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1.  Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index 
Felix, Janine F. | Bradfield, Jonathan P. | Monnereau, Claire | van der Valk, Ralf J.P. | Stergiakouli, Evie | Chesi, Alessandra | Gaillard, Romy | Feenstra, Bjarke | Thiering, Elisabeth | Kreiner-Møller, Eskil | Mahajan, Anubha | Pitkänen, Niina | Joro, Raimo | Cavadino, Alana | Huikari, Ville | Franks, Steve | Groen-Blokhuis, Maria M. | Cousminer, Diana L. | Marsh, Julie A. | Lehtimäki, Terho | Curtin, John A. | Vioque, Jesus | Ahluwalia, Tarunveer S. | Myhre, Ronny | Price, Thomas S. | Vilor-Tejedor, Natalia | Yengo, Loïc | Grarup, Niels | Ntalla, Ioanna | Ang, Wei | Atalay, Mustafa | Bisgaard, Hans | Blakemore, Alexandra I. | Bonnefond, Amelie | Carstensen, Lisbeth | Eriksson, Johan | Flexeder, Claudia | Franke, Lude | Geller, Frank | Geserick, Mandy | Hartikainen, Anna-Liisa | Haworth, Claire M.A. | Hirschhorn, Joel N. | Hofman, Albert | Holm, Jens-Christian | Horikoshi, Momoko | Hottenga, Jouke Jan | Huang, Jinyan | Kadarmideen, Haja N. | Kähönen, Mika | Kiess, Wieland | Lakka, Hanna-Maaria | Lakka, Timo A. | Lewin, Alexandra M. | Liang, Liming | Lyytikäinen, Leo-Pekka | Ma, Baoshan | Magnus, Per | McCormack, Shana E. | McMahon, George | Mentch, Frank D. | Middeldorp, Christel M. | Murray, Clare S. | Pahkala, Katja | Pers, Tune H. | Pfäffle, Roland | Postma, Dirkje S. | Power, Christine | Simpson, Angela | Sengpiel, Verena | Tiesler, Carla M. T. | Torrent, Maties | Uitterlinden, André G. | van Meurs, Joyce B. | Vinding, Rebecca | Waage, Johannes | Wardle, Jane | Zeggini, Eleftheria | Zemel, Babette S. | Dedoussis, George V. | Pedersen, Oluf | Froguel, Philippe | Sunyer, Jordi | Plomin, Robert | Jacobsson, Bo | Hansen, Torben | Gonzalez, Juan R. | Custovic, Adnan | Raitakari, Olli T. | Pennell, Craig E. | Widén, Elisabeth | Boomsma, Dorret I. | Koppelman, Gerard H. | Sebert, Sylvain | Järvelin, Marjo-Riitta | Hyppönen, Elina | McCarthy, Mark I. | Lindi, Virpi | Harri, Niinikoski | Körner, Antje | Bønnelykke, Klaus | Heinrich, Joachim | Melbye, Mads | Rivadeneira, Fernando | Hakonarson, Hakon | Ring, Susan M. | Smith, George Davey | Sørensen, Thorkild I.A. | Timpson, Nicholas J. | Grant, Struan F.A. | Jaddoe, Vincent W.V.
Human Molecular Genetics  2015;25(2):389-403.
A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10−8) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10−10) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index.
doi:10.1093/hmg/ddv472
PMCID: PMC4854022  PMID: 26604143
2.  Meta-analysis of rare and common exome chip variants identifies S1PR4 and other loci influencing blood cell traits 
Pankratz, Nathan | Schick, Ursula M | Zhou, Yi | Zhou, Wei | Ahluwalia, Tarunveer Singh | Allende, Maria Laura | Auer, Paul L | Bork-Jensen, Jette | Brody, Jennifer A | Chen, Ming-Huei | Clavo, Vinna | Eicher, John D | Grarup, Niels | Hagedorn, Elliott J | Hu, Bella | Hunker, Kristina | Johnson, Andrew D | Leusink, Maarten | Lu, Yingchang | Lyytikäinen, Leo-Pekka | Manichaikul, Ani | Marioni, Riccardo E | Nalls, Mike A | Pazoki, Raha | Smith, Albert Vernon | van Rooij, Frank J A | Yang, Min-Lee | Zhang, Xiaoling | Zhang, Yan | Asselbergs, Folkert W | Boerwinkle, Eric | Borecki, Ingrid B | Bottinger, Erwin P | Cushman, Mary | de Bakker, Paul I W | Deary, Ian J | Dong, Liguang | Feitosa, Mary F | Floyd, James S | Franceschini, Nora | Franco, Oscar H | Garcia, Melissa E | Grove, Megan L | Gudnason, Vilmundur | Hansen, Torben | Harris, Tamara B | Hofman, Albert | Jackson, Rebecca D | Jia, Jia | Kähönen, Mika | Launer, Lenore J | Lehtimäki, Terho | Liewald, David C | Linneberg, Allan | Liu, Yongmei | Loos, Ruth J F | Nguyen, Vy M | Numans, Mattijs E | Pedersen, Oluf | Psaty, Bruce M | Raitakari, Olli T | Rich, Stephen S | Rivadeneira, Fernando | Di Sant, Amanda M Rosa | Rotter, Jerome I | Starr, John M | Taylor, Kent D | Thuesen, Betina Heinsbæk | Tracy, Russell P | Uitterlinden, Andre G | Wang, Jiansong | Wang, Judy | Dehghan, Abbas | Huo, Yong | Cupples, L Adrienne | Wilson, James G | Proia, Richard L | Zon, Leonard I | O’Donnell, Christopher J | Reiner, Alex P | Ganesh, Santhi K
Nature genetics  2016;48(8):867-876.
Hematologic measures such as hematocrit and white blood cell (WBC) count are heritable and clinically relevant. Erythrocyte and WBC phenotypes were analyzed with Illumina HumanExome BeadChip genotypes in 52,531 individuals (37,775 of European ancestry; 11,589 African Americans; 3,167 Hispanic Americans) from 16 population-based cohorts. We then performed replication analyses of novel discoveries in 18,018 European American women and 5,261 Han Chinese. We identified and replicated four novel erythrocyte trait-locus associations (CEP89, SHROOM3, FADS2, and APOE) and six novel WBC loci for neutrophil count (S1PR4), monocyte count (BTBD8, NLRP12, and IL17RA), eosinophil count (IRF1), and total WBC (MYB). The novel association of a rare missense variant in S1PR4 supports the role of sphingosine-1-phosphate signaling in leukocyte trafficking and circulating neutrophil counts. Loss-of-function experiments of S1pr4 in mouse and zebrafish demonstrated phenotypes consistent with the association observed in humans and altered kinetics of neutrophil recruitment and resolution in response to tissue injury.
doi:10.1038/ng.3607
PMCID: PMC5145000  PMID: 27399967
3.  Metabolic profiling of pregnancy: cross-sectional and longitudinal evidence 
BMC Medicine  2016;14:205.
Background
Pregnancy triggers well-known alterations in maternal glucose and lipid balance but its overall effects on systemic metabolism remain incompletely understood.
Methods
Detailed molecular profiles (87 metabolic measures and 37 cytokines) were measured for up to 4260 women (24–49 years, 322 pregnant) from three population-based cohorts in Finland. Circulating molecular concentrations in pregnant women were compared to those in non-pregnant women. Metabolic profiles were also reassessed for 583 women 6 years later to uncover the longitudinal metabolic changes in response to change in the pregnancy status.
Results
Compared to non-pregnant women, all lipoprotein subclasses and lipids were markedly increased in pregnant women. The most pronounced differences were observed for the intermediate-density, low-density and high-density lipoprotein triglyceride concentrations. Large differences were also seen for many fatty acids and amino acids. Pregnant women also had higher concentrations of low-grade inflammatory marker glycoprotein acetyls, higher concentrations of interleukin-18 and lower concentrations of interleukin-12p70. The changes in metabolic concentrations for women who were not pregnant at baseline but pregnant 6 years later (or vice versa) matched (or were mirror-images of) the cross-sectional association pattern. Cross-sectional results were consistent across the three cohorts and similar longitudinal changes were seen for 653 women in 4-year and 497 women in 10-year follow-up. For multiple metabolic measures, the changes increased in magnitude across the three trimesters.
Conclusions
Pregnancy initiates substantial metabolic and inflammatory changes in the mothers. Comprehensive characterisation of normal pregnancy is important for gaining understanding of the key nutrients for fetal growth and development. These findings also provide a valuable molecular reference in relation to studies of adverse pregnancy outcomes.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-016-0733-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s12916-016-0733-0
PMCID: PMC5153817  PMID: 27955712
Pregnancy; Trimesters; Postpartum; Metabolomics; Cytokines; Lipoprotein lipids; Fatty acids; Amino acids; Hormones; Inflammation; Metabolic networks
4.  A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape 
Ried, Janina S. | Jeff M., Janina | Chu, Audrey Y. | Bragg-Gresham, Jennifer L. | van Dongen, Jenny | Huffman, Jennifer E. | Ahluwalia, Tarunveer S. | Cadby, Gemma | Eklund, Niina | Eriksson, Joel | Esko, Tõnu | Feitosa, Mary F. | Goel, Anuj | Gorski, Mathias | Hayward, Caroline | Heard-Costa, Nancy L. | Jackson, Anne U. | Jokinen, Eero | Kanoni, Stavroula | Kristiansson, Kati | Kutalik, Zoltán | Lahti, Jari | Luan, Jian'an | Mägi, Reedik | Mahajan, Anubha | Mangino, Massimo | Medina-Gomez, Carolina | Monda, Keri L. | Nolte, Ilja M. | Pérusse, Louis | Prokopenko, Inga | Qi, Lu | Rose, Lynda M. | Salvi, Erika | Smith, Megan T. | Snieder, Harold | Stančáková, Alena | Ju Sung, Yun | Tachmazidou, Ioanna | Teumer, Alexander | Thorleifsson, Gudmar | van der Harst, Pim | Walker, Ryan W. | Wang, Sophie R. | Wild, Sarah H. | Willems, Sara M. | Wong, Andrew | Zhang, Weihua | Albrecht, Eva | Couto Alves, Alexessander | Bakker, Stephan J. L. | Barlassina, Cristina | Bartz, Traci M. | Beilby, John | Bellis, Claire | Bergman, Richard N. | Bergmann, Sven | Blangero, John | Blüher, Matthias | Boerwinkle, Eric | Bonnycastle, Lori L. | Bornstein, Stefan R. | Bruinenberg, Marcel | Campbell, Harry | Chen, Yii-Der Ida | Chiang, Charleston W. K. | Chines, Peter S. | Collins, Francis S | Cucca, Fracensco | Cupples, L Adrienne | D'Avila, Francesca | de Geus, Eco J .C. | Dedoussis, George | Dimitriou, Maria | Döring, Angela | Eriksson, Johan G. | Farmaki, Aliki-Eleni | Farrall, Martin | Ferreira, Teresa | Fischer, Krista | Forouhi, Nita