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1.  Trends in Parent-Child Correlations of Childhood Body Mass Index during the Development of the Obesity Epidemic 
PLoS ONE  2014;9(10):e109932.
Background
The intergenerational resemblance in body mass index may have increased during the development of the obesity epidemic due to changes in environment and/or expression of genetic predisposition.
Objectives
This study investigates trends in intergenerational correlations of childhood body mass index (BMI; kg/m2) during the emergence of the obesity epidemic.
Methods
The study population was derived from the Copenhagen School Health Records Register, which includes height and weight measurements since birth year 1930. Mothers and fathers with BMIs available at ages 7 (n = 25,923 and n = 20,972) or 13 years (n = 26,750 and n = 21,397), respectively, were linked through the civil registration system introduced in 1968 to their children with BMIs available at age 7 years. Age- and sex-specific BMI z-scores were calculated. Correlations were estimated across eight intervals of child birth years (1952–1989) separately by sex. Trends in these correlations were examined. Whereas the mother-child correlations reflected the biological relationship, a likely decline in the assignment of non-biological fathers through the registration system across time must be considered when interpreting the father-child correlations.
Results
The BMI correlations between mothers and sons ranged from 0.29–0.36 and they decreased marginally, albeit significantly across time at ages 7–7 years (−0.002/year, p = 0.006), whereas those at 13–7 years remained stable (<0.0004/year, p = 0.96). Mother-daughter correlations ranged from 0.30–0.34, and they were stable at ages 7–7 years (0.0001/year, p = 0.84) and at 13–7 years (0.0004/year, p = 0.56). In contrast, father-son correlations increased significantly during this period, both at ages 7–7 (0.002/year, p = 0.007) and at ages 13–7 years (0.003/year, p<0.001), whereas the increase in father-daughter correlations were insignificant both at ages 7–7 (0.001/year, p = 0.37) and at ages 13–7 years (0.001/year, p = 0.18).
Conclusion
During the obesity epidemics development, the intergenerational resemblance with mothers remained stable, whereas the father-child BMI resemblance increased, possibly reflecting changes in family relationships, and unlikely to have influenced the epidemic.
doi:10.1371/journal.pone.0109932
PMCID: PMC4201474  PMID: 25329656
2.  Long-term risk of cardiovascular and cerebrovascular disease after removal of the colonic microbiota by colectomy: a cohort study based on the Danish National Patient Register from 1996 to 2014 
BMJ Open  2015;5(12):e008702.
Objectives
The hypothesis of the study was that if the gut microbiota is involved in the development of atherosclerotic cardiovascular and cerebrovascular diseases (CVDs), total colectomy may reduce the long-term risk of CVDs. The aim was therefore to investigate the risk of CVD in patients after a total colectomy compared with patients undergoing other types of surgery, which are not expected to alter the gut microbiota or the CVD risk.
Setting
The Danish National Patient Register including all hospital discharges in Denmark from 1996 to 2014.
Participants
Patients (n=1530) aged 45 years and above and surviving 1000 days after total colectomy without CVDs were selected and matched with five control patients who were also free of CVD 1000 days after other types of surgery. The five control patients were randomly selected from each of the three surgical groups: orthopaedic surgery, surgery in the gastrointestinal tract leaving it intact and other surgeries not related to the gastrointestinal tract or CVD (n=22 950).
Primary and secondary outcome measures
The primary outcome was the first occurring CVD event in any of the seven diagnostic domains (hypertensive disorders, acute ischaemic heart diseases, chronic ischaemic heart disease, cardiac arrhythmias, heart failure, cerebrovascular diseases and other arterial diseases) and the secondary outcomes were the first occurring event within each of these domains.
Results
Estimated by Cox proportional hazard models, the HRs of the composite CVD end point for patients with colectomy compared with the control patients were not significantly reduced (HR=0.94, 95% confidence limits 0.85 to 1.04). Among the seven CVD domains, only the risk of hypertensive disorders was significantly reduced (HR=0.85, 0.73 to 0.98).
Conclusions
Colectomy did not reduce the general risk of CVD, but reduced the risk of hypertensive disorders, most likely due to salt and water depletion induced by colectomy. These results encourage a reappraisal of the associations between gut microbiota and CVD.
doi:10.1136/bmjopen-2015-008702
PMCID: PMC4680005  PMID: 26671951
VASCULAR MEDICINE; EPIDEMIOLOGY; colectomy
3.  Fibronectin as predictor of cirrhosis in men who abuse alcohol 
In a study of 142 male alcohol abusers without evidence of cirrhosis the presence of intralobular fibronectin in the liver was investigated in relation to the subsequent development of the disease. All 142 initial biopsy samples showed preserved architecture. During a follow up period of 10-13 years 23 patients (16%) developed cirrhosis. Twelve of 110 patients with normal or slightly increased amounts of parenchymal fibronectin in the initial biopsy specimen developed cirrhosis, whereas eight out of 27 patients with moderately increased amounts and three out of five with significantly increased amounts later developed the disease (p<0·005).
Semiquantitative assessment of the amount of parenchymal fibronectin at an early stage of alcoholic liver disease is of definite predictive value for the development of cirrhosis.
Images
PMCID: PMC2546159  PMID: 3135046
4.  Energy Balance Measurement: When Something is Not Better than Nothing 
Energy intake (EI) and physical activity energy expenditure (PAEE) are key modifiable determinants of energy balance, traditionally assessed by self-report despite its repeated demonstration of considerable inaccuracies. We argue here that it is time to move from the common view that self-reports of EI and PAEE are imperfect, but nevertheless deserving of use, to a view commensurate with the evidence that self-reports of EI and PAEE are so poor that they are wholly unacceptable for scientific research on EI and PAEE. While new strategies for objectively determining energy balance are in their infancy, it is unacceptable to use decidedly inaccurate instruments, which may misguide health care policies, future research, and clinical judgment. The scientific and medical communities should discontinue reliance on self-reported EI and PAEE. Researchers and sponsors should develop objective measures of energy balance.
doi:10.1038/ijo.2014.199
PMCID: PMC4430460  PMID: 25394308
6.  Genetic and environmental influences on adult human height across birth cohorts from 1886 to 1994 
Jelenkovic, Aline | Hur, Yoon-Mi | Sund, Reijo | Yokoyama, Yoshie | Siribaddana, Sisira H | Hotopf, Matthew | Sumathipala, Athula | Rijsdijk, Fruhling | Tan, Qihua | Zhang, Dongfeng | Pang, Zengchang | Aaltonen, Sari | Heikkilä, Kauko | Öncel, Sevgi Y | Aliev, Fazil | Rebato, Esther | Tarnoki, Adam D | Tarnoki, David L | Christensen, Kaare | Skytthe, Axel | Kyvik, Kirsten O | Silberg, Judy L | Eaves, Lindon J | Maes, Hermine H | Cutler, Tessa L | Hopper, John L | Ordoñana, Juan R | Sánchez-Romera, Juan F | Colodro-Conde, Lucia | Cozen, Wendy | Hwang, Amie E | Mack, Thomas M | Sung, Joohon | Song, Yun-Mi | Yang, Sarah | Lee, Kayoung | Franz, Carol E | Kremen, William S | Lyons, Michael J | Busjahn, Andreas | Nelson, Tracy L | Whitfield, Keith E | Kandler, Christian | Jang, Kerry L | Gatz, Margaret | Butler, David A | Stazi, Maria A | Fagnani, Corrado | D'Ippolito, Cristina | Duncan, Glen E | Buchwald, Dedra | Derom, Catherine A | Vlietinck, Robert F | Loos, Ruth JF | Martin, Nicholas G | Medland, Sarah E | Montgomery, Grant W | Jeong, Hoe-Uk | Swan, Gary E | Krasnow, Ruth | Magnusson, Patrik KE | Pedersen, Nancy L | Dahl-Aslan, Anna K | McAdams, Tom A | Eley, Thalia C | Gregory, Alice M | Tynelius, Per | Baker, Laura A | Tuvblad, Catherine | Bayasgalan, Gombojav | Narandalai, Danshiitsoodol | Lichtenstein, Paul | Spector, Timothy D | Mangino, Massimo | Lachance, Genevieve | Bartels, Meike | van Beijsterveldt, Toos CEM | Willemsen, Gonneke | Burt, S Alexandra | Klump, Kelly L | Harris, Jennifer R | Brandt, Ingunn | Nilsen, Thomas Sevenius | Krueger, Robert F | McGue, Matt | Pahlen, Shandell | Corley, Robin P | Hjelmborg, Jacob v B | Goldberg, Jack H | Iwatani, Yoshinori | Watanabe, Mikio | Honda, Chika | Inui, Fujio | Rasmussen, Finn | Huibregtse, Brooke M | Boomsma, Dorret I | Sørensen, Thorkild I A | Kaprio, Jaakko | Silventoinen, Karri
eLife  null;5:e20320.
