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1.  DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases 
Ligthart, Symen | Marzi, Carola | Aslibekyan, Stella | Mendelson, Michael M. | Conneely, Karen N. | Tanaka, Toshiko | Colicino, Elena | Waite, Lindsay L. | Joehanes, Roby | Guan, Weihua | Brody, Jennifer A. | Elks, Cathy | Marioni, Riccardo | Jhun, Min A. | Agha, Golareh | Bressler, Jan | Ward-Caviness, Cavin K. | Chen, Brian H. | Huan, Tianxiao | Bakulski, Kelly | Salfati, Elias L. | Fiorito, Giovanni | Wahl, Simone | Schramm, Katharina | Sha, Jin | Hernandez, Dena G. | Just, Allan C. | Smith, Jennifer A. | Sotoodehnia, Nona | Pilling, Luke C. | Pankow, James S. | Tsao, Phil S. | Liu, Chunyu | Zhao, Wei | Guarrera, Simonetta | Michopoulos, Vasiliki J. | Smith, Alicia K. | Peters, Marjolein J. | Melzer, David | Vokonas, Pantel | Fornage, Myriam | Prokisch, Holger | Bis, Joshua C. | Chu, Audrey Y. | Herder, Christian | Grallert, Harald | Yao, Chen | Shah, Sonia | McRae, Allan F. | Lin, Honghuang | Horvath, Steve | Fallin, Daniele | Hofman, Albert | Wareham, Nicholas J. | Wiggins, Kerri L. | Feinberg, Andrew P. | Starr, John M. | Visscher, Peter M. | Murabito, Joanne M. | Kardia, Sharon L. R. | Absher, Devin M. | Binder, Elisabeth B. | Singleton, Andrew B. | Bandinelli, Stefania | Peters, Annette | Waldenberger, Melanie | Matullo, Giuseppe | Schwartz, Joel D. | Demerath, Ellen W. | Uitterlinden, André G. | van Meurs, Joyce B. J. | Franco, Oscar H. | Chen, Yii-Der Ida | Levy, Daniel | Turner, Stephen T. | Deary, Ian J. | Ressler, Kerry J. | Dupuis, Josée | Ferrucci, Luigi | Ong, Ken K. | Assimes, Themistocles L. | Boerwinkle, Eric | Koenig, Wolfgang | Arnett, Donna K. | Baccarelli, Andrea A. | Benjamin, Emelia J. | Dehghan, Abbas
Genome Biology  2016;17:255.
Background
Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation.
Results
We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 × 10–7) in the discovery panel of European ancestry and replicated (P < 2.29 × 10–4) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 × 10–5), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 × 10–3), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58 × 10–5). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants.
Conclusion
We have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-016-1119-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s13059-016-1119-5
PMCID: PMC5151130  PMID: 27955697
Inflammation; DNA methylation; Epigenome-wide association study; C-reactive protein; Body mass index; Diabetes; Coronary heart disease
2.  A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration 
de Vries, Paul S. | Chasman, Daniel I. | Sabater-Lleal, Maria | Chen, Ming-Huei | Huffman, Jennifer E. | Steri, Maristella | Tang, Weihong | Teumer, Alexander | Marioni, Riccardo E. | Grossmann, Vera | Hottenga, Jouke J. | Trompet, Stella | Müller-Nurasyid, Martina | Zhao, Jing Hua | Brody, Jennifer A. | Kleber, Marcus E. | Guo, Xiuqing | Wang, Jie Jin | Auer, Paul L. | Attia, John R. | Yanek, Lisa R. | Ahluwalia, Tarunveer S. | Lahti, Jari | Venturini, Cristina | Tanaka, Toshiko | Bielak, Lawrence F. | Joshi, Peter K. | Rocanin-Arjo, Ares | Kolcic, Ivana | Navarro, Pau | Rose, Lynda M. | Oldmeadow, Christopher | Riess, Helene | Mazur, Johanna | Basu, Saonli | Goel, Anuj | Yang, Qiong | Ghanbari, Mohsen | Willemsen, Gonneke | Rumley, Ann | Fiorillo, Edoardo | de Craen, Anton J. M. | Grotevendt, Anne | Scott, Robert | Taylor, Kent D. | Delgado, Graciela E. | Yao, Jie | Kifley, Annette | Kooperberg, Charles | Qayyum, Rehan | Lopez, Lorna M. | Berentzen, Tina L. | Räikkönen, Katri | Mangino, Massimo | Bandinelli, Stefania | Peyser, Patricia A. | Wild, Sarah | Trégouët, David-Alexandre | Wright, Alan F. | Marten, Jonathan | Zemunik, Tatijana | Morrison, Alanna C. | Sennblad, Bengt | Tofler, Geoffrey | de Maat, Moniek P. M. | de Geus, Eco J. C. | Lowe, Gordon D. | Zoledziewska, Magdalena | Sattar, Naveed | Binder, Harald | Völker, Uwe | Waldenberger, Melanie | Khaw, Kay-Tee | Mcknight, Barbara | Huang, Jie | Jenny, Nancy S. | Holliday, Elizabeth G. | Qi, Lihong | Mcevoy, Mark G. | Becker, Diane M. | Starr, John M. | Sarin, Antti-Pekka | Hysi, Pirro G. | Hernandez, Dena G. | Jhun, Min A. | Campbell, Harry | Hamsten, Anders | Rivadeneira, Fernando | Mcardle, Wendy L. | Slagboom, P. Eline | Zeller, Tanja | Koenig, Wolfgang | Psaty, Bruce M. | Haritunians, Talin | Liu, Jingmin | Palotie, Aarno | Uitterlinden, André G. | Stott, David J. | Hofman, Albert | Franco, Oscar H. | Polasek, Ozren | Rudan, Igor | Morange, Pierre-Emmanuel | Wilson, James F. | Kardia, Sharon L. R. | Ferrucci, Luigi | Spector, Tim D. | Eriksson, Johan G. | Hansen, Torben | Deary, Ian J. | Becker, Lewis C. | Scott, Rodney J. | Mitchell, Paul | März, Winfried | Wareham, Nick J. | Peters, Annette | Greinacher, Andreas | Wild, Philipp S. | Jukema, J. Wouter | Boomsma, Dorret I. | Hayward, Caroline | Cucca, Francesco | Tracy, Russell | Watkins, Hugh | Reiner, Alex P. | Folsom, Aaron R. | Ridker, Paul M. | O'Donnell, Christopher J. | Smith, Nicholas L. | Strachan, David P. | Dehghan, Abbas
Human Molecular Genetics  2015;25(2):358-370.
Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.
doi:10.1093/hmg/ddv454
PMCID: PMC4715256  PMID: 26561523
3.  Facebook Advertising Across an Engagement Spectrum: A Case Example for Public Health Communication 
Background
The interpersonal, dialogic features of social networking sites have untapped potential for public health communication. We ran a Facebook advertising campaign to raise statewide awareness of Michigan’s newborn screening and biobanking programs.
Objective
We ran a Facebook advertising campaign to stimulate public engagement on the complex and sensitive issue of Michigan’s newborn screening and biobank programs.
Methods
We ran an 11-week, US $15,000 Facebook advertising campaign engaging Michigan Facebook users aged 18-64 years about the state’s newborn screening and population biobank programs, and we used a novel “engagement spectrum” framework to contextualize and evaluate engagement outcomes ranging from observation to multi-way conversation.
Results
The campaign reached 1.88 million Facebook users, yielding a range of engagement outcomes across ad sets that varied by objective, content, budget, duration, and bid type. Ad sets yielded 9009 page likes (US $4125), 15,958 website clicks (US $5578), and 12,909 complete video views to 100% (US $3750). “Boosted posts” yielded 528 comments and 35,966 page post engagements (US $1500). Overall, the campaign led to 452 shares and 642 comments, including 176 discussing newborn screening and biobanking.
Conclusions
Facebook advertising campaigns can efficiently reach large populations and achieve a range of engagement outcomes by diversifying ad types, bid types, and content. This campaign provided a population-based approach to communication that also increased transparency on a sensitive and complex topic by creating a forum for multi-way interaction.
doi:10.2196/publichealth.5623
PMCID: PMC4906239  PMID: 27244774
Internet; facebook; social media; facebook advertising campaign; social media engagement; health communication; social networking; biobanking; neonatal screening; infant; newborn screening
4.  Applying novel methods for assessing individual- and neighborhood-level social and psychosocial environment interactions with genetic factors in the prediction of depressive symptoms in the Multi-Ethnic Study of Atherosclerosis 
Behavior genetics  2015;46(1):89-99.
Background
Complex illnesses, like depression, are thought to arise from the interplay between psychosocial stressors and genetic predispositions. Approaches that take into account both personal and neighborhood factors and that consider gene regions as well as individual SNPs may be necessary to capture these interactions across race and ethnic groups.
Methods
We used novel gene-region based analysis methods (Sequence Kernel Association Test (SKAT) and meta-analysis (MetaSKAT), Gene-Environment Set Association Test (GESAT)), as well as traditional linear models to identify gene region and SNP × psychosocial factor interactions at the individual- and neighborhood-level, across multiple race/ethnicities.
Results
Multiple regions identified in SKAT analyses showed evidence of a significant gene-region association with averaged depressive symptom scores across race/ethnicity (MetaSKAT p-values < 0.001). One region × neighborhood-environment interaction was significantly associated with averaged depressive symptom score across race/ethnicity after multiple testing correction (chr 18:21454070-21494070, Fisher's combined p-value = 0.001).
Conclusions
The examination of gene regions jointly with environmental factors measured at multiple levels (individuals and their contexts) may shed light on the etiology of depressive illness across race/ethnicities.
doi:10.1007/s10519-015-9734-6
PMCID: PMC4720563  PMID: 26254610
Gene × environment; depressive symptoms; GESAT; gene-set testing; gene environment set association testing
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.  Rare, low frequency, and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans 
Molecular psychiatry  2015;21(5):601-607.
The common nonsynonymous variant rs16969968 in the α5 nicotinic receptor subunit gene (CHRNA5) is the strongest genetic risk factor for nicotine dependence in European Americans and contributes to risk in African Americans. To comprehensively examine whether other CHRNA5 coding variation influences nicotine dependence risk, we performed targeted sequencing on 1582 nicotine dependent cases (Fagerström Test for Nicotine Dependence score≥4) and 1238 non-dependent controls, with independent replication of common and low frequency variants using 12 studies with exome chip data. Nicotine dependence was examined using logistic regression with individual common variants (MAF≥0.05), aggregate low frequency variants (0.05>MAF≥0.005), and aggregate rare variants (MAF<0.005). Meta-analysis of primary results was performed with replication studies containing 12 174 heavy and 11 290 light smokers. Next-generation sequencing with 180X coverage identified 24 nonsynonymous variants and 2 frameshift deletions in CHRNA5, including 9 novel variants in the 2820 subjects. Meta-analysis confirmed the risk effect of the only common variant (rs16969968, European ancestry: OR=1.3, p=3.5×10−11; African ancestry: OR=1.3, p=0.01) and demonstrated that 3 low frequency variants contributed an independent risk (aggregate term, European ancestry: OR=1.3, p=0.005; African ancestry: OR=1.4, p=0.0006). The remaining 22 rare coding variants were associated with increased risk of nicotine dependence in the European American primary sample (OR=12.9, p=0.01) and in the same risk direction in African Americans (OR=1.5, p=0.37). Our results indicate that common, low frequency and rare CHRNA5 coding variants are independently associated with nicotine dependence risk. These newly identified variants likely influence risk for smoking-related diseases such as lung cancer.
doi:10.1038/mp.2015.105
PMCID: PMC4740321  PMID: 26239294
8.  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
9.  Effect of demographics on excretion of key urinary factors related to kidney stone risk 
Urology  2015;86(4):690-696.
Objective
To investigate the effect of demographics including age and sex on excretion of four key urinary factors (calcium (Ca), magnesium (Mg), oxalate (Ox) and uric acid (UA)) related to kidney stone risk.
Methods
Twenty-four hour urine samples were collected from non-Hispanic white sibships in Rochester, MN. Height, weight, blood pressure, serum creatinine and cystatin C (CC) were measured. Diet was assessed using the Viocare food frequency questionnaire. Effects of demographics and dietary elements on urinary excretions were evaluated in univariate, multivariate, and interaction models that included age, sex, and body mass index (BMI).