G. | Friedrich, Nele | Gjesing, Anette Prior | Glorioso, Nicola | Graff, Mariaelisa | Grallert, Harald | Grarup, Niels | Gräßler, Jürgen | Grewal, Jagvir | Hamsten, Anders | Harder, Marie Neergaard | Hartman, Catharina A. | Hassinen, Maija | Hastie, Nicholas | Hattersley, Andrew Tym | Havulinna, Aki S. | Heliövaara, Markku | Hillege, Hans | Hofman, Albert | Holmen, Oddgeir | Homuth, Georg | Hottenga, Jouke-Jan | Hui, Jennie | Husemoen, Lise Lotte | Hysi, Pirro G. | Isaacs, Aaron | Ittermann, Till | Jalilzadeh, Shapour | James, Alan L. | Jørgensen, Torben | Jousilahti, Pekka | Jula, Antti | Marie Justesen, Johanne | Justice, Anne E. | Kähönen, Mika | Karaleftheri, Maria | Tee Khaw, Kay | Keinanen-Kiukaanniemi, Sirkka M. | Kinnunen, Leena | Knekt, Paul B. | Koistinen, Heikki A. | Kolcic, Ivana | Kooner, Ishminder K. | Koskinen, Seppo | Kovacs, Peter | Kyriakou, Theodosios | Laitinen, Tomi | Langenberg, Claudia | Lewin, Alexandra M. | Lichtner, Peter | Lindgren, Cecilia M. | Lindström, Jaana | Linneberg, Allan | Lorbeer, Roberto | Lorentzon, Mattias | Luben, Robert | Lyssenko, Valeriya | Männistö, Satu | Manunta, Paolo | Leach, Irene Mateo | McArdle, Wendy L. | Mcknight, Barbara | Mohlke, Karen L. | Mihailov, Evelin | Milani, Lili | Mills, Rebecca | Montasser, May E. | Morris, Andrew P. | Müller, Gabriele | Musk, Arthur W. | Narisu, Narisu | Ong, Ken K. | Oostra, Ben A. | Osmond, Clive | Palotie, Aarno | Pankow, James S. | Paternoster, Lavinia | Penninx, Brenda W. | Pichler, Irene | Pilia, Maria G. | Polašek, Ozren | Pramstaller, Peter P. | Raitakari, Olli T | Rankinen, Tuomo | Rao, D. C. | Rayner, Nigel W. | Ribel-Madsen, Rasmus | Rice, Treva K. | Richards, Marcus | Ridker, Paul M. | Rivadeneira, Fernando | Ryan, Kathy A. | Sanna, Serena | Sarzynski, Mark A. | Scholtens, Salome | Scott, Robert A. | Sebert, Sylvain | Southam, Lorraine | Sparsø, Thomas Hempel | Steinthorsdottir, Valgerdur | Stirrups, Kathleen | Stolk, Ronald P. | Strauch, Konstantin | Stringham, Heather M. | Swertz, Morris A. | Swift, Amy J. | Tönjes, Anke | Tsafantakis, Emmanouil | van der Most, Peter J. | Van Vliet-Ostaptchouk, Jana V. | Vandenput, Liesbeth | Vartiainen, Erkki | Venturini, Cristina | Verweij, Niek | Viikari, Jorma S. | Vitart, Veronique | Vohl, Marie-Claude | Vonk, Judith M. | Waeber, Gérard | Widén, Elisabeth | Willemsen, Gonneke | Wilsgaard, Tom | Winkler, Thomas W. | Wright, Alan F. | Yerges-Armstrong, Laura M. | Hua Zhao, Jing | Carola Zillikens, M. | Boomsma, Dorret I. | Bouchard, Claude | Chambers, John C. | Chasman, Daniel I. | Cusi, Daniele | Gansevoort, Ron T. | Gieger, Christian | Hansen, Torben | Hicks, Andrew A. | Hu, Frank | Hveem, Kristian | Jarvelin, Marjo-Riitta | Kajantie, Eero | Kooner, Jaspal S. | Kuh, Diana | Kuusisto, Johanna | Laakso, Markku | Lakka, Timo A. | Lehtimäki, Terho | Metspalu, Andres | Njølstad, Inger | Ohlsson, Claes | Oldehinkel, Albertine J. | Palmer, Lyle J. | Pedersen, Oluf | Perola, Markus | Peters, Annette | Psaty, Bruce M. | Puolijoki, Hannu | Rauramaa, Rainer | Rudan, Igor | Salomaa, Veikko | Schwarz, Peter E. H. | Shudiner, Alan R. | Smit, Jan H. | Sørensen, Thorkild I. A. | Spector, Timothy D. | Stefansson, Kari | Stumvoll, Michael | Tremblay, Angelo | Tuomilehto, Jaakko | Uitterlinden, André G. | Uusitupa, Matti | Völker, Uwe | Vollenweider, Peter | Wareham, Nicholas J. | Watkins, Hugh | Wilson, James F. | Zeggini, Eleftheria | Abecasis, Goncalo R. | Boehnke, Michael | Borecki, Ingrid B. | Deloukas, Panos | van Duijn, Cornelia M. | Fox, Caroline | Groop, Leif C. | Heid, Iris M. | Hunter, David J. | Kaplan, Robert C. | McCarthy, Mark I. | North, Kari E. | O'Connell, Jeffrey R. | Schlessinger, David | Thorsteinsdottir, Unnur | Strachan, David P. | Frayling, Timothy | Hirschhorn, Joel N. | Müller-Nurasyid, Martina | Loos, Ruth J. F.
Nature Communications  2016;7:13357.
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.
Past genome-wide associate studies have identified hundreds of genetic loci that influence body size and shape when examined one trait at a time. Here, Jeff and colleagues develop an aggregate score of various body traits, and use meta-analysis to find new loci linked to body shape.
doi:10.1038/ncomms13357
PMCID: PMC5114527  PMID: 27876822
5.  Genome-wide association study identifies 74 loci associated with educational attainment 
Okbay, Aysu | Beauchamp, Jonathan P. | Fontana, Mark A. | Lee, James J. | Pers, Tune H. | Rietveld, Cornelius A. | Turley, Patrick | Chen, Guo-Bo | Emilsson, Valur | Meddens, S. Fleur W. | Oskarsson, Sven | Pickrell, Joseph K. | Thom, Kevin | Timshel, Pascal | de Vlaming, Ronald | Abdellaoui, Abdel | Ahluwalia, Tarunveer S. | Bacelis, Jonas | Baumbach, Clemens | Bjornsdottir, Gyda | Brandsma, Johannes H. | Concas, Maria Pina | Derringer, Jaime | Furlotte, Nicholas A. | Galesloot, Tessel E. | Girotto, Giorgia | Gupta, Richa | Hall, Leanne M. | Harris, Sarah E. | Hofer, Edith | Horikoshi, Momoko | Huffman, Jennifer E. | Kaasik, Kadri | Kalafati, Ioanna P. | Karlsson, Robert | Kong, Augustine | Lahti, Jari | van der Lee, Sven J. | de Leeuw, Christiaan | Lind, Penelope A. | Lindgren, Karl-Oskar | Liu, Tian | Mangino, Massimo | Marten, Jonathan | Mihailov, Evelin | Miller, Michael B. | van der Most, Peter J. | Oldmeadow, Christopher | Payton, Antony | Pervjakova, Natalia | Peyrot, Wouter J. | Qian, Yong | Raitakari, Olli | Rueedi, Rico | Salvi, Erika | Schmidt, Börge | Schraut, Katharina E. | Shi, Jianxin | Smith, Albert V. | Poot, Raymond A. | Pourcain, Beate | Teumer, Alexander | Thorleifsson, Gudmar | Verweij, Niek | Vuckovic, Dragana | Wellmann, Juergen | Westra, Harm-Jan | Yang, Jingyun | Zhao, Wei | Zhu, Zhihong | Alizadeh, Behrooz Z. | Amin, Najaf | Bakshi, Andrew | Baumeister, Sebastian E. | Biino, Ginevra | Bønnelykke, Klaus | Boyle, Patricia A. | Campbell, Harry | Cappuccio, Francesco P. | Davies, Gail | De Neve, Jan-Emmanuel | Deloukas, Panos | Demuth, Ilja | Ding, Jun | Eibich, Peter | Eisele, Lewin | Eklund, Niina | Evans68, David M. | Faul, Jessica D. | Feitosa, Mary F. | Forstner, Andreas J. | Gandin, Ilaria | Gunnarsson, Bjarni | Halldórsson, Bjarni V. | Harris, Tamara B. | Heath, Andrew C. | Hocking, Lynne J. | Holliday, Elizabeth G. | Homuth, Georg | Horan, Michael A. | Hottenga, Jouke-Jan | de Jager, Philip L. | Joshi, Peter K. | Jugessur, Astanand | Kaakinen, Marika A. | Kähönen, Mika | Kanoni, Stavroula | Keltigangas-Järvinen, Liisa | Kiemeney, Lambertus A.L.M. | Kolcic, Ivana | Koskinen, Seppo | Kraja, Aldi T. | Kroh, Martin | Kutalik, Zoltan | Latvala, Antti | Launer, Lenore J. | Lebreton, Maël P. | Levinson, Douglas F. | Lichtenstein, Paul | Lichtner, Peter | Liewald, David C.M. | Loukola, Anu | Madden, Pamela A. | Mägi, Reedik | Mäki-Opas, Tomi | Marioni, Riccardo E. | Marques-Vidal, Pedro | Meddens, Gerardus A. | McMahon, George | Meisinger, Christa | Meitinger, Thomas | Milaneschi, Yusplitri | Milani, Lili | Montgomery, Grant W. | Myhre, Ronny | Nelson, Christopher P. | Nyholt, Dale R. | Ollier, William E.R. | Palotie, Aarno | Paternoster, Lavinia | Pedersen, Nancy L. | Petrovic, Katja E. | Porteous, David J. | Räikkönen, Katri | Ring, Susan M. | Robino, Antonietta | Rostapshova, Olga | Rudan, Igor | Rustichini, Aldo | Salomaa, Veikko | Sanders, Alan R. | Sarin, Antti-Pekka | Schmidt, Helena | Scott, Rodney J. | Smith, Blair H. | Smith, Jennifer A. | Staessen, Jan A. | Steinhagen-Thiessen, Elisabeth | Strauch, Konstantin | Terracciano, Antonio | Tobin, Martin D. | Ulivi, Sheila | Vaccargiu, Simona | Quaye, Lydia | van Rooij, Frank J.A. | Venturini, Cristina | Vinkhuyzen, Anna A.E. | Völker, Uwe | Völzke, Henry | Vonk, Judith M. | Vozzi, Diego | Waage, Johannes | Ware, Erin B. | Willemsen, Gonneke | Attia, John R. | Bennett, David A. | Berger, Klaus | Bertram, Lars | Bisgaard, Hans | Boomsma, Dorret I. | Borecki, Ingrid B. | Bultmann, Ute | Chabris, Christopher F. | Cucca, Francesco | Cusi, Daniele | Deary, Ian J. | Dedoussis, George V. | van Duijn, Cornelia M. | Eriksson, Johan G. | Franke, Barbara | Franke, Lude | Gasparini, Paolo | Gejman, Pablo V. | Gieger, Christian | Grabe, Hans-Jörgen | Gratten, Jacob | Groenen, Patrick J.F. | Gudnason, Vilmundur | van der Harst, Pim | Hayward, Caroline | Hinds, David A. | Hoffmann, Wolfgang | Hyppönen, Elina | Iacono, William G. | Jacobsson, Bo | Järvelin, Marjo-Riitta | Jöckel, Karl-Heinz | Kaprio, Jaakko | Kardia, Sharon L.R. | Lehtimäki, Terho | Lehrer, Steven F. | Magnusson, Patrik K.E. | Martin, Nicholas G. | McGue, Matt | Metspalu, Andres | Pendleton, Neil | Penninx, Brenda W.J.H. | Perola, Markus | Pirastu, Nicola | Pirastu, Mario | Polasek, Ozren | Posthuma, Danielle | Power, Christine | Province, Michael A. | Samani, Nilesh J. | Schlessinger, David | Schmidt, Reinhold | Sørensen, Thorkild I.A. | Spector, Tim D. | Stefansson, Kari | Thorsteinsdottir, Unnur | Thurik, A. Roy | Timpson, Nicholas J. | Tiemeier, Henning | Tung, Joyce Y. | Uitterlinden, André G. | Vitart, Veronique | Vollenweider, Peter | Weir, David R. | Wilson, James F. | Wright, Alan F. | Conley, Dalton C. | Krueger, Robert F. | Smith, George Davey | Hofman, Albert | Laibson, David I. | Medland, Sarah E. | Meyer, Michelle N. | Yang, Jian | Johannesson, Magnus | Visscher, Peter M. | Esko, Tõnu | Koellinger, Philipp D. | Cesarini, David | Benjamin, Daniel J.
Nature  2016;533(7604):539-542.