Human height variation is determined by genetic and environmental factors, but it remains unclear whether their influences differ across birth-year cohorts. We conducted an individual-based pooled analysis of 40 twin cohorts including 143,390 complete twin pairs born 1886–1994. Although genetic variance showed a generally increasing trend across the birth-year cohorts, heritability estimates (0.69-0.84 in men and 0.53-0.78 in women) did not present any clear pattern of secular changes. Comparing geographic-cultural regions (Europe, North America and Australia, and East Asia), total height variance was greatest in North America and Australia and lowest in East Asia, but no clear pattern in the heritability estimates across the birth-year cohorts emerged. Our findings do not support the hypothesis that heritability of height is lower in populations with low living standards than in affluent populations, nor that heritability of height will increase within a population as living standards improve.
DOI: http://dx.doi.org/10.7554/eLife.20320.001
doi:10.7554/eLife.20320
PMCID: PMC5156525  PMID: 27964777
height; twins; heritability; birth cohorts; CODATwins project; Human
7.  Childhood body mass index growth trajectories and endometrial cancer risk 
International Journal of Cancer  2016;140(2):310-315.
Previously, we found that excess weight already in childhood has positive associations with endometrial cancer; however, associations with changes in body mass index (BMI) during childhood are not well understood. Therefore, we examined whether growth in childhood BMI is associated with endometrial cancer and its sub‐types. A cohort of 155,505 girls from the Copenhagen School Health Records Register with measured weights and heights at the ages of 6–14 years and born 1930–1989 formed the analytical population. BMI was transformed to age‐specific z scores. Using linear spline multilevel models, each girl's BMI growth trajectory was estimated as the deviance from the average trajectory for three different growth periods (6.25–7.99, 8.0–10.99, 11.0–14.0 years). Via a link to health registers, 1,020 endometrial cancer cases were identified, and Cox regressions were performed. A greater gain in BMI during childhood was positively associated with endometrial cancer but no differences between the different growth periods were detected in models adjusted for baseline BMI. The hazard ratios for the associations with overall growth during childhood per 0.1 z score increase were 1.15 (95% confidence interval [CI]: 1.07–1.24) for all endometrial cancers, 1.12 (95% CI: 1.04–1.21) for estrogen‐dependent cancers, 1.16 (95% CI: 1.06–1.26) for endometrioid adenocarcinomas and 1.46 (95% CI: 1.16–1.84) for non‐estrogen‐dependent cancers. Growth in BMI in early life is positively linked to later endometrial cancer risk. We did not identify any sensitive childhood growth period, which suggests that excess gain in BMI during the entire childhood period should be avoided.
What's new?
High body mass index (BMI) early in life is linked to an increased risk of endometrial cancer in adulthood. Potentially influencing that association are the amount by which BMI increases in childhood, as well as the timing of BMI increase. Here, analyses of data from the Copenhagen School Health Records Register for girls ages 6 to 14 shows that endometrial cancer risk is increased by greater BMI gain across ages, while the specific age at which BMI increases occurs has little impact. Excess BMI gain at any time during childhood could set the stage for endometrial carcinogenesis.
doi:10.1002/ijc.30464
PMCID: PMC5132154  PMID: 27718528
body weights and measures; child; endometrial neoplasms; growth and development; obesity
8.  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
9.  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
10.  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
11.  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
12.  Genetic evidence for causal relationships between maternal obesity-related traits and birth weight 
JAMA  2016;315(11):1129-1140.
Structured abstract
Importance
Neonates born to overweight/obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal nature of these associations is uncertain.
Objective
To test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight.
Design, Setting and Participants
We used Mendelian randomization to test whether maternal BMI and obesity-related traits are causally related to offspring birth weight. Mendelian randomization makes use of the fact that genotypes are randomly determined at conception and are thus not confounded by non-genetic factors. Data were analysed on 30,487 women from 18 studies. Participants were of European ancestry from population- or community-based studies located in Europe, North America or Australia and participating in the Early Growth Genetics (EGG) Consortium. Live, term, singleton offspring born between 1929 and 2013 were included. We tested associations between a genetic score of 30 BMI-associated single nucleotide polymorphisms (SNPs) and (i) maternal BMI and (ii) birth weight, to estimate the causal relationship between BMI and birth weight. Analyses were repeated for other obesity-related traits.
Exposures
Genetic scores for BMI, fasting glucose level, type 2 diabetes, systolic blood pressure (SBP), triglyceride level, HDL-cholesterol level, vitamin D status and adiponectin level.
Main Outcome(s) and Measure(s)
Offspring birth weight measured by trained study personnel (n=2 studies), from medical records (n= 10 studies) or from maternal report (n=6 studies).
Results
Among the 30,487 newborns the mean birth weight in the various cohorts ranged from 3325 g to 3679 g. The genetic score for BMI was associated with a 2g (95%CI: 0, 3g) higher offspring birth weight per maternal BMI-raising allele (P=0.008). The maternal genetic scores for fasting glucose and SBP were also associated with birth weight with effect sizes of 8g (95%CI: 6, 10g) per glucose-raising allele (P=7×10−14) and −4g (95%CI: −6, −2g) per SBP-raising allele (P=1×10−5), respectively. A 1 standard deviation (1 SD ≈ 4kg/m2) genetically higher maternal BMI was associated with a 55g (95% CI: 17, 93g) higher birth weight. A 1-SD genetically higher maternal fasting glucose (≈ 0.4mmol/L) or SBP (10mmHg) were associated with a 114g (95%CI: 80, 147g) higher or −208g (95% CI: −394, −21g) lower birth weight, respectively. For BMI and fasting glucose these genetic associations were consistent with the observational associations, but for SBP, the genetic and observational associations were in opposite directions.
Conclusions and Relevance
In this Mendelian randomization study of more than 30,000 women with singleton offspring from 18 studies, genetically elevated maternal BMI and blood glucose levels were potentially causally associated with higher offspring birth weight, whereas genetically elevated maternal systolic blood pressure was shown to be potentially causally related to lower birth weight. If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight-related birth outcomes.
doi:10.1001/jama.2016.1975
PMCID: PMC4811305  PMID: 26978208
14.  The Validation and Assessment of Machine Learning: A Game of Prediction from High-Dimensional Data 
PLoS ONE  2009;4(8):e6287.
