-wide analysis revealed that the implicated loci were enriched for genes expressed across all brain regions (most strongly in the cerebellum). Enrichment was exclusive to genes expressed in neurons but not oligodendrocytes or astrocytes. Finally, we report genetic correlations between cognitive ability and disparate phenotypes including psychiatric disorders, several autoimmune disorders, longevity, and maternal age at first birth.

%B Cell Rep %V 21 %P 2597-2613 %8 2017 Nov 28 %G eng %N 9 %R 10.1016/j.celrep.2017.11.028 %0 Journal Article %J Am J Hum Genet %D 2018 %T Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders. %A Ligthart, Symen %A Vaez, Ahmad %A Võsa, Urmo %A Stathopoulou, Maria G %A de Vries, Paul S %A Prins, Bram P %A van der Most, Peter J %A Tanaka, Toshiko %A Naderi, Elnaz %A Rose, Lynda M %A Wu, Ying %A Karlsson, Robert %A Barbalic, Maja %A Lin, Honghuang %A Pool, Rene %A Zhu, Gu %A Mace, Aurelien %A Sidore, Carlo %A Trompet, Stella %A Mangino, Massimo %A Sabater-Lleal, Maria %A Kemp, John P %A Abbasi, Ali %A Kacprowski, Tim %A Verweij, Niek %A Smith, Albert V %A Huang, Tao %A Marzi, Carola %A Feitosa, Mary F %A Lohman, Kurt K %A Kleber, Marcus E %A Milaneschi, Yuri %A Mueller, Christian %A Huq, Mahmudul %A Vlachopoulou, Efthymia %A Lyytikäinen, Leo-Pekka %A Oldmeadow, Christopher %A Deelen, Joris %A Perola, Markus %A Zhao, Jing Hua %A Feenstra, Bjarke %A Amini, Marzyeh %A Lahti, Jari %A Schraut, Katharina E %A Fornage, Myriam %A Suktitipat, Bhoom %A Chen, Wei-Min %A Li, Xiaohui %A Nutile, Teresa %A Malerba, Giovanni %A Luan, Jian'an %A Bak, Tom %A Schork, Nicholas %A del Greco M, Fabiola %A Thiering, Elisabeth %A Mahajan, Anubha %A Marioni, Riccardo E %A Mihailov, Evelin %A Eriksson, Joel %A Ozel, Ayse Bilge %A Zhang, Weihua %A Nethander, Maria %A Cheng, Yu-Ching %A Aslibekyan, Stella %A Ang, Wei %A Gandin, Ilaria %A Yengo, Loic %A Portas, Laura %A Kooperberg, Charles %A Hofer, Edith %A Rajan, Kumar B %A Schurmann, Claudia %A den Hollander, Wouter %A Ahluwalia, Tarunveer S %A Zhao, Jing %A Draisma, Harmen H M %A Ford, Ian %A Timpson, Nicholas %A Teumer, Alexander %A Huang, Hongyan %A Wahl, Simone %A Liu, Yongmei %A Huang, Jie %A Uh, Hae-Won %A Geller, Frank %A Joshi, Peter K %A Yanek, Lisa R %A Trabetti, Elisabetta %A Lehne, Benjamin %A Vozzi, Diego %A Verbanck, Marie %A Biino, Ginevra %A Saba, Yasaman %A Meulenbelt, Ingrid %A O'Connell, Jeff R %A Laakso, Markku %A Giulianini, Franco %A Magnusson, Patrik K E %A Ballantyne, Christie M %A Hottenga, Jouke Jan %A Montgomery, Grant W %A Rivadineira, Fernando %A Rueedi, Rico %A Steri, Maristella %A Herzig, Karl-Heinz %A Stott, David J %A Menni, Cristina %A Frånberg, Mattias %A St Pourcain, Beate %A Felix, Stephan B %A Pers, Tune H %A Bakker, Stephan J L %A Kraft, Peter %A Peters, Annette %A Vaidya, Dhananjay %A Delgado, Graciela %A Smit, Johannes H %A Großmann, Vera %A Sinisalo, Juha %A Seppälä, Ilkka %A Williams, Stephen R %A Holliday, Elizabeth G %A Moed, Matthijs %A Langenberg, Claudia %A Räikkönen, Katri %A Ding, Jingzhong %A Campbell, Harry %A Sale, Michèle M %A Chen, Yii-der I %A James, Alan L %A