Summary
Educational attainment (EA) is strongly influenced by social and other environmental factors, but genetic factors are also estimated to account for at least 20% of the variation across individuals1. We report the results of a genome-wide association study (GWAS) for EA that extends our earlier discovery sample1,2 of 101,069 individuals to 293,723 individuals, and a replication in an independent sample of 111,349 individuals from the UK Biobank. We now identify 74 genome-wide significant loci associated with number of years of schooling completed. Single-nucleotide polymorphisms (SNPs) associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioral phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because EA is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric disease.
doi:10.1038/nature17671
PMCID: PMC4883595  PMID: 27225129
6.  Genetic variants associated with subjective well-being, depressive symptoms and neuroticism identified through genome-wide analyses 
Okbay, Aysu | Baselmans, Bart M L | De Neve, Jan-Emmanuel | Turley, Patrick | Nivard, Michel G | Fontana, Mark Alan | Meddens, S Fleur W | Linnér, Richard Karlsson | Rietveld, Cornelius A | Derringer, Jaime | Gratten, Jacob | Lee, James J | Liu, Jimmy Z | de Vlaming, Ronald | Ahluwalia, Tarunveer S | Buchwald, Jadwiga | Cavadino, Alana | Frazier-Wood, Alexis C | Davies, Gail | Furlotte, Nicholas A | Garfield, Victoria | Geisel, Marie Henrike | Gonzalez, Juan R | Haitjema, Saskia | Karlsson, Robert | van der Laan, Sander W | Ladwig, Karl-Heinz | Lahti, Jari | van der Lee, Sven J | Miller, Michael B | Lind, Penelope A | Liu, Tian | Matteson, Lindsay | Mihailov, Evelin | Minica, Camelia C | Nolte, Ilja M | Mook-Kanamori, Dennis O | van der Most, Peter J | Oldmeadow, Christopher | Qian, Yong | Raitakari, Olli | Rawal, Rajesh | Realo, Anu | Rueedi, Rico | Schmidt, Börge | Smith, Albert V | Stergiakouli, Evie | Tanaka, Toshiko | Taylor, Kent | Thorleifsson, Gudmar | Wedenoja, Juho | Wellmann, Juergen | Westra, Harm-Jan | Willems, Sara M | Zhao, Wei | Amin, Najaf | Bakshi, Andrew | Bergmann, Sven | Bjornsdottir, Gyda | Boyle, Patricia A | Cherney, Samantha | Cox, Simon R | Davis, Oliver S P | Ding, Jun | Direk, Nese | Eibich, Peter | Emeny, Rebecca T | Fatemifar, Ghazaleh | Faul, Jessica D | Ferrucci, Luigi | Forstner, Andreas J | Gieger, Christian | Gupta, Richa | Harris, Tamara B | Harris, Juliette M | Holliday, Elizabeth G | Hottenga, Jouke-Jan | De Jager, Philip L | Kaakinen, Marika A | Kajantie, Eero | Karhunen, Ville | Kolcic, Ivana | Kumari, Meena | Launer, Lenore J | Franke, Lude | Li-Gao, Ruifang | Liewald, David C | Koini, Marisa | Loukola, Anu | Marques-Vidal, Pedro | Montgomery, Grant W | Mosing, Miriam A | Paternoster, Lavinia | Pattie, Alison | Petrovic, Katja E | Pulkki-Råback, Laura | Quaye, Lydia | Räikkönen, Katri | Rudan, Igor | Scott, Rodney J | Smith, Jennifer A | Sutin, Angelina R | Trzaskowski, Maciej | Vinkhuyzen, Anna E | Yu, Lei | Zabaneh, Delilah | Attia, John R | Bennett, David A | Berger, Klaus | Bertram, Lars | Boomsma, Dorret I | Snieder, Harold | Chang, Shun-Chiao | Cucca, Francesco | Deary, Ian J | van Duijn, Cornelia M | Eriksson, Johan G | Bültmann, Ute | de Geus, Eco J C | Groenen, Patrick J F | Gudnason, Vilmundur | Hansen, Torben | Hartman, Catharine A | Haworth, Claire M A | Hayward, Caroline | Heath, Andrew C | Hinds, David A | Hyppönen, Elina | Iacono, William G | Järvelin, Marjo-Riitta | Jöckel, Karl-Heinz | Kaprio, Jaakko | Kardia, Sharon L R | Keltikangas-Järvinen, Liisa | Kraft, Peter | Kubzansky, Laura D | Lehtimäki, Terho | Magnusson, Patrik K E | Martin, Nicholas G | McGue, Matt | Metspalu, Andres | Mills, Melinda | de Mutsert, Renée | Oldehinkel, Albertine J | Pasterkamp, Gerard | Pedersen, Nancy L | Plomin, Robert | Polasek, Ozren | Power, Christine | Rich, Stephen S | Rosendaal, Frits R | den Ruijter, Hester M | Schlessinger, David | Schmidt, Helena | Svento, Rauli | Schmidt, Reinhold | Alizadeh, Behrooz Z | Sørensen, Thorkild I A | Spector, Tim D | Starr, John M | Stefansson, Kari | Steptoe, Andrew | Terracciano, Antonio | Thorsteinsdottir, Unnur | Thurik, A Roy | Timpson, Nicholas J | Tiemeier, Henning | Uitterlinden, André G | Vollenweider, Peter | Wagner, Gert G | Weir, David R | Yang, Jian | Conley, Dalton C | Smith, George Davey | Hofman, Albert | Johannesson, Magnus | Laibson, David I | Medland, Sarah E | Meyer, Michelle N | Pickrell, Joseph K | Esko, Tõnu | Krueger, Robert F | Beauchamp, Jonathan P | Koellinger, Philipp D | Benjamin, Daniel J | Bartels, Meike | Cesarini, David
Nature genetics  2016;48(6):624-633.
We conducted genome-wide association studies of three phenotypes: subjective well-being (N = 298,420), depressive symptoms (N = 161,460), and neuroticism (N = 170,910). We identified three variants associated with subjective well-being, two with depressive symptoms, and eleven with neuroticism, including two inversion polymorphisms. The two depressive symptoms loci replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ^| ≈ 0.8) strengthen the overall credibility of the findings, and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal/pancreas tissues are strongly enriched for association.
doi:10.1038/ng.3552
PMCID: PMC4884152  PMID: 27089181
7.  Metabolic signatures of birthweight in 18 288 adolescents and adults 
Background: Lower birthweight is associated with increased susceptibility to cardiometabolic diseases in adulthood, but the underlying molecular pathways are incompletely understood. We examined associations of birthweight with a comprehensive metabolic profile measured in adolescents and adults.
Methods: High-throughput nuclear magnetic resonance metabolomics and biochemical assays were used to quantify 87 circulating metabolic measures in seven cohorts from Finland and the UK, comprising altogether 18 288 individuals (mean age 26 years, range 15–75). Metabolic associations with birthweight were assessed by linear regression models adjusted for sex, gestational age and age at blood sampling. The metabolic associations with birthweight were compared with the corresponding associations with adult body mass index (BMI).
Results: Lower birthweight adjusted for gestational age was adversely associated with cardiometabolic biomarkers, including lipoprotein subclasses, fatty acids, amino acids and markers of inflammation and impaired liver function (P < 0.0015 for 46 measures). Associations were consistent across cohorts with different ages at metabolic profiling, but the magnitudes were weak. The pattern of metabolic deviations associated with lower birthweight resembled the metabolic signature of higher adult BMI (R2 = 0.77) assessed at the same time as the metabolic profiling. The resemblance indicated that 1 kg lower birthweight is associated with similar metabolic aberrations as caused by 0.92 units higher BMI in adulthood.
Conclusions: Lower birthweight adjusted for gestational age is associated with adverse biomarker aberrations across multiple metabolic pathways. Coherent metabolic signatures between lower birthweight and higher adult adiposity suggest that shared molecular pathways may potentially underpin the metabolic deviations. However, the magnitudes of metabolic associations with birthweight are modest in comparison to the effects of adiposity, implying that birthweight is only a weak indicator of the metabolic risk profile in adulthood.
doi:10.1093/ije/dyw255
PMCID: PMC5100627  PMID: 27892411
Fetal programming; metabolic signatures; metabolomics; adiposity; fatty acids; amino acids
8.  Genome-Wide Meta-Analysis of Sciatica in Finnish Population 
PLoS ONE  2016;11(10):e0163877.
Sciatica or the sciatic syndrome is a common and often disabling low back disorder in the working-age population. It has a relatively high heritability but poorly understood molecular mechanisms. The Finnish population is a genetic isolate where small founder population and bottleneck events have led to enrichment of certain rare and low frequency variants. We performed here the first genome-wide association (GWAS) and meta-analysis of sciatica. The meta-analysis was conducted across two GWAS covering 291 Finnish sciatica cases and 3671 controls genotyped and imputed at 7.7 million autosomal variants. The most promising loci (p<1x10-6) were replicated in 776 Finnish sciatica patients and 18,489 controls. We identified five intragenic variants, with relatively low frequencies, at two novel loci associated with sciatica at genome-wide significance. These included chr9:14344410:I (rs71321981) at 9p22.3 (NFIB gene; p = 1.30x10-8, MAF = 0.08) and four variants at 15q21.2: rs145901849, rs80035109, rs190200374 and rs117458827 (MYO5A; p = 1.34x10-8, MAF = 0.06; p = 2.32x10-8, MAF = 0.07; p = 3.85x10-8, MAF = 0.06; p = 4.78x10-8, MAF = 0.07, respectively). The most significant association in the meta-analysis, a single base insertion rs71321981 within the regulatory region of the transcription factor NFIB, replicated in an independent Finnish population sample (p = 0.04). Despite identifying 15q21.2 as a promising locus, we were not able to replicate it. It was differentiated; the lead variants within 15q21.2 were more frequent in Finland (6–7%) than in other European populations (1–2%). Imputation accuracies of the three significantly associated variants (chr9:14344410:I, rs190200374, and rs80035109) were validated by genotyping. In summary, our results suggest a novel locus, 9p22.3 (NFIB), which may be involved in susceptibility to sciatica. In addition, another locus, 15q21.2, emerged as a promising one, but failed to replicate.
