Person: Salem, Rany M
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Salem
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Rany M
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Salem, Rany M
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Publication New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism(2012) Horikoshi, Momoko; Yaghootkar, Hanieh; Mook-Kanamori, Dennis O.; Sovio, Ulla; Taal, H. Rob; Hennig, Branwen J.; Bradfield, Jonathan P.; St. Pourcain, Beate; Evans, David M.; Charoen, Pimphen; Kaakinen, Marika; Cousminer, Diana L.; Lehtimäki, Terho; Kreiner-Møller, Eskil; Warrington, Nicole M.; Bustamante, Mariona; Feenstra, Bjarke; Berry, Diane J.; Thiering, Elisabeth; Pfab, Thiemo; Barton, Sheila J.; Shields, Beverley M.; Kerkhof, Marjan; van Leeuwen, Elisabeth M.; Fulford, Anthony J.; Kutalik, Zoltán; Zhao, Jing Hua; den Hoed, Marcel; Mahajan, Anubha; Lindi, Virpi; Goh, Liang-Kee; Hottenga, Jouke-Jan; Wu, Ying; Raitakari, Olli T.; Harder, Marie N.; Meirhaeghe, Aline; Ntalla, Ioanna; Salem, Rany M; Jameson, Karen A.; Zhou, Kaixin; Monies, Dorota M.; Lagou, Vasiliki; Kirin, Mirna; Heikkinen, Jani; Adair, Linda S.; Alkuraya, Fowzan S.; Al-Odaib, Ali; Amouyel, Philippe; Andersson, Ehm Astrid; Bennett, Amanda J.; Blakemore, Alexandra I.F.; Buxton, Jessica L.; Dallongeville, Jean; Das, Shikta; de Geus, Eco J. C.; Estivill, Xavier; Flexeder, Claudia; Froguel, Philippe; Geller, Frank; Godfrey, Keith M.; Gottrand, Frédéric; Groves, Christopher J.; Hansen, Torben; Hirschhorn, Joel; Hofman, Albert; Hollegaard, Mads V.; Hougaard, David M.; Hyppönen, Elina; Inskip, Hazel M.; Isaacs, Aaron; Jørgensen, Torben; Kanaka-Gantenbein, Christina; Kemp, John P.; Kiess, Wieland; Kilpeläinen, Tuomas O.; Klopp, Norman; Knight, Bridget A.; Kuzawa, Christopher W.; McMahon, George; Newnham, John P.; Niinikoski, Harri; Oostra, Ben A.; Pedersen, Louise; Postma, Dirkje S.; Ring, Susan M.; Rivadeneira, Fernando; Robertson, Neil R.; Sebert, Sylvain; Simell, Olli; Slowinski, Torsten; Tiesler, Carla M.T.; Tönjes, Anke; Vaag, Allan; Viikari, Jorma S.; Vink, Jacqueline M.; Vissing, Nadja Hawwa; Wareham, Nicholas J.; Willemsen, Gonneke; Witte, Daniel R.; Zhang, Haitao; Zhao, Jianhua; Wilson, James F.; Stumvoll, Michael; Prentice, Andrew M.; Meyer, Brian F.; Pearson, Ewan R.; Boreham, Colin A.G.; Cooper, Cyrus; Gillman, Matthew; Dedoussis, George V.; Moreno, Luis A; Pedersen, Oluf; Saarinen, Maiju; Mohlke, Karen L.; Boomsma, Dorret I.; Saw, Seang-Mei; Lakka, Timo A.; Körner, Antje; Loos, Ruth J.F.; Ong, Ken K.; Vollenweider, Peter; van Duijn, Cornelia M.; Koppelman, Gerard H.; Hattersley, Andrew T.; Holloway, John W.; Hocher, Berthold; Heinrich, Joachim; Power, Chris; Melbye, Mads; Guxens, Mònica; Pennell, Craig E.; Bønnelykke, Klaus; Bisgaard, Hans; Eriksson, Johan G.; Widén, Elisabeth; Hakonarson, Hakon; Uitterlinden, André G.; Pouta, Anneli; Lawlor, Debbie A.; Smith, George Davey; Frayling, Timothy M.; McCarthy, Mark I.; Grant, Struan F.A.; Jaddoe, Vincent W.V.; Jarvelin, Marjo-Riitta; Timpson, Nicholas J.; Prokopenko, Inga; Freathy, Rachel M.Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood1. Previous genome-wide association studies identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes, and a second variant, near CCNL1, with no obvious link to adult traits2. In an expanded genome-wide association meta-analysis and follow-up study (up to 69,308 individuals of European descent from 43 studies), we have now extended the number of genome-wide significant loci to seven, accounting for a similar proportion of variance to maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes; ADRB1 with adult blood pressure; and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.Publication Directional dominance on stature and cognition in diverse human populations(2015) Joshi, Peter K.; Esko, Tõnu; 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; 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; 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; 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, Phillip; 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; 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; Perola, Markus; Polašek, Ozren; Wilson, James F.