Results
Samples were available from 709 individuals. In multivariate models, sex was a significant predictor of all four urinary factors, age was significant for all but UA excretion, and serum creatinine was significant only for Ca and Mg excretion (p<0.05). BMI or weight positively correlated with Mg, Ox and UA excretion (p<0.05). Use of a thiazide diuretic (lower) and dietary protein (higher) were associated with Ca excretion, while dietary Ca was associated with higher Mg excretion. Urinary UA excretion increased with animal protein intake and CC estimated glomerular filtration rate (eGFR), and was lower with concurrent loop diuretic use. Significant interaction effects on urinary UA excretion were observed for loop diuretic use and sex, eGFR and sex, age and animal protein intake, and BMI and eGFR (p<0.05).
Conclusions
Age and sex influence excretion of key urinary factors related to kidney stone risk, and should be taken into account when evaluating kidney stone patients.
doi:10.1016/j.urology.2015.07.012
PMCID: PMC4592816  PMID: 26206452
Calcium; Diet; Nephrolithiasis; Oxalate; Uric acid
10.  GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium 
Aging Cell  2016;15(5):792-800.
Summary
Decline in muscle strength with aging is an important predictor of health trajectory in the elderly. Several factors, including genetics, are proposed contributors to variability in muscle strength. To identify genetic contributors to muscle strength, a meta‐analysis of genomewide association studies of handgrip was conducted. Grip strength was measured using a handheld dynamometer in 27 581 individuals of European descent over 65 years of age from 14 cohort studies. Genomewide association analysis was conducted on ~2.7 million imputed and genotyped variants (SNPs). Replication of the most significant findings was conducted using data from 6393 individuals from three cohorts. GWAS of lower body strength was also characterized in a subset of cohorts. Two genomewide significant (P‐value< 5 × 10−8) and 39 suggestive (P‐value< 5 × 10−5) associations were observed from meta‐analysis of the discovery cohorts. After meta‐analysis with replication cohorts, genomewide significant association was observed for rs752045 on chromosome 8 (β = 0.47, SE = 0.08, P‐value = 5.20 × 10−10). This SNP is mapped to an intergenic region and is located within an accessible chromatin region (DNase hypersensitivity site) in skeletal muscle myotubes differentiated from the human skeletal muscle myoblasts cell line. This locus alters a binding motif of the CCAAT/enhancer‐binding protein‐β (CEBPB) that is implicated in muscle repair mechanisms. GWAS of lower body strength did not yield significant results. A common genetic variant in a chromosomal region that regulates myotube differentiation and muscle repair may contribute to variability in grip strength in the elderly. Further studies are needed to uncover the mechanisms that link this genetic variant with muscle strength.
doi:10.1111/acel.12468
PMCID: PMC5013019  PMID: 27325353
aging; genomewide association; meta‐analysis; muscle strength; older adults; SNP
11.  GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium 
Aging Cell  2016;15(5):792-800.
Summary
Decline in muscle strength with aging is an important predictor of health trajectory in the elderly. Several factors, including genetics, are proposed contributors to variability in muscle strength. To identify genetic contributors to muscle strength, a meta‐analysis of genomewide association studies of handgrip was conducted. Grip strength was measured using a handheld dynamometer in 27 581 individuals of European descent over 65 years of age from 14 cohort studies. Genomewide association analysis was conducted on ~2.7 million imputed and genotyped variants (SNPs). Replication of the most significant findings was conducted using data from 6393 individuals from three cohorts. GWAS of lower body strength was also characterized in a subset of cohorts. Two genomewide significant (P‐value< 5 × 10−8) and 39 suggestive (P‐value< 5 × 10−5) associations were observed from meta‐analysis of the discovery cohorts. After meta‐analysis with replication cohorts, genomewide significant association was observed for rs752045 on chromosome 8 (β = 0.47, SE = 0.08, P‐value = 5.20 × 10−10). This SNP is mapped to an intergenic region and is located within an accessible chromatin region (DNase hypersensitivity site) in skeletal muscle myotubes differentiated from the human skeletal muscle myoblasts cell line. This locus alters a binding motif of the CCAAT/enhancer‐binding protein‐β (CEBPB) that is implicated in muscle repair mechanisms. GWAS of lower body strength did not yield significant results. A common genetic variant in a chromosomal region that regulates myotube differentiation and muscle repair may contribute to variability in grip strength in the elderly. Further studies are needed to uncover the mechanisms that link this genetic variant with muscle strength.
doi:10.1111/acel.12468
PMCID: PMC5013019  PMID: 27325353
aging; genomewide association; meta‐analysis; muscle strength; older adults; SNP
12.  Uric Acid: A Missing Link Between Hypertensive Pregnancy Disorders and Future Cardiovascular Disease? 
Mayo Clinic proceedings  2015;90(9):1207-1216.
Objective
To determine whether women who had a hypertensive pregnancy disorder (HPD) have elevated uric acid concentrations decades after pregnancy, when compared to women who had normotensive pregnancies.
Patients and Methods
The Genetic Epidemiology Network of Arteriopathy study measured uric acid concentrations in Hispanic (30%), non-Hispanic white (28%), and non-Hispanic black (42%) women (60 ± 10 years of age). This cross-sectional study was conducted between July 1, 2000 and December 31, 2004. Hispanic participants were recruited from families with high rates of diabetes, whereas non-Hispanic participants were recruited from families with high rates of hypertension. This analysis compared uric acid concentrations in women with a history of normotensive (n=1,846) or hypertensive (n=408) pregnancies by logistic regression.
Results
Women who had a HPD had higher uric acid concentrations (Median: 5.7 vs. 5.3 mg/dL, P<.001) and were more likely to have uric acid concentrations above 5.5 mg/dl (54.4% vs. 42.4%, P=.001) than women who had normotensive pregnancies. These differences persisted after adjusting for traditional cardiovascular risk factors, co-morbidities and other factors that affect uric acid concentrations. A family-based subgroup analysis comparing uric acid concentrations in women who had a HPD (n=308) and their parous sisters who had normotensive pregnancies (n=250) gave similar results (Median uric acid concentrations: 5.7 vs. 5.2 mg/dl, P=0.02; Proportion of women with uric acid >5.5 mg/dl: 54.0% vs. 40.3%, P<.001).
