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1.  Physical and neuro-behavioural determinants of reproductive onset and success 
Nature genetics  2016;48(6):617-623.
The ages of puberty, first sexual intercourse and first birth signify the onset of reproductive ability, behaviour and success, respectively. These sequenced events have behavioural, physiological and health significance, and may also influence overall reproductive fitness. In a genome-wide association study of 125,667 white men and women aged 40-69 in the UK Biobank Study, we identify 38 sequence variants with association P-values <5×10-8 with age at first sexual intercourse. Findings were taken forward in up to 241,910 men and women from deCODE Iceland and 20,187 from Women’s Genome Health Study. Several of these loci also exhibit strong associations with behavioural traits (rs4856591 in CADM2 and risk taking propensity: P=4.3×10-10; rs73195303 in MSRA and irritable temperament: P=5.8×10-11) and other reproductive traits (rs67229052 in ESR1 and both age at first birth: P=1.2x10-13 and number of children: P=4.8×10-12; rs2188151 in SEMA3F and age at first birth: P=8.76×10-15). In Mendelian randomisation analyses, we demonstrate likely causal influences of earlier puberty timing on earlier first sexual intercourse, earlier first birth and fewer years of education. In turn, likely causal consequences of earlier first sexual intercourse include reproductive, educational, psychiatric and cardiometabolic outcomes. These findings point to the existence of developmental and neuro-behavioural regulators of reproductive activity and success.
doi:10.1038/ng.3551
PMCID: PMC5238953  PMID: 27089180
2.  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
3.  Epigenetic and genetic components of height regulation 
Nature Communications  2016;7:13490.
Adult height is a highly heritable trait. Here we identified 31.6 million sequence variants by whole-genome sequencing of 8,453 Icelanders and tested them for association with adult height by imputing them into 88,835 Icelanders. Here we discovered 13 novel height associations by testing four different models including parent-of-origin (|β|=0.4–10.6 cm). The minor alleles of three parent-of-origin signals associate with less height only when inherited from the father and are located within imprinted regions (IGF2-H19 and DLK1-MEG3). We also examined the association of these sequence variants in a set of 12,645 Icelanders with birth length measurements. Two of the novel variants, (IGF2-H19 and TET1), show significant association with both adult height and birth length, indicating a role in early growth regulation. Among the parent-of-origin signals, we observed opposing parental effects raising questions about underlying mechanisms. These findings demonstrate that common variations affect human growth by parental imprinting.
Adult height has a strong genetic component and is highly heritable. Here the authors whole-genome sequence 8,453 Icelanders and find novel parent-of-origin derived associations in IGF2-H19 and DLK1-MEG3.
doi:10.1038/ncomms13490
PMCID: PMC5116096  PMID: 27848971
4.  Multi-nucleotide de novo Mutations in Humans 
PLoS Genetics  2016;12(11):e1006315.
Mutation of the DNA molecule is one of the most fundamental processes in biology. In this study, we use 283 parent-offspring trios to estimate the rate of mutation for both single nucleotide variants (SNVs) and short length variants (indels) in humans and examine the mutation process. We found 17812 SNVs, corresponding to a mutation rate of 1.29 × 10−8 per position per generation (PPPG) and 1282 indels corresponding to a rate of 9.29 × 10−10 PPPG. We estimate that around 3% of human de novo SNVs are part of a multi-nucleotide mutation (MNM), with 558 (3.1%) of mutations positioned less than 20kb from another mutation in the same individual (median distance of 525bp). The rate of de novo mutations is greater in late replicating regions (p = 8.29 × 10−19) and nearer recombination events (p = 0.0038) than elsewhere in the genome.
Author Summary
In each generation new genetic variants are introduced by mutations. In this study we use whole genome sequence data from Icelandic families to directly observe such new mutations. Our estimate of the mutation rate implies that a newborn with 30-year-old parents will on average carry 75 new SNV mutations and 6 new short indel mutations. We observe that some of the found mutations occur much closer together than would be expected by chance. Our analysis shows that mutational hotspots cannot explain this clustering, instead the clustering mutations are likely created by a single mutational event. We observe a different composition for mutations that cluster very close together compared to more distant clustering mutations. This suggests that there is likely more than one type of underlying mutational mechanism creating the multi nucleotide mutation events. We furthermore observe a higher mutation rate near recombination events but find that this effect cannot explain the large number of clustering mutations that we observe.
doi:10.1371/journal.pgen.1006315
PMCID: PMC5147774  PMID: 27846220
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.  HLA class II sequence variants influence tuberculosis risk in populations of European ancestry 
Nature genetics  2016;48(3):318-322.
Mycobacterium tuberculosis (M. tuberculosis) infections cause 9.0 million new tuberculosis (TB) cases and 1.5 million deaths annually1. To search for sequence variants that confer risk of TB we tested 28.3 million variants identified through whole-genome sequencing of 2,636 Icelanders for association with TB (8,162 cases and 277,643 controls), pulmonary TB (PTB), and M. tuberculosis infection. We found association of three sequence variants in the HLA class II region: rs557011[T] (MAF=40.2%) with M. tuberculosis infection (OR =1.14, P=3.1×10-13) and PTB (OR=1.25, P=5.8×10-12) and rs9271378[G] (MAF=32.5%) with PTB (OR=0.78, P=2.5×10-12), both located between HLA-DQA1 and HLA-DRB1. Finally, a missense variant p.Ala210Thr in HLA-DQA1, (MAF=19.1%, rs9272785) shows association with M. tuberculosis infection (P=9.3×10-9, OR=1.14). The association of these variants with PTB was replicated in large samples of European ancestry from Russia and Croatia (P< 5.9×10-4). These findings demonstrate that the HLA class II region contributes to the complex genetic risk of tuberculosis, possibly through reduced presentation of protective M. tuberculosis antigens to T cells.
doi:10.1038/ng.3498
PMCID: PMC5081101  PMID: 26829749
9.  A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis 
Rivas, Manuel A. | Graham, Daniel | Sulem, Patrick | Stevens, Christine | Desch, A. Nicole | Goyette, Philippe | Gudbjartsson, Daniel | Jonsdottir, Ingileif | Thorsteinsdottir, Unnur | Degenhardt, Frauke | Mucha, Sören | Kurki, Mitja I. | Li, Dalin | D'Amato, Mauro | Annese, Vito | Vermeire, Severine | Weersma, Rinse K. | Halfvarson, Jonas | Paavola-Sakki, Paulina | Lappalainen, Maarit | Lek, Monkol | Cummings, Beryl | Tukiainen, Taru | Haritunians, Talin | Halme, Leena | Koskinen, Lotta L. E. | Ananthakrishnan, Ashwin N. | Luo, Yang | Heap, Graham A. | Visschedijk, Marijn C. | MacArthur, Daniel G. | Neale, Benjamin M. | Ahmad, Tariq | Anderson, Carl A. | Brant, Steven R. | Duerr, Richard H. | Silverberg, Mark S. | Cho, Judy H | Palotie, Aarno | Saavalainen, Päivi | Kontula, Kimmo | Färkkilä, Martti | McGovern, Dermot P. B. | Franke, Andre | Stefansson, Kari | Rioux, John D. | Xavier, Ramnik J. | Daly, Mark J. | Barrett, J. | de Lane, K. | Edwards, C. | Hart, A. | Hawkey, C. | Jostins, L. | Kennedy, N. | Lamb, C. | Lee, J. | Lees, C. | Mansfield, J. | Mathew, C. | Mowatt, C. | Newman, B. | Nimmo, E. | Parkes, M. | Pollard, M. | Prescott, N. | Randall, J. | Rice, D. | Satsangi, J. | Simmons, A. | Tremelling, M. | Uhlig, H. | Wilson, D. | Abraham, C. | Achkar, J. P. | Bitton, A. | Boucher, G. | Croitoru, K. | Fleshner, P. | Glas, J. | Kugathasan, S. | Limbergen, J. V. | Milgrom, R. | Proctor, D. | Regueiro, M. | Schumm, P. L. | Sharma, Y. | Stempak, J. M. | Targan, S. R. | Wang, M. H.