Ruggiero, Daniela %A Soranzo, Nicole %A Hartman, Catharina A %A Smith, Erin N %A Berenson, Gerald S %A Fuchsberger, Christian %A Hernandez, Dena %A Tiesler, Carla M T %A Giedraitis, Vilmantas %A Liewald, David %A Fischer, Krista %A Mellström, Dan %A Larsson, Anders %A Wang, Yunmei %A Scott, William R %A Lorentzon, Matthias %A Beilby, John %A Ryan, Kathleen A %A Pennell, Craig E %A Vuckovic, Dragana %A Balkau, Beverly %A Concas, Maria Pina %A Schmidt, Reinhold %A Mendes de Leon, Carlos F %A Bottinger, Erwin P %A Kloppenburg, Margreet %A Paternoster, Lavinia %A Boehnke, Michael %A Musk, A W %A Willemsen, Gonneke %A Evans, David M %A Madden, Pamela A F %A Kähönen, Mika %A Kutalik, Zoltán %A Zoledziewska, Magdalena %A Karhunen, Ville %A Kritchevsky, Stephen B %A Sattar, Naveed %A Lachance, Genevieve %A Clarke, Robert %A Harris, Tamara B %A Raitakari, Olli T %A Attia, John R %A van Heemst, Diana %A Kajantie, Eero %A Sorice, Rossella %A Gambaro, Giovanni %A Scott, Robert A %A Hicks, Andrew A %A Ferrucci, Luigi %A Standl, Marie %A Lindgren, Cecilia M %A Starr, John M %A Karlsson, Magnus %A Lind, Lars %A Li, Jun Z %A Chambers, John C %A Mori, Trevor A %A de Geus, Eco J C N %A Heath, Andrew C %A Martin, Nicholas G %A Auvinen, Juha %A Buckley, Brendan M %A de Craen, Anton J M %A Waldenberger, Melanie %A Strauch, Konstantin %A Meitinger, Thomas %A Scott, Rodney J %A McEvoy, Mark %A Beekman, Marian %A Bombieri, Cristina %A Ridker, Paul M %A Mohlke, Karen L %A Pedersen, Nancy L %A Morrison, Alanna C %A Boomsma, Dorret I %A Whitfield, John B %A Strachan, David P %A Hofman, Albert %A Vollenweider, Peter %A Cucca, Francesco %A Jarvelin, Marjo-Riitta %A Jukema, J Wouter %A Spector, Tim D %A Hamsten, Anders %A Zeller, Tanja %A Uitterlinden, André G %A Nauck, Matthias %A Gudnason, Vilmundur %A Qi, Lu %A Grallert, Harald %A Borecki, Ingrid B %A Rotter, Jerome I %A März, Winfried %A Wild, Philipp S %A Lokki, Marja-Liisa %A Boyle, Michael %A Salomaa, Veikko %A Melbye, Mads %A Eriksson, Johan G %A Wilson, James F %A Penninx, Brenda W J H %A Becker, Diane M %A Worrall, Bradford B %A Gibson, Greg %A Krauss, Ronald M %A Ciullo, Marina %A Zaza, Gianluigi %A Wareham, Nicholas J %A Oldehinkel, Albertine J %A Palmer, Lyle J %A Murray, Sarah S %A Pramstaller, Peter P %A Bandinelli, Stefania %A Heinrich, Joachim %A Ingelsson, Erik %A Deary, Ian J %A Mägi, Reedik %A Vandenput, Liesbeth %A van der Harst, Pim %A Desch, Karl C %A Kooner, Jaspal S %A Ohlsson, Claes %A Hayward, Caroline %A Lehtimäki, Terho %A Shuldiner, Alan R %A Arnett, Donna K %A Beilin, Lawrence J %A Robino, Antonietta %A Froguel, Philippe %A Pirastu, Mario %A Jess, Tine %A Koenig, Wolfgang %A Loos, Ruth J F %A Evans, Denis A %A Schmidt, Helena %A Smith, George Davey %A Slagboom, P Eline %A Eiriksdottir, Gudny %A Morris, Andrew P %A Psaty, Bruce M %A Tracy, Russell P %A Nolte, Ilja M %A Boerwinkle, Eric %A Visvikis-Siest, Sophie %A Reiner, Alex P %A Gross, Myron %A Bis, Joshua C %A Franke, Lude %A Franco, Oscar H %A Benjamin, Emelia J %A Chasman, Daniel I %A Dupuis, Josée %A Snieder, Harold %A Dehghan, Abbas %A Alizadeh, Behrooz Z %X