Conclusion
Decades after pregnancy, women who had a HPD have higher uric acid concentrations. This effect does not appear to be explained by a familial predisposition to elevated uric acid concentrations.
doi:10.1016/j.mayocp.2015.05.020
PMCID: PMC4567408  PMID: 26260220
hypertensive pregnancy disorders; uric acid; hypertension; diabetes; coronary heart disease; chronic kidney disease
13.  Set-based Tests for Genetic Association in Longitudinal Studies 
Biometrics  2015;71(3):606-615.
Summary
Genetic association studies with longitudinal markers of chronic diseases (e.g., blood pressure, body mass index) provide a valuable opportunity to explore how genetic variants affect traits over time by utilizing the full trajectory of longitudinal outcomes. Since these traits are likely influenced by the joint effect of multiple variants in a gene, a joint analysis of these variants considering linkage disequilibrium (LD) may help to explain additional phenotypic variation. In this article, we propose a longitudinal genetic random field model (LGRF), to test the association between a phenotype measured repeatedly during the course of an observational study and a set of genetic variants. Generalized score type tests are developed, which we show are robust to misspefication of within-subject correlation, a feature that is desirable for longitudinal analysis. In addition, a joint test incorporating gene-time interaction is further proposed. Computational advancement is made for scalable implementation of the proposed methods in large-scale genome-wide association studies (GWAS). The proposed methods are evaluated through extensive simulation studies and illustrated using data from the Multi-Ethnic Study of Atherosclerosis (MESA). Our simulation results indicate substantial gain in power using LGRF when compared with two commonly used existing alternatives: (i) single marker tests using longitudinal outcome and (ii) existing gene-based tests using the average value of repeated measurements as the outcome.
doi:10.1111/biom.12310
PMCID: PMC4601568  PMID: 25854837
Genetic association; Generalized estimating equations; Generalized score test; Longitudinal study; Multi-marker test; Random field
14.  Life course socioeconomic status and DNA methylation in genes related to stress reactivity and inflammation: The multi-ethnic study of atherosclerosis 
Epigenetics  2015;10(10):958-969.
Epigenetic changes, such as DNA methylation, have been hypothesized to provide a link between the social environment and disease development. The purpose of this study was to examine associations between life course measures of socioeconomic status (SES) and DNA methylation (DNAm) in 18 genes related to stress reactivity and inflammation using a multi-level modeling approach that treats DNAm measurements as repeat measures within an individual. DNAm and gene expression were assessed in purified monocytes for a random subsample of 1,264 non-Hispanic white, African-American, and Hispanic participants aged 55–94 from the Multi-Ethnic Study of Atherosclerosis (MESA). After correction for multiple testing, we found that low childhood SES was associated with DNAm in 3 stress-related genes (AVP, FKBP5, OXTR) and 2 inflammation-related genes (CCL1, CD1D), low adult SES was associated with DNAm in one stress-related gene (AVP) and 5 inflammation-related genes (CD1D, F8, KLRG1, NLRP12, TLR3), and social mobility was associated with DNAm in 3 stress-related genes (AVP, FKBP5, OXTR) and 7 inflammation-related genes (CCL1, CD1D, F8, KLRG1, NLRP12, PYDC1, TLR3). In general, low SES was associated with increased DNAm. Expression data was available for 7 genes that showed a significant relationship between SES and DNAm. In 5 of these 7 genes (CD1D, F8, FKBP5, KLRG1, NLRP12), DNAm was associated with gene expression for at least one transcript, providing evidence of the potential functional consequences of alterations in DNAm related to SES. The results of this study reflect the biological complexity of epigenetic data and underscore the need for multi-disciplinary approaches to study how DNAm may contribute to the social patterning of disease.
doi:10.1080/15592294.2015.1085139
PMCID: PMC4844216  PMID: 26295359
DNA methylation; gene expression; inflammation; socioeconomic status; stress reactivity
15.  Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function 
Pattaro, Cristian | Teumer, Alexander | Gorski, Mathias | Chu, Audrey Y. | Li, Man | Mijatovic, Vladan | Garnaas, Maija | Tin, Adrienne | Sorice, Rossella | Li, Yong | Taliun, Daniel | Olden, Matthias | Foster, Meredith | Yang, Qiong | Chen, Ming-Huei | Pers, Tune H. | Johnson, Andrew D. | Ko, Yi-An | Fuchsberger, Christian | Tayo, Bamidele | Nalls, Michael | Feitosa, Mary F. | Isaacs, Aaron | Dehghan, Abbas | d’Adamo, Pio | Adeyemo, Adebowale | Dieffenbach, Aida Karina | Zonderman, Alan B. | Nolte, Ilja M. | van der Most, Peter J. | Wright, Alan F. | Shuldiner, Alan R. | Morrison, Alanna C. | Hofman, Albert | Smith, Albert V. | Dreisbach, Albert W. | Franke, Andre | Uitterlinden, Andre G. | Metspalu, Andres | Tonjes, Anke | Lupo, Antonio | Robino, Antonietta | Johansson, Åsa | Demirkan, Ayse | Kollerits, Barbara | Freedman, Barry I. | Ponte, Belen | Oostra, Ben A. | Paulweber, Bernhard | Krämer, Bernhard K. | Mitchell, Braxton D. | Buckley, Brendan M. | Peralta, Carmen A. | Hayward, Caroline | Helmer, Catherine | Rotimi, Charles N. | Shaffer, Christian M. | Müller, Christian | Sala, Cinzia | van Duijn, Cornelia M. | Saint-Pierre, Aude | Ackermann, Daniel | Shriner, Daniel | Ruggiero, Daniela | Toniolo, Daniela | Lu, Yingchang | Cusi, Daniele | Czamara, Darina | Ellinghaus, David | Siscovick, David S. | Ruderfer, Douglas | Gieger, Christian | Grallert, Harald | Rochtchina, Elena | Atkinson, Elizabeth J. | Holliday, Elizabeth G. | Boerwinkle, Eric | Salvi, Erika | Bottinger, Erwin P. | Murgia, Federico | Rivadeneira, Fernando | Ernst, Florian | Kronenberg, Florian | Hu, Frank B. | Navis, Gerjan J. | Curhan, Gary C. | Ehret, George B. | Homuth, Georg | Coassin, Stefan | Thun, Gian-Andri | Pistis, Giorgio | Gambaro, Giovanni | Malerba, Giovanni | Montgomery, Grant W. | Eiriksdottir, Gudny | Jacobs, Gunnar | Li, Guo | Wichmann, H.