Nature Communications  2016;7:12342.
Protein-truncating variants protective against human disease provide in vivo validation of therapeutic targets. Here we used targeted sequencing to conduct a search for protein-truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associated with the same disease. Through replication genotyping and imputation we found that a predicted protein-truncating variant (rs36095412, p.R179X, genotyped in 11,148 ulcerative colitis patients and 295,446 controls, MAF=up to 0.78%) in RNF186, a single-exon ring finger E3 ligase with strong colonic expression, protects against ulcerative colitis (overall P=6.89 × 10−7, odds ratio=0.30). We further demonstrate that the truncated protein exhibits reduced expression and altered subcellular localization, suggesting the protective mechanism may reside in the loss of an interaction or function via mislocalization and/or loss of an essential transmembrane domain.
While hundreds of loci are linked with inflammatory bowel diseases (IBDs), the functional consequences of the associated variants remain unclear. Here, the authors screened in ulcerative colitis (UC) patients' genomes for protein-truncating variants near IBD loci, and identify a protein truncating variant in RNF186 to be protective against UC.
doi:10.1038/ncomms12342
PMCID: PMC4980482  PMID: 27503255
10.  Common variants upstream of KDR encoding VEGFR2 and in TTC39B associate with endometriosis 
Nature Communications  2016;7:12350.
We conducted a genome-wide association scan (GWAS) of endometriosis using 25.5 million sequence variants detected through whole-genome sequencing (WGS) of 8,453 Icelanders and imputed into 1,840 cases and 129,016 control women, followed by testing of associated variants in Danish samples. Here we report the discovery of a new endometriosis susceptibility locus on 4q12 (rs17773813[G], OR=1.28; P=3.8 × 10−11), upstream of KDR encoding vascular endothelial growth factor receptor 2 (VEGFR2). The variant correlates with disease severity (P=0.0046) when moderate/severe endometriosis cases are tested against minimal/mild cases. We further report association of rs519664[T] in TTC39B on 9p22 with endometriosis (P=4.8 × 10−10; OR=1.29). The involvement of KDR in endometriosis risk highlights the importance of the VEGF pathway in the pathogenesis of the disease.
Endometriosis is a common gynaecological disease but the underlying pathogenesis is poorly understood, however there is a strong familial component. Here the authors conduct a genome wide association study and identify a novel susceptibility locus that correlates with disease severity.
doi:10.1038/ncomms12350
PMCID: PMC4962463  PMID: 27453397
11.  Genome-wide association study identifies multiple susceptibility loci for multiple myeloma 
Nature Communications  2016;7:12050.
Multiple myeloma (MM) is a plasma cell malignancy with a significant heritable basis. Genome-wide association studies have transformed our understanding of MM predisposition, but individual studies have had limited power to discover risk loci. Here we perform a meta-analysis of these GWAS, add a new GWAS and perform replication analyses resulting in 9,866 cases and 239,188 controls. We confirm all nine known risk loci and discover eight new loci at 6p22.3 (rs34229995, P=1.31 × 10−8), 6q21 (rs9372120, P=9.09 × 10−15), 7q36.1 (rs7781265, P=9.71 × 10−9), 8q24.21 (rs1948915, P=4.20 × 10−11), 9p21.3 (rs2811710, P=1.72 × 10−13), 10p12.1 (rs2790457, P=1.77 × 10−8), 16q23.1 (rs7193541, P=5.00 × 10−12) and 20q13.13 (rs6066835, P=1.36 × 10−13), which localize in or near to JARID2, ATG5, SMARCD3, CCAT1, CDKN2A, WAC, RFWD3 and PREX1. These findings provide additional support for a polygenic model of MM and insight into the biological basis of tumour development.
Previous genome-wide association studies have identified loci associated with the risk of multiple myeloma. Here, the authors present a meta-analysis of six genome wide association studies of the disease and identify eight new loci; functional studies identify genes as candidates for the basis of these associations.
doi:10.1038/ncomms12050
PMCID: PMC4932178  PMID: 27363682
12.  Shared Genetic Risk Factors of Intracranial, Abdominal, and Thoracic Aneurysms 
van ’t Hof, Femke N. G. | Ruigrok, Ynte M. | Lee, Cue Hyunkyu | Ripke, Stephan | Anderson, Graig | de Andrade, Mariza | Baas, Annette F. | Blankensteijn, Jan D. | Böttinger, Erwin P. | Bown, Matthew J. | Broderick, Joseph | Bijlenga, Philippe | Carrell, David S. | Crawford, Dana C. | Crosslin, David R. | Ebeling, Christian | Eriksson, Johan G. | Fornage, Myriam | Foroud, Tatiana | von und zu Fraunberg, Mikael | Friedrich, Christoph M. | Gaál, Emília I. | Gottesman, Omri | Guo, Dong‐Chuan | Harrison, Seamus C. | Hernesniemi, Juha | Hofman, Albert | Inoue, Ituro | Jääskeläinen, Juha E. | Jones, Gregory T. | Kiemeney, Lambertus A. L. M. | Kivisaari, Riku | Ko, Nerissa | Koskinen, Seppo | Kubo, Michiaki | Kullo, Iftikhar J. | Kuivaniemi, Helena | Kurki, Mitja I. | Laakso, Aki | Lai, Dongbing | Leal, Suzanne M. | Lehto, Hanna | LeMaire, Scott A. | Low, Siew‐Kee | Malinowski, Jennifer | McCarty, Catherine A. | Milewicz, Dianna M. | Mosley, Thomas H. | Nakamura, Yusuke | Nakaoka, Hirofumi | Niemelä, Mika | Pacheco, Jennifer | Peissig, Peggy L. | Pera, Joanna | Rasmussen‐Torvik, Laura | Ritchie, Marylyn D. | Rivadeneira, Fernando | van Rij, Andre M. | Santos‐Cortez, Regie Lyn P. | Saratzis, Athanasios | Slowik, Agnieszka | Takahashi, Atsushi | Tromp, Gerard | Uitterlinden, André G. | Verma, Shefali S. | Vermeulen, Sita H. | Wang, Gao T. | Han, Buhm | Rinkel, Gabriël J. E. | de Bakker, Paul I. W. | Bown, Matthew J. | Harrison, Seamus C. | Saratzis, Athanasios | Verissimo, Ana | Wright, Benjamin J. | Bumpstead, Suzannah | Baas, Annette F. | Gretarsdottir, Solveig | Badger, Stephen A. | Child, Anne H. | Clough, Rachel E. | Cockerill, Gillian | Hafez, Hany | Scott, D. Julian A. | Futers, Simon | Sohrabi, Soroush | Smith, Alberto | Thompson, Matthew M. | van Bockxmeer, Frank M. | Matthiasson, Stefan E. | Thorleifsson, Gudmar | Thorsteinsdottir, Unnur | Blankensteijn, Jan D. | Teijink, Joep A. W. | Wijmenga, Cisca | de Graaf, Jacqueline | Kiemeney, Lambertus A. | Palmen, Jutta | Smith, Andrew J. | Lindholt, Jes S. | Bradley, Declan T. | Waltham, Matthew | Edkins, Sarah | Gwilliam, Rhian | Hunt, Sarah E. | Potter, Simon | Golledge, Jonathan | Eriksson, Per | Norman, Paul E. | Powell, Janet T. | Stefansson, Kari | Thompson, John R. | Humphries, Steve E. | Sayers, Robert D. | Deloukas, Panos | Samani, Nilesh J. | Jones, Gregory T. | Phillip, L. Victoria | van Rij, Andre M. | Hill, Geraldine B. | Williams, Michael J. A. | Thomson, Ian A. | Krysa, Jo | Wilkins, Gerard T. | Merriman, Tony R. | Vasudevan, Thodor M. | Lewis, David R. | Blair, Ross D. | Hill, Andrew A.