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

%B Am J Hum Genet %V 103 %P 691-706 %8 2018 Nov 01 %G eng %N 5 %R 10.1016/j.ajhg.2018.09.009 %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 %0 Journal Article %J Nat Commun %D 2018 %T Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. %A Davies, Gail %A Lam, Max %A Harris, Sarah E %A Trampush, Joey W %A Luciano, Michelle %A Hill, W David %A Hagenaars, Saskia P %A Ritchie, Stuart J %A Marioni, Riccardo E %A Fawns-Ritchie, Chloe %A Liewald, David C M %A Okely, Judith A %A Ahola-Olli, Ari V %A Barnes, Catriona L K %A Bertram, Lars %A Bis, Joshua C %A Burdick, Katherine E %A Christoforou, Andrea %A DeRosse, Pamela %A Djurovic, Srdjan %A Espeseth, Thomas %A Giakoumaki, Stella %A Giddaluru, Sudheer %A Gustavson, Daniel E %A Hayward, Caroline %A Hofer, Edith %A Ikram, M Arfan %A Karlsson, Robert %A Knowles, Emma %A Lahti, Jari %A Leber, Markus %A Li, Shuo %A Mather, Karen A %A Melle, Ingrid %A Morris, Derek %A Oldmeadow, Christopher %A Palviainen, Teemu %A Payton, Antony %A Pazoki, Raha %A Petrovic, Katja %A Reynolds, Chandra A %A Sargurupremraj, Muralidharan %A Scholz, Markus %A Smith, Jennifer A %A Smith, Albert V %A Terzikhan, Natalie %A Thalamuthu, Anbupalam %A Trompet, Stella %A van der Lee, Sven J %A Ware, Erin B %A Windham, B Gwen %A Wright, Margaret J %A Yang, Jingyun %A Yu, Jin %A Ames, David %A Amin, Najaf %A Amouyel, Philippe %A Andreassen, Ole A %A Armstrong, Nicola J %A Assareh, Amelia A %A Attia, John R %A Attix, Deborah %A Avramopoulos, Dimitrios %A Bennett, David A %A Böhmer, Anne C %A Boyle, Patricia A %A Brodaty, Henry %A Campbell, Harry %A Cannon, Tyrone D %A Cirulli, Elizabeth T %A Congdon, Eliza %A Conley, Emily Drabant %A Corley, Janie %A Cox, Simon R %A Dale, Anders M %A Dehghan, Abbas %A Dick, Danielle %A Dickinson, Dwight %A Eriksson, Johan G %A Evangelou, Evangelos %A Faul, Jessica D %A Ford, Ian %A Freimer, Nelson A %A Gao, He %A Giegling, Ina %A Gillespie, Nathan A %A Gordon, Scott D %A Gottesman, Rebecca F %A Griswold, Michael E %A Gudnason, Vilmundur %A Harris, Tamara B %A Hartmann, Annette M %A Hatzimanolis, Alex %A Heiss, Gerardo %A Holliday, Elizabeth G %A Joshi, Peter K %A Kähönen, Mika %A Kardia, Sharon L R %A Karlsson, Ida %A Kleineidam, Luca %A Knopman, David S %A Kochan, Nicole A %A Konte, Bettina %A Kwok, John B %A Le Hellard, Stephanie %A Lee, Teresa %A Lehtimäki, Terho %A Li, Shu-Chen %A Liu, Tian %A Koini, Marisa %A London, Edythe %A Longstreth, Will T %A Lopez, Oscar L %A Loukola, Anu %A Luck, Tobias %A Lundervold, Astri J %A Lundquist, Anders %A Lyytikäinen, Leo-Pekka %A Martin, Nicholas G %A Montgomery, Grant W %A Murray, Alison D %A Need, Anna C %A Noordam, Raymond %A Nyberg, Lars %A Ollier, William %A Papenberg, Goran %A Pattie, Alison %A Polasek, Ozren %A Poldrack, Russell A %A Psaty, Bruce M %A Reppermund, Simone %A Riedel-Heller, Steffi G %A Rose, Richard J %A Rotter, Jerome I %A Roussos, Panos %A Rovio, Suvi P %A Saba, Yasaman %A Sabb, Fred W %A Sachdev, Perminder S %A Satizabal, Claudia L %A Schmid, Matthias %A Scott, Rodney J %A Scult, Matthew A %A Simino, Jeannette %A Slagboom, P Eline %A Smyrnis, Nikolaos %A Soumaré, Aïcha %A Stefanis, Nikos C %A Stott, David J %A Straub, Richard E %A Sundet, Kjetil %A Taylor, Adele M %A Taylor, Kent D %A Tzoulaki, Ioanna %A Tzourio, Christophe %A Uitterlinden, Andre %A Vitart, Veronique %A Voineskos, Aristotle N %A Kaprio, Jaakko %A Wagner, Michael %A Wagner, Holger %A Weinhold, Leonie %A Wen, K Hoyan %A Widen, Elisabeth %A Yang, Qiong %A Zhao, Wei %A Adams, Hieab H H %A Arking, Dan E %A Bilder, Robert M %A Bitsios, Panos %A Boerwinkle, Eric %A Chiba-Falek, Ornit %A Corvin, Aiden %A De Jager, Philip L %A Debette, Stephanie %A Donohoe, Gary %A Elliott, Paul %A Fitzpatrick, Annette L %A Gill, Michael %A Glahn, David C %A Hägg, Sara %A Hansell, Narelle K %A Hariri, Ahmad R %A Ikram, M Kamran %A Jukema, J Wouter %A Vuoksimaa, Eero %A Keller, Matthew C %A Kremen, William S %A Launer, Lenore %A Lindenberger, Ulman %A Palotie, Aarno %A Pedersen, Nancy L %A Pendleton, Neil %A Porteous, David J %A Räikkönen, Katri %A Raitakari, Olli T %A Ramirez, Alfredo %A Reinvang, Ivar %A Rudan, Igor %A Schmidt, Reinhold %A Schmidt, Helena %A Schofield, Peter W %A Schofield, Peter R %A Starr, John M %A Steen, Vidar M %A Trollor, Julian N %A Turner, Steven T %A van Duijn, Cornelia M %A Villringer, Arno %A Weinberger, Daniel R %A Weir, David R %A Wilson, James F %A Malhotra, Anil %A McIntosh, Andrew M %A Gale, Catharine R %A Seshadri, Sudha %A Mosley, Thomas H %A Bressler, Jan %A Lencz, Todd %A Deary, Ian J %X

General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.