In applied statistics, tools from machine learning are popular for analyzing complex and high-dimensional data. However, few theoretical results are available that could guide to the appropriate machine learning tool in a new application. Initial development of an overall strategy thus often implies that multiple methods are tested and compared on the same set of data. This is particularly difficult in situations that are prone to over-fitting where the number of subjects is low compared to the number of potential predictors. The article presents a game which provides some grounds for conducting a fair model comparison. Each player selects a modeling strategy for predicting individual response from potential predictors. A strictly proper scoring rule, bootstrap cross-validation, and a set of rules are used to make the results obtained with different strategies comparable. To illustrate the ideas, the game is applied to data from the Nugenob Study where the aim is to predict the fat oxidation capacity based on conventional factors and high-dimensional metabolomics data. Three players have chosen to use support vector machines, LASSO, and random forests, respectively.
doi:10.1371/journal.pone.0006287
PMCID: PMC2716515  PMID: 19652722
15.  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
16.  Genetic and environmental influences on height from infancy to early adulthood: An individual-based pooled analysis of 45 twin cohorts 
Jelenkovic, Aline | Sund, Reijo | Hur, Yoon-Mi | Yokoyama, Yoshie | Hjelmborg, Jacob v. B. | Möller, Sören | Honda, Chika | Magnusson, Patrik K. E. | Pedersen, Nancy L. | Ooki, Syuichi | Aaltonen, Sari | Stazi, Maria A. | Fagnani, Corrado | D’Ippolito, Cristina | Freitas, Duarte L. | Maia, José Antonio | Ji, Fuling | Ning, Feng | Pang, Zengchang | Rebato, Esther | Busjahn, Andreas | Kandler, Christian | Saudino, Kimberly J. | Jang, Kerry L. | Cozen, Wendy | Hwang, Amie E. | Mack, Thomas M. | Gao, Wenjing | Yu, Canqing | Li, Liming | Corley, Robin P. | Huibregtse, Brooke M. | Derom, Catherine A. | Vlietinck, Robert F. | Loos, Ruth J. F. | Heikkilä, Kauko | Wardle, Jane | Llewellyn, Clare H. | Fisher, Abigail | McAdams, Tom A. | Eley, Thalia C. | Gregory, Alice M. | He, Mingguang | Ding, Xiaohu | Bjerregaard-Andersen, Morten | Beck-Nielsen, Henning | Sodemann, Morten | Tarnoki, Adam D. | Tarnoki, David L. | Knafo-Noam, Ariel | Mankuta, David | Abramson, Lior | Burt, S. Alexandra | Klump, Kelly L. | Silberg, Judy L. | Eaves, Lindon J. | Maes, Hermine H. | Krueger, Robert F. | McGue, Matt | Pahlen, Shandell | Gatz, Margaret | Butler, David A. | Bartels, Meike | van Beijsterveldt, Toos C. E. M. | Craig, Jeffrey M. | Saffery, Richard | Dubois, Lise | Boivin, Michel | Brendgen, Mara | Dionne, Ginette | Vitaro, Frank | Martin, Nicholas G. | Medland, Sarah E. | Montgomery, Grant W. | Swan, Gary E. | Krasnow, Ruth | Tynelius, Per | Lichtenstein, Paul | Haworth, Claire M. A. | Plomin, Robert | Bayasgalan, Gombojav | Narandalai, Danshiitsoodol | Harden, K. Paige | Tucker-Drob, Elliot M. | Spector, Timothy | Mangino, Massimo | Lachance, Genevieve | Baker, Laura A. | Tuvblad, Catherine | Duncan, Glen E. | Buchwald, Dedra | Willemsen, Gonneke | Skytthe, Axel | Kyvik, Kirsten O. | Christensen, Kaare | Öncel, Sevgi Y. | Aliev, Fazil | Rasmussen, Finn | Goldberg, Jack H. | Sørensen, Thorkild I. A. | Boomsma, Dorret I. | Kaprio, Jaakko | Silventoinen, Karri
Scientific Reports  2016;6:28496.
Height variation is known to be determined by both genetic and environmental factors, but a systematic description of how their influences differ by sex, age and global regions is lacking. We conducted an individual-based pooled analysis of 45 twin cohorts from 20 countries, including 180,520 paired measurements at ages 1–19 years. The proportion of height variation explained by shared environmental factors was greatest in early childhood, but these effects remained present until early adulthood. Accordingly, the relative genetic contribution increased with age and was greatest in adolescence (up to 0.83 in boys and 0.76 in girls). Comparing geographic-cultural regions (Europe, North-America and Australia, and East-Asia), genetic variance was greatest in North-America and Australia and lowest in East-Asia, but the relative proportion of genetic variation was roughly similar across these regions. Our findings provide further insights into height variation during childhood and adolescence in populations representing different ethnicities and exposed to different environments.
doi:10.1038/srep28496
PMCID: PMC4917845  PMID: 27333805
17.  Associations between birth weight and colon and rectal cancer risk in adulthood 
Cancer Epidemiology  2016;42:181-185.
Highlights
•High birth weight is associated with an increased risk of adult colon cancer.•High birth weight is associated with a decreased risk of adult rectal cancer.•Colon and rectal cancer should investigated as two separate entities in investigations of the early life origins of disease as they may arise through different biological mechanisms.
Background
Birth weight has inconsistent associations with colorectal cancer, possibly due to different anatomic features of the colon versus the rectum. The aim of this study was to investigate the association between birth weight and colon and rectal cancers separately.
Methods
193,306 children, born from 1936 to 1972, from the Copenhagen School Health Record Register were followed prospectively in Danish health registers. Colon and rectal cancer cases were defined using the International Classification of Disease version 10 (colon: C18.0–18.9, rectal: 19.9 and 20.9). Only cancers classified as adenocarcinomas were included in the analyses. Cox regressions were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Analyses were stratified by birth cohort and sex.
Results
During 3.8 million person-years of follow-up, 1465 colon and 961 rectal adenocarcinomas were identified. No significant sex differences were observed; therefore combined results are presented. Birth weight was positively associated with colon cancers with a HR of 1.14 (95% CI, 1.04–1.26) per kilogram of birth weight. For rectal cancer a significant association was not observed for birth weights below 3.5 kg. Above 3.5 kg an inverse association was observed (at 4.5 kg, HR = 0.77 [95% CI, 0.61–0.96]). Further, the associations between birth weight and colon and rectal cancer differed significantly from each other (p = 0.006).
Conclusions
Birth weight is positively associated with the risk of adult colon cancer, whereas the results for rectal cancer were inverse only above values of 3.5 kg. The results underline the importance of investigating colon and rectal cancer as two different entities.
doi:10.1016/j.canep.2016.05.003
PMCID: PMC4911557  PMID: 27203465
Birth weight; Childhood; Cohort; Colon cancer; Colorectal cancer; Proportional hazards model; Prospective studies; Rectal cancer
18.  Effect of Smoking on Blood Pressure and Resting Heart Rate: A Mendelian Randomisation Meta-Analysis in the CARTA Consortium 
Background
Smoking is an important cardiovascular disease risk factor, but the mechanisms linking smoking to blood pressure are poorly understood.