doi:10.1371/journal.pone.0163877
PMCID: PMC5072673  PMID: 27764105
9.  Genetic variants associated with subjective well-being, depressive symptoms and neuroticism identified through genome-wide analyses 
Okbay, Aysu | Baselmans, Bart M.L. | De Neve, Jan-Emmanuel | Turley, Patrick | Nivard, Michel G. | Fontana, Mark Alan | Meddens, S. Fleur W. | Linnér, Richard Karlsson | Rietveld, Cornelius A. | Derringer, Jaime | Gratten, Jacob | Lee, James J. | Liu, Jimmy Z. | de Vlaming, Ronald | Ahluwalia, Tarunveer S. | Buchwald, Jadwiga | Cavadino, Alana | Frazier-Wood, Alexis C. | Furlotte, Nicholas A. | Garfield, Victoria | Geisel, Marie Henrike | Gonzalez, Juan R. | Haitjema, Saskia | Karlsson, Robert | van der Laan, Sander W. | Ladwig, Karl-Heinz | Lahti, Jari | van der Lee, Sven J. | Lind, Penelope A. | Liu, Tian | Matteson, Lindsay | Mihailov, Evelin | Miller, Michael B. | Minica, Camelia C. | Nolte, Ilja M. | Mook-Kanamori, Dennis | van der Most, Peter J. | Oldmeadow, Christopher | Qian, Yong | Raitakari, Olli | Rawal, Rajesh | Realo, Anu | Rueedi, Rico | Schmidt, Börge | Smith, Albert V. | Stergiakouli, Evie | Tanaka, Toshiko | Taylor, Kent | Wedenoja, Juho | Wellmann, Juergen | Westra, Harm-Jan | Willems, Sara M. | Zhao, Wei | Amin, Najaf | Bakshi, Andrew | Boyle, Patricia A. | Cherney, Samantha | Cox, Simon R. | Davies, Gail | Davis, Oliver S.P. | Ding, Jun | Direk, Nese | Eibich, Peter | Emeny, Rebecca T. | Fatemifar, Ghazaleh | Faul, Jessica D. | Ferrucci, Luigi | Forstner, Andreas | Gieger, Christian | Gupta, Richa | Harris, Tamara B. | Harris, Juliette M. | Holliday, Elizabeth G. | Hottenga, Jouke-Jan | De Jager, Philip L. | Kaakinen, Marika A. | Kajantie, Eero | Karhunen, Ville | Kolcic, Ivana | Kumari, Meena | Launer, Lenore J. | Franke, Lude | Li-Gao, Ruifang | Koini, Marisa | Loukola, Anu | Marques-Vidal, Pedro | Montgomery, Grant W. | Mosing, Miriam A. | Paternoster, Lavinia | Pattie, Alison | Petrovic, Katja E. | Pulkki-Råback, Laura | Quaye, Lydia | Räikkönen, Katri | Rudan, Igor | Scott, Rodney J. | Smith, Jennifer A. | Sutin, Angelina R. | Trzaskowski, Maciej | Vinkhuyzen, Anna E. | Yu, Lei | Zabaneh, Delilah | Attia, John R. | Bennett, David A. | Berger, Klaus | Bertram, Lars | Boomsma, Dorret I. | Snieder, Harold | Chang, Shun-Chiao | Cucca, Francesco | Deary, Ian J. | van Duijn, Cornelia M. | Eriksson, Johan G. | Bültmann, Ute | de Geus, Eco J.C. | Groenen, Patrick J.F. | Gudnason, Vilmundur | Hansen, Torben | Hartman, Catharine A. | Haworth, Claire M.A. | Hayward, Caroline | Heath, Andrew C. | Hinds, David A. | Hyppönen, Elina | Iacono, William G. | Järvelin, Marjo-Riitta | Jöckel, Karl-Heinz | Kaprio, Jaakko | Kardia, Sharon L.R. | Keltikangas-Järvinen, Liisa | Kraft, Peter | Kubzansky, Laura D. | Lehtimäki, Terho | Magnusson, Patrik K.E. | Martin, Nicholas G. | McGue, Matt | Metspalu, Andres | Mills, Melinda | de Mutsert, Renée | Oldehinkel, Albertine J. | Pasterkamp, Gerard | Pedersen, Nancy L. | Plomin, Robert | Polasek, Ozren | Power, Christine | Rich, Stephen S. | Rosendaal, Frits R. | den Ruijter, Hester M. | Schlessinger, David | Schmidt, Helena | Svento, Rauli | Schmidt, Reinhold | Alizadeh, Behrooz Z. | Sørensen, Thorkild I.A. | Spector, Tim D. | Steptoe, Andrew | Terracciano, Antonio | Thurik, A. Roy | Timpson, Nicholas J. | Tiemeier, Henning | Uitterlinden, André G. | Vollenweider, Peter | Wagner, Gert G. | Weir, David R. | Yang, Jian | Conley, Dalton C. | Smith, George Davey | Hofman, Albert | Johannesson, Magnus | Laibson, David I. | Medland, Sarah E. | Meyer, Michelle N. | Pickrell, Joseph K. | Esko, Tõnu | Krueger, Robert F. | Beauchamp, Jonathan P. | Koellinger, Philipp D. | Benjamin, Daniel J. | Bartels, Meike | Cesarini, David
Nature genetics  2016;48(6):624-633.
We conducted genome-wide association studies of three phenotypes: subjective well-being (N = 298,420), depressive symptoms (N = 161,460), and neuroticism (N = 170,910). We identified three variants associated with subjective well-being, two with depressive symptoms, and eleven with neuroticism, including two inversion polymorphisms. The two depressive symptoms loci replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ̂| ≈ 0.8) strengthen the overall credibility of the findings, and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal/pancreas tissues are strongly enriched for association.
doi:10.1038/ng.3552
PMCID: PMC4884152  PMID: 27089181
10.  No Association of Coronary Artery Disease with X-Chromosomal Variants in Comprehensive International Meta-Analysis 
Loley, Christina | Alver, Maris | Assimes, Themistocles L. | Bjonnes, Andrew | Goel, Anuj | Gustafsson, Stefan | Hernesniemi, Jussi | Hopewell, Jemma C. | Kanoni, Stavroula | Kleber, Marcus E. | Lau, King Wai | Lu, Yingchang | Lyytikäinen, Leo-Pekka | Nelson, Christopher P. | Nikpay, Majid | Qu, Liming | Salfati, Elias | Scholz, Markus | Tukiainen, Taru | Willenborg, Christina | Won, Hong-Hee | Zeng, Lingyao | Zhang, Weihua | Anand, Sonia S. | Beutner, Frank | Bottinger, Erwin P. | Clarke, Robert | Dedoussis, George | Do, Ron | Esko, Tõnu | Eskola, Markku | Farrall, Martin | Gauguier, Dominique | Giedraitis, Vilmantas | Granger, Christopher B. | Hall, Alistair S. | Hamsten, Anders | Hazen, Stanley L. | Huang, Jie | Kähönen, Mika | Kyriakou, Theodosios | Laaksonen, Reijo | Lind, Lars | Lindgren, Cecilia | Magnusson, Patrik K. E. | Marouli, Eirini | Mihailov, Evelin | Morris, Andrew P. | Nikus, Kjell | Pedersen, Nancy | Rallidis, Loukianos | Salomaa, Veikko | Shah, Svati H. | Stewart, Alexandre F. R. | Thompson, John R. | Zalloua, Pierre A. | Chambers, John C. | Collins, Rory | Ingelsson, Erik | Iribarren, Carlos | Karhunen, Pekka J. | Kooner, Jaspal S. | Lehtimäki, Terho | Loos, Ruth J. F. | März, Winfried | McPherson, Ruth | Metspalu, Andres | Reilly, Muredach P. | Ripatti, Samuli | Sanghera, Dharambir K. | Thiery, Joachim | Watkins, Hugh | Deloukas, Panos | Kathiresan, Sekar | Samani, Nilesh J. | Schunkert, Heribert | Erdmann, Jeanette | König, Inke R.
Scientific Reports  2016;6:35278.
In recent years, genome-wide association studies have identified 58 independent risk loci for coronary artery disease (CAD) on the autosome. However, due to the sex-specific data structure of the X chromosome, it has been excluded from most of these analyses. While females have 2 copies of chromosome X, males have only one. Also, one of the female X chromosomes may be inactivated. Therefore, special test statistics and quality control procedures are required. Thus, little is known about the role of X-chromosomal variants in CAD. To fill this gap, we conducted a comprehensive X-chromosome-wide meta-analysis including more than 43,000 CAD cases and 58,000 controls from 35 international study cohorts. For quality control, sex-specific filters were used to adequately take the special structure of X-chromosomal data into account. For single study analyses, several logistic regression models were calculated allowing for inactivation of one female X-chromosome, adjusting for sex and investigating interactions between sex and genetic variants. Then, meta-analyses including all 35 studies were conducted using random effects models. None of the investigated models revealed genome-wide significant associations for any variant. Although we analyzed the largest-to-date sample, currently available methods were not able to detect any associations of X-chromosomal variants with CAD.
doi:10.1038/srep35278
PMCID: PMC5059659  PMID: 27731410
11.  Effects of hormonal contraception on systemic metabolism: cross-sectional and longitudinal evidence 
Background: Hormonal contraception is commonly used worldwide, but its systemic effects across lipoprotein subclasses, fatty acids, circulating metabolites and cytokines remain poorly understood.
Methods: A comprehensive molecular profile (75 metabolic measures and 37 cytokines) was measured for up to 5841 women (age range 24–49 years) from three population-based cohorts. Women using combined oral contraceptive pills (COCPs) or progestin-only contraceptives (POCs) were compared with those who did not use hormonal contraception. Metabolomics profiles were reassessed for 869 women after 6 years to uncover the metabolic effects of starting, stopping and persistently using hormonal contraception.
Results: The comprehensive molecular profiling allowed multiple new findings on the metabolic associations with the use of COCPs. They were positively associated with lipoprotein subclasses, including all high-density lipoprotein (HDL) subclasses. The associations with fatty acids and amino acids were strong and variable in direction. COCP use was negatively associated with albumin and positively associated with creatinine and inflammatory markers, including glycoprotein acetyls and several growth factors and interleukins. Our findings also confirmed previous results e.g. for increased circulating triglycerides and HDL cholesterol. Starting COCPs caused similar metabolic changes to those observed cross-sectionally: the changes were maintained in consistent users and normalized in those who stopped using. In contrast, POCs were only weakly associated with metabolic and inflammatory markers. Results were consistent across all cohorts and for different COCP preparations and different types of POC delivery.
Conclusions: Use of COCPs causes widespread metabolic and inflammatory effects. However, persistent use does not appear to accumulate the effects over time and the metabolic perturbations are reversed upon discontinuation. POCs have little effect on systemic metabolism and inflammation.
doi:10.1093/ije/dyw147
PMCID: PMC5100613  PMID: 27538888
hormonal contraception; combined oral contraceptive pills; progestin-only contraceptives; metabolomics; cytokines; inflammation; amino acids; fatty acids; lipoproteins; hormones; risk factors
12.  Genome-wide association study of copy number variation with lung function identifies a novel signal of association near BANP for forced vital capacity 
BMC Genetics  2016;17:116.
Background
Genome-wide association studies of Single Nucleotide Polymorphisms (SNPs) have identified 55 SNPs associated with lung function. However, little is known about the effect of copy number variants (CNVs) on lung function, although CNVs represent a significant proportion of human genetic polymorphism. To assess the effect of CNVs on lung function quantitative traits, we measured copy number at 2788 previously characterised, common copy number variable regions in 6 independent cohorts (n = 24,237) using intensity data from SNP genotyping experiments. We developed a pipeline for genome-wide association analysis and meta-analysis of CNV genotypes measured across multiple studies using SNP genotype array intensity data from different platform technologies. We then undertook cohort-level genome-wide association studies of CNV with lung function in a subset of 4 cohorts (n < =12,403) with lung function measurements and meta-analysed the results. Follow-up was undertaken for CNVs which were well tagged by SNPs, in up to 146,871 individuals.
Results
We generated robust copy number calls for 1962 out of 2788 (70 %) known CNV regions genome-wide, with 1103 measured with compatible class frequencies in at least 2 cohorts. We report a novel CNV association (discovery P = 0.0007) with Forced Vital Capacity (FVC) downstream of BANP on chromosome 16 that shows evidence of replication by a tag SNP in two independent studies (replication P = 0.004). In addition, we provide suggestive evidence (discovery P = 0.0002) for a role of complex copy number variation at a previously reported lung function locus, containing the rootletin gene CROCC, that is not tagged by SNPs.
Conclusions
We demonstrate how common CNV regions can be reliably and consistently called across cohorts, using an existing calling algorithm and rigorous quality control steps, using SNP genotyping array intensity data. Although many common biallelic CNV regions were well-tagged by common SNPs, we also identified associations with untagged mulitallelic CNV regions thereby illustrating the potential of our approach to identify some of the missing heritability of complex traits.
Electronic supplementary material
The online version of this article (doi:10.1186/s12863-016-0423-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s12863-016-0423-0
PMCID: PMC4981989  PMID: 27514831
Copy number variation; Lung function; Genome-wide association study
13.  Metabolic profiling of alcohol consumption in 9778 young adults 
Background: High alcohol consumption is a major cause of morbidity, yet alcohol is associated with both favourable and adverse effects on cardiometabolic risk markers. We aimed to characterize the associations of usual alcohol consumption with a comprehensive systemic metabolite profile in young adults.
Methods: Cross-sectional associations of alcohol intake with 86 metabolic measures were assessed for 9778 individuals from three population-based cohorts from Finland (age 24–45 years, 52% women). Metabolic changes associated with change in alcohol intake during 6-year follow-up were further examined for 1466 individuals. Alcohol intake was assessed by questionnaires. Circulating lipids, fatty acids and metabolites were quantified by high-throughput nuclear magnetic resonance metabolomics and biochemical assays.