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.Publication Recurring exon deletions in the haptoglobin (HP) gene associate with lower blood cholesterol levels(2016) Boettger, Linda M.; Salem, Rany M; Handsaker, Robert; Peloso, Gina; Kathiresan, Sekar; Hirschhorn, Joel; McCarroll, StevenTwo exons of the human haptoglobin (HP) gene exhibit copy number variation that affects HP multimerization and underlies one of the first protein polymorphisms identified in humans. The evolutionary origins and medical significance of this polymorphism have been uncertain. Here we show that this variation has likely arisen from the recurring reversion of an ancient hominin-specific duplication of these exons. Though this polymorphism has been largely invisible to genome-wide genetic studies to date, we describe a way to analyze it by imputation from SNP haplotypes and find among 22,288 individuals that these HP exonic deletions associate with reduced LDL and total cholesterol levels. We show that these deletions, and a SNP that affects HP expression, are the likely drivers of the strong but complex association of cholesterol levels to SNPs near HP. Recurring exonic deletions in the haptoglobin gene likely enhance human health by lowering cholesterol levels in the blood.Publication Efficient Bayesian mixed model analysis increases association power in large cohorts(2014) Loh, Po-Ru; Tucker, George; Bulik-Sullivan, Brendan K; Vilhjálmsson, Bjarni J; Finucane, Hilary K; Salem, Rany M; Chasman, Daniel; Ridker, Paul; Neale, Benjamin; Berger, Bonnie; Patterson, Nick; Price, AlkesLinear mixed models are a powerful statistical tool for identifying genetic associations and avoiding confounding. However, existing methods are computationally intractable in large cohorts, and may not optimize power. All existing methods require time cost O(MN2) (where N = #samples and M = #SNPs) and implicitly assume an infinitesimal genetic architecture in which effect sizes are normally distributed, which can limit power. Here, we present a far more efficient mixed model association method, BOLT-LMM, which requires only a small number of O(MN)-time iterations and increases power by modeling more realistic, non-infinitesimal genetic architectures via a Bayesian mixture prior on marker effect sizes. We applied BOLT-LMM to nine quantitative traits in 23,294 samples from the Women’s Genome Health Study (WGHS) and observed significant increases in power, consistent with simulations. Theory and simulations show that the boost in power increases with cohort size, making BOLT-LMM appealing for GWAS in large cohorts.Publication New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes(Public Library of Science, 2012) Sandholm, Niina; Salem, Rany M; McKnight, Amy Jayne; Brennan, Eoin P.; Forsblom, Carol; Isakova, Tamara; McKay, Gareth J.; Williams, Winfred; Sadlier, Denise M.; Mäkinen, Ville-Petteri; Swan, Elizabeth J.; Palmer, Cameron Douglas; Boright, Andrew P.; Ahlqvist, Emma; Deshmukh, Harshal A.; Keller, Benjamin J.; Huang, Huateng; Ahola, Aila J.; Fagerholm, Emma; Gordin, Daniel; Harjutsalo, Valma; He, Bing; Heikkilä, Outi; Hietala, Kustaa; Kytö, Janne; Lahermo, Päivi; Lehto, Markku; Lithovius, Raija; Österholm, Anne-May; Parkkonen, Maija; Pitkäniemi, Janne; Rosengård-Bärlund, Milla; Saraheimo, Markku; Sarti, Cinzia; Söderlund, Jenny; Soro-Paavonen, Aino; Syreeni, Anna; Thorn, Lena M.; Tikkanen, Heikki; Tolonen, Nina; Tryggvason, Karl; Tuomilehto, Jaakko; Wadén, Johan; Gill, Geoffrey V.; Prior, Sarah Virginie; Guiducci, Candace; Mirel, Daniel B.; Taylor, Andrew; Hosseini, S. Mohsen; Parving, Hans-Henrik; Rossing, Peter; Tarnow, Lise; Ladenvall, Claes; Alhenc-Gelas, François; Lefebvre, Pierre; Rigalleau, Vincent; Roussel, Ronan; Tregouet, David-Alexandre; Maestroni, Anna; Maestroni, Silvia; Falhammar, Henrik; Gu, Tianwei; Möllsten, Anna; Cimponeriu, Danut; Ioana, Mihai; Mota, Maria; Mota, Eugen; Serafinceanu, Cristian; Stavarachi, Monica; Hanson, Robert L.; Nelson, Robert G.; Kretzler, Matthias; Colhoun, Helen M.; Panduru, Nicolae Mircea; Gu, Harvest F.; Brismar, Kerstin; Zerbini, Gianpaolo; Hadjadj, Samy; Marre, Michel; Groop, Leif; Lajer, Maria; Bull, Shelley B.; Waggott, Daryl; Paterson, Andrew D.; Savage, David A.; Bain, Stephen C.; Martin, Finian; Hirschhorn, Joel; Godson, Catherine; Florez, Jose; Groop, Per-Henrik; Maxwell, Alexander P.Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ∼2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2×\(10^{−8}\)) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0×\(10^{−9}\)). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-β1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1×\(10^{−7}\)), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.