Methods and Results
Data on 141,317 participants (62,666 never, 40,669 former, 37,982 current smokers) from 23 population-based studies were included in observational and Mendelian randomisation (MR) meta-analyses of the associations of smoking status and smoking heaviness with systolic and diastolic blood pressure (SBP, DBP), hypertension, and resting heart rate. For the MR analyses, a genetic variant rs16969968/rs1051730 was used as a proxy for smoking heaviness in current smokers. In observational analyses, current as compared with never smoking was associated with lower SBP, DBP, and lower hypertension risk, but with higher resting heart rate. In observational analyses amongst current smokers, one cigarette/day higher level of smoking heaviness was associated with higher (0.21 beats/minute; 95% CI 0.19; 0.24) resting heart rate, and slightly higher DBP (0.05 mmHg; 95% CI 0.02; 0.08) and SBP (0.08 mmHg; 95% CI 0.03; 0.13). However, in MR analyses amongst current smokers, while each smoking increasing allele of rs16969968/rs1051730 was associated with higher resting heart rate (0.36 beats/minute/allele; 95% CI 0.18; 0.54), there was no strong association with DBP, SBP, or hypertension. This would suggest a 7 beats/minute higher heart rate in those who smoke 20 cigarettes/day.
Conclusions
This MR meta-analysis supports a causal association of smoking heaviness with higher level of resting heart rate, but not with blood pressure. These findings suggest that part of the cardiovascular risk of smoking may operate through increasing resting heart rate.
doi:10.1161/CIRCGENETICS.115.001225
PMCID: PMC4684098  PMID: 26538566
blood pressure; hypertension; Mendelian randomization; heart rate; smoking
20.  Zygosity Differences in Height and Body Mass Index of Twins From Infancy to Old Age: A Study of the CODATwins Project 
Jelenkovic, Aline | Yokoyama, Yoshie | Sund, Reijo | Honda, Chika | Bogl, Leonie H. | Aaltonen, Sari | Ji, Fuling | Ning, Feng | Pang, Zengchang | Ordoñana, Juan R. | Sánchez-Romera, Juan F. | Colodro-Conde, Lucia | Burt, S. Alexandra | Klump, Kelly L. | Medland, Sarah E. | Montgomery, Grant W. | Kandler, Christian | McAdams, Tom A. | Eley, Thalia C. | Gregory, Alice M. | Saudino, Kimberly J. | Dubois, Lise | Boivin, Michel | Tarnoki, Adam D. | Tarnoki, David L. | Haworth, Claire M. A. | Plomin, Robert | Öncel, Sevgi Y. | Aliev, Fazil | Stazi, Maria A. | Fagnani, Corrado | D’Ippolito, Cristina | Craig, Jeffrey M. | Saffery, Richard | Siribaddana, Sisira H. | Hotopf, Matthew | Sumathipala, Athula | Rijsdijk, Fruhling | Spector, Timothy | Mangino, Massimo | Lachance, Genevieve | Gatz, Margaret | Butler, David A. | Bayasgalan, Gombojav | Narandalai, Danshiitsoodol | Freitas, Duarte L. | Maia, José Antonio | Harden, K. Paige | Tucker-Drob, Elliot M. | Kim, Bia | Chong, Youngsook | Hong, Changhee | Shin, Hyun Jung | Christensen, Kaare | Skytthe, Axel | Kyvik, Kirsten O. | Derom, Catherine A. | Vlietinck, Robert F. | Loos, Ruth J. F. | Cozen, Wendy | Hwang, Amie E. | Mack, Thomas M. | He, Mingguang | Ding, Xiaohu | Chang, Billy | Silberg, Judy L. | Eaves, Lindon J. | Maes, Hermine H. | Cutler, Tessa L. | Hopper, John L. | Aujard, Kelly | Magnusson, Patrik K. E. | Pedersen, Nancy L. | Dahl Aslan, Anna K. | Song, Yun-Mi | Yang, Sarah | Lee, Kayoung | Baker, Laura A. | Tuvblad, Catherine | Bjerregaard-Andersen, Morten | Beck-Nielsen, Henning | Sodemann, Morten | Heikkilä, Kauko | Tan, Qihua | Zhang, Dongfeng | Swan, Gary E. | Krasnow, Ruth | Jang, Kerry L. | Knafo-Noam, Ariel | Mankuta, David | Abramson, Lior | Lichtenstein, Paul | Krueger, Robert F. | McGue, Matt | Pahlen, Shandell | Tynelius, Per | Duncan, Glen E. | Buchwald, Dedra | Corley, Robin P. | Huibregtse, Brooke M. | Nelson, Tracy L. | Whitfield, Keith E. | Franz, Carol E. | Kremen, William S. | Lyons, Michael J. | Ooki, Syuichi | Brandt, Ingunn | Nilsen, Thomas Sevenius | Inui, Fujio | Watanabe, Mikio | Bartels, Meike | van Beijsterveldt, Toos C. E. M. | Wardle, Jane | Llewellyn, Clare H. | Fisher, Abigail | Rebato, Esther | Martin, Nicholas G. | Iwatani, Yoshinori | Hayakawa, Kazuo | Sung, Joohon | Harris, Jennifer R. | Willemsen, Gonneke | Busjahn, Andreas | Goldberg, Jack H. | Rasmussen, Finn | Hur, Yoon-Mi | Boomsma, Dorret I. | Sørensen, Thorkild I. A. | Kaprio, Jaakko | Silventoinen, Karri
A trend toward greater body size in dizygotic (DZ) than in monozygotic (MZ) twins has been suggested by some but not all studies, and this difference may also vary by age. We analyzed zygosity differences in mean values and variances of height and body mass index (BMI) among male and female twins from infancy to old age. Data were derived from an international database of 54 twin cohorts participating in the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins), and included 842,951 height and BMI measurements from twins aged 1 to 102 years. The results showed that DZ twins were consistently taller than MZ twins, with differences of up to 2.0 cm in childhood and adolescence and up to 0.9 cm in adulthood. Similarly, a greater mean BMI of up to 0.3 kg/m2 in childhood and adolescence and up to 0.2 kg/m2 in adulthood was observed in DZ twins, although the pattern was less consistent. DZ twins presented up to 1.7% greater height and 1.9% greater BMI than MZ twins; these percentage differences were largest in middle and late childhood and decreased with age in both sexes. The variance of height was similar in MZ and DZ twins at most ages. In contrast, the variance of BMI was significantly higher in DZ than in MZ twins, particularly in childhood. In conclusion, DZ twins were generally taller and had greater BMI than MZ twins, but the differences decreased with age in both sexes.
doi:10.1017/thg.2015.57
PMCID: PMC4605819  PMID: 26337138
twins; height; BMI; zygosity differences
21.  Association between Maternal Fish Consumption and Gestational Weight Gain: Influence of Molecular Genetic Predisposition to Obesity 
PLoS ONE  2016;11(3):e0150105.
Background
Studies suggest that fish consumption can restrict weight gain. However, little is known about how fish consumption affects gestational weight gain (GWG), and whether this relationship depends on genetic makeup.
Objective
To examine the association between fish consumption and GWG, and whether this relationship is dependent on molecular genetic predisposition to obesity.
Design
A nested case-cohort study based on the Danish National Birth Cohort (DNBC) sampling the most obese women (n = 990) and a random sample of the remaining participants (n = 1,128). Replication of statistically significant findings was attempted in the Avon Longitudinal Study of Parents and Children (ALSPAC) (n = 4,841). We included 32 body mass index (BMI) associated single nucleotide polymorphisms (SNPs) and 5 SNPs found associated with GWG. BMI associated SNPs were combined in a genetic risk score (GRS). Associations between consumption of fish, GRS or individual variants and GWG were analysed, and interactions between fish and the GRS or individual variants were examined.
Results
In the DNBC, each portion/week (150 g) of fatty fish was associated with a higher GWG of 0.58 kg (95% CI: 0.16, 0.99, P<0.01). For total fish and lean fish, similar patterns were observed, but these associations were not statistically significant. We found no association between GRS and GWG, and no interactions between GRS and dietary fish on GWG. However, we found an interaction between the PPARG Pro12Ala variant and dietary fish. Each additional Pro12Ala G-allele was associated with a GWG of -0.83 kg (95% CI: -1.29, -0.37, P<0.01) per portion/week of dietary fish, with the same pattern for both lean and fatty fish. In ALSPAC, we were unable to replicate these findings.