%B Nat Commun %V 9 %P 2098 %8 2018 May 29 %G eng %N 1 %R 10.1038/s41467-018-04362-x %0 Journal Article %J Nat Commun %D 2019 %T Associations of autozygosity with a broad range of human phenotypes. %A Clark, David W %A Okada, Yukinori %A Moore, Kristjan H S %A Mason, Dan %A Pirastu, Nicola %A Gandin, Ilaria %A Mattsson, Hannele %A Barnes, Catriona L K %A Lin, Kuang %A Zhao, Jing Hua %A Deelen, Patrick %A Rohde, Rebecca %A Schurmann, Claudia %A Guo, Xiuqing %A Giulianini, Franco %A Zhang, Weihua %A Medina-Gómez, Carolina %A Karlsson, Robert %A Bao, Yanchun %A Bartz, Traci M %A Baumbach, Clemens %A Biino, Ginevra %A Bixley, Matthew J %A Brumat, Marco %A Chai, Jin-Fang %A Corre, Tanguy %A Cousminer, Diana L %A Dekker, Annelot M %A Eccles, David A %A van Eijk, Kristel R %A Fuchsberger, Christian %A Gao, He %A Germain, Marine %A Gordon, Scott D %A de Haan, Hugoline G %A Harris, Sarah E %A Hofer, Edith %A Huerta-Chagoya, Alicia %A Igartua, Catherine %A Jansen, Iris E %A Jia, Yucheng %A Kacprowski, Tim %A Karlsson, Torgny %A Kleber, Marcus E %A Li, Shengchao Alfred %A Li-Gao, Ruifang %A Mahajan, Anubha %A Matsuda, Koichi %A Meidtner, Karina %A Meng, Weihua %A Montasser, May E %A van der Most, Peter J %A Munz, Matthias %A Nutile, Teresa %A Palviainen, Teemu %A Prasad, Gauri %A Prasad, Rashmi B %A Priyanka, Tallapragada Divya Sri %A Rizzi, Federica %A Salvi, Erika %A Sapkota, Bishwa R %A Shriner, Daniel %A Skotte, Line %A Smart, Melissa C %A Smith, Albert Vernon %A van der Spek, Ashley %A Spracklen, Cassandra N %A Strawbridge, Rona J %A Tajuddin, Salman M %A Trompet, Stella %A Turman, Constance %A Verweij, Niek %A Viberti, Clara %A Wang, Lihua %A Warren, Helen R %A Wootton, Robyn E %A Yanek, Lisa R %A Yao, Jie %A Yousri, Noha A %A Zhao, Wei %A Adeyemo, Adebowale A %A Afaq, Saima %A Aguilar-Salinas, Carlos Alberto %A Akiyama, Masato %A Albert, Matthew L %A Allison, Matthew A %A Alver, Maris %A Aung, Tin %A Azizi, Fereidoun %A Bentley, Amy R %A Boeing, Heiner %A Boerwinkle, Eric %A Borja, Judith B %A de Borst, Gert J %A Bottinger, Erwin P %A Broer, Linda %A Campbell, Harry %A Chanock, Stephen %A Chee, Miao-Li %A Chen, Guanjie %A Chen, Yii-der I %A Chen, Zhengming %A Chiu, Yen-Feng %A Cocca, Massimiliano %A Collins, Francis S %A Concas, Maria Pina %A Corley, Janie %A Cugliari, Giovanni %A van Dam, Rob M %A Damulina, Anna %A Daneshpour, Maryam S %A Day, Felix R %A Delgado, Graciela E %A Dhana, Klodian %A Doney, Alexander S F %A Dörr, Marcus %A Doumatey, Ayo P %A Dzimiri, Nduna %A Ebenesersdóttir, S Sunna %A Elliott, Joshua %A Elliott, Paul %A Ewert, Ralf %A Felix, Janine F %A Fischer, Krista %A Freedman, Barry I %A Girotto, Giorgia %A Goel, Anuj %A Gögele, Martin %A Goodarzi, Mark O %A Graff, Mariaelisa %A Granot-Hershkovitz, Einat %A Grodstein, Francine %A Guarrera, Simonetta %A Gudbjartsson, Daniel F %A Guity, Kamran %A Gunnarsson, Bjarni %A Guo, Yu %A Hagenaars, Saskia P %A Haiman, Christopher A %A Halevy, Avner %A Harris, Tamara B %A Hedayati, Mehdi %A van Heel, David A %A Hirata, Makoto %A Höfer, Imo %A Hsiung, Chao Agnes %A Huang, Jinyan %A Hung, Yi-Jen %A Ikram, M Arfan %A Jagadeesan, Anuradha %A Jousilahti, Pekka %A Kamatani, Yoichiro %A Kanai, Masahiro %A Kerrison, Nicola D %A Kessler, Thorsten %A Khaw, Kay-Tee %A Khor, Chiea Chuen %A de Kleijn, Dominique P V %A Koh, Woon-Puay %A Kolcic, Ivana %A Kraft, Peter %A Krämer, Bernhard K %A Kutalik, Zoltán %A Kuusisto, Johanna %A Langenberg, Claudia %A Launer, Lenore J %A Lawlor, Deborah A %A Lee, I-Te %A Lee, Wen-Jane %A Lerch, Markus M %A Li, Liming %A Liu, Jianjun %A Loh, Marie %A London, Stephanie J %A Loomis, Stephanie %A Lu, Yingchang %A Luan, Jian'an %A Mägi, Reedik %A Manichaikul, Ani W %A Manunta, Paolo %A Másson, Gísli %A Matoba, Nana %A Mei, Xue W %A Meisinger, Christa %A Meitinger, Thomas %A Mezzavilla, Massimo %A Milani, Lili %A Millwood, Iona Y %A Momozawa, Yukihide %A Moore, Amy %A Morange, Pierre-Emmanuel %A Moreno-Macias, Hortensia %A Mori, Trevor A %A Morrison, Alanna C %A Muka, Taulant %A Murakami, Yoshinori %A Murray, Alison D %A de Mutsert, Renée %A Mychaleckyj, Josyf C %A Nalls, Mike A %A Nauck, Matthias %A Neville, Matt J %A Nolte, Ilja M %A Ong, Ken K %A Orozco, Lorena %A Padmanabhan, Sandosh %A Pálsson, Gunnar %A Pankow, James S %A Pattaro, Cristian %A Pattie, Alison %A Polasek, Ozren %A Poulter, Neil %A Pramstaller, Peter P %A Quintana-Murci, Lluis %A Räikkönen, Katri %A Ralhan, Sarju %A Rao, Dabeeru C %A van Rheenen, Wouter %A Rich, Stephen S %A Ridker, Paul M %A Rietveld, Cornelius A %A Robino, Antonietta %A van Rooij, Frank J A %A Ruggiero, Daniela %A Saba, Yasaman %A Sabanayagam, Charumathi %A Sabater-Lleal, Maria %A Sala, Cinzia Felicita %A Salomaa, Veikko %A Sandow, Kevin %A Schmidt, Helena %A Scott, Laura J %A Scott, William R %A Sedaghati-Khayat, Bahareh %A Sennblad, Bengt %A van Setten, Jessica %A Sever, Peter J %A Sheu, Wayne H-H %A Shi, Yuan %A Shrestha, Smeeta %A Shukla, Sharvari Rahul %A Sigurdsson, Jon K %A Sikka, Timo Tonis %A Singh, Jai Rup %A Smith, Blair H %A Stančáková, Alena %A Stanton, Alice %A Starr, John M %A Stefansdottir, Lilja %A Straker, Leon %A Sulem, Patrick %A Sveinbjornsson, Gardar %A Swertz, Morris A %A Taylor, Adele M %A Taylor, Kent D %A Terzikhan, Natalie %A Tham, Yih-Chung %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Tillander, Annika %A Tracy, Russell P %A Tusié-Luna, Teresa %A Tzoulaki, Ioanna %A Vaccargiu, Simona %A Vangipurapu, Jagadish %A Veldink, Jan H %A Vitart, Veronique %A Völker, Uwe %A Vuoksimaa, Eero %A Wakil, Salma M %A Waldenberger, Melanie %A Wander, Gurpreet S %A Wang, Ya Xing %A Wareham, Nicholas J %A Wild, Sarah %A Yajnik, Chittaranjan S %A Yuan, Jian-Min %A Zeng, Lingyao %A Zhang, Liang %A Zhou, Jie %A Amin, Najaf %A Asselbergs, Folkert W %A Bakker, Stephan J L %A Becker, Diane M %A Lehne, Benjamin %A Bennett, David A %A van den Berg, Leonard H %A Berndt, Sonja I %A Bharadwaj, Dwaipayan %A Bielak, Lawrence F %A Bochud, Murielle %A Boehnke, Mike %A Bouchard, Claude %A Bradfield, Jonathan P %A Brody, Jennifer A %A Campbell, Archie %A Carmi, Shai %A Caulfield, Mark J %A Cesarini, David %A Chambers, John C %A Chandak, Giriraj Ratan %A Cheng, Ching-Yu %A Ciullo, Marina %A Cornelis, Marilyn %A Cusi, Daniele %A Smith, George Davey %A Deary, Ian J %A Dorajoo, Rajkumar %A van Duijn, Cornelia M %A Ellinghaus, David %A Erdmann, Jeanette %A Eriksson, Johan G %A Evangelou, Evangelos %A Evans, Michele K %A Faul, Jessica D %A Feenstra, Bjarke %A Feitosa, Mary %A Foisy, Sylvain %A Franke, Andre %A Friedlander, Yechiel %A Gasparini, Paolo %A Gieger, Christian %A Gonzalez, Clicerio %A Goyette, Philippe %A Grant, Struan F A %A Griffiths, Lyn R %A Groop, Leif %A Gudnason, Vilmundur %A Gyllensten, Ulf %A Hakonarson, Hakon %A Hamsten, Anders %A van der Harst, Pim %A Heng, Chew-Kiat %A Hicks, Andrew A %A Hochner, Hagit %A Huikuri, Heikki %A Hunt, Steven C %A Jaddoe, Vincent W V %A De Jager, Philip L %A Johannesson, Magnus %A Johansson, Asa %A Jonas, Jost B %A Jukema, J Wouter %A Junttila, Juhani %A Kaprio, Jaakko %A Kardia, Sharon L R %A Karpe, Fredrik %A Kumari, Meena %A Laakso, Markku %A van der Laan, Sander W %A Lahti, Jari %A Laudes, Matthias %A Lea, Rodney A %A Lieb, Wolfgang %A Lumley, Thomas %A Martin, Nicholas G %A März, Winfried %A Matullo, Giuseppe %A McCarthy, Mark I %A Medland, Sarah E %A Merriman, Tony R %A Metspalu, Andres %A Meyer, Brian F %A Mohlke, Karen L %A Montgomery, Grant W %A Mook-Kanamori, Dennis %A Munroe, Patricia B %A North, Kari E %A Nyholt, Dale R %A O'Connell, Jeffery R %A Ober, Carole %A Oldehinkel, Albertine J %A Palmas, Walter %A Palmer, Colin %A Pasterkamp, Gerard G %A Patin, Etienne %A Pennell, Craig E %A Perusse, Louis %A Peyser, Patricia A %A Pirastu, Mario %A Polderman, Tinca J C %A Porteous, David J %A Posthuma, Danielle %A Psaty, Bruce M %A Rioux, John D %A Rivadeneira, Fernando %A Rotimi, Charles %A Rotter, Jerome I %A Rudan, Igor %A den Ruijter, Hester M %A Sanghera, Dharambir K %A Sattar, Naveed %A Schmidt, Reinhold %A Schulze, Matthias B %A Schunkert, Heribert %A Scott, Robert A %A Shuldiner, Alan R %A Sim, Xueling %A Small, Neil %A Smith, Jennifer A %A Sotoodehnia, Nona %A Tai, E-Shyong %A Teumer, Alexander %A Timpson, Nicholas J %A Toniolo, Daniela %A Trégouët, David-Alexandre %A Tuomi, Tiinamaija %A Vollenweider, Peter %A Wang, Carol A %A Weir, David R %A Whitfield, John B %A Wijmenga, Cisca %A Wong, Tien-Yin %A Wright, John %A Yang, Jingyun %A Yu, Lei %A Zemel, Babette S %A Zonderman, Alan B %A Perola, Markus %A Magnusson, Patrik K E %A Uitterlinden, André G %A Kooner, Jaspal S %A Chasman, Daniel I %A Loos, Ruth J F %A Franceschini, Nora %A Franke, Lude %A Haley, Chris S %A Hayward, Caroline %A Walters, Robin G %A Perry, John R B %A Esko, Tõnu %A Helgason, Agnar %A Stefansson, Kari %A Joshi, Peter K %A Kubo, Michiaki %A Wilson, James F %X