-Erich | Campbell, Harry | Schmidt, Helena | Wallaschofski, Henri | Völzke, Henry | Brenner, Hermann | Kroemer, Heyo K. | Kramer, Holly | Lin, Honghuang | Leach, I. Mateo | Ford, Ian | Guessous, Idris | Rudan, Igor | Prokopenko, Inga | Borecki, Ingrid | Heid, Iris M. | Kolcic, Ivana | Persico, Ivana | Jukema, J. Wouter | Wilson, James F. | Felix, Janine F. | Divers, Jasmin | Lambert, Jean-Charles | Stafford, Jeanette M. | Gaspoz, Jean-Michel | Smith, Jennifer A. | Faul, Jessica D. | Wang, Jie Jin | Ding, Jingzhong | Hirschhorn, Joel N. | Attia, John | Whitfield, John B. | Chalmers, John | Viikari, Jorma | Coresh, Josef | Denny, Joshua C. | Karjalainen, Juha | Fernandes, Jyotika K. | Endlich, Karlhans | Butterbach, Katja | Keene, Keith L. | Lohman, Kurt | Portas, Laura | Launer, Lenore J. | Lyytikäinen, Leo-Pekka | Yengo, Loic | Franke, Lude | Ferrucci, Luigi | Rose, Lynda M. | Kedenko, Lyudmyla | Rao, Madhumathi | Struchalin, Maksim | Kleber, Marcus E. | Cavalieri, Margherita | Haun, Margot | Cornelis, Marilyn C. | Ciullo, Marina | Pirastu, Mario | de Andrade, Mariza | McEvoy, Mark A. | Woodward, Mark | Adam, Martin | Cocca, Massimiliano | Nauck, Matthias | Imboden, Medea | Waldenberger, Melanie | Pruijm, Menno | Metzger, Marie | Stumvoll, Michael | Evans, Michele K. | Sale, Michele M. | Kähönen, Mika | Boban, Mladen | Bochud, Murielle | Rheinberger, Myriam | Verweij, Niek | Bouatia-Naji, Nabila | Martin, Nicholas G. | Hastie, Nick | Probst-Hensch, Nicole | Soranzo, Nicole | Devuyst, Olivier | Raitakari, Olli | Gottesman, Omri | Franco, Oscar H | Polasek, Ozren | Gasparini, Paolo | Munroe, Patricia B. | Ridker, Paul M. | Mitchell, Paul | Muntner, Paul | Meisinger, Christa | Smit, Johannes H. | Kovacs, Peter | Wild, Philipp S. | Froguel, Philippe | Rettig, Rainer | Magi, Reedik | Biffar, Reiner | Schmidt, Reinhold | Middelberg, Rita PS | Carroll, Robert J. | Penninx, Brenda W. | Scott, Rodney J. | Katz, Ronit | Sedaghat, Sanaz | Wild, Sarah H. | Kardia, Sharon L.R. | Ulivi, Sheila | Hwang, Shih-Jen | Enroth, Stefan | Kloiber, Stefan | Trompet, Stella | Stengel, Benedicte | Hancock, Stephen J. | Turner, Stephen T. | Rosas, Sylvia E. | Stracke, Sylvia | Harris, Tamara B. | Zeller, Tanja | Zemunik, Tatijana | Lehtimäki, Terho | Illig, Thomas | Aspelund, Thor | Nikopensius, Tiit | Esko, Tonu | Tanaka, Toshiko | Gyllensten, Ulf | Völker, Uwe | Emilsson, Valur | Vitart, Veronique | Aalto, Ville | Gudnason, Vilmundur | Chouraki, Vincent | Chen, Wei-Min | Igl, Wilmar | März, Winfried | Koenig, Wolfgang | Lieb, Wolfgang | Loos, Ruth J. F. | Liu, Yongmei | Snieder, Harold | Pramstaller, Peter P. | Parsa, Afshin | O’Connell, Jeffrey R. | Susztak, Katalin | Hamet, Pavel | Tremblay, Johanne | de Boer, Ian H. | Böger, Carsten A. | Goessling, Wolfram | Chasman, Daniel I. | Köttgen, Anna | Kao, WH Linda | Fox, Caroline S.
Nature communications  2016;7:10023.
Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, nineteen associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biologic pathways.
doi:10.1038/ncomms10023
PMCID: PMC4735748  PMID: 26831199
16.  Contribution of common non-synonymous variants in PCSK1 to body mass index variation and risk of obesity: a systematic review and meta-analysis with evidence from up to 331 175 individuals 
Human Molecular Genetics  2015;24(12):3582-3594.
Polymorphisms rs6232 and rs6234/rs6235 in PCSK1 have been associated with extreme obesity [e.g. body mass index (BMI) ≥ 40 kg/m2], but their contribution to common obesity (BMI ≥ 30 kg/m2) and BMI variation in a multi-ethnic context is unclear. To fill this gap, we collected phenotypic and genetic data in up to 331 175 individuals from diverse ethnic groups. This process involved a systematic review of the literature in PubMed, Web of Science, Embase and the NIH GWAS catalog complemented by data extraction from pre-existing GWAS or custom-arrays in consortia and single studies. We employed recently developed global meta-analytic random-effects methods to calculate summary odds ratios (OR) and 95% confidence intervals (CIs) or beta estimates and standard errors (SE) for the obesity status and BMI analyses, respectively. Significant associations were found with binary obesity status for rs6232 (OR = 1.15, 95% CI 1.06–1.24, P = 6.08 × 10−6) and rs6234/rs6235 (OR = 1.07, 95% CI 1.04–1.10, P = 3.00 × 10−7). Similarly, significant associations were found with continuous BMI for rs6232 (β = 0.03, 95% CI 0.00–0.07; P = 0.047) and rs6234/rs6235 (β = 0.02, 95% CI 0.00–0.03; P = 5.57 × 10−4). Ethnicity, age and study ascertainment significantly modulated the association of PCSK1 polymorphisms with obesity. In summary, we demonstrate evidence that common gene variation in PCSK1 contributes to BMI variation and susceptibility to common obesity in the largest known meta-analysis published to date in genetic epidemiology.
doi:10.1093/hmg/ddv097
PMCID: PMC4498155  PMID: 25784503
17.  Innovating Consent for Pediatric HCT patients 
Bone marrow transplantation  2016;51(6):885-888.
doi:10.1038/bmt.2016.10
PMCID: PMC4896835  PMID: 26926228
18.  Association of a 62 Variant Type 2 Diabetes Genetic Risk Score with Markers of Subclinical Atherosclerosis: A Transethnic, Multicenter Study 
Background
Type 2 diabetes (T2D) and cardiovascular disease (CVD) share risk factors and subclinical atherosclerosis (SCA) predicts events in those with and without diabetes. T2D genetic risk may predict both T2D and SCA. We hypothesized that greater T2D genetic risk is associated with higher extent of SCA.