Conclusion
We found no consistent evidence of association between fish consumption and GWG, and our results indicate that the association between dietary fish and GWG has little or no dependency on GRS or individual SNPs.
doi:10.1371/journal.pone.0150105
PMCID: PMC4773113  PMID: 26930408
22.  Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels 
Kilpeläinen, Tuomas O. | Carli, Jayne F. Martin | Skowronski, Alicja A. | Sun, Qi | Kriebel, Jennifer | Feitosa, Mary F | Hedman, Åsa K. | Drong, Alexander W. | Hayes, James E. | Zhao, Jinghua | Pers, Tune H. | Schick, Ursula | Grarup, Niels | Kutalik, Zoltán | Trompet, Stella | Mangino, Massimo | Kristiansson, Kati | Beekman, Marian | Lyytikäinen, Leo-Pekka | Eriksson, Joel | Henneman, Peter | Lahti, Jari | Tanaka, Toshiko | Luan, Jian'an | Greco M, Fabiola Del | Pasko, Dorota | Renström, Frida | Willems, Sara M. | Mahajan, Anubha | Rose, Lynda M. | Guo, Xiuqing | Liu, Yongmei | Kleber, Marcus E. | Pérusse, Louis | Gaunt, Tom | Ahluwalia, Tarunveer S. | Ju Sung, Yun | Ramos, Yolande F. | Amin, Najaf | Amuzu, Antoinette | Barroso, Inês | Bellis, Claire | Blangero, John | Buckley, Brendan M. | Böhringer, Stefan | I Chen, Yii-Der | de Craen, Anton J. N. | Crosslin, David R. | Dale, Caroline E. | Dastani, Zari | Day, Felix R. | Deelen, Joris | Delgado, Graciela E. | Demirkan, Ayse | Finucane, Francis M. | Ford, Ian | Garcia, Melissa E. | Gieger, Christian | Gustafsson, Stefan | Hallmans, Göran | Hankinson, Susan E. | Havulinna, Aki S | Herder, Christian | Hernandez, Dena | Hicks, Andrew A. | Hunter, David J. | Illig, Thomas | Ingelsson, Erik | Ioan-Facsinay, Andreea | Jansson, John-Olov | Jenny, Nancy S. | Jørgensen, Marit E. | Jørgensen, Torben | Karlsson, Magnus | Koenig, Wolfgang | Kraft, Peter | Kwekkeboom, Joanneke | Laatikainen, Tiina | Ladwig, Karl-Heinz | LeDuc, Charles A. | Lowe, Gordon | Lu, Yingchang | Marques-Vidal, Pedro | Meisinger, Christa | Menni, Cristina | Morris, Andrew P. | Myers, Richard H. | Männistö, Satu | Nalls, Mike A. | Paternoster, Lavinia | Peters, Annette | Pradhan, Aruna D. | Rankinen, Tuomo | Rasmussen-Torvik, Laura J. | Rathmann, Wolfgang | Rice, Treva K. | Brent Richards, J | Ridker, Paul M. | Sattar, Naveed | Savage, David B. | Söderberg, Stefan | Timpson, Nicholas J. | Vandenput, Liesbeth | van Heemst, Diana | Uh, Hae-Won | Vohl, Marie-Claude | Walker, Mark | Wichmann, Heinz-Erich | Widén, Elisabeth | Wood, Andrew R. | Yao, Jie | Zeller, Tanja | Zhang, Yiying | Meulenbelt, Ingrid | Kloppenburg, Margreet | Astrup, Arne | Sørensen, Thorkild I. A. | Sarzynski, Mark A. | Rao, D. C. | Jousilahti, Pekka | Vartiainen, Erkki | Hofman, Albert | Rivadeneira, Fernando | Uitterlinden, André G. | Kajantie, Eero | Osmond, Clive | Palotie, Aarno | Eriksson, Johan G. | Heliövaara, Markku | Knekt, Paul B. | Koskinen, Seppo | Jula, Antti | Perola, Markus | Huupponen, Risto K. | Viikari, Jorma S. | Kähönen, Mika | Lehtimäki, Terho | Raitakari, Olli T. | Mellström, Dan | Lorentzon, Mattias | Casas, Juan P. | Bandinelli, Stefanie | März, Winfried | Isaacs, Aaron | van Dijk, Ko W. | van Duijn, Cornelia M. | Harris, Tamara B. | Bouchard, Claude | Allison, Matthew A. | Chasman, Daniel I. | Ohlsson, Claes | Lind, Lars | Scott, Robert A. | Langenberg, Claudia | Wareham, Nicholas J. | Ferrucci, Luigi | Frayling, Timothy M. | Pramstaller, Peter P. | Borecki, Ingrid B. | Waterworth, Dawn M. | Bergmann, Sven | Waeber, Gérard | Vollenweider, Peter | Vestergaard, Henrik | Hansen, Torben | Pedersen, Oluf | Hu, Frank B. | Eline Slagboom, P | Grallert, Harald | Spector, Tim D. | Jukema, J.W. | Klein, Robert J. | Schadt, Erik E | Franks, Paul W. | Lindgren, Cecilia M. | Leibel, Rudolph L. | Loos, Ruth J. F.
Nature Communications  2016;7:10494.
Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10−6 in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10−8) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.
This meta-analysis of genome-wide association studies identifies four genetic loci associated with circulating leptin levels independent of adiposity. Examination in mouse adipose tissue explants provides functional support for the leptin-associated loci.