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.

%B Nat Commun %V 10 %P 4957 %8 2019 Oct 31 %G eng %N 1 %R 10.1038/s41467-019-12283-6 %0 Journal Article %J Am J Clin Nutr %D 2019 %T Disentangling the genetics of lean mass. %A Karasik, David %A Zillikens, M Carola %A Hsu, Yi-Hsiang %A Aghdassi, Ali %A Åkesson, Kristina %A Amin, Najaf %A Barroso, Inês %A Bennett, David A %A Bertram, Lars %A Bochud, Murielle %A Borecki, Ingrid B %A Broer, Linda %A Buchman, Aron S %A Byberg, Liisa %A Campbell, Harry %A Campos-Obando, Natalia %A Cauley, Jane A %A Cawthon, Peggy M %A Chambers, John C %A Chen, Zhao %A Cho, Nam H %A Choi, Hyung Jin %A Chou, Wen-Chi %A Cummings, Steven R %A de Groot, Lisette C P G M %A De Jager, Phillip L %A Demuth, Ilja %A Diatchenko, Luda %A Econs, Michael J %A Eiriksdottir, Gudny %A Enneman, Anke W %A Eriksson, Joel %A Eriksson, Johan G %A Estrada, Karol %A Evans, Daniel S %A Feitosa, Mary F %A Fu, Mao %A Gieger, Christian %A Grallert, Harald %A Gudnason, Vilmundur %A Lenore, Launer J %A Hayward, Caroline %A Hofman, Albert %A Homuth, Georg %A Huffman, Kim M %A Husted, Lise B %A Illig, Thomas %A Ingelsson, Erik %A Ittermann, Till %A Jansson, John-Olov %A Johnson, Toby %A Biffar, Reiner %A Jordan, Joanne M %A Jula, Antti %A Karlsson, Magnus %A Khaw, Kay-Tee %A Kilpeläinen, Tuomas O %A Klopp, Norman %A Kloth, Jacqueline S L %A Koller, Daniel L %A Kooner, Jaspal S %A Kraus, William E %A Kritchevsky, Stephen %A Kutalik, Zoltán %A Kuulasmaa, Teemu %A Kuusisto, Johanna %A Laakso, Markku %A Lahti, Jari %A Lang, Thomas %A Langdahl, Bente L %A Lerch, Markus M %A Lewis, Joshua R %A Lill, Christina %A Lind, Lars %A Lindgren, Cecilia %A Liu, Yongmei %A Livshits, Gregory %A Ljunggren, Osten %A Loos, Ruth J F %A Lorentzon, Mattias %A Luan, Jian'an %A Luben, Robert N %A Malkin, Ida %A McGuigan, Fiona E %A Medina-Gómez, Carolina %A Meitinger, Thomas %A Melhus, Håkan %A Mellström, Dan %A Michaëlsson, Karl %A Mitchell, Braxton D %A Morris, Andrew P %A Mosekilde, Leif %A Nethander, Maria %A Newman, Anne B %A O'Connell, Jeffery R %A Oostra, Ben A %A Orwoll, Eric S %A Palotie, Aarno %A Peacock, Munro %A Perola, Markus %A Peters, Annette %A Prince, Richard L %A Psaty, Bruce M %A Räikkönen, Katri %A Ralston, Stuart H %A Ripatti, Samuli %A Rivadeneira, Fernando %A Robbins, John A %A Rotter, Jerome I %A Rudan, Igor %A Salomaa, Veikko %A Satterfield, Suzanne %A Schipf, Sabine %A Shin, Chan Soo %A Smith, Albert V %A Smith, Shad B %A Soranzo, Nicole %A Spector, Timothy D %A Stančáková, Alena %A Stefansson, Kari %A Steinhagen-Thiessen, Elisabeth %A Stolk, Lisette %A Streeten, Elizabeth A %A Styrkarsdottir, Unnur %A Swart, Karin M A %A Thompson, Patricia %A Thomson, Cynthia A %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Tikkanen, Emmi %A Tranah, Gregory J %A Uitterlinden, André G %A van Duijn, Cornelia M %A van Schoor, Natasja M %A Vandenput, Liesbeth %A Vollenweider, Peter %A Völzke, Henry %A Wactawski-Wende, Jean %A Walker, Mark %A J Wareham, Nicholas %A Waterworth, Dawn %A Weedon, Michael N %A Wichmann, H-Erich %A Widen, Elisabeth %A Williams, Frances M K %A Wilson, James F %A Wright, Nicole C %A Yerges-Armstrong, Laura M %A Yu, Lei %A Zhang, Weihua %A Zhao, Jing Hua %A Zhou, Yanhua %A Nielson, Carrie M %A Harris, Tamara B %A Demissie, Serkalem %A Kiel, Douglas P %A Ohlsson, Claes %X

Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass.

Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci.

Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms).

Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection.

Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.