Methods and Results
In a cross-sectional analysis including up to 9,210 European Americans, 3,773 African Americans, 1,446 Hispanic Americans and 773 Chinese Americans without known CVD and enrolled in the FHS, CARDIA, MESA and GENOA studies, we tested a 62 T2D-loci genetic risk score (GRS62) for association with measures of SCA, including coronary artery (CACS) or abdominal aortic calcium score, common (CCA-IMT) and internal carotid artery intima-media thickness, and ankle-brachial index (ABI). We used ancestry-stratified linear regression models, with random effects accounting for family relatedness when appropriate, applying a genetic-only (adjusted for sex) and a full SCA risk factors adjusted model (significance = p<0.01 = 0.05/5, number of traits analyzed). An inverse association with CACS in MESA Europeans (fully-adjusted p=0.004) and with CCA-IMT in FHS (p=0.009) was not confirmed in other study cohorts, either separately or in meta-analysis. Secondary analyses showed no consistent associations with β-cell and insulin resistance sub-GRS in FHS and CARDIA.
Conclusions
SCA does not have a major genetic component linked to a burden of 62 T2D loci identified by large genome-wide association studies. A shared T2D-SCA genetic basis, if any, might become apparent from better functional information about both T2D and CVD risk loci.
doi:10.1161/CIRCGENETICS.114.000740
PMCID: PMC4472563  PMID: 25805414
genetic association; risk assessment; subclinical atherosclerosis risk factor; type 2 diabetes mellitus; cardiovascular disease
19.  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
20.  Genome-wide Studies of Verbal Declarative Memory in Nondemented Older People: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium 
Debette, Stéphanie | Ibrahim Verbaas, Carla A. | Bressler, Jan | Schuur, Maaike | Smith, Albert | Bis, Joshua C. | Davies, Gail | Wolf, Christiane | Gudnason, Vilmundur | Chibnik, Lori B. | Yang, Qiong | deStefano, Anita L. | de Quervain, Dominique J.F. | Srikanth, Velandai | Lahti, Jari | Grabe, Hans J. | Smith, Jennifer A. | Priebe, Lutz | Yu, Lei | Karbalai, Nazanin | Hayward, Caroline | Wilson, James F. | Campbell, Harry | Petrovic, Katja | Fornage, Myriam | Chauhan, Ganesh | Yeo, Robin | Boxall, Ruth | Becker, James | Stegle, Oliver | Mather, Karen A. | Chouraki, Vincent | Sun, Qi | Rose, Lynda M. | Resnick, Susan | Oldmeadow, Christopher | Kirin, Mirna | Wright, Alan F. | Jonsdottir, Maria K. | Au, Rhoda | Becker, Albert | Amin, Najaf | Nalls, Mike A. | Turner, Stephen T. | Kardia, Sharon L.R. | Oostra, Ben | Windham, Gwen | Coker, Laura H. | Zhao, Wei | Knopman, David S. | Heiss, Gerardo | Griswold, Michael E. | Gottesman, Rebecca F. | Vitart, Veronique | Hastie, Nicholas D. | Zgaga, Lina | Rudan, Igor | Polasek, Ozren | Holliday, Elizabeth G. | Schofield, Peter | Choi, Seung Hoan | Tanaka, Toshiko | An, Yang | Perry, Rodney T. | Kennedy, Richard E. | Sale, Michèle M. | Wang, Jing | Wadley, Virginia G. | Liewald, David C. | Ridker, Paul M. | Gow, Alan J. | Pattie, Alison | Starr, John M. | Porteous, David | Liu, Xuan | Thomson, Russell | Armstrong, Nicola J. | Eiriksdottir, Gudny | Assareh, Arezoo A. | Kochan, Nicole A. | Widen, Elisabeth | Palotie, Aarno | Hsieh, Yi-Chen | Eriksson, Johan G. | Vogler, Christian | van Swieten, John C. | Shulman, Joshua M. | Beiser, Alexa | Rotter, Jerome | Schmidt, Carsten O. | Hoffmann, Wolfgang | Nöthen, Markus M. | Ferrucci, Luigi | Attia, John | Uitterlinden, Andre G. | Amouyel, Philippe | Dartigues, Jean-François | Amieva, Hélène | Räikkönen, Katri | Garcia, Melissa | Wolf, Philip A. | Hofman, Albert | Longstreth, W.T. | Psaty, Bruce M. | Boerwinkle, Eric | DeJager, Philip L. | Sachdev, Perminder S. | Schmidt, Reinhold | Breteler, Monique M.B. | Teumer, Alexander | Lopez, Oscar L. | Cichon, Sven | Chasman, Daniel I. | Grodstein, Francine | Müller-Myhsok, Bertram | Tzourio, Christophe | Papassotiropoulos, Andreas | Bennett, David A. | Ikram, Arfan M. | Deary, Ian J. | van Duijn, Cornelia M. | Launer, Lenore | Fitzpatrick, Annette L. | Seshadri, Sudha | Mosley, Thomas H.
Biological psychiatry  2014;77(8):749-763.
BACKGROUND
Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting.
METHODS
We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia-and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10−6) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults.
RESULTS
rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10−10) and replication cohorts (p = 5.65 × 10−8). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10−8, and rs6813517 [SPOCK3], p = 2.58 × 10−8) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism.