doi:10.1038/ncomms10494
PMCID: PMC4740377  PMID: 26833098
23.  New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk 
Lu, Yingchang | Day, Felix R. | Gustafsson, Stefan | Buchkovich, Martin L. | Na, Jianbo | Bataille, Veronique | Cousminer, Diana L. | Dastani, Zari | Drong, Alexander W. | Esko, Tõnu | Evans, David M. | Falchi, Mario | Feitosa, Mary F. | Ferreira, Teresa | Hedman, Åsa K. | Haring, Robin | Hysi, Pirro G. | Iles, Mark M. | Justice, Anne E. | Kanoni, Stavroula | Lagou, Vasiliki | Li, Rui | Li, Xin | Locke, Adam | Lu, Chen | Mägi, Reedik | Perry, John R. B. | Pers, Tune H. | Qi, Qibin | Sanna, Marianna | Schmidt, Ellen M. | Scott, William R. | Shungin, Dmitry | Teumer, Alexander | Vinkhuyzen, Anna A. E. | Walker, Ryan W. | Westra, Harm-Jan | Zhang, Mingfeng | Zhang, Weihua | Zhao, Jing Hua | Zhu, Zhihong | Afzal, Uzma | Ahluwalia, Tarunveer Singh | Bakker, Stephan J. L. | Bellis, Claire | Bonnefond, Amélie | Borodulin, Katja | Buchman, Aron S. | Cederholm, Tommy | Choh, Audrey C. | Choi, Hyung Jin | Curran, Joanne E. | de Groot, Lisette C. P. G. M. | De Jager, Philip L. | Dhonukshe-Rutten, Rosalie A. M. | Enneman, Anke W. | Eury, Elodie | Evans, Daniel S. | Forsen, Tom | Friedrich, Nele | Fumeron, Frédéric | Garcia, Melissa E. | Gärtner, Simone | Han, Bok-Ghee | Havulinna, Aki S. | Hayward, Caroline | Hernandez, Dena | Hillege, Hans | Ittermann, Till | Kent, Jack W. | Kolcic, Ivana | Laatikainen, Tiina | Lahti, Jari | Leach, Irene Mateo | Lee, Christine G. | Lee, Jong-Young | Liu, Tian | Liu, Youfang | Lobbens, Stéphane | Loh, Marie | Lyytikäinen, Leo-Pekka | Medina-Gomez, Carolina | Michaëlsson, Karl | Nalls, Mike A. | Nielson, Carrie M. | Oozageer, Laticia | Pascoe, Laura | Paternoster, Lavinia | Polašek, Ozren | Ripatti, Samuli | Sarzynski, Mark A. | Shin, Chan Soo | Narančić, Nina Smolej | Spira, Dominik | Srikanth, Priya | Steinhagen-Thiessen, Elisabeth | Sung, Yun Ju | Swart, Karin M. A. | Taittonen, Leena | Tanaka, Toshiko | Tikkanen, Emmi | van der Velde, Nathalie | van Schoor, Natasja M. | Verweij, Niek | Wright, Alan F. | Yu, Lei | Zmuda, Joseph M. | Eklund, Niina | Forrester, Terrence | Grarup, Niels | Jackson, Anne U. | Kristiansson, Kati | Kuulasmaa, Teemu | Kuusisto, Johanna | Lichtner, Peter | Luan, Jian'an | Mahajan, Anubha | Männistö, Satu | Palmer, Cameron D. | Ried, Janina S. | Scott, Robert A. | Stancáková, Alena | Wagner, Peter J. | Demirkan, Ayse | Döring, Angela | Gudnason, Vilmundur | Kiel, Douglas P. | Kühnel, Brigitte | Mangino, Massimo | Mcknight, Barbara | Menni, Cristina | O'Connell, Jeffrey R. | Oostra, Ben A. | Shuldiner, Alan R. | Song, Kijoung | Vandenput, Liesbeth | van Duijn, Cornelia M. | Vollenweider, Peter | White, Charles C. | Boehnke, Michael | Boettcher, Yvonne | Cooper, Richard S. | Forouhi, Nita G. | Gieger, Christian | Grallert, Harald | Hingorani, Aroon | Jørgensen, Torben | Jousilahti, Pekka | Kivimaki, Mika | Kumari, Meena | Laakso, Markku | Langenberg, Claudia | Linneberg, Allan | Luke, Amy | Mckenzie, Colin A. | Palotie, Aarno | Pedersen, Oluf | Peters, Annette | Strauch, Konstantin | Tayo, Bamidele O. | Wareham, Nicholas J. | Bennett, David A. | Bertram, Lars | Blangero, John | Blüher, Matthias | Bouchard, Claude | Campbell, Harry | Cho, Nam H. | Cummings, Steven R. | Czerwinski, Stefan A. | Demuth, Ilja | Eckardt, Rahel | Eriksson, Johan G. | Ferrucci, Luigi | Franco, Oscar H. | Froguel, Philippe | Gansevoort, Ron T. | Hansen, Torben | Harris, Tamara B. | Hastie, Nicholas | Heliövaara, Markku | Hofman, Albert | Jordan, Joanne M. | Jula, Antti | Kähönen, Mika | Kajantie, Eero | Knekt, Paul B. | Koskinen, Seppo | Kovacs, Peter | Lehtimäki, Terho | Lind, Lars | Liu, Yongmei | Orwoll, Eric S. | Osmond, Clive | Perola, Markus | Pérusse, Louis | Raitakari, Olli T. | Rankinen, Tuomo | Rao, D. C. | Rice, Treva K. | Rivadeneira, Fernando | Rudan, Igor | Salomaa, Veikko | Sørensen, Thorkild I. A. | Stumvoll, Michael | Tönjes, Anke | Towne, Bradford | Tranah, Gregory J. | Tremblay, Angelo | Uitterlinden, André G. | van der Harst, Pim | Vartiainen, Erkki | Viikari, Jorma S. | Vitart, Veronique | Vohl, Marie-Claude | Völzke, Henry | Walker, Mark | Wallaschofski, Henri | Wild, Sarah | Wilson, James F. | Yengo, Loïc | Bishop, D. Timothy | Borecki, Ingrid B. | Chambers, John C. | Cupples, L. Adrienne | Dehghan, Abbas | Deloukas, Panos | Fatemifar, Ghazaleh | Fox, Caroline | Furey, Terrence S. | Franke, Lude | Han, Jiali | Hunter, David J. | Karjalainen, Juha | Karpe, Fredrik | Kaplan, Robert C. | Kooner, Jaspal S. | McCarthy, Mark I. | Murabito, Joanne M. | Morris, Andrew P. | Bishop, Julia A. N. | North, Kari E. | Ohlsson, Claes | Ong, Ken K. | Prokopenko, Inga | Richards, J. Brent | Schadt, Eric E. | Spector, Tim D. | Widén, Elisabeth | Willer, Cristen J. | Yang, Jian | Ingelsson, Erik | Mohlke, Karen L. | Hirschhorn, Joel N. | Pospisilik, John Andrew | Zillikens, M. Carola | Lindgren, Cecilia | Kilpeläinen, Tuomas Oskari | Loos, Ruth J. F.
Nature Communications  2016;7:10495.
To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10−8), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.
A genome-wide association meta-analysis study here shows novel genetic loci to be associated to body fat percentage, and describes cross-phenotype association that further demonstrate a close relationship between adiposity and cardiovascular disease risk.
doi:10.1038/ncomms10495
PMCID: PMC4740398  PMID: 26833246
24.  Directional dominance on stature and cognition in diverse human populations 