Background
Intracranial aneurysms (IAs), abdominal aortic aneurysms (AAAs), and thoracic aortic aneurysms (TAAs) all have a familial predisposition. Given that aneurysm types are known to co‐occur, we hypothesized that there may be shared genetic risk factors for IAs, AAAs, and TAAs.
Methods and Results
We performed a mega‐analysis of 1000 Genomes Project‐imputed genome‐wide association study (GWAS) data of 4 previously published aneurysm cohorts: 2 IA cohorts (in total 1516 cases, 4305 controls), 1 AAA cohort (818 cases, 3004 controls), and 1 TAA cohort (760 cases, 2212 controls), and observed associations of 4 known IA, AAA, and/or TAA risk loci (9p21, 18q11, 15q21, and 2q33) with consistent effect directions in all 4 cohorts. We calculated polygenic scores based on IA‐, AAA‐, and TAA‐associated SNPs and tested these scores for association to case‐control status in the other aneurysm cohorts; this revealed no shared polygenic effects. Similarly, linkage disequilibrium–score regression analyses did not show significant correlations between any pair of aneurysm subtypes. Last, we evaluated the evidence for 14 previously published aneurysm risk single‐nucleotide polymorphisms through collaboration in extended aneurysm cohorts, with a total of 6548 cases and 16 843 controls (IA) and 4391 cases and 37 904 controls (AAA), and found nominally significant associations for IA risk locus 18q11 near RBBP8 to AAA (odds ratio [OR]=1.11; P=4.1×10−5) and for TAA risk locus 15q21 near FBN1 to AAA (OR=1.07; P=1.1×10−3).
Conclusions
Although there was no evidence for polygenic overlap between IAs, AAAs, and TAAs, we found nominally significant effects of two established risk loci for IAs and TAAs in AAAs. These two loci will require further replication.
doi:10.1161/JAHA.115.002603
PMCID: PMC5015357  PMID: 27418160
abdominal aortic aneurysm; genome wide association study; intracranial aneurysm; thoracic aortic aneurysm; Inflammation; Vascular Biology; Ischemic Stroke
13.  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
14.  Meta-analysis of genome-wide association studies identifies 10 loci influencing allergic sensitization 
Nature genetics  2013;45(8):902-906.
Allergen-specific IgE (allergic sensitization) plays a central role in the pathogenesis of allergic disease. We performed the first large-scale genome wide association study (GWAS) of allergic sensitization in 5,789 affected individuals and 10,056 controls and followed up the top SNP from 26 loci in 6,114 affected individuals and 9,920 controls. We increased the number of susceptibility loci with genome-wide significant association to allergic sensitization from three to 10, including SNPs in or near TLR6, C11orf30, STAT6, SLC25A46, HLA-DQB1, IL1RL1, LPP, MYC, IL2 and HLA-B. All the top-SNPs were associated with allergic symptoms in an independent study. Risk variants at these 10 loci were estimated to account for at least 25% of allergic sensitization and allergic rhinitis. Understanding the molecular mechanisms underlying these associations may provide novel insight into the etiology of allergic disease.
doi:10.1038/ng.2694
PMCID: PMC4922420  PMID: 23817571
15.  Polygenic Overlap Between C-Reactive Protein, Plasma Lipids and Alzheimer's Disease 
Circulation  2015;131(23):2061-2069.
Background
Epidemiological findings suggest a relationship between Alzheimer's disease (AD), inflammation and dyslipidemia, although the nature of this relationship is not well understood. We investigated whether this phenotypic association arises from a shared genetic basis.
Methods and Results
Using summary statistics (p-values and odds ratios) from genome-wide association studies of over 200,000 individuals, we investigated overlap in single nucleotide polymorphisms (SNPs) associated with clinically diagnosed AD and C-reactive protein (CRP), triglycerides (TG), high- (HDL) and low-density lipoprotein (LDL) levels. We found up to 50-fold enrichment of AD SNPs for different levels of association with CRP, LDL, HDL and TG SNPs using an FDR threshold < 0.05. By conditioning on polymorphisms associated with the four phenotypes, we identified 55 loci associated with increased AD risk. We then conducted a meta-analysis of these 55 variants across four independent AD cohorts (total n = 29,054 AD cases and 114,824 healthy controls) and discovered two genome-wide significant variants on chromosome 4 (rs13113697, closest gene HS3ST1, odds ratio (OR) = 1.07, 95% confidence interval (CI) = 1.05-1.11, p = 2.86 × 10−8) and chromosome 10 (rs7920721, closest gene ECHDC3, OR = 1.07, 95% CI = 1.04-1.11, p = 3.38 × 10−8). We also found that gene expression of HS3ST1 and ECHDC3 was altered in AD brains compared with control brains.
Conclusions
We demonstrate genetic overlap between AD, CRP, and plasma lipids. By conditioning on the genetic association with the cardiovascular phenotypes, we identify novel AD susceptibility loci including two genome-wide significant variants conferring increased risk for Alzheimer's disease.
doi:10.1161/CIRCULATIONAHA.115.015489
PMCID: PMC4677995  PMID: 25862742
Alzheimer's disease; inflammation; plasma lipids; GWAS
16.  Genetic overlap between Alzheimer’s disease and Parkinson’s disease at the MAPT locus 
Molecular psychiatry  2015;20(12):1588-1595.
We investigated genetic overlap between Alzheimer’s disease (AD) and Parkinson’s disease (PD). Using summary statistics (p-values) from large recent genomewide association studies (GWAS) (total n = 89,904 individuals), we sought to identify single nucleotide polymorphisms (SNPs) associating with both AD and PD. We found and replicated association of both AD and PD with the A allele of rs393152 within the extended MAPT region on chromosome 17 (meta analysis p-value across 5 independent AD cohorts = 1.65 × 10−7). In independent datasets, we found a dose-dependent effect of the A allele of rs393152 on intra-cerebral MAPT transcript levels and volume loss within the entorhinal cortex and hippocampus. Our findings identify the tau-associated MAPT locus as a site of genetic overlap between AD and PD and extending prior work, we show that the MAPT region increases risk of Alzheimer’s neurodegeneration.