CONCLUSIONS
This largest study to date exploring the genetics of memory function in ~ 40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.
doi:10.1016/j.biopsych.2014.08.027
PMCID: PMC4513651  PMID: 25648963
Alzheimer disease; Dementia; Epidemiology; Genetics; Population-based; Verbal declarative memory
21.  Multi-Ethnic Genome-Wide Association Study of Cerebral White Matter Hyperintensities on MRI 
Verhaaren, Benjamin F.J. | Debette, Stéphanie | Bis, Joshua C. | Smith, Jennifer A. | Ikram, M. Kamran | Adams, Hieab H. | Beecham, Ashley H. | Rajan, Kumar B. | Lopez, Lorna M. | Barral, Sandra | van Buchem, Mark A. | van der Grond, Jeroen | Smith, Albert V. | Hegenscheid, Katrin | Aggarwal, Neelum T. | de Andrade, Mariza | Atkinson, Elizabeth J. | Beekman, Marian | Beiser, Alexa S. | Blanton, Susan H. | Boerwinkle, Eric | Brickman, Adam M. | Bryan, R. Nick | Chauhan, Ganesh | Chen, Christopher P.L.H. | Chouraki, Vincent | de Craen, Anton J.M. | Crivello, Fabrice | Deary, Ian J. | Deelen, Joris | De Jager, Philip L. | Dufouil, Carole | Elkind, Mitchell S.V. | Evans, Denis A. | Freudenberger, Paul | Gottesman, Rebecca F. | Guðnason, Vilmundur | Habes, Mohamad | Heckbert, Susan R. | Heiss, Gerardo | Hilal, Saima | Hofer, Edith | Hofman, Albert | Ibrahim-Verbaas, Carla A. | Knopman, David S. | Lewis, Cora E. | Liao, Jiemin | Liewald, David C.M. | Luciano, Michelle | van der Lugt, Aad | Martinez, Oliver O. | Mayeux, Richard | Mazoyer, Bernard | Nalls, Mike | Nauck, Matthias | Niessen, Wiro J. | Oostra, Ben A. | Psaty, Bruce M. | Rice, Kenneth M. | Rotter, Jerome I. | von Sarnowski, Bettina | Schmidt, Helena | Schreiner, Pamela J. | Schuur, Maaike | Sidney, Stephen S. | Sigurdsson, Sigurdur | Slagboom, P. Eline | Stott, David J.M. | van Swieten, John C. | Teumer, Alexander | Töglhofer, Anna Maria | Traylor, Matthew | Trompet, Stella | Turner, Stephen T. | Tzourio, Christophe | Uh, Hae-Won | Uitterlinden, André G. | Vernooij, Meike W. | Wang, Jing J. | Wong, Tien Y. | Wardlaw, Joanna M. | Windham, B. Gwen | Wittfeld, Katharina | Wolf, Christiane | Wright, Clinton B. | Yang, Qiong | Zhao, Wei | Zijdenbos, Alex | Jukema, J. Wouter | Sacco, Ralph L. | Kardia, Sharon L.R. | Amouyel, Philippe | Mosley, Thomas H. | Longstreth, W. T. | DeCarli, Charles C. | van Duijn, Cornelia M. | Schmidt, Reinhold | Launer, Lenore J. | Grabe, Hans J. | Seshadri, Sudha S. | Ikram, M. Arfan | Fornage, Myriam
Background
The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multi-ethnic genome-wide association studies.
Methods and Results
We included 21,079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (N=17,936), African (N=1,943), Hispanic (N=795), and Asian (N=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each SNP and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (p=2.7×10−19) and identified novel loci on chr10q24 (p=1.6×10−9) and chr2p21 (p=4.4×10−8). In the multi-ethnic meta-analysis, we identified two additional loci, on chr1q22 (p=2.0×10−8) and chr2p16 (p=1.5×10−8). The novel loci contained genes that have been implicated in Alzheimer’s disease (chr2p21, chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24, chr2p16).
Conclusions
We identified four novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of white matter hyperintensities in addition to previously-proposed ischemic mechanisms.
doi:10.1161/CIRCGENETICS.114.000858
PMCID: PMC4427240  PMID: 25663218
Genome Wide Association Study; cerebral small vessel disease; single nucleotide polymorphisms cerebrovascular disorders; white matter disease; hypertension; high blood pressure
22.  Key influence of sex on urine volume and osmolality 
Background
Demographics influence kidney stone risk and the type of stone that is more likely to form. Common kidney stone risk factors include having a low urine volume and a high urine concentration. The goal of the current study was to evaluate the effect of demographics on urinary concentration and osmole excretion.
Methods
Twenty-four-hour urine samples were collected from non-Hispanic white sibships in Rochester, MN. Height, weight, blood pressure, serum creatinine, and cystatin C were measured. Diet was assessed using the Viocare food frequency questionnaire. Effects of demographics and dietary elements on urine osmolality and volume were evaluated in bivariate and multivariable models, as well as models that included dietary interactions with age, sex, and weight.
Results
Samples were available from 709 individuals (mean age 66 ± 9 years, 59 % female). Across the age spectrum, males had higher urine osmolality (~140 mOsm/kg, p < 0.0001) and total osmole excretion (~270 mOsm, p < 0.0001) compared to females. For any given urine volume, males had a consistently higher urine osmolality (~140 mOsm/kg, p < 0.0001). In multivariable models, urine osmolality declined with age and water intake and remained higher in males than females. Urine osmolality positively associated with weight and animal protein intake. Higher urine volume associated with larger water intake. An interaction revealed that greater body weight was associated with larger changes in urine osmolality as oxalate intake increased (p = 0.04).
Conclusion
Data from this study support the hypothesis that there are sex differences in thirst and vasopressin action. This trend in urine concentration is also consistent with known epidemiologic patterns of urinary stone disease risk.
Electronic supplementary material
The online version of this article (doi:10.1186/s13293-016-0063-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s13293-016-0063-0
PMCID: PMC4748596  PMID: 26865949
Urine osmolality; Diet; Nephrolithiasis; Urine volume
23.  Variants for HDL-C, LDL-C and Triglycerides Identified from Admixture Mapping and Fine-Mapping Analysis in African-American Families 
Background
Admixture mapping of lipids was followed-up by family-based association analysis to identify variants for cardiovascular disease in African-Americans.
Methods and Results
The present study conducted admixture mapping analysis for total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides. The analysis was performed in 1,905 unrelated African-American subjects from the National Heart, Lung and Blood Institute’s Family Blood Pressure Program. Regions showing admixture evidence were followed-up with family-based association analysis in 3,556 African-American subjects from the FBPP. The admixture mapping and family-based association analyses were adjusted for age, age2, sex, body-mass-index, and genome-wide mean ancestry to minimize the confounding due to population stratification. Regions that were suggestive of local ancestry association evidence were found on chromosomes 7 (LDL-C), 8 (HDL-C), 14 (triglycerides) and 19 (total cholesterol and triglycerides). In the fine-mapping analysis, 52,939 SNPs were tested and 11 SNPs (8 independent SNPs) showed nominal significant association with HDL-C (2 SNPs), LDL-C (4 SNPs) and triglycerides (5 SNPs). The family data was used in the fine-mapping to identify SNPs that showed novel associations with lipids and regions including genes with known associations for cardiovascular disease.