Results: Increased alcohol intake was associated with cardiometabolic risk markers across multiple metabolic pathways, including higher lipid concentrations in HDL subclasses and smaller LDL particle size, increased proportions of monounsaturated fatty acids and decreased proportion of omega-6 fatty acids, lower concentrations of glutamine and citrate (P < 0.001 for 56 metabolic measures). Many metabolic biomarkers displayed U-shaped associations with alcohol consumption. Results were coherent for men and women, consistent across the three cohorts and similar if adjusting for body mass index, smoking and physical activity. The metabolic changes accompanying change in alcohol intake during follow-up resembled the cross-sectional association pattern (R2 = 0.83, slope = 0.72 ± 0.04).
Conclusions: Alcohol consumption is associated with a complex metabolic signature, including aberrations in multiple biomarkers for elevated cardiometabolic risk. The metabolic signature tracks with long-term changes in alcohol consumption. These results elucidate the double-edged effects of alcohol on cardiovascular risk.
doi:10.1093/ije/dyw175
PMCID: PMC5100616  PMID: 27494945
Alcohol; risk factors; metabolomics; fatty acids; metabolic profiling
14.  Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function 
Pattaro, Cristian | Teumer, Alexander | Gorski, Mathias | Chu, Audrey Y. | Li, Man | Mijatovic, Vladan | Garnaas, Maija | Tin, Adrienne | Sorice, Rossella | Li, Yong | Taliun, Daniel | Olden, Matthias | Foster, Meredith | Yang, Qiong | Chen, Ming-Huei | Pers, Tune H. | Johnson, Andrew D. | Ko, Yi-An | Fuchsberger, Christian | Tayo, Bamidele | Nalls, Michael | Feitosa, Mary F. | Isaacs, Aaron | Dehghan, Abbas | d’Adamo, Pio | Adeyemo, Adebowale | Dieffenbach, Aida Karina | Zonderman, Alan B. | Nolte, Ilja M. | van der Most, Peter J. | Wright, Alan F. | Shuldiner, Alan R. | Morrison, Alanna C. | Hofman, Albert | Smith, Albert V. | Dreisbach, Albert W. | Franke, Andre | Uitterlinden, Andre G. | Metspalu, Andres | Tonjes, Anke | Lupo, Antonio | Robino, Antonietta | Johansson, Åsa | Demirkan, Ayse | Kollerits, Barbara | Freedman, Barry I. | Ponte, Belen | Oostra, Ben A. | Paulweber, Bernhard | Krämer, Bernhard K. | Mitchell, Braxton D. | Buckley, Brendan M. | Peralta, Carmen A. | Hayward, Caroline | Helmer, Catherine | Rotimi, Charles N. | Shaffer, Christian M. | Müller, Christian | Sala, Cinzia | van Duijn, Cornelia M. | Saint-Pierre, Aude | Ackermann, Daniel | Shriner, Daniel | Ruggiero, Daniela | Toniolo, Daniela | Lu, Yingchang | Cusi, Daniele | Czamara, Darina | Ellinghaus, David | Siscovick, David S. | Ruderfer, Douglas | Gieger, Christian | Grallert, Harald | Rochtchina, Elena | Atkinson, Elizabeth J. | Holliday, Elizabeth G. | Boerwinkle, Eric | Salvi, Erika | Bottinger, Erwin P. | Murgia, Federico | Rivadeneira, Fernando | Ernst, Florian | Kronenberg, Florian | Hu, Frank B. | Navis, Gerjan J. | Curhan, Gary C. | Ehret, George B. | Homuth, Georg | Coassin, Stefan | Thun, Gian-Andri | Pistis, Giorgio | Gambaro, Giovanni | Malerba, Giovanni | Montgomery, Grant W. | Eiriksdottir, Gudny | Jacobs, Gunnar | Li, Guo | Wichmann, H.-Erich | Campbell, Harry | Schmidt, Helena | Wallaschofski, Henri | Völzke, Henry | Brenner, Hermann | Kroemer, Heyo K. | Kramer, Holly | Lin, Honghuang | Leach, I. Mateo | Ford, Ian | Guessous, Idris | Rudan, Igor | Prokopenko, Inga | Borecki, Ingrid | Heid, Iris M. | Kolcic, Ivana | Persico, Ivana | Jukema, J. Wouter | Wilson, James F. | Felix, Janine F. | Divers, Jasmin | Lambert, Jean-Charles | Stafford, Jeanette M. | Gaspoz, Jean-Michel | Smith, Jennifer A. | Faul, Jessica D. | Wang, Jie Jin | Ding, Jingzhong | Hirschhorn, Joel N. | Attia, John | Whitfield, John B. | Chalmers, John | Viikari, Jorma | Coresh, Josef | Denny, Joshua C. | Karjalainen, Juha | Fernandes, Jyotika K. | Endlich, Karlhans | Butterbach, Katja | Keene, Keith L. | Lohman, Kurt | Portas, Laura | Launer, Lenore J. | Lyytikäinen, Leo-Pekka | Yengo, Loic | Franke, Lude | Ferrucci, Luigi | Rose, Lynda M. | Kedenko, Lyudmyla | Rao, Madhumathi | Struchalin, Maksim | Kleber, Marcus E. | Cavalieri, Margherita | Haun, Margot | Cornelis, Marilyn C. | Ciullo, Marina | Pirastu, Mario | de Andrade, Mariza | McEvoy, Mark A. | Woodward, Mark | Adam, Martin | Cocca, Massimiliano | Nauck, Matthias | Imboden, Medea | Waldenberger, Melanie | Pruijm, Menno | Metzger, Marie | Stumvoll, Michael | Evans, Michele K. | Sale, Michele M. | Kähönen, Mika | Boban, Mladen | Bochud, Murielle | Rheinberger, Myriam | Verweij, Niek | Bouatia-Naji, Nabila | Martin, Nicholas G. | Hastie, Nick | Probst-Hensch, Nicole | Soranzo, Nicole | Devuyst, Olivier | Raitakari, Olli | Gottesman, Omri | Franco, Oscar H | Polasek, Ozren | Gasparini, Paolo | Munroe, Patricia B. | Ridker, Paul M. | Mitchell, Paul | Muntner, Paul | Meisinger, Christa | Smit, Johannes H. | Kovacs, Peter | Wild, Philipp S. | Froguel, Philippe | Rettig, Rainer | Magi, Reedik | Biffar, Reiner | Schmidt, Reinhold | Middelberg, Rita PS | Carroll, Robert J. | Penninx, Brenda W. | Scott, Rodney J. | Katz, Ronit | Sedaghat, Sanaz | Wild, Sarah H. | Kardia, Sharon L.R. | Ulivi, Sheila | Hwang, Shih-Jen | Enroth, Stefan | Kloiber, Stefan | Trompet, Stella | Stengel, Benedicte | Hancock, Stephen J. | Turner, Stephen T. | Rosas, Sylvia E. | Stracke, Sylvia | Harris, Tamara B. | Zeller, Tanja | Zemunik, Tatijana | Lehtimäki, Terho | Illig, Thomas | Aspelund, Thor | Nikopensius, Tiit | Esko, Tonu | Tanaka, Toshiko | Gyllensten, Ulf | Völker, Uwe | Emilsson, Valur | Vitart, Veronique | Aalto, Ville | Gudnason, Vilmundur | Chouraki, Vincent | Chen, Wei-Min | Igl, Wilmar | März, Winfried | Koenig, Wolfgang | Lieb, Wolfgang | Loos, Ruth J. F. | Liu, Yongmei | Snieder, Harold | Pramstaller, Peter P. | Parsa, Afshin | O’Connell, Jeffrey R. | Susztak, Katalin | Hamet, Pavel | Tremblay, Johanne | de Boer, Ian H. | Böger, Carsten A. | Goessling, Wolfram | Chasman, Daniel I. | Köttgen, Anna | Kao, WH Linda | Fox, Caroline S.
Nature communications  2016;7:10023.
Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, nineteen associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biologic pathways.
doi:10.1038/ncomms10023
PMCID: PMC4735748  PMID: 26831199
15.  Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels 
van Leeuwen, Elisabeth M | Sabo, Aniko | Bis, Joshua C | Huffman, Jennifer E | Manichaikul, Ani | Smith, Albert V | Feitosa, Mary F | Demissie, Serkalem | Joshi, Peter K | Duan, Qing | Marten, Jonathan | van Klinken, Jan B | Surakka, Ida | Nolte, Ilja M | Zhang, Weihua | Mbarek, Hamdi | Li-Gao, Ruifang | Trompet, Stella | Verweij, Niek | Evangelou, Evangelos | Lyytikäinen, Leo-Pekka | Tayo, Bamidele O | Deelen, Joris | van der Most, Peter J | van der Laan, Sander W | Arking, Dan E | Morrison, Alanna | Dehghan, Abbas | Franco, Oscar H | Hofman, Albert | Rivadeneira, Fernando | Sijbrands, Eric J | Uitterlinden, Andre G | Mychaleckyj, Josyf C | Campbell, Archie | Hocking, Lynne J | Padmanabhan, Sandosh | Brody, Jennifer A | Rice, Kenneth M | White, Charles C | Harris, Tamara | Isaacs, Aaron | Campbell, Harry | Lange, Leslie A | Rudan, Igor | Kolcic, Ivana | Navarro, Pau | Zemunik, Tatijana | Salomaa, Veikko | Kooner, Angad S | Kooner, Jaspal S | Lehne, Benjamin | Scott, William R | Tan, Sian-Tsung | de Geus, Eco J | Milaneschi, Yuri | Penninx, Brenda W J H | Willemsen, Gonneke | de Mutsert, Renée | Ford, Ian | Gansevoort, Ron T | Segura-Lepe, Marcelo P | Raitakari, Olli T | Viikari, Jorma S | Nikus, Kjell | Forrester, Terrence | McKenzie, Colin A | de Craen, Anton J M | de Ruijter, Hester M | Pasterkamp, Gerard | Snieder, Harold | Oldehinkel, Albertine J | Slagboom, P Eline | Cooper, Richard S | Kähönen, Mika | Lehtimäki, Terho | Elliott, Paul | van der Harst, Pim | Jukema, J Wouter | Mook-Kanamori, Dennis O | Boomsma, Dorret I | Chambers, John C | Swertz, Morris | Ripatti, Samuli | Willems van Dijk, Ko | Vitart, Veronique | Polasek, Ozren | Hayward, Caroline | Wilson, James G | Wilson, James F | Gudnason, Vilmundur | Rich, Stephen S | Psaty, Bruce M | Borecki, Ingrid B | Boerwinkle, Eric | Rotter, Jerome I | Cupples, L Adrienne | van Duijn, Cornelia M
Journal of Medical Genetics  2016;53(7):441-449.
Background
So far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels.
Methods
We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from ∼60 000 individuals in the discovery stage and ∼90 000 samples in the replication stage.
Results
Our study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene.
Conclusions
This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.
doi:10.1136/jmedgenet-2015-103439
PMCID: PMC4941146  PMID: 27036123
Complex traits; Epidemiology; Genetics; Genome-wide; circulating lipid levels
16.  A genome-wide association meta-analysis on apolipoprotein A-IV concentrations 
Human Molecular Genetics  2016;25(16):3635-3646.