doi:10.1038/mp.2015.6
PMCID: PMC4539304  PMID: 25687773
17.  Genetic fine-mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci 
Gaulton, Kyle J | Ferreira, Teresa | Lee, Yeji | Raimondo, Anne | Mägi, Reedik | Reschen, Michael E | Mahajan, Anubha | Locke, Adam | Rayner, N William | Robertson, Neil | Scott, Robert A | Prokopenko, Inga | Scott, Laura J | Green, Todd | Sparso, Thomas | Thuillier, Dorothee | Yengo, Loic | Grallert, Harald | Wahl, Simone | Frånberg, Mattias | Strawbridge, Rona J | Kestler, Hans | Chheda, Himanshu | Eisele, Lewin | Gustafsson, Stefan | Steinthorsdottir, Valgerdur | Thorleifsson, Gudmar | Qi, Lu | Karssen, Lennart C | van Leeuwen, Elisabeth M | Willems, Sara M | Li, Man | Chen, Han | Fuchsberger, Christian | Kwan, Phoenix | Ma, Clement | Linderman, Michael | Lu, Yingchang | Thomsen, Soren K | Rundle, Jana K | Beer, Nicola L | van de Bunt, Martijn | Chalisey, Anil | Kang, Hyun Min | Voight, Benjamin F | Abecasis, Goncalo R | Almgren, Peter | Baldassarre, Damiano | Balkau, Beverley | Benediktsson, Rafn | Blüher, Matthias | Boeing, Heiner | Bonnycastle, Lori L | Borringer, Erwin P | Burtt, Noël P | Carey, Jason | Charpentier, Guillaume | Chines, Peter S | Cornelis, Marilyn C | Couper, David J | Crenshaw, Andrew T | van Dam, Rob M | Doney, Alex SF | Dorkhan, Mozhgan | Edkins, Sarah | Eriksson, Johan G | Esko, Tonu | Eury, Elodie | Fadista, João | Flannick, Jason | Fontanillas, Pierre | Fox, Caroline | Franks, Paul W | Gertow, Karl | Gieger, Christian | Gigante, Bruna | Gottesman, Omri | Grant, George B | Grarup, Niels | Groves, Christopher J | Hassinen, Maija | Have, Christian T | Herder, Christian | Holmen, Oddgeir L | Hreidarsson, Astradur B | Humphries, Steve E | Hunter, David J | Jackson, Anne U | Jonsson, Anna | Jørgensen, Marit E | Jørgensen, Torben | Kao, Wen-Hong L | Kerrison, Nicola D | Kinnunen, Leena | Klopp, Norman | Kong, Augustine | Kovacs, Peter | Kraft, Peter | Kravic, Jasmina | Langford, Cordelia | Leander, Karin | Liang, Liming | Lichtner, Peter | Lindgren, Cecilia M | Lindholm, Eero | Linneberg, Allan | Liu, Ching-Ti | Lobbens, Stéphane | Luan, Jian’an | Lyssenko, Valeriya | Mӓnnistö, Satu | McLeod, Olga | Meyer, Julia | Mihailov, Evelin | Mirza, Ghazala | Mühleisen, Thomas W | Müller-Nurasyid, Martina | Navarro, Carmen | Nöthen, Markus M | Oskolkov, Nikolay N | Owen, Katharine R | Palli, Domenico | Pechlivanis, Sonali | Peltonen, Leena | Perry, John RB | Platou, Carl GP | Roden, Michael | Ruderfer, Douglas | Rybin, Denis | van der Schouw, Yvonne T | Sennblad, Bengt | Sigurđsson, Gunnar | Stančáková, Alena | Steinbach, Gerald | Storm, Petter | Strauch, Konstantin | Stringham, Heather M | Sun, Qi | Thorand, Barbara | Tikkanen, Emmi | Tonjes, Anke | Trakalo, Joseph | Tremoli, Elena | Tuomi, Tiinamaija | Wennauer, Roman | Wiltshire, Steven | Wood, Andrew R | Zeggini, Eleftheria | Dunham, Ian | Birney, Ewan | Pasquali, Lorenzo | Ferrer, Jorge | Loos, Ruth JF | Dupuis, Josée | Florez, Jose C | Boerwinkle, Eric | Pankow, James S | van Duijn, Cornelia | Sijbrands, Eric | Meigs, James B | Hu, Frank B | Thorsteinsdottir, Unnur | Stefansson, Kari | Lakka, Timo A | Rauramaa, Rainer | Stumvoll, Michael | Pedersen, Nancy L | Lind, Lars | Keinanen-Kiukaanniemi, Sirkka M | Korpi-Hyövӓlti, Eeva | Saaristo, Timo E | Saltevo, Juha | Kuusisto, Johanna | Laakso, Markku | Metspalu, Andres | Erbel, Raimund | Jöckel, Karl-Heinz | Moebus, Susanne | Ripatti, Samuli | Salomaa, Veikko | Ingelsson, Erik | Boehm, Bernhard O | Bergman, Richard N | Collins, Francis S | Mohlke, Karen L | Koistinen, Heikki | Tuomilehto, Jaakko | Hveem, Kristian | Njølstad, Inger | Deloukas, Panagiotis | Donnelly, Peter J | Frayling, Timothy M | Hattersley, Andrew T | de Faire, Ulf | Hamsten, Anders | Illig, Thomas | Peters, Annette | Cauchi, Stephane | Sladek, Rob | Froguel, Philippe | Hansen, Torben | Pedersen, Oluf | Morris, Andrew D | Palmer, Collin NA | Kathiresan, Sekar | Melander, Olle | Nilsson, Peter M | Groop, Leif C | Barroso, Inês | Langenberg, Claudia | Wareham, Nicholas J | O’Callaghan, Christopher A | Gloyn, Anna L | Altshuler, David | Boehnke, Michael | Teslovich, Tanya M | McCarthy, Mark I | Morris, Andrew P
Nature genetics  2015;47(12):1415-1425.