Conclusions
This study identified regions on chromosomes 7, 8, 14 and 19 and 11 SNPs from the fine-mapping analysis that were associated with HDL-C, LDL-C and triglycerides for further studies of cardiovascular disease in African-Americans.
doi:10.1161/CIRCGENETICS.114.000481
PMCID: PMC4378661  PMID: 25552592
lipids; genetics; association studies; African-Americans; admixture mapping analysis
24.  Genome-Wide Association Analysis of Plasma B-Type Natriuretic Peptide in African Americans: The Jackson Heart Study 
Background
Numerous experimental studies suggest that B-type natriuretic peptide (BNP) is cardioprotective, yet in clinical studies, higher plasma BNP concentrations have been associated with incident cardiovascular disease and higher left ventricular mass (LVM). Genetic association studies may allow us to determine the true causal directions without confounding by compensatory mechanisms.
Methods and Results
We performed meta-analysis of two genome-wide association (GWA) results from a total of 2,790 African Americans. We assumed an additive genetic model in association analysis of imputed 2.5 million SNP dosages with residuals generated from multivariable-adjusted logarithmically-transformed BNP controlling for relevant covariates and population stratification. Two loci were genome-wide significant, a candidate gene locus NPPB (rs198389, p-value=1.18×10−09) and novel missense variant in the KLKB1 locus (rs3733402, p-value=1.75×10−11) that explained 0.4% and 1.9% of variation in log BNP concentration, respectively. The observed increase in BNP concentration was proportional to the number of effect allele copies, an average of 8.1 pg/dl increase associated with two allele copies. SNPs in this loci were subsequently cross-checked with GWA results for the aldosterone-to-renin ratio in individuals of European ancestry, and only rs3733402 was genome-wide significant (p<5.0×10−8), suggesting possible shared genetic architecture for these two pathways. Other statistically significant relations for these SNPs included: rs198389 with systolic blood pressure in blacks (COGENT consortium) rs198389 and rs3733402 with LVM in whites (EchoGEN consortium).
Conclusions
These findings improve our knowledge of the genetic basis of BNP variation in African Americans, demonstrate possible shared allelic architecture for BNP with ARR and motivate further studies of underlying mechanisms.
doi:10.1161/CIRCGENETICS.114.000900
PMCID: PMC4426827  PMID: 25561047
genetic association; genetics; association studies; Genome Wide Association Study; genotype
25.  Expert and Advocacy Group Consensus Findings on the Horizon of Public Health Genetic Testing 
Healthcare  2016;4(1):14.
Description: Among the two leading causes of death in the United States, each responsible for one in every four deaths, heart disease costs Americans $300 billion, while cancer costs Americans $216 billion per year. They also rank among the top three causes of death in Europe and Asia. In 2012 the University of Michigan Center for Public Health and Community Genomics and Genetic Alliance, with the support of the Centers for Disease Control and Prevention Office of Public Health Genomics, hosted a conference in Atlanta, Georgia to consider related action strategies based on public health genomics. The aim of the conference was consensus building on recommendations to implement genetic screening for three major heritable contributors to these mortality and cost figures: hereditary breast and ovarian cancer (HBOC), familial hypercholesterolemia (FH), and Lynch syndrome (LS). Genetic applications for these three conditions are labeled with a “Tier 1” designation by the U.S. Centers for Disease Control and Prevention because they have been fully validated and clinical practice guidelines based on systematic review support them. Methodology: The conference followed a deliberative sequence starting with nationally recognized clinical and public health presenters for each condition, followed by a Patient and Community Perspectives Panel, working group sessions for each of the conditions, and a final plenary session. The 74 conference participants represented disease research and advocacy, public health, medicine and nursing, genetics, governmental health agencies, and industry. Participants drew on a public health framework interconnecting policy, clinical intervention, surveillance, and educational functions for their deliberations. Results: Participants emphasized the importance of collaboration between clinical, public health, and advocacy groups in implementing Tier 1 genetic screening. Advocacy groups could help with individual and institutional buy-in of Tier 1 programs. Groups differed on funding strategies, with alternative options such as large-scale federal funding and smaller scale, incremental funding solutions proposed. Piggybacking on existing federal breast and colorectal cancer control programs was suggested. Public health departments need to assess what information is now being collected by their state cancer registries. The groups advised that information on cascade screening of relatives be included in toolkits for use by states. Participants stressed incorporation of family history into health department breast cancer screening programs, and clinical HBOC data into state surveillance systems. The carrying out of universal LS screening of tumors in those with colorectal cancer was reviewed. Expansion of universal screening to include endometrial tumors was discussed, as was the application of guidelines recommending cholesterol screening of children 9–11 years old. States more advanced in terms of Tier 1 testing could serve as models and partners with other states launching screening and surveillance programs. A multidisciplinary team of screening program champions was suggested as a means of raising awareness among the consumer and health care communities. Participants offered multiple recommendations regarding use of electronic health records, including flagging of at-risk family members and utilization of state-level health information exchanges. The paper contains an update of policy developments and happenings for all three Tier 1 conditions, as well as identified gaps. Conclusions: Implementation of cascade screening of family members for HBOC and FH, and universal screening for LS in CRC tumors has reached a point of readiness within the U.S., with creative solutions at hand. Facilitating factors such as screening coverage through the Patient Protection and Affordable Care Act, and state health information exchanges can be tapped. Collaboration is needed between public health departments, health care systems, disease advocacy groups, and industry to fully realize Tier 1 genetic screening. State health department and disease networks currently engaged in Tier 1 screening can serve as models for the launch of new initiatives.
doi:10.3390/healthcare4010014
PMCID: PMC4934548  PMID: 27417602
health policy; genomics; cascade screening; electronic health records; surveillance; hereditary breast and ovarian cancer; familial hypercholesterolemia; Lynch syndrome; consumer advocacy; consensus

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