Apolipoprotein A-IV (apoA-IV) is a major component of HDL and chylomicron particles and is involved in reverse cholesterol transport. It is an early marker of impaired renal function. We aimed to identify genetic loci associated with apoA-IV concentrations and to investigate relationships with known susceptibility loci for kidney function and lipids. A genome-wide association meta-analysis on apoA-IV concentrations was conducted in five population-based cohorts (n = 13,813) followed by two additional replication studies (n = 2,267) including approximately 10 M SNPs. Three independent SNPs from two genomic regions were significantly associated with apoA-IV concentrations: rs1729407 near APOA4 (P = 6.77 × 10 − 44), rs5104 in APOA4 (P = 1.79 × 10−24) and rs4241819 in KLKB1 (P = 5.6 × 10−14). Additionally, a look-up of the replicated SNPs in downloadable GWAS meta-analysis results was performed on kidney function (defined by eGFR), HDL-cholesterol and triglycerides. From these three SNPs mentioned above, only rs1729407 showed an association with HDL-cholesterol (P = 7.1 × 10 − 07). Moreover, weighted SNP-scores were built involving known susceptibility loci for the aforementioned traits (53, 70 and 38 SNPs, respectively) and were associated with apoA-IV concentrations. This analysis revealed a significant and an inverse association for kidney function with apoA-IV concentrations (P = 5.5 × 10−05). Furthermore, an increase of triglyceride-increasing alleles was found to decrease apoA-IV concentrations (P = 0.0078). In summary, we identified two independent SNPs located in or next the APOA4 gene and one SNP in KLKB1. The association of KLKB1 with apoA-IV suggests an involvement of apoA-IV in renal metabolism and/or an interaction within HDL particles. Analyses of SNP-scores indicate potential causal effects of kidney function and by lesser extent triglycerides on apoA-IV concentrations.
doi:10.1093/hmg/ddw211
PMCID: PMC5179953  PMID: 27412012
17.  Correction: The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study 
Winkler, Thomas W. | Justice, Anne E. | Graff, Mariaelisa | Barata, Llilda | Feitosa, Mary F. | Chu, Su | Czajkowski, Jacek | Esko, Tõnu | Fall, Tove | Kilpeläinen, Tuomas O. | Lu, Yingchang | Mägi, Reedik | Mihailov, Evelin | Pers, Tune H. | Rüeger, Sina | Teumer, Alexander | Ehret, Georg B. | Ferreira, Teresa | Heard-Costa, Nancy L. | Karjalainen, Juha | Lagou, Vasiliki | Mahajan, Anubha | Neinast, Michael D. | Prokopenko, Inga | Simino, Jeannette | Teslovich, Tanya M. | Jansen, Rick | Westra, Harm-Jan | White, Charles C. | Absher, Devin | Ahluwalia, Tarunveer S. | Ahmad, Shafqat | Albrecht, Eva | Alves, Alexessander Couto | Bragg-Gresham, Jennifer L. | de Craen, Anton J. M. | Bis, Joshua C. | Bonnefond, Amélie | Boucher, Gabrielle | Cadby, Gemma | Cheng, Yu-Ching | Chiang, Charleston W. K. | Delgado, Graciela | Demirkan, Ayse | Dueker, Nicole | Eklund, Niina | Eiriksdottir, Gudny | Eriksson, Joel | Feenstra, Bjarke | Fischer, Krista | Frau, Francesca | Galesloot, Tessel E. | Geller, Frank | Goel, Anuj | Gorski, Mathias | Grammer, Tanja B. | Gustafsson, Stefan | Haitjema, Saskia | Hottenga, Jouke-Jan | Huffman, Jennifer E. | Jackson, Anne U. | Jacobs, Kevin B. | Johansson, Åsa | Kaakinen, Marika | Kleber, Marcus E. | Lahti, Jari | Mateo Leach, Irene | Lehne, Benjamin | Liu, Youfang | Lo, Ken Sin | Lorentzon, Mattias | Luan, Jian'an | Madden, Pamela A. F. | Mangino, Massimo | McKnight, Barbara | Medina-Gomez, Carolina | Monda, Keri L. | Montasser, May E. | Müller, Gabriele | Müller-Nurasyid, Martina | Nolte, Ilja M. | Panoutsopoulou, Kalliope | Pascoe, Laura | Paternoster, Lavinia | Rayner, Nigel W. | Renström, Frida | Rizzi, Federica | Rose, Lynda M. | Ryan, Kathy A. | Salo, Perttu | Sanna, Serena | Scharnagl, Hubert | Shi, Jianxin | Smith, Albert Vernon | Southam, Lorraine | Stančáková, Alena | Steinthorsdottir, Valgerdur | Strawbridge, Rona J. | Sung, Yun Ju | Tachmazidou, Ioanna | Tanaka, Toshiko | Thorleifsson, Gudmar | Trompet, Stella | Pervjakova, Natalia | Tyrer, Jonathan P. | Vandenput, Liesbeth | van der Laan, Sander W | van der Velde, Nathalie | van Setten, Jessica | van Vliet-Ostaptchouk, Jana V. | Verweij, Niek | Vlachopoulou, Efthymia | Waite, Lindsay L. | Wang, Sophie R. | Wang, Zhaoming | Wild, Sarah H. | Willenborg, Christina | Wilson, James F. | Wong, Andrew | Yang, Jian | Yengo, Loïc | Yerges-Armstrong, Laura M. | Yu, Lei | Zhang, Weihua | Zhao, Jing Hua | Andersson, Ehm A. | Bakker, Stephan J. L. | Baldassarre, Damiano | Banasik, Karina | Barcella, Matteo | Barlassina, Cristina | Bellis, Claire | Benaglio, Paola | Blangero, John | Blüher, Matthias | Bonnet, Fabrice | Bonnycastle, Lori L. | Boyd, Heather A. | Bruinenberg, Marcel | Buchman, Aron S | Campbell, Harry | Chen, Yii-Der Ida | Chines, Peter S. | Claudi-Boehm, Simone | Cole, John | Collins, Francis S. | de Geus, Eco J. C. | de Groot, Lisette C. P. G. M. | Dimitriou, Maria | Duan, Jubao | Enroth, Stefan | Eury, Elodie | Farmaki, Aliki-Eleni | Forouhi, Nita G. | Friedrich, Nele | Gejman, Pablo V. | Gigante, Bruna | Glorioso, Nicola | Go, Alan S. | Gottesman, Omri | Gräßler, Jürgen | Grallert, Harald | Grarup, Niels | Gu, Yu-Mei | Broer, Linda | Ham, Annelies C. | Hansen, Torben | Harris, Tamara B. | Hartman, Catharina A. | Hassinen, Maija | Hastie, Nicholas | Hattersley, Andrew T. | Heath, Andrew C. | Henders, Anjali K. | Hernandez, Dena | Hillege, Hans | Holmen, Oddgeir | Hovingh, Kees G | Hui, Jennie | Husemoen, Lise L. | Hutri-Kähönen, Nina | Hysi, Pirro G. | Illig, Thomas | De Jager, Philip L. | Jalilzadeh, Shapour | Jørgensen, Torben | Jukema, J. Wouter | Juonala, Markus | Kanoni, Stavroula | Karaleftheri, Maria | Khaw, Kay Tee | Kinnunen, Leena | Kittner, Steven J. | Koenig, Wolfgang | Kolcic, Ivana | Kovacs, Peter | Krarup, Nikolaj T. | Kratzer, Wolfgang | Krüger, Janine | Kuh, Diana | Kumari, Meena | Kyriakou, Theodosios | Langenberg, Claudia | Lannfelt, Lars | Lanzani, Chiara | Lotay, Vaneet | Launer, Lenore J. | Leander, Karin | Lindström, Jaana | Linneberg, Allan | Liu, Yan-Ping | Lobbens, Stéphane | Luben, Robert | Lyssenko, Valeriya | Männistö, Satu | Magnusson, Patrik K. | McArdle, Wendy L. | Menni, Cristina | Merger, Sigrun | Milani, Lili | Montgomery, Grant W. | Morris, Andrew P. | Narisu, Narisu | Nelis, Mari | Ong, Ken K. | Palotie, Aarno | Pérusse, Louis | Pichler, Irene | Pilia, Maria G. | Pouta, Anneli | Rheinberger, Myriam | Ribel-Madsen, Rasmus | Richards, Marcus | Rice, Kenneth M. | Rice, Treva K. | Rivolta, Carlo | Salomaa, Veikko | Sanders, Alan R. | Sarzynski, Mark A. | Scholtens, Salome | Scott, Robert A. | Scott, William R. | Sebert, Sylvain | Sengupta, Sebanti | Sennblad, Bengt | Seufferlein, Thomas | Silveira, Angela | Slagboom, P. Eline | Smit, Jan H. | Sparsø, Thomas H. | Stirrups, Kathleen | Stolk, Ronald P. | Stringham, Heather M. | Swertz, Morris A | Swift, Amy J. | Syvänen, Ann-Christine | Tan, Sian-Tsung | Thorand, Barbara | Tönjes, Anke | Tremblay, Angelo | Tsafantakis, Emmanouil | van der Most, Peter J. | Völker, Uwe | Vohl, Marie-Claude | Vonk, Judith M. | Waldenberger, Melanie | Walker, Ryan W. | Wennauer, Roman | Widén, Elisabeth | Willemsen, Gonneke | Wilsgaard, Tom | Wright, Alan F. | Zillikens, M. Carola | van Dijk, Suzanne C. | van Schoor, Natasja M. | Asselbergs, Folkert W. | de Bakker, Paul I. W. | Beckmann, Jacques S. | Beilby, John | Bennett, David A. | Bergman, Richard N. | Bergmann, Sven | Böger, Carsten A. | Boehm, Bernhard O. | Boerwinkle, Eric | Boomsma, Dorret I. | Bornstein, Stefan R. | Bottinger, Erwin P. | Bouchard, Claude | Chambers, John C. | Chanock, Stephen J. | Chasman, Daniel I. | Cucca, Francesco | Cusi, Daniele | Dedoussis, George | Erdmann, Jeanette | Eriksson, Johan G. | Evans, Denis A. | de Faire, Ulf | Farrall, Martin | Ferrucci, Luigi | Ford, Ian | Franke, Lude | Franks, Paul W. | Froguel, Philippe | Gansevoort, Ron T. | Gieger, Christian | Grönberg, Henrik | Gudnason, Vilmundur | Gyllensten, Ulf | Hall, Per | Hamsten, Anders | van der Harst, Pim | Hayward, Caroline | Heliövaara, Markku | Hengstenberg, Christian | Hicks, Andrew A | Hingorani, Aroon | Hofman, Albert | Hu, Frank | Huikuri, Heikki V. | Hveem, Kristian | James, Alan L. | Jordan, Joanne M. | Jula, Antti | Kähönen, Mika | Kajantie, Eero | Kathiresan, Sekar | Kiemeney, Lambertus A. L. M. | Kivimaki, Mika | Knekt, Paul B. | Koistinen, Heikki A. | Kooner, Jaspal S. | Koskinen, Seppo | Kuusisto, Johanna | Maerz, Winfried | Martin, Nicholas G | Laakso, Markku | Lakka, Timo A. | Lehtimäki, Terho | Lettre, Guillaume | Levinson, Douglas F. | Lind, Lars | Lokki, Marja-Liisa | Mäntyselkä, Pekka | Melbye, Mads | Metspalu, Andres | Mitchell, Braxton D. | Moll, Frans L. | Murray, Jeffrey C. | Musk, Arthur W. | Nieminen, Markku S. | Njølstad, Inger | Ohlsson, Claes | Oldehinkel, Albertine J. | Oostra, Ben A. | Palmer, Lyle J | Pankow, James S. | Pasterkamp, Gerard | Pedersen, Nancy L. | Pedersen, Oluf | Penninx, Brenda W. | Perola, Markus | Peters, Annette | Polašek, Ozren | Pramstaller, Peter P. | Psaty, Bruce M. | Qi, Lu | Quertermous, Thomas | Raitakari, Olli T. | Rankinen, Tuomo | Rauramaa, Rainer | Ridker, Paul M. | Rioux, John D. | Rivadeneira, Fernando | Rotter, Jerome I. | Rudan, Igor | den Ruijter, Hester M. | Saltevo, Juha | Sattar, Naveed | Schunkert, Heribert | Schwarz, Peter E. H. | Shuldiner, Alan R. | Sinisalo, Juha | Snieder, Harold | Sørensen, Thorkild I. A. | Spector, Tim D. | Staessen, Jan A. | Stefania, Bandinelli | Thorsteinsdottir, Unnur | Stumvoll, Michael | Tardif, Jean-Claude | Tremoli, Elena | Tuomilehto, Jaakko | Uitterlinden, André G. | Uusitupa, Matti | Verbeek, André L. M. | Vermeulen, Sita H. | Viikari, Jorma S. | Vitart, Veronique | Völzke, Henry | Vollenweider, Peter | Waeber, Gérard | Walker, Mark | Wallaschofski, Henri | Wareham, Nicholas J. | Watkins, Hugh | Zeggini, Eleftheria | Chakravarti, Aravinda | Clegg, Deborah J. | Cupples, L. Adrienne | Gordon-Larsen, Penny | Jaquish, Cashell E. | Rao, D. C. | Abecasis, Goncalo R. | Assimes, Themistocles L. | Barroso, Inês | Berndt, Sonja I. | Boehnke, Michael | Deloukas, Panos | Fox, Caroline S. | Groop, Leif C. | Hunter, David J. | Ingelsson, Erik | Kaplan, Robert C. | McCarthy, Mark I. | Mohlke, Karen L. | O'Connell, Jeffrey R. | Schlessinger, David | Strachan, David P. | Stefansson, Kari | van Duijn, Cornelia M. | Hirschhorn, Joel N. | Lindgren, Cecilia M. | Heid, Iris M. | North, Kari E. | Borecki, Ingrid B. | Kutalik, Zoltán | Loos, Ruth J. F.