We performed fine-mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in/near KCNQ1. “Credible sets” of variants most likely to drive each distinct signal mapped predominantly to non-coding sequence, implying that T2D association is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine-mapping implicated rs10830963 as driving T2D association. We confirmed that this T2D-risk allele increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D-risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
doi:10.1038/ng.3437
PMCID: PMC4666734  PMID: 26551672
18.  Genetic fine-mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci 
Gaulton, Kyle J | Ferreira, Teresa | Lee, Yeji | Raimondo, Anne | Mägi, Reedik | Reschen, Michael E | Mahajan, Anubha | Locke, Adam | Rayner, N William | Robertson, Neil | Scott, Robert A | Prokopenko, Inga | Scott, Laura J | Green, Todd | Sparso, Thomas | Thuillier, Dorothee | Yengo, Loic | Grallert, Harald | Wahl, Simone | Frånberg, Mattias | Strawbridge, Rona J | Kestler, Hans | Chheda, Himanshu | Eisele, Lewin | Gustafsson, Stefan | Steinthorsdottir, Valgerdur | Thorleifsson, Gudmar | Qi, Lu | Karssen, Lennart C | van Leeuwen, Elisabeth M | Willems, Sara M | Li, Man | Chen, Han | Fuchsberger, Christian | Kwan, Phoenix | Ma, Clement | Linderman, Michael | Lu, Yingchang | Thomsen, Soren K | Rundle, Jana K | Beer, Nicola L | van de Bunt, Martijn | Chalisey, Anil | Kang, Hyun Min | Voight, Benjamin F | Abecasis, Goncalo R | Almgren, Peter | Baldassarre, Damiano | Balkau, Beverley | Benediktsson, Rafn | Blüher, Matthias | Boeing, Heiner | Bonnycastle, Lori L | Borringer, Erwin P | Burtt, Noël P | Carey, Jason | Charpentier, Guillaume | Chines, Peter S | Cornelis, Marilyn C | Couper, David J | Crenshaw, Andrew T | van Dam, Rob M | Doney, Alex SF | Dorkhan, Mozhgan | Edkins, Sarah | Eriksson, Johan G | Esko, Tonu | Eury, Elodie | Fadista, João | Flannick, Jason | Fontanillas, Pierre | Fox, Caroline | Franks, Paul W | Gertow, Karl | Gieger, Christian | Gigante, Bruna | Gottesman, Omri | Grant, George B | Grarup, Niels | Groves, Christopher J | Hassinen, Maija | Have, Christian T | Herder, Christian | Holmen, Oddgeir L | Hreidarsson, Astradur B | Humphries, Steve E | Hunter, David J | Jackson, Anne U | Jonsson, Anna | Jørgensen, Marit E | Jørgensen, Torben | Kao, Wen-Hong L | Kerrison, Nicola D | Kinnunen, Leena | Klopp, Norman | Kong, Augustine | Kovacs, Peter | Kraft, Peter | Kravic, Jasmina | Langford, Cordelia | Leander, Karin | Liang, Liming | Lichtner, Peter | Lindgren, Cecilia M | Lindholm, Eero | Linneberg, Allan | Liu, Ching-Ti | Lobbens, Stéphane | Luan, Jian’an | Lyssenko, Valeriya | Männistö, Satu | McLeod, Olga | Meyer, Julia | Mihailov, Evelin | Mirza, Ghazala | Mühleisen, Thomas W | Müller-Nurasyid, Martina | Navarro, Carmen | Nöthen, Markus M | Oskolkov, Nikolay N | Owen, Katharine R | Palli, Domenico | Pechlivanis, Sonali | Peltonen, Leena | Perry, John RB | Platou, Carl GP | Roden, Michael | Ruderfer, Douglas | Rybin, Denis | van der Schouw, Yvonne T | Sennblad, Bengt | Sigurðsson, Gunnar | Stančáková, Alena | Steinbach, Gerald | Storm, Petter | Strauch, Konstantin | Stringham, Heather M | Sun, Qi | Thorand, Barbara | Tikkanen, Emmi | Tonjes, Anke | Trakalo, Joseph | Tremoli, Elena | Tuomi, Tiinamaija | Wennauer, Roman | Wiltshire, Steven | Wood, Andrew R | Zeggini, Eleftheria | Dunham, Ian | Birney, Ewan | Pasquali, Lorenzo | Ferrer, Jorge | Loos, Ruth JF | Dupuis, Josée | Florez, Jose C | Boerwinkle, Eric | Pankow, James S | van Duijn, Cornelia | Sijbrands, Eric | Meigs, James B | Hu, Frank B | Thorsteinsdottir, Unnur | Stefansson, Kari | Lakka, Timo A | Rauramaa, Rainer | Stumvoll, Michael | Pedersen, Nancy L | Lind, Lars | Keinanen-Kiukaanniemi, Sirkka M | Korpi-Hyövälti, Eeva | Saaristo, Timo E | Saltevo, Juha | Kuusisto, Johanna | Laakso, Markku | Metspalu, Andres | Erbel, Raimund | Jöckel, Karl-Heinz | Moebus, Susanne | Ripatti, Samuli | Salomaa, Veikko | Ingelsson, Erik | Boehm, Bernhard O | Bergman, Richard N | Collins, Francis S | Mohlke, Karen L | Koistinen, Heikki | Tuomilehto, Jaakko | Hveem, Kristian | Njølstad, Inger | Deloukas, Panagiotis | Donnelly, Peter J | Frayling, Timothy M | Hattersley, Andrew T | de Faire, Ulf | Hamsten, Anders | Illig, Thomas | Peters, Annette | Cauchi, Stephane | Sladek, Rob | Froguel, Philippe | Hansen, Torben | Pedersen, Oluf | Morris, Andrew D | Palmer, Collin NA | Kathiresan, Sekar | Melander, Olle | Nilsson, Peter M | Groop, Leif C | Barroso, Inês | Langenberg, Claudia | Wareham, Nicholas J | O’Callaghan, Christopher A | Gloyn, Anna L | Altshuler, David | Boehnke, Michael | Teslovich, Tanya M | McCarthy, Mark I | Morris, Andrew P
Nature genetics  2015;47(12):1415-1425.
We performed fine-mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in/near KCNQ1. “Credible sets” of variants most likely to drive each distinct signal mapped predominantly to non-coding sequence, implying that T2D association is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine-mapping implicated rs10830963 as driving T2D association. We confirmed that this T2D-risk allele increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D-risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
doi:10.1038/ng.3437
PMCID: PMC4666734  PMID: 26551672
19.  Parental Origin of Interstitial Duplications at 15q11.2-q13.3 in Schizophrenia and Neurodevelopmental Disorders 
PLoS Genetics  2016;12(5):e1005993.
Duplications at 15q11.2-q13.3 overlapping the Prader-Willi/Angelman syndrome (PWS/AS) region have been associated with developmental delay (DD), autism spectrum disorder (ASD) and schizophrenia (SZ). Due to presence of imprinted genes within the region, the parental origin of these duplications may be key to the pathogenicity. Duplications of maternal origin are associated with disease, whereas the pathogenicity of paternal ones is unclear. To clarify the role of maternal and paternal duplications, we conducted the largest and most detailed study to date of parental origin of 15q11.2-q13.3 interstitial duplications in DD, ASD and SZ cohorts. We show, for the first time, that paternal duplications lead to an increased risk of developing DD/ASD/multiple congenital anomalies (MCA), but do not appear to increase risk for SZ. The importance of the epigenetic status of 15q11.2-q13.3 duplications was further underlined by analysis of a number of families, in which the duplication was paternally derived in the mother, who was unaffected, whereas her offspring, who inherited a maternally derived duplication, suffered from psychotic illness. Interestingly, the most consistent clinical characteristics of SZ patients with 15q11.2-q13.3 duplications were learning or developmental problems, found in 76% of carriers. Despite their lower pathogenicity, paternal duplications are less frequent in the general population with a general population prevalence of 0.0033% compared to 0.0069% for maternal duplications. This may be due to lower fecundity of male carriers and differential survival of embryos, something echoed in the findings that both types of duplications are de novo in just over 50% of cases. Isodicentric chromosome 15 (idic15) or interstitial triplications were not observed in SZ patients or in controls. Overall, this study refines the distinct roles of maternal and paternal interstitial duplications at 15q11.2-q13.3, underlining the critical importance of maternally expressed imprinted genes in the contribution of Copy Number Variants (CNVs) at this interval to the incidence of psychotic illness. This work will have tangible benefits for patients with 15q11.2-q13.3 duplications by aiding genetic counseling.