%B Am J Clin Nutr %V 109 %P 276-287 %8 2019 Feb 01 %G eng %N 2 %R 10.1093/ajcn/nqy272 %0 Journal Article %J Mol Psychiatry %D 2022 %T Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning. %A Lahti, Jari %A Tuominen, Samuli %A Yang, Qiong %A Pergola, Giulio %A Ahmad, Shahzad %A Amin, Najaf %A Armstrong, Nicola J %A Beiser, Alexa %A Bey, Katharina %A Bis, Joshua C %A Boerwinkle, Eric %A Bressler, Jan %A Campbell, Archie %A Campbell, Harry %A Chen, Qiang %A Corley, Janie %A Cox, Simon R %A Davies, Gail %A De Jager, Philip L %A Derks, Eske M %A Faul, Jessica D %A Fitzpatrick, Annette L %A Fohner, Alison E %A Ford, Ian %A Fornage, Myriam %A Gerring, Zachary %A Grabe, Hans J %A Grodstein, Francine %A Gudnason, Vilmundur %A Simonsick, Eleanor %A Holliday, Elizabeth G %A Joshi, Peter K %A Kajantie, Eero %A Kaprio, Jaakko %A Karell, Pauliina %A Kleineidam, Luca %A Knol, Maria J %A Kochan, Nicole A %A Kwok, John B %A Leber, Markus %A Lam, Max %A Lee, Teresa %A Li, Shuo %A Loukola, Anu %A Luck, Tobias %A Marioni, Riccardo E %A Mather, Karen A %A Medland, Sarah %A Mirza, Saira S %A Nalls, Mike A %A Nho, Kwangsik %A O'Donnell, Adrienne %A Oldmeadow, Christopher %A Painter, Jodie %A Pattie, Alison %A Reppermund, Simone %A Risacher, Shannon L %A Rose, Richard J %A Sadashivaiah, Vijay %A Scholz, Markus %A Satizabal, Claudia L %A Schofield, Peter W %A Schraut, Katharina E %A Scott, Rodney J %A Simino, Jeannette %A Smith, Albert V %A Smith, Jennifer A %A Stott, David J %A Surakka, Ida %A Teumer, Alexander %A Thalamuthu, Anbupalam %A Trompet, Stella %A Turner, Stephen T %A van der Lee, Sven J %A Villringer, Arno %A Völker, Uwe %A Wilson, Robert S %A Wittfeld, Katharina %A Vuoksimaa, Eero %A Xia, Rui %A Yaffe, Kristine %A Yu, Lei %A Zare, Habil %A Zhao, Wei %A Ames, David %A Attia, John %A Bennett, David A %A Brodaty, Henry %A Chasman, Daniel I %A Goldman, Aaron L %A Hayward, Caroline %A Ikram, M Arfan %A Jukema, J Wouter %A Kardia, Sharon L R %A Lencz, Todd %A Loeffler, Markus %A Mattay, Venkata S %A Palotie, Aarno %A Psaty, Bruce M %A Ramirez, Alfredo %A Ridker, Paul M %A Riedel-Heller, Steffi G %A Sachdev, Perminder S %A Saykin, Andrew J %A Scherer, Martin %A Schofield, Peter R %A Sidney, Stephen %A Starr, John M %A Trollor, Julian %A Ulrich, William %A Wagner, Michael %A Weir, David R %A Wilson, James F %A Wright, Margaret J %A Weinberger, Daniel R %A Debette, Stephanie %A Eriksson, Johan G %A Mosley, Thomas H %A Launer, Lenore J %A van Duijn, Cornelia M %A Deary, Ian J %A Seshadri, Sudha %A Räikkönen, Katri %X

Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.

%B Mol Psychiatry %8 2022 Aug 16 %G eng %R 10.1038/s41380-022-01710-8 %0 Journal Article %J medRxiv %D 2023 %T Whole genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles. %A Huffman, Jennifer E %A Nicolas, Jayna %A Hahn, Julie %A Heath, Adam S %A Raffield, Laura M %A Yanek, Lisa R %A Brody, Jennifer A %A Thibord, Florian %A Almasy, Laura %A Bartz, Traci M %A Bielak, Lawrence F %A Bowler, Russell P %A Carrasquilla, Germán D %A Chasman, Daniel I %A Chen, Ming-Huei %A Emmert, David B %A Ghanbari, Mohsen %A Haessle, Jeffery %A Hottenga, Jouke-Jan %A Kleber, Marcus E %A Le, Ngoc-Quynh %A Lee, Jiwon %A Lewis, Joshua P %A Li-Gao, Ruifang %A Luan, Jian'an %A Malmberg, Anni %A Mangino, Massimo %A Marioni, Riccardo E %A Martinez-Perez, Angel %A Pankratz, Nathan %A Polasek, Ozren %A Richmond, Anne %A Rodriguez, Benjamin At %A Rotter, Jerome I %A Steri, Maristella %A Suchon, Pierre %A Trompet, Stella %A Weiss, Stefan %A Zare, Marjan %A Auer, Paul %A Cho, Michael H %A Christofidou, Paraskevi %A Davies, Gail %A de Geus, Eco %A Deleuze, Jean-Francois %A Delgado, Graciela E %A Ekunwe, Lynette %A Faraday, Nauder %A Gögele, Martin %A Greinacher, Andreas %A He, Gao %A Howard, Tom %A Joshi, Peter K %A Kilpeläinen, Tuomas O %A Lahti, Jari %A Linneberg, Allan %A Naitza, Silvia %A Noordam, Raymond %A Paüls-Vergés, Ferran %A Rich, Stephen S %A Rosendaal, Frits R %A Rudan, Igor %A Ryan, Kathleen A %A Souto, Juan Carlos %A van Rooij, Frank Ja %A Wang, Heming %A Zhao, Wei %A Becker, Lewis C %A Beswick, Andrew %A Brown, Michael R %A Cade, Brian E %A Campbell, Harry %A Cho, Kelly %A Crapo, James D %A Curran, Joanne E %A de Maat, Moniek Pm %A Doyle, Margaret %A Elliott, Paul %A Floyd, James S %A Fuchsberger, Christian %A Grarup, Niels %A Guo, Xiuqing %A Harris, Sarah E %A Hou, Lifang %A Kolcic, Ivana %A Kooperberg, Charles %A Menni, Cristina %A Nauck, Matthias %A O'Connell, Jeffrey R %A Orrù, Valeria %A Psaty, Bruce M %A Räikkönen, Katri %A Smith, Jennifer A %A Soria, José Manuel %A Stott, David J %A van Hylckama Vlieg, Astrid %A Watkins, Hugh %A Willemsen, Gonneke %A Wilson, Peter %A Ben-Shlomo, Yoav %A Blangero, John %A Boomsma, Dorret %A Cox, Simon R %A Dehghan, Abbas %A Eriksson, Johan G %A Fiorillo, Edoardo %A Fornage, Myriam %A Hansen, Torben %A Hayward, Caroline %A Ikram, M Arfan %A Jukema, J Wouter %A Kardia, Sharon Lr %A Lange, Leslie A %A März, Winfried %A Mathias, Rasika A %A Mitchell, Braxton D %A Mook-Kanamori, Dennis O %A Morange, Pierre-Emmanuel %A Pedersen, Oluf %A Pramstaller, Peter P %A Redline, Susan %A Reiner, Alexander %A Ridker, Paul M %A Silverman, Edwin K %A Spector, Tim D %A Völker, Uwe %A Wareham, Nick %A Wilson, James F %A Yao, Jie %A Trégouët, David-Alexandre %A Johnson, Andrew D %A Wolberg, Alisa S %A de Vries, Paul S %A Sabater-Lleal, Maria %A Morrison, Alanna C %A Smith, Nicholas L %X