Joshi, Peter K. | Esko, Tonu | Mattsson, Hannele | Eklund, Niina | Gandin, Ilaria | Nutile, Teresa | Jackson, Anne U. | Schurmann, Claudia | Smith, Albert V. | Zhang, Weihua | Okada, Yukinori | Stančáková, Alena | Faul, Jessica D. | Zhao, Wei | Bartz, Traci M. | Concas, Maria Pina | Franceschini, Nora | Enroth, Stefan | Vitart, Veronique | Trompet, Stella | Guo, Xiuqing | Chasman, Daniel I. | O’Connel, Jeffery R. | Corre, Tanguy | Nongmaithem, Suraj S. | Chen, Yuning | Mangino, Massimo | Ruggiero, Daniela | Traglia, Michela | Farmaki, Aliki-Eleni | Kacprowski, Tim | Bjonnes, Andrew | van der Spek, Ashley | Wu, Ying | Giri, Anil K. | Yanek, Lisa R. | Wang, Lihua | Hofer, Edith | Rietveld, Cornelius A. | McLeod, Olga | Cornelis, Marilyn C. | Pattaro, Cristian | Verweij, Niek | Baumbach, Clemens | Abdellaoui, Abdel | Warren, Helen R. | Vuckovic, Dragana | Mei, Hao | Bouchard, Claude | Perry, John R.B. | Cappellani, Stefania | Mirza, Saira S. | Benton, Miles C. | Broeckel, Ulrich | Medland, Sarah E. | Lind, Penelope A. | Malerba, Giovanni | Drong, Alexander | Yengo, Loic | Bielak, Lawrence F. | Zhi, Degui | van der Most, Peter J. | Shriner, Daniel | Mägi, Reedik | Hemani, Gibran | Karaderi, Tugce | Wang, Zhaoming | Liu, Tian | Demuth, Ilja | Zhao, Jing Hua | Meng, Weihua | Lataniotis, Lazaros | van der Laan, Sander W. | Bradfield, Jonathan P. | Wood, Andrew R. | Bonnefond, Amelie | Ahluwalia, Tarunveer S. | Hall, Leanne M. | Salvi, Erika | Yazar, Seyhan | Carstensen, Lisbeth | de Haan, Hugoline G. | Abney, Mark | Afzal, Uzma | Allison, Matthew A. | Amin, Najaf | Asselbergs, Folkert W. | Bakker, Stephan J.L. | Barr, R. Graham | Baumeister, Sebastian E. | Benjamin, Daniel J. | Bergmann, Sven | Boerwinkle, Eric | Bottinger, Erwin P. | Campbell, Archie | Chakravarti, Aravinda | Chan, Yingleong | Chanock, Stephen J. | Chen, Constance | Chen, Y.-D. Ida | Collins, Francis S. | Connell, John | Correa, Adolfo | Cupples, L. Adrienne | Smith, George Davey | Davies, Gail | Dörr, Marcus | Ehret, Georg | Ellis, Stephen B. | Feenstra, Bjarke | Feitosa, Mary F. | Ford, Ian | Fox, Caroline S. | Frayling, Timothy M. | Friedrich, Nele | Geller, Frank | Scotland, Generation | Gillham-Nasenya, Irina | Gottesman, Omri | Graff, Misa | Grodstein, Francine | Gu, Charles | Haley, Chris | Hammond, Christopher J. | Harris, Sarah E. | Harris, Tamara B. | Hastie, Nicholas D. | Heard-Costa, Nancy L. | Heikkilä, Kauko | Hocking, Lynne J. | Homuth, Georg | Hottenga, Jouke-Jan | Huang, Jinyan | Huffman, Jennifer E. | Hysi, Pirro G. | Ikram, M. Arfan | Ingelsson, Erik | Joensuu, Anni | Johansson, Åsa | Jousilahti, Pekka | Jukema, J. Wouter | Kähönen, Mika | Kamatani, Yoichiro | Kanoni, Stavroula | Kerr, Shona M. | Khan, Nazir M. | Koellinger, Philipp | Koistinen, Heikki A. | Kooner, Manraj K. | Kubo, Michiaki | Kuusisto, Johanna | Lahti, Jari | Launer, Lenore J. | Lea, Rodney A. | Lehne, Benjamin | Lehtimäki, Terho | Liewald, David C.M. | Lind, Lars | Loh, Marie | Lokki, Marja-Liisa | London, Stephanie J. | Loomis, Stephanie J. | Loukola, Anu | Lu, Yingchang | Lumley, Thomas | Lundqvist, Annamari | Männistö, Satu | Marques-Vidal, Pedro | Masciullo, Corrado | Matchan, Angela | Mathias, Rasika A. | Matsuda, Koichi | Meigs, James B. | Meisinger, Christa | Meitinger, Thomas | Menni, Cristina | Mentch, Frank D. | Mihailov, Evelin | Milani, Lili | Montasser, May E. | Montgomery, Grant W. | Morrison, Alanna | Myers, Richard H. | Nadukuru, Rajiv | Navarro, Pau | Nelis, Mari | Nieminen, Markku S. | Nolte, Ilja M. | O’Connor, George T. | Ogunniyi, Adesola | Padmanabhan, Sandosh | Palmas, Walter R. | Pankow, James S. | Patarcic, Inga | Pavani, Francesca | Peyser, Patricia A. | Pietilainen, Kirsi | Poulter, Neil | Prokopenko, Inga | Ralhan, Sarju | Redmond, Paul | Rich, Stephen S. | Rissanen, Harri | Robino, Antonietta | Rose, Lynda M. | Rose, Richard | Sala, Cinzia | Salako, Babatunde | Salomaa, Veikko | Sarin, Antti-Pekka | Saxena, Richa | Schmidt, Helena | Scott, Laura J. | Scott, William R. | Sennblad, Bengt | Seshadri, Sudha | Sever, Peter | Shrestha, Smeeta | Smith, Blair H. | Smith, Jennifer A. | Soranzo, Nicole | Sotoodehnia, Nona | Southam, Lorraine | Stanton, Alice V. | Stathopoulou, Maria G. | Strauch, Konstantin | Strawbridge, Rona J. | Suderman, Matthew J. | Tandon, Nikhil | Tang, Sian-Tsun | Taylor, Kent D. | Tayo, Bamidele O. | Töglhofer, Anna Maria | Tomaszewski, Maciej | Tšernikova, Natalia | Tuomilehto, Jaakko | Uitterlinden, Andre G. | Vaidya, Dhananjay | van Hylckama Vlieg, Astrid | van Setten, Jessica | Vasankari, Tuula | Vedantam, Sailaja | Vlachopoulou, Efthymia | Vozzi, Diego | Vuoksimaa, Eero | Waldenberger, Melanie | Ware, Erin B. | Wentworth-Shields, William | Whitfield, John B. | Wild, Sarah | Willemsen, Gonneke | Yajnik, Chittaranjan S. | Yao, Jie | Zaza, Gianluigi | Zhu, Xiaofeng | Project, The BioBank Japan | Salem, Rany M. | Melbye, Mads | Bisgaard, Hans | Samani, Nilesh J. | Cusi, Daniele | Mackey, David A. | Cooper, Richard S. | Froguel, Philippe | Pasterkamp, Gerard | Grant, Struan F.A. | Hakonarson, Hakon | Ferrucci, Luigi | Scott, Robert A. | Morris, Andrew D. | Palmer, Colin N.A. | Dedoussis, George | Deloukas, Panos | Bertram, Lars | Lindenberger, Ulman | Berndt, Sonja I. | Lindgren, Cecilia M. | Timpson, Nicholas J. | Tönjes, Anke | Munroe, Patricia B. | Sørensen, Thorkild I.A. | Rotimi, Charles N. | Arnett, Donna K. | Oldehinkel, Albertine J. | Kardia, Sharon L.R. | Balkau, Beverley | Gambaro, Giovanni | Morris, Andrew P. | Eriksson, Johan G. | Wright, Margie J. | Martin, Nicholas G. | Hunt, Steven C. | Starr, John M. | Deary, Ian J. | Griffiths, Lyn R. | Tiemeier, Henning | Pirastu, Nicola | Kaprio, Jaakko | Wareham, Nicholas J. | Pérusse, Louis | Wilson, James G. | Girotto, Giorgia | Caulfield, Mark J. | Raitakari, Olli | Boomsma, Dorret I. | Gieger, Christian | van der Harst, Pim | Hicks, Andrew A. | Kraft, Peter | Sinisalo, Juha | Knekt, Paul | Johannesson, Magnus | Magnusson, Patrik K.E. | Hamsten, Anders | Schmidt, Reinhold | Borecki, Ingrid B. | Vartiainen, Erkki | Becker, Diane M. | Bharadwaj, Dwaipayan | Mohlke, Karen L. | Boehnke, Michael | van Duijn, Cornelia M. | Sanghera, Dharambir K. | Teumer, Alexander | Zeggini, Eleftheria | Metspalu, Andres | Gasparini, Paolo | Ulivi, Sheila | Ober, Carole | Toniolo, Daniela | Rudan, Igor | Porteous, David J. | Ciullo, Marina | Spector, Tim D. | Hayward, Caroline | Dupuis, Josée | Loos, Ruth J.F. | Wright, Alan F. | Chandak, Giriraj R. | Vollenweider, Peter | Shuldiner, Alan | Ridker, Paul M. | Rotter, Jerome I. | Sattar, Naveed | Gyllensten, Ulf | North, Kari E. | Pirastu, Mario | Psaty, Bruce M. | Weir, David R. | Laakso, Markku | Gudnason, Vilmundur | Takahashi, Atsushi | Chambers, John C. | Kooner, Jaspal S. | Strachan, David P. | Campbell, Harry | Hirschhorn, Joel N. | Perola, Markus | Polašek, Ozren | Wilson, James F.