Author Summary
The genetic interval 15q11.2-q13.3 on human chromosome 15 contains several so-called “imprinted genes” which are subject to epigenetic marking leading to activity from only one parental copy. This is in contrast to non-imprinted genes, whose activity is independent of their parent-of-origin. Deletions affecting the 15q11.2-q13.3 interval cause Prader-Willi and Angelman syndromes (PWS/AS), depending on whether the deletions are paternally or maternally derived respectively. Duplications at the PWS/AS interval region may also lead to neurodevelopmental disorders, including developmental delay (DD), autism spectrum disorder (ASD) and schizophrenia (SZ). Due to presence of imprinted genes within the region, the parental origin of these duplications may be key to the pathogenicity. We show, for the first time, that paternal duplications lead to an increased risk of developing DD/ASD/multiple congenital anomalies (MCA) but, unlike maternal duplication, do not appear to increase risk for SZ. This study refines the distinct roles of maternal and paternal duplications at 15q11.2-q13.3, underlining the critical importance of maternally active imprinted genes in the contribution to the incidence of psychotic illness. This work will have tangible benefits for patients with 15q11.2-q13.3 duplications by aiding genetic counseling.
doi:10.1371/journal.pgen.1005993
PMCID: PMC4859484  PMID: 27153221
20.  Large-scale genomic analyses link reproductive ageing to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair 
Day, Felix R. | Ruth, Katherine S. | Thompson, Deborah J. | Lunetta, Kathryn L. | Pervjakova, Natalia | Chasman, Daniel I. | Stolk, Lisette | Finucane, Hilary K. | Sulem, Patrick | Bulik-Sullivan, Brendan | Esko, Tõnu | Johnson, Andrew D. | Elks, Cathy E. | Franceschini, Nora | He, Chunyan | Altmaier, Elisabeth | Brody, Jennifer A. | Franke, Lude L. | Huffman, Jennifer E. | Keller, Margaux F. | McArdle, Patrick F. | Nutile, Teresa | Porcu, Eleonora | Robino, Antonietta | Rose, Lynda M. | Schick, Ursula M. | Smith, Jennifer A. | Teumer, Alexander | Traglia, Michela | Vuckovic, Dragana | Yao, Jie | Zhao, Wei | Albrecht, Eva | Amin, Najaf | Corre, Tanguy | Hottenga, Jouke-Jan | Mangino, Massimo | Smith, Albert V. | Tanaka, Toshiko | Abecasis, Goncalo | Andrulis, Irene L. | Anton-Culver, Hoda | Antoniou, Antonis C. | Arndt, Volker | Arnold, Alice M. | Barbieri, Caterina | Beckmann, Matthias W. | Beeghly-Fadiel, Alicia | Benitez, Javier | Bernstein, Leslie | Bielinski, Suzette J. | Blomqvist, Carl | Boerwinkle, Eric | Bogdanova, Natalia V. | Bojesen, Stig E. | Bolla, Manjeet K. | Borresen-Dale, Anne-Lise | Boutin, Thibaud S | Brauch, Hiltrud | Brenner, Hermann | Brüning, Thomas | Burwinkel, Barbara | Campbell, Archie | Campbell, Harry | Chanock, Stephen J. | Chapman, J. Ross | Chen, Yii-Der Ida | Chenevix-Trench, Georgia | Couch, Fergus J. | Coviello, Andrea D. | Cox, Angela | Czene, Kamila | Darabi, Hatef | De Vivo, Immaculata | Demerath, Ellen W. | Dennis, Joe | Devilee, Peter | Dörk, Thilo | dos-Santos-Silva, Isabel | Dunning, Alison M. | Eicher, John D. | Fasching, Peter A. | Faul, Jessica D. | Figueroa, Jonine | Flesch-Janys, Dieter | Gandin, Ilaria | Garcia, Melissa E. | García-Closas, Montserrat | Giles, Graham G. | Girotto, Giorgia G. | Goldberg, Mark S. | González-Neira, Anna | Goodarzi, Mark O. | Grove, Megan L. | Gudbjartsson, Daniel F. | Guénel, Pascal | Guo, Xiuqing | Haiman, Christopher A. | Hall, Per | Hamann, Ute | Henderson, Brian E. | Hocking, Lynne J. | Hofman, Albert | Homuth, Georg | Hooning, Maartje J. | Hopper, John L. | Hu, Frank B. | Huang, Jinyan | Humphreys, Keith | Hunter, David J. | Jakubowska, Anna | Jones, Samuel E. | Kabisch, Maria | Karasik, David | Knight, Julia A. | Kolcic, Ivana | Kooperberg, Charles | Kosma, Veli-Matti | Kriebel, Jennifer | Kristensen, Vessela | Lambrechts, Diether | Langenberg, Claudia | Li, Jingmei | Li, Xin | Lindström, Sara | Liu, Yongmei | Luan, Jian’an | Lubinski, Jan | Mägi, Reedik | Mannermaa, Arto | Manz, Judith | Margolin, Sara | Marten, Jonathan | Martin, Nicholas G. | Masciullo, Corrado | Meindl, Alfons | Michailidou, Kyriaki | Mihailov, Evelin | Milani, Lili | Milne, Roger L. | Müller-Nurasyid, Martina | Nalls, Michael | Neale, Ben M. | Nevanlinna, Heli | Neven, Patrick | Newman, Anne B. | Nordestgaard, Børge G. | Olson, Janet E. | Padmanabhan, Sandosh | Peterlongo, Paolo | Peters, Ulrike | Petersmann, Astrid | Peto, Julian | Pharoah, Paul D.P. | Pirastu, Nicola N. | Pirie, Ailith | Pistis, Giorgio | Polasek, Ozren | Porteous, David | Psaty, Bruce M. | Pylkäs, Katri | Radice, Paolo | Raffel, Leslie J. | Rivadeneira, Fernando | Rudan, Igor | Rudolph, Anja | Ruggiero, Daniela | Sala, Cinzia F. | Sanna, Serena | Sawyer, Elinor J. | Schlessinger, David | Schmidt, Marjanka K. | Schmidt, Frank | Schmutzler, Rita K. | Schoemaker, Minouk J. | Scott, Robert A. | Seynaeve, Caroline M. | Simard, Jacques | Sorice, Rossella | Southey, Melissa C. | Stöckl, Doris | Strauch, Konstantin | Swerdlow, Anthony | Taylor, Kent D. | Thorsteinsdottir, Unnur | Toland, Amanda E. | Tomlinson, Ian | Truong, Thérèse | Tryggvadottir, Laufey | Turner, Stephen T. | Vozzi, Diego | Wang, Qin | Wellons, Melissa | Willemsen, Gonneke | Wilson, James F. | Winqvist, Robert | Wolffenbuttel, Bruce B.H.R. | Wright, Alan F. | Yannoukakos, Drakoulis | Zemunik, Tatijana | Zheng, Wei | Zygmunt, Marek | Bergmann, Sven | Boomsma, Dorret I. | Buring, Julie E. | Ferrucci, Luigi | Montgomery, Grant W. | Gudnason, Vilmundur | Spector, Tim D. | van Duijn, Cornelia M | Alizadeh, Behrooz Z. | Ciullo, Marina | Crisponi, Laura | Easton, Douglas F. | Gasparini, Paolo P. | Gieger, Christian | Harris, Tamara B. | Hayward, Caroline | Kardia, Sharon L.R. | Kraft, Peter | McKnight, Barbara | Metspalu, Andres | Morrison, Alanna C. | Reiner, Alex P. | Ridker, Paul M. | Rotter, Jerome I. | Toniolo, Daniela | Uitterlinden, André G. | Ulivi, Sheila | Völzke, Henry | Wareham, Nicholas J. | Weir, David R. | Yerges-Armstrong, Laura M. | Price, Alkes L. | Stefansson, Kari | Visser, Jenny A. | Ong, Ken K. | Chang-Claude, Jenny | Murabito, Joanne M. | Perry, John R.B. | Murray, Anna
Nature genetics  2015;47(11):1294-1303.
Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ~70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two harbouring additional rare missense alleles of large effect. We found enrichment of signals in/near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses revealed a major association with DNA damage-response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomisation analyses supported a causal effect of later ANM on breast cancer risk (~6% risk increase per-year, P=3×10−14), likely mediated by prolonged sex hormone exposure, rather than DDR mechanisms.
doi:10.1038/ng.3412
PMCID: PMC4661791  PMID: 26414677
21.  Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture 
Zheng, Hou-Feng | Forgetta, Vincenzo | Hsu, Yi-Hsiang | Estrada, Karol | Rosello-Diez, Alberto | Leo, Paul J | Dahia, Chitra L | Park-Min, Kyung Hyun | Tobias, Jonathan H | Kooperberg, Charles | Kleinman, Aaron | Styrkarsdottir, Unnur | Liu, Ching-Ti | Uggla, Charlotta | Evans, Daniel S | Nielson, Carrie M | Walter, Klaudia | Pettersson-Kymmer, Ulrika | McCarthy, Shane | Eriksson, Joel | Kwan, Tony | Jhamai, Mila | Trajanoska, Katerina | Memari, Yasin | Min, Josine | Huang, Jie | Danecek, Petr | Wilmot, Beth | Li, Rui | Chou, Wen-Chi | Mokry, Lauren E | Moayyeri, Alireza | Claussnitzer, Melina | Cheng, Chia-Ho | Cheung, Warren | Medina-Gómez, Carolina | Ge, Bing | Chen, Shu-Huang | Choi, Kwangbom | Oei, Ling | Fraser, James | Kraaij, Robert | Hibbs, Matthew A | Gregson, Celia L | Paquette, Denis | Hofman, Albert | Wibom, Carl | Tranah, Gregory J | Marshall, Mhairi | Gardiner, Brooke B | Cremin, Katie | Auer, Paul | Hsu, Li | Ring, Sue | Tung, Joyce Y | Thorleifsson, Gudmar | Enneman, Anke W | van Schoor, Natasja M | de Groot, Lisette C.P.G.M. | van der Velde, Nathalie | Melin, Beatrice | Kemp, John P | Christiansen, Claus | Sayers, Adrian | Zhou, Yanhua | Calderari, Sophie | van Rooij, Jeroen | Carlson, Chris | Peters, Ulrike | Berlivet, Soizik | Dostie, Josée | Uitterlinden, Andre G | Williams, Stephen R. | Farber, Charles | Grinberg, Daniel | LaCroix, Andrea Z | Haessler, Jeff | Chasman, Daniel I | Giulianini, Franco | Rose, Lynda M | Ridker, Paul M | Eisman, John A | Nguyen, Tuan V | Center, Jacqueline R | Nogues, Xavier | Garcia-Giralt, Natalia | Launer, Lenore L | Gudnason, Vilmunder | Mellström, Dan | Vandenput, Liesbeth | Karlsson, Magnus K | Ljunggren, Östen | Svensson, Olle | Hallmans, Göran | Rousseau, François | Giroux, Sylvie | Bussière, Johanne | Arp, Pascal P | Koromani, Fjorda | Prince, Richard L | Lewis, Joshua R | Langdahl, Bente L | Hermann, A Pernille | Jensen, Jens-Erik B | Kaptoge, Stephen | Khaw, Kay-Tee | Reeve, Jonathan | Formosa, Melissa M | Xuereb-Anastasi, Angela | Åkesson, Kristina | McGuigan, Fiona E | Garg, Gaurav | Olmos, Jose M | Zarrabeitia, Maria T | Riancho, Jose A | Ralston, Stuart H | Alonso, Nerea | Jiang, Xi | Goltzman, David | Pastinen, Tomi | Grundberg, Elin | Gauguier, Dominique | Orwoll, Eric S | Karasik, David | Davey-Smith, George | Smith, Albert V | Siggeirsdottir, Kristin | Harris, Tamara B | Zillikens, M Carola | van Meurs, Joyce BJ | Thorsteinsdottir, Unnur | Maurano, Matthew T | Timpson, Nicholas J | Soranzo, Nicole | Durbin, Richard | Wilson, Scott G | Ntzani, Evangelia E | Brown, Matthew A | Stefansson, Kari | Hinds, David A | Spector, Tim | Cupples, L Adrienne | Ohlsson, Claes | Greenwood, Celia MT | Jackson, Rebecca D | Rowe, David W | Loomis, Cynthia A | Evans, David M | Ackert-Bicknell, Cheryl L | Joyner, Alexandra L | Duncan, Emma L | Kiel, Douglas P | Rivadeneira, Fernando | Richards, J Brent
Nature  2015;526(7571):112-117.
SUMMARY
The extent to which low-frequency (minor allele frequency [MAF] between 1–5%) and rare (MAF ≤ 1%) variants contribute to complex traits and disease in the general population is largely unknown. Bone mineral density (BMD) is highly heritable, is a major predictor of osteoporotic fractures and has been previously associated with common genetic variants1–8, and rare, population-specific, coding variants9. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n=2,882 from UK10K), whole-exome sequencing (n= 3,549), deep imputation of genotyped samples using a combined UK10K/1000Genomes reference panel (n=26,534), and de-novo replication genotyping (n= 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size 4-fold larger than the mean of previously reported common variants for lumbar spine BMD8 (rs11692564[T], MAF = 1.7%, replication effect size = +0.20 standard deviations [SD], Pmeta = 2×10−14), which was also associated with a decreased risk of fracture (OR = 0.85; P = 2×10−11; ncases = 98,742 and ncontrols = 409,511). Using an En1Cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, likely as a consequence of high bone turn-over. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817[T], MAF = 1.1%, replication effect size = +0.39 SD, Pmeta = 1×10−11). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.
doi:10.1038/nature14878
PMCID: PMC4755714  PMID: 26367794 CAMSID: cams5439
22.  Gene co-expression analysis identifies brain regions and cell types involved in migraine pathophysiology: a GWAS-based study using the Allen Human Brain Atlas 
Human Genetics  2016;135:425-439.
Migraine is a common disabling neurovascular brain disorder typically characterised by attacks of severe headache and associated with autonomic and neurological symptoms. Migraine is caused by an interplay of genetic and environmental factors. Genome-wide association studies (GWAS) have identified over a dozen genetic loci associated with migraine. Here, we integrated migraine GWAS data with high-resolution spatial gene expression data of normal adult brains from the Allen Human Brain Atlas to identify specific brain regions and molecular pathways that are possibly involved in migraine pathophysiology. To this end, we used two complementary methods. In GWAS data from 23,285 migraine cases and 95,425 controls, we first studied modules of co-expressed genes that were calculated based on human brain expression data for enrichment of genes that showed association with migraine. Enrichment of a migraine GWAS signal was found for five modules that suggest involvement in migraine pathophysiology of: (i) neurotransmission, protein catabolism and mitochondria in the cortex; (ii) transcription regulation in the cortex and cerebellum; and (iii) oligodendrocytes and mitochondria in subcortical areas. Second, we used the high-confidence genes from the migraine GWAS as a basis to construct local migraine-related co-expression gene networks. Signatures of all brain regions and pathways that were prominent in the first method also surfaced in the second method, thus providing support that these brain regions and pathways are indeed involved in migraine pathophysiology.