PLoS Genetics  2016;12(6):e1006166.
doi:10.1371/journal.pgen.1006166
PMCID: PMC4927064  PMID: 27355579
18.  Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption 
Cornelis, Marilyn C | Byrne, Enda M | Esko, Tõnu | Nalls, Michael A | Ganna, Andrea | Paynter, Nina | Monda, Keri L | Amin, Najaf | Fischer, Krista | Renstrom, Frida | Ngwa, Julius S | Huikari, Ville | Cavadino, Alana | Nolte, Ilja M | Teumer, Alexander | Yu, Kai | Marques-Vidal, Pedro | Rawal, Rajesh | Manichaikul, Ani | Wojczynski, Mary K | Vink, Jacqueline M | Zhao, Jing Hua | Burlutsky, George | Lahti, Jari | Mikkilä, Vera | Lemaitre, Rozenn N | Eriksson, Joel | Musani, Solomon K | Tanaka, Toshiko | Geller, Frank | Luan, Jian’an | Hui, Jennie | Mägi, Reedik | Dimitriou, Maria | Garcia, Melissa E | Ho, Weang-Kee | Wright, Margaret J | Rose, Lynda M | Magnusson, Patrik KE | Pedersen, Nancy L | Couper, David | Oostra, Ben A | Hofman, Albert | Ikram, Mohammad Arfan | Tiemeier, Henning W | Uitterlinden, Andre G | van Rooij, Frank JA | Barroso, Inês | Johansson, Ingegerd | Xue, Luting | Kaakinen, Marika | Milani, Lili | Power, Chris | Snieder, Harold | Stolk, Ronald P | Baumeister, Sebastian E | Biffar, Reiner | Gu, Fangyi | Bastardot, François | Kutalik, Zoltán | Jacobs, David R | Forouhi, Nita G | Mihailov, Evelin | Lind, Lars | Lindgren, Cecilia | Michaëlsson, Karl | Morris, Andrew | Jensen, Majken | Khaw, Kay-Tee | Luben, Robert N | Wang, Jie Jin | Männistö, Satu | Perälä, Mia-Maria | Kähönen, Mika | Lehtimäki, Terho | Viikari, Jorma | Mozaffarian, Dariush | Mukamal, Kenneth | Psaty, Bruce M | Döring, Angela | Heath, Andrew C | Montgomery, Grant W | Dahmen, Norbert | Carithers, Teresa | Tucker, Katherine L | Ferrucci, Luigi | Boyd, Heather A | Melbye, Mads | Treur, Jorien L | Mellström, Dan | Hottenga, Jouke Jan | Prokopenko, Inga | Tönjes, Anke | Deloukas, Panos | Kanoni, Stavroula | Lorentzon, Mattias | Houston, Denise K | Liu, Yongmei | Danesh, John | Rasheed, Asif | Mason, Marc A | Zonderman, Alan B | Franke, Lude | Kristal, Bruce S | Karjalainen, Juha | Reed, Danielle R | Westra, Harm-Jan | Evans, Michele K | Saleheen, Danish | Harris, Tamara B | Dedoussis, George | Curhan, Gary | Stumvoll, Michael | Beilby, John | Pasquale, Louis R | Feenstra, Bjarke | Bandinelli, Stefania | Ordovas, Jose M | Chan, Andrew T | Peters, Ulrike | Ohlsson, Claes | Gieger, Christian | Martin, Nicholas G | Waldenberger, Melanie | Siscovick, David S | Raitakari, Olli | Eriksson, Johan G | Mitchell, Paul | Hunter, David J | Kraft, Peter | Rimm, Eric B | Boomsma, Dorret I | Borecki, Ingrid B | Loos, Ruth JF | Wareham, Nicholas J | Vollenweider, Peter | Caporaso, Neil | Grabe, Hans Jörgen | Neuhouser, Marian L | Wolffenbuttel, Bruce HR | Hu, Frank B | Hyppönen, Elina | Järvelin, Marjo-Riitta | Cupples, L Adrienne | Franks, Paul W | Ridker, Paul M | van Duijn, Cornelia M | Heiss, Gerardo | Metspalu, Andres | North, Kari E | Ingelsson, Erik | Nettleton, Jennifer A | van Dam, Rob M | Chasman, Daniel I
Molecular psychiatry  2014;20(5):647-656.
doi:10.1038/mp.2014.107
PMCID: PMC4388784  PMID: 25288136
19.  Prolonged sleep restriction induces changes in pathways involved in cholesterol metabolism and inflammatory responses 
Scientific Reports  2016;6:24828.
Sleep loss and insufficient sleep are risk factors for cardiometabolic diseases, but data on how insufficient sleep contributes to these diseases are scarce. These questions were addressed using two approaches: an experimental, partial sleep restriction study (14 cases and 7 control subjects) with objective verification of sleep amount, and two independent epidemiological cohorts (altogether 2739 individuals) with questions of sleep insufficiency. In both approaches, blood transcriptome and serum metabolome were analysed. Sleep loss decreased the expression of genes encoding cholesterol transporters and increased expression in pathways involved in inflammatory responses in both paradigms. Metabolomic analyses revealed lower circulating large HDL in the population cohorts among subjects reporting insufficient sleep, while circulating LDL decreased in the experimental sleep restriction study. These findings suggest that prolonged sleep deprivation modifies inflammatory and cholesterol pathways at the level of gene expression and serum lipoproteins, inducing changes toward potentially higher risk for cardiometabolic diseases.
doi:10.1038/srep24828
PMCID: PMC4840329  PMID: 27102866
20.  Novel Loci Associated with Usual Sleep Duration: The CHARGE Consortium Genome-Wide Association Study 
Gottlieb, Daniel J. | Hek, Karin | Chen, Ting-hsu | Watson, Nathaniel F. | Eiriksdottir, Gudny | Byrne, Enda M. | Cornelis, Marilyn | Warby, Simon C. | Bandinelli, Stefania | Cherkas, Lynn | Evans, Daniel S. | Grabe, Hans J. | Lahti, Jari | Li, Man | Lehtimäki, Terho | Lumley, Thomas | Marciante, Kristin D. | Pérusse, Louis | Psaty, Bruce M. | Robbins, John | Tranah, Gregory J. | Vink, Jacqueline M. | Wilk, Jemma B. | Stafford, Jeanette M. | Bellis, Claire | Biffar, Reiner | Bouchard, Claude | Cade, Brian | Curhan, Gary C. | Eriksson, Johan G. | Ewert, Ralf | Ferrucci, Luigi | Fülöp, Tibor | Gehrman, Philip R. | Goodloe, Robert | Harris, Tamara B. | Heath, Andrew C. | Hernandez, Dena | Hofman, Albert | Hottenga, Jouke-Jan | Hunter, David J. | Jensen, Majken K. | Johnson, Andrew D. | Kähönen, Mika | Kao, Linda | Kraft, Peter | Larkin, Emma K. | Lauderdale, Diane S. | Luik, Annemarie I. | Medici, Marco | Montgomery, Grant W. | Palotie, Aarno | Patel, Sanjay R. | Pistis, Giorgio | Porcu, Eleonora | Quaye, Lydia | Raitakari, Olli | Redline, Susan | Rimm, Eric B. | Rotter, Jerome I. | Smith, Albert V. | Spector, Tim D. | Teumer, Alexander | Uitterlinden, André G. | Vohl, Marie-Claude | Widen, Elisabeth | Willemsen, Gonneke | Young, Terry | Zhang, Xiaoling | Liu, Yongmei | Blangero, John | Boomsma, Dorret I. | Gudnason, Vilmundur | Hu, Frank | Mangino, Massimo | Martin, Nicholas G. | O’Connor, George T. | Stone, Katie L. | Tanaka, Toshiko | Viikari, Jorma | Gharib, Sina A. | Punjabi, Naresh M. | Räikkönen, Katri | Völzke, Henry | Mignot, Emmanuel | Tiemeier, Henning
Molecular psychiatry  2014;20(10):1232-1239.
Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study of usual sleep duration was conducted using 18 population-based cohorts totaling 47,180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35–80 kb upstream from the thyroid-specific transcription factor PAX8 (lowest p=1.1 ×10−9). This finding was replicated in an African-American sample of 4771 individuals (lowest p=9.3 × 10−4). The strongest combined association was at rs1823125 (p=1.5 × 10−10, minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 minutes longer per night. The alleles associated with longer sleep duration were associated in previous genome-wide association studies with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.
doi:10.1038/mp.2014.133
PMCID: PMC4430294  PMID: 25469926
Sleep; Genome-wide association study
21.  A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease 
Nikpay, Majid | Goel, Anuj | Won, Hong-Hee | Hall, Leanne M | Willenborg, Christina | Kanoni, Stavroula | Saleheen, Danish | Kyriakou, Theodosios | Nelson, Christopher P | Hopewell, Jemma C | Webb, Thomas R | Zeng, Lingyao | Dehghan, Abbas | Alver, Maris | Armasu, Sebastian M | Auro, Kirsi | Bjonnes, Andrew | Chasman, Daniel I | Chen, Shufeng | Ford, Ian | Franceschini, Nora | Gieger, Christian | Grace, Christopher | Gustafsson, Stefan | Huang, Jie | Hwang, Shih-Jen | Kim, Yun Kyoung | Kleber, Marcus E | Lau, King Wai | Lu, Xiangfeng | Lu, Yingchang | Lyytikäinen, Leo-Pekka | Mihailov, Evelin | Morrison, Alanna C | Pervjakova, Natalia | Qu, Liming | Rose, Lynda M | Salfati, Elias | Saxena, Richa | Scholz, Markus | Smith, Albert V | Tikkanen, Emmi | Uitterlinden, Andre | Yang, Xueli | Zhang, Weihua | Zhao, Wei | de Andrade, Mariza | de Vries, Paul S | van Zuydam, Natalie R | Anand, Sonia S | Bertram, Lars | Beutner, Frank | Dedoussis, George | Frossard, Philippe | Gauguier, Dominique | Goodall, Alison H | Gottesman, Omri | Haber, Marc | Han, Bok-Ghee | Huang, Jianfeng | Jalilzadeh, Shapour | Kessler, Thorsten | König, Inke R | Lannfelt, Lars | Lieb, Wolfgang | Lind, Lars | Lindgren, Cecilia M | Lokki, Marja-Liisa | Magnusson, Patrik K | Mallick, Nadeem H | Mehra, Narinder | Meitinger, Thomas | Memon, Fazal-ur-Rehman | Morris, Andrew P | Nieminen, Markku S | Pedersen, Nancy L | Peters, Annette | Rallidis, Loukianos S | Rasheed, Asif | Samuel, Maria | Shah, Svati H | Sinisalo, Juha | Stirrups, Kathleen E | Trompet, Stella | Wang, Laiyuan | Zaman, Khan S | Ardissino, Diego | Boerwinkle, Eric | Borecki, Ingrid B | Bottinger, Erwin P | Buring, Julie E | Chambers, John C | Collins, Rory | Cupples, L Adrienne | Danesh, John | Demuth, Ilja | Elosua, Roberto | Epstein, Stephen E | Esko, Tõnu | Feitosa, Mary F | Franco, Oscar H | Franzosi, Maria Grazia | Granger, Christopher B | Gu, Dongfeng | Gudnason, Vilmundur | Hall, Alistair S | Hamsten, Anders | Harris, Tamara B | Hazen, Stanley L | Hengstenberg, Christian | Hofman, Albert | Ingelsson, Erik | Iribarren, Carlos | Jukema, J Wouter | Karhunen, Pekka J | Kim, Bong-Jo | Kooner, Jaspal S | Kullo, Iftikhar J | Lehtimäki, Terho | Loos, Ruth J F | Melander, Olle | Metspalu, Andres | März, Winfried | Palmer, Colin N | Perola, Markus | Quertermous, Thomas | Rader, Daniel J | Ridker, Paul M | Ripatti, Samuli | Roberts, Robert | Salomaa, Veikko | Sanghera, Dharambir K | Schwartz, Stephen M | Seedorf, Udo | Stewart, Alexandre F | Stott, David J | Thiery, Joachim | Zalloua, Pierre A | O’Donnell, Christopher J | Reilly, Muredach P | Assimes, Themistocles L | Thompson, John R | Erdmann, Jeanette | Clarke, Robert | Watkins, Hugh | Kathiresan, Sekar | McPherson, Ruth | Deloukas, Panos | Schunkert, Heribert | Samani, Nilesh J | Farrall, Martin
Nature genetics  2015;47(10):1121-1130.
Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association studies (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of 185 thousand CAD cases and controls, interrogating 6.7 million common (MAF>0.05) as well as 2.7 million low frequency (0.005
doi:10.1038/ng.3396
PMCID: PMC4589895  PMID: 26343387
Gottlieb, Daniel J. | Hek, Karin | Chen, Ting-hsu | Watson, Nathaniel F. | Eiriksdottir, Gudny | Byrne, Enda M. | Cornelis, Marilyn | Warby, Simon C. | Bandinelli, Stefania | Cherkas, Lynn | Evans, Daniel S. | Grabe, Hans J. | Lahti, Jari | Li, Man | Lehtimäki, Terho | Lumley, Thomas | Marciante, Kristin D. | Pérusse, Louis | Psaty, Bruce M. | Robbins, John | Tranah, Gregory J. | Vink, Jacqueline M. | Wilk, Jemma B. | Stafford, Jeanette M. | Bellis, Claire | Biffar, Reiner | Bouchard, Claude | Cade, Brian | Curhan, Gary C. | Eriksson, Johan G. | Ewert, Ralf | Ferrucci, Luigi | Fülöp, Tibor | Gehrman, Philip R. | Goodloe, Robert | Harris, Tamara B. | Heath, Andrew C. | Hernandez, Dena | Hofman, Albert | Hottenga, Jouke-Jan | Hunter, David J. | Jensen, Majken K. | Johnson, Andrew D. | Kähönen, Mika | Kao, Linda | Kraft, Peter | Larkin, Emma K. | Lauderdale, Diane S. | Luik, Annemarie I. | Medici, Marco | Montgomery, Grant W. | Palotie, Aarno | Patel, Sanjay R. | Pistis, Giorgio | Porcu, Eleonora | Quaye, Lydia | Raitakari, Olli | Redline, Susan | Rimm, Eric B. | Rotter, Jerome I. | Smith, Albert V. | Spector, Tim D. | Teumer, Alexander | Uitterlinden, André G. | Vohl, Marie-Claude | Widen, Elisabeth | Willemsen, Gonneke | Young, Terry | Zhang, Xiaoling | Liu, Yongmei | Blangero, John | Boomsma, Dorret I. | Gudnason, Vilmundur | Hu, Frank | Mangino, Massimo | Martin, Nicholas G. | O’Connor, George T. | Stone, Katie L. | Tanaka, Toshiko | Viikari, Jorma | Gharib, Sina A. | Punjabi, Naresh M. | Räikkönen, Katri | Völzke, Henry | Mignot, Emmanuel | Tiemeier, Henning
Molecular psychiatry  2014;20(10):1232-1239.
Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study of usual sleep duration was conducted using 18 population-based cohorts totaling 47,180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35-80 kb upstream from the thyroid-specific transcription factor PAX8 (lowest p=1.1 × 10−9). This finding was replicated in an African-American sample of 4771 individuals (lowest p=9.3 × 10−4). The strongest combined association was at rs1823125 (p=1.5 × 10−10, minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 minutes longer per night. The alleles associated with longer sleep duration were associated in previous genome-wide association studies with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.
doi:10.1038/mp.2014.133
PMCID: PMC4430294  PMID: 25469926
Sleep; Genome-wide association study
Fan, Qiao | Verhoeven, Virginie J. M. | Wojciechowski, Robert | Barathi, Veluchamy A. | Hysi, Pirro G. | Guggenheim, Jeremy A. | Höhn, René | Vitart, Veronique | Khawaja, Anthony P. | Yamashiro, Kenji | Hosseini, S Mohsen | Lehtimäki, Terho | Lu, Yi | Haller, Toomas | Xie, Jing | Delcourt, Cécile | Pirastu, Mario | Wedenoja, Juho | Gharahkhani, Puya | Venturini, Cristina | Miyake, Masahiro | Hewitt, Alex W. | Guo, Xiaobo | Mazur, Johanna | Huffman, Jenifer E. | Williams, Katie M. | Polasek, Ozren | Campbell, Harry | Rudan, Igor | Vatavuk, Zoran | Wilson, James F. | Joshi, Peter K. | McMahon, George | St Pourcain, Beate | Evans, David M. | Simpson, Claire L. | Schwantes-An, Tae-Hwi | Igo, Robert P. | Mirshahi, Alireza | Cougnard-Gregoire, Audrey | Bellenguez, Céline | Blettner, Maria | Raitakari, Olli | Kähönen, Mika | Seppala, Ilkka | Zeller, Tanja | Meitinger, Thomas | Ried, Janina S. | Gieger, Christian | Portas, Laura | van Leeuwen, Elisabeth M. | Amin, Najaf | Uitterlinden, André G. | Rivadeneira, Fernando | Hofman, Albert | Vingerling, Johannes R. | Wang, Ya Xing | Wang, Xu | Tai-Hui Boh, Eileen | Ikram, M. Kamran | Sabanayagam, Charumathi | Gupta, Preeti | Tan, Vincent | Zhou, Lei | Ho, Candice E. H. | Lim, Wan'e | Beuerman, Roger W. | Siantar, Rosalynn | Tai, E-Shyong | Vithana, Eranga | Mihailov, Evelin | Khor, Chiea-Chuen | Hayward, Caroline | Luben, Robert N. | Foster, Paul J. | Klein, Barbara E. K. | Klein, Ronald | Wong, Hoi-Suen | Mitchell, Paul | Metspalu, Andres | Aung, Tin | Young, Terri L. | He, Mingguang | Pärssinen, Olavi | van Duijn, Cornelia M. | Jin Wang, Jie | Williams, Cathy | Jonas, Jost B. | Teo, Yik-Ying | Mackey, David A. | Oexle, Konrad | Yoshimura, Nagahisa | Paterson, Andrew D. | Pfeiffer, Norbert | Wong, Tien-Yin | Baird, Paul N. | Stambolian, Dwight | Wilson, Joan E. Bailey | Cheng, Ching-Yu | Hammond, Christopher J. | Klaver, Caroline C. W. | Saw, Seang-Mei | Rahi, Jugnoo S. | Korobelnik, Jean-François | Kemp, John P. | Timpson, Nicholas J. | Smith, George Davey | Craig, Jamie E. | Burdon, Kathryn P. | Fogarty, Rhys D. | Iyengar, Sudha K. | Chew, Emily | Janmahasatian, Sarayut | Martin, Nicholas G. | MacGregor, Stuart | Xu, Liang | Schache, Maria | Nangia, Vinay | Panda-Jonas, Songhomitra | Wright, Alan F. | Fondran, Jeremy R. | Lass, Jonathan H. | Feng, Sheng | Zhao, Jing Hua | Khaw, Kay-Tee | Wareham, Nick J. | Rantanen, Taina | Kaprio, Jaakko | Pang, Chi Pui | Chen, Li Jia | Tam, Pancy O. | Jhanji, Vishal | Young, Alvin L. | Döring, Angela | Raffel, Leslie J. | Cotch, Mary-Frances | Li, Xiaohui | Yip, Shea Ping | Yap, Maurice K.H. | Biino, Ginevra | Vaccargiu, Simona | Fossarello, Maurizio | Fleck, Brian | Yazar, Seyhan | Tideman, Jan Willem L. | Tedja, Milly | Deangelis, Margaret M. | Morrison, Margaux | Farrer, Lindsay | Zhou, Xiangtian | Chen, Wei | Mizuki, Nobuhisa | Meguro, Akira | Mäkelä, Kari Matti
Nature Communications  2016;7:11008.
Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P<8.5 × 10−5), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia.
This report by the Consortium for Refractive Error and Myopia uses gene-environment-wide interaction study (GEWIS) to identify genetic loci that affect environmental influence in myopia development, and identifies ethnic specific genetic loci that attribute to eye refractive errors.
doi:10.1038/ncomms11008
PMCID: PMC4820539  PMID: 27020472
Nature Communications  2016;7:11122.
Genome-wide association studies have identified numerous loci linked with complex diseases, for which the molecular mechanisms remain largely unclear. Comprehensive molecular profiling of circulating metabolites captures highly heritable traits, which can help to uncover metabolic pathophysiology underlying established disease variants. We conduct an extended genome-wide association study of genetic influences on 123 circulating metabolic traits quantified by nuclear magnetic resonance metabolomics from up to 24,925 individuals and identify eight novel loci for amino acids, pyruvate and fatty acids. The LPA locus link with cardiovascular risk exemplifies how detailed metabolic profiling may inform underlying aetiology via extensive associations with very-low-density lipoprotein and triglyceride metabolism. Genetic fine mapping and Mendelian randomization uncover wide-spread causal effects of lipoprotein(a) on overall lipoprotein metabolism and we assess potential pleiotropic consequences of genetically elevated lipoprotein(a) on diverse morbidities via electronic health-care records. Our findings strengthen the argument for safe LPA-targeted intervention to reduce cardiovascular risk.
Circulating metabolites reflect human health and disease. Here, Kettunen et al. perform a genome-wide association study on 123 circulating metabolic traits and identify novel genetic loci influencing systemic metabolism. They also link new molecular pathways with a known cardiovascular risk factor Lp(a).
doi:10.1038/ncomms11122
PMCID: PMC4814583  PMID: 27005778
Scientific Reports  2016;6:23207.
Asymmetric and symmetric dimethylarginines (ADMA and SDMA) impair nitric oxide bioavailability and have been implicated in the pathogenesis of atrial fibrillation (AF). Alanine–glyoxylate aminotransferase 2 (AGXT2) is the only enzyme capable of metabolizing both of the dimethylarginines. We hypothesized that two functional AGXT2 missense variants (rs37369, V140I; rs16899974, V498L) are associated with AF and its cardioembolic complications. Association analyses were conducted using 1,834 individulas with AF and 7,159 unaffected individuals from two coronary angiography cohorts and a cohort comprising patients undergoing clinical exercise testing. In coronary angiography patients without structural heart disease, the minor A allele of rs16899974 was associated with any AF (OR = 2.07, 95% CI 1.59-2.68), and with paroxysmal AF (OR = 1.98, 95% CI 1.44–2.74) and chronic AF (OR = 2.03, 95% CI 1.35–3.06) separately. We could not replicate the association with AF in the other two cohorts. However, the A allele of rs16899974 was nominally associated with ischemic stroke risk in the meta-analysis of WTCCC2 ischemic stroke cohorts (3,548 cases, 5,972 controls) and with earlier onset of first-ever ischemic stroke (360 cases) in the cohort of clinical exercise test patients. In conclusion, AGXT2 variations may be involved in the pathogenesis of AF and its age-related thromboembolic complications.
doi:10.1038/srep23207
PMCID: PMC4794714  PMID: 26984639

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