UNLABELLED: Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole genome sequencing (WGS) data provides better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the NHLBI's Trans-Omics for Precision Medicine (TOPMed) program (n=32,572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (n=131,340) imputed to the TOPMed or Haplotype Reference Consortium panel. We identified 18 loci that have not been identified in prior genetic studies of fibrinogen. Of these, four are driven by common variants of small effect with reported MAF at least 10% higher in African populations. Three ( , and signals contain predicted deleterious missense variants. Two loci, and , each harbor two conditionally distinct, non-coding variants. The gene region encoding the protein chain subunits ( ), contains 7 distinct signals, including one novel signal driven by rs28577061, a variant common (MAF=0.180) in African reference panels but extremely rare (MAF=0.008) in Europeans. Through phenome-wide association studies in the VA Million Veteran Program, we found associations between fibrinogen polygenic risk scores and thrombotic and inflammatory disease phenotypes, including an association with gout. Our findings demonstrate the utility of WGS to augment genetic discovery in diverse populations and offer new insights for putative mechanisms of fibrinogen regulation.

KEY POINTS: Largest and most diverse genetic study of plasma fibrinogen identifies 54 regions (18 novel), housing 69 conditionally distinct variants (20 novel).Sufficient power achieved to identify signal driven by African population variant.Links to (1) liver enzyme, blood cell and lipid genetic signals, (2) liver regulatory elements, and (3) thrombotic and inflammatory disease.

%B medRxiv %8 2023 Jun 12 %G eng %R 10.1101/2023.06.07.23291095 %0 Journal Article %J Alzheimers Res Ther %D 2024 %T Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance. %A Mei, Hao %A Simino, Jeannette %A Li, Lianna %A Jiang, Fan %A Bis, Joshua C %A Davies, Gail %A Hill, W David %A Xia, Charley %A Gudnason, Vilmundur %A Yang, Qiong %A Lahti, Jari %A Smith, Jennifer A %A Kirin, Mirna %A De Jager, Philip %A Armstrong, Nicola J %A Ghanbari, Mohsen %A Kolcic, Ivana %A Moran, Christopher %A Teumer, Alexander %A Sargurupremraj, Murali %A Mahmud, Shamsed %A Fornage, Myriam %A Zhao, Wei %A Satizabal, Claudia L %A Polasek, Ozren %A Räikkönen, Katri %A Liewald, David C %A Homuth, Georg %A Callisaya, Michele %A Mather, Karen A %A Windham, B Gwen %A Zemunik, Tatijana %A Palotie, Aarno %A Pattie, Alison %A van der Auwera, Sandra %A Thalamuthu, Anbupalam %A Knopman, David S %A Rudan, Igor %A Starr, John M %A Wittfeld, Katharina %A Kochan, Nicole A %A Griswold, Michael E %A Vitart, Veronique %A Brodaty, Henry %A Gottesman, Rebecca %A Cox, Simon R %A Psaty, Bruce M %A Boerwinkle, Eric %A Chasman, Daniel I %A Grodstein, Francine %A Sachdev, Perminder S %A Srikanth, Velandai %A Hayward, Caroline %A Wilson, James F %A Eriksson, Johan G %A Kardia, Sharon L R %A Grabe, Hans J %A Bennett, David A %A Ikram, M Arfan %A Deary, Ian J %A van Duijn, Cornelia M %A Launer, Lenore %A Fitzpatrick, Annette L %A Seshadri, Sudha %A Bressler, Jan %A Debette, Stephanie %A Mosley, Thomas H %K Aged %K Cognition %K Genome-Wide Association Study %K Humans %K Memory %K MicroRNAs %K Multiomics %K Polymorphism, Single Nucleotide %X

BACKGROUND: Uncovering the functional relevance underlying verbal declarative memory (VDM) genome-wide association study (GWAS) results may facilitate the development of interventions to reduce age-related memory decline and dementia.

METHODS: We performed multi-omics and pathway enrichment analyses of paragraph (PAR-dr) and word list (WL-dr) delayed recall GWAS from 29,076 older non-demented individuals of European descent. We assessed the relationship between single-variant associations and expression quantitative trait loci (eQTLs) in 44 tissues and methylation quantitative trait loci (meQTLs) in the hippocampus. We determined the relationship between gene associations and transcript levels in 53 tissues, annotation as immune genes, and regulation by transcription factors (TFs) and microRNAs. To identify significant pathways, gene set enrichment was tested in each cohort and meta-analyzed across cohorts. Analyses of differential expression in brain tissues were conducted for pathway component genes.

RESULTS: The single-variant associations of VDM showed significant linkage disequilibrium (LD) with eQTLs across all tissues and meQTLs within the hippocampus. Stronger WL-dr gene associations correlated with reduced expression in four brain tissues, including the hippocampus. More robust PAR-dr and/or WL-dr gene associations were intricately linked with immunity and were influenced by 31 TFs and 2 microRNAs. Six pathways, including type I diabetes, exhibited significant associations with both PAR-dr and WL-dr. These pathways included fifteen MHC genes intricately linked to VDM performance, showing diverse expression patterns based on cognitive status in brain tissues.

CONCLUSIONS: VDM genetic associations influence expression regulation via eQTLs and meQTLs. The involvement of TFs, microRNAs, MHC genes, and immune-related pathways contributes to VDM performance in older individuals.

%B Alzheimers Res Ther %V 16 %P 14 %8 2024 Jan 20 %G eng %N 1 %R 10.1186/s13195-023-01376-6