Electronic supplementary material
The online version of this article (doi:10.1007/s00439-016-1638-x) contains supplementary material, which is available to authorized users.
doi:10.1007/s00439-016-1638-x
PMCID: PMC4796339  PMID: 26899160
23.  The impact of low-frequency and rare variants on lipid levels 
Surakka, Ida | Horikoshi, Momoko | Mägi, Reedik | Sarin, Antti-Pekka | Mahajan, Anubha | Lagou, Vasiliki | Marullo, Letizia | Ferreira, Teresa | Miraglio, Benjamin | Timonen, Sanna | Kettunen, Johannes | Pirinen, Matti | Karjalainen, Juha | Thorleifsson, Gudmar | Hägg, Sara | Hottenga, Jouke-Jan | Isaacs, Aaron | Ladenvall, Claes | Beekman, Marian | Esko, Tõnu | Ried, Janina S | Nelson, Christopher P | Willenborg, Christina | Gustafsson, Stefan | Westra, Harm-Jan | Blades, Matthew | de Craen, Anton JM | de Geus, Eco J | Deelen, Joris | Grallert, Harald | Hamsten, Anders | Havulinna, Aki S. | Hengstenberg, Christian | Houwing-Duistermaat, Jeanine J | Hyppönen, Elina | Karssen, Lennart C | Lehtimäki, Terho | Lyssenko, Valeriya | Magnusson, Patrik KE | Mihailov, Evelin | Müller-Nurasyid, Martina | Mpindi, John-Patrick | Pedersen, Nancy L | Penninx, Brenda WJH | Perola, Markus | Pers, Tune H | Peters, Annette | Rung, Johan | Smit, Johannes H | Steinthorsdottir, Valgerdur | Tobin, Martin D | Tsernikova, Natalia | van Leeuwen, Elisabeth M | Viikari, Jorma S | Willems, Sara M | Willemsen, Gonneke | Schunkert, Heribert | Erdmann, Jeanette | Samani, Nilesh J | Kaprio, Jaakko | Lind, Lars | Gieger, Christian | Metspalu, Andres | Slagboom, P Eline | Groop, Leif | van Duijn, Cornelia M | Eriksson, Johan G | Jula, Antti | Salomaa, Veikko | Boomsma, Dorret I | Power, Christine | Raitakari, Olli T | Ingelsson, Erik | Järvelin, Marjo-Riitta | Stefansson, Kari | Franke, Lude | Ikonen, Elina | Kallioniemi, Olli | Pietiäinen, Vilja | Lindgren, Cecilia M | Thorsteinsdottir, Unnur | Palotie, Aarno | McCarthy, Mark I | Morris, Andrew P | Prokopenko, Inga | Ripatti, Samuli
Nature genetics  2015;47(6):589-597.
Using a genome-wide screen of 9.6 million genetic variants achieved through 1000 Genomes imputation in 62,166 samples, we identify association to lipids in 93 loci including 79 previously identified loci with new lead-SNPs, 10 new loci, 15 loci with a low-frequency and 10 loci with missense lead-SNPs, and, 2 loci with an accumulation of rare variants. In six loci, SNPs with established function in lipid genetics (CELSR2, GCKR, LIPC, and APOE), or candidate missense mutations with predicted damaging function (CD300LG and TM6SF2), explained the locus associations. The low-frequency variants increased the proportion of variance explained, particularly for LDL-C and TC. Altogether, our results highlight the impact of low-frequency variants in complex traits and show that imputation offers a cost-effective alternative to re-sequencing.
doi:10.1038/ng.3300
PMCID: PMC4757735  PMID: 25961943
24.  Rare coding variants and X-linked loci associated with age at menarche 
Lunetta, Kathryn L. | Day, Felix R. | Sulem, Patrick | Ruth, Katherine S. | Tung, Joyce Y. | Hinds, David A. | Esko, Tõnu | Elks, Cathy E | Altmaier, Elisabeth | He, Chunyan | Huffman, Jennifer E. | Mihailov, Evelin | Porcu, Eleonora | Robino, Antonietta | Rose, Lynda M. | Schick, Ursula M. | Stolk, Lisette | Teumer, Alexander | Thompson, Deborah J. | Traglia, Michela | Wang, Carol A. | Yerges-Armstrong, Laura M. | Antoniou, Antonis C. | Barbieri, Caterina | Coviello, Andrea D. | Cucca, Francesco | Demerath, Ellen W. | Dunning, Alison M. | Gandin, Ilaria | Grove, Megan L. | Gudbjartsson, Daniel F. | Hocking, Lynne J. | Hofman, Albert | Huang, Jinyan | Jackson, Rebecca D. | Karasik, David | Kriebel, Jennifer | Lange, Ethan M. | Lange, Leslie A. | Langenberg, Claudia | Li, Xin | Luan, Jian’an | Mägi, Reedik | Morrison, Alanna C. | Padmanabhan, Sandosh | Pirie, Ailith | Polasek, Ozren | Porteous, David | Reiner, Alex P. | Rivadeneira, Fernando | Rudan, Igor | Sala, Cinzia F. | Schlessinger, David | Scott, Robert A. | Stöckl, Doris | Visser, Jenny A. | Völker, Uwe | Vozzi, Diego | Wilson, James G. | Zygmunt, Marek | Boerwinkle, Eric | Buring, Julie E. | Crisponi, Laura | Easton, Douglas F. | Hayward, Caroline | Hu, Frank B. | Liu, Simin | Metspalu, Andres | Pennell, Craig E. | Ridker, Paul M. | Strauch, Konstantin | Streeten, Elizabeth A. | Toniolo, Daniela | Uitterlinden, André G. | Ulivi, Sheila | Völzke, Henry | Wareham, Nicholas J. | Wellons, Melissa | Franceschini, Nora | Chasman, Daniel I. | Thorsteinsdottir, Unnur | Murray, Anna | Stefansson, Kari | Murabito, Joanne M. | Ong, Ken K. | Perry, John R.B.
Nature communications  2015;6:7756.
More than one hundred loci have been identified for age at menarche by genome-wide association studies (GWAS), but collectively these explain only ~3% of the trait variance. Here, we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08%-4.6%; effect sizes 0.08-1.25 years/allele; P<5×10−8). Additionally, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4×10−13) and FAAH2 (rs5914101, P=4.9×10−10). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-years later menarche (P=2.8×10−11), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively these novel variants explain ~0.5% variance, indicating these overlooked sources of variation do not substantially explain the ‘missing heritability’ of this complex trait.
doi:10.1038/ncomms8756
PMCID: PMC4538850  PMID: 26239645
25.  Common and rare variants associating with serum levels of creatine kinase and lactate dehydrogenase 
Nature Communications  2016;7:10572.
Creatine kinase (CK) and lactate dehydrogenase (LDH) are widely used markers of tissue damage. To search for sequence variants influencing serum levels of CK and LDH, 28.3 million sequence variants identified through whole-genome sequencing of 2,636 Icelanders were imputed into 63,159 and 98,585 people with CK and LDH measurements, respectively. Here we describe 13 variants associating with serum CK and 16 with LDH levels, including four that associate with both. Among those, 15 are non-synonymous variants and 12 have a minor allele frequency below 5%. We report sequence variants in genes encoding the enzymes being measured (CKM and LDHA), as well as in genes linked to muscular (ANO5) and immune/inflammatory function (CD163/CD163L1, CSF1, CFH, HLA-DQB1, LILRB5, NINJ1 and STAB1). A number of the genes are linked to the mononuclear/phagocyte system and clearance of enzymes from the serum. This highlights the variety in the sources of normal diversity in serum levels of enzymes.
Creatine kinase (CK) and lactate dehydrogenase (LDH) are biomarkers of tissue damages including myopathy and myocardial infarction. Here, Patrick Sulem and colleagues perform a genome-wide association study to identify common and rare genetic variants that associates with serum CK or LDH levels.
doi:10.1038/ncomms10572
PMCID: PMC4742860  PMID: 26838040

Results 1-25 (184)