Nature  2015;523(7561):459-462.
Homozygosity has long been associated with rare, often devastating, Mendelian disorders1 and Darwin was one of the first to recognise that inbreeding reduces evolutionary fitness2. However, the effect of the more distant parental relatedness common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity, ROH), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power3,4. Here we use ROH to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts and find statistically significant associations between summed runs of homozygosity (SROH) and four complex traits: height, forced expiratory lung volume in 1 second (FEV1), general cognitive ability (g) and educational attainment (nominal p<1 × 10−300, 2.1 × 10−6, 2.5 × 10−10, 1.8 × 10−10). In each case increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing convincing evidence for the first time that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples5,6, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein (LDL) cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection7, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
doi:10.1038/nature14618
PMCID: PMC4516141  PMID: 26131930
25.  Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation 
Kato, Norihiro | Loh, Marie | Takeuchi, Fumihiko | Verweij, Niek | Wang, Xu | Zhang, Weihua | Kelly, Tanika N | Saleheen, Danish | Lehne, Benjamin | Leach, Irene Mateo | Drong, Alexander W | Abbott, James | Wahl, Simone | Tan, Sian-Tsung | Scott, William R | Campanella, Gianluca | Chadeau-Hyam, Marc | Afzal, Uzma | Ahluwalia, Tarunveer S | Bonder, Marc Jan | Chen, Peng | Dehghan, Abbas | Edwards, Todd L | Esko, Tõnu | Go, Min Jin | Harris, Sarah E | Hartiala, Jaana | Kasela, Silva | Kasturiratne, Anuradhani | Khor, Chiea-Chuen | Kleber, Marcus E | Li, Huaixing | Yu Mok, Zuan | Nakatochi, Masahiro | Sapari, Nur Sabrina | Saxena, Richa | Stewart, Alexandre F R | Stolk, Lisette | Tabara, Yasuharu | Teh, Ai Ling | Wu, Ying | Wu, Jer-Yuarn | Zhang, Yi | Aits, Imke | Da Silva Couto Alves, Alexessander | Das, Shikta | Dorajoo, Rajkumar | Hopewell, Jemma C | Kim, Yun Kyoung | Koivula, Robert W | Luan, Jian’an | Lyytikäinen, Leo-Pekka | Nguyen, Quang N | Pereira, Mark A | Postmus, Iris | Raitakari, Olli T | Bryan, Molly Scannell | Scott, Robert A | Sorice, Rossella | Tragante, Vinicius | Traglia, Michela | White, Jon | Yamamoto, Ken | Zhang, Yonghong | Adair, Linda S | Ahmed, Alauddin | Akiyama, Koichi | Asif, Rasheed | Aung, Tin | Barroso, Inês | Bjonnes, Andrew | Braun, Timothy R | Cai, Hui | Chang, Li-Ching | Chen, Chien-Hsiun | Cheng, Ching-Yu | Chong, Yap-Seng | Collins, Rory | Courtney, Regina | Davies, Gail | Delgado, Graciela | Do, Loi D | Doevendans, Pieter A | Gansevoort, Ron T | Gao, Yu-Tang | Grammer, Tanja B | Grarup, Niels | Grewal, Jagvir | Gu, Dongfeng | Wander, Gurpreet S | Hartikainen, Anna-Liisa | Hazen, Stanley L | He, Jing | Heng, Chew-Kiat | Hixson, James E | Hofman, Albert | Hsu, Chris | Huang, Wei | Husemoen, Lise L N | Hwang, Joo-Yeon | Ichihara, Sahoko | Igase, Michiya | Isono, Masato | Justesen, Johanne M | Katsuya, Tomohiro | Kibriya, Muhammad G | Kim, Young Jin | Kishimoto, Miyako | Koh, Woon-Puay | Kohara, Katsuhiko | Kumari, Meena | Kwek, Kenneth | Lee, Nanette R | Lee, Jeannette | Liao, Jiemin | Lieb, Wolfgang | Liewald, David C M | Matsubara, Tatsuaki | Matsushita, Yumi | Meitinger, Thomas | Mihailov, Evelin | Milani, Lili | Mills, Rebecca | Mononen, Nina | Müller-Nurasyid, Martina | Nabika, Toru | Nakashima, Eitaro | Ng, Hong Kiat | Nikus, Kjell | Nutile, Teresa | Ohkubo, Takayoshi | Ohnaka, Keizo | Parish, Sarah | Paternoster, Lavinia | Peng, Hao | Peters, Annette | Pham, Son T | Pinidiyapathirage, Mohitha J | Rahman, Mahfuzar | Rakugi, Hiromi | Rolandsson, Olov | Ann Rozario, Michelle | Ruggiero, Daniela | Sala, Cinzia F | Sarju, Ralhan | Shimokawa, Kazuro | Snieder, Harold | Sparsø, Thomas | Spiering, Wilko | Starr, John M | Stott, David J | Stram, Daniel O | Sugiyama, Takao | Szymczak, Silke | Tang, W H Wilson | Tong, Lin | Trompet, Stella | Turjanmaa, Väinö | Ueshima, Hirotsugu | Uitterlinden, André G | Umemura, Satoshi | Vaarasmaki, Marja | van Dam, Rob M | van Gilst, Wiek H | van Veldhuisen, Dirk J | Viikari, Jorma S | Waldenberger, Melanie | Wang, Yiqin | Wang, Aili | Wilson, Rory | Wong, Tien-Yin | Xiang, Yong-Bing | Yamaguchi, Shuhei | Ye, Xingwang | Young, Robin D | Young, Terri L | Yuan, Jian-Min | Zhou, Xueya | Asselbergs, Folkert W | Ciullo, Marina | Clarke, Robert | Deloukas, Panos | Franke, Andre | Franks, Paul W | Franks, Steve | Friedlander, Yechiel | Gross, Myron D | Guo, Zhirong | Hansen, Torben | Jarvelin, Marjo-Riitta | Jørgensen, Torben | Jukema, J Wouter | kähönen, Mika | Kajio, Hiroshi | Kivimaki, Mika | Lee, Jong-Young | Lehtimäki, Terho | Linneberg, Allan | Miki, Tetsuro | Pedersen, Oluf | Samani, Nilesh J | Sørensen, Thorkild I A | Takayanagi, Ryoichi | Toniolo, Daniela | Ahsan, Habibul | Allayee, Hooman | Chen, Yuan-Tsong | Danesh, John | Deary, Ian J | Franco, Oscar H | Franke, Lude | Heijman, Bastiaan T | Holbrook, Joanna D | Isaacs, Aaron | Kim, Bong-Jo | Lin, Xu | Liu, Jianjun | März, Winfried | Metspalu, Andres | Mohlke, Karen L | Sanghera, Dharambir K | Shu, Xiao-Ou | van Meurs, Joyce B J | Vithana, Eranga | Wickremasinghe, Ananda R | Wijmenga, Cisca | Wolffenbuttel, Bruce H W | Yokota, Mitsuhiro | Zheng, Wei | Zhu, Dingliang | Vineis, Paolo | Kyrtopoulos, Soterios A | Kleinjans, Jos C S | McCarthy, Mark I | Soong, Richie | Gieger, Christian | Scott, James | Teo, Yik-Ying | He, Jiang | Elliott, Paul | Tai, E Shyong | van der Harst, Pim | Kooner, Jaspal S | Chambers, John C
Nature genetics  2015;47(11):1282-1293.
We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10−11 to 5.0 × 10−21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10−6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.
doi:10.1038/ng.3405
PMCID: PMC4719169  PMID: 26390057

Results 1-25 (129)