@article {1544, title = {Ultraconserved elements in the human genome: association and transmission analyses of highly constrained single-nucleotide polymorphisms.}, journal = {Genetics}, volume = {192}, year = {2012}, month = {2012 Sep}, pages = {253-66}, abstract = {

Ultraconserved elements in the human genome likely harbor important biological functions as they are dosage sensitive and are able to direct tissue-specific expression. Because they are under purifying selection, variants in these elements may have a lower frequency in the population but a higher likelihood of association with complex traits. We tested a set of highly constrained SNPs (hcSNPs) distributed genome-wide among ultraconserved and nearly ultraconserved elements for association with seven traits related to reproductive (age at natural menopause, number of children, age at first child, and age at last child) and overall [longevity, body mass index (BMI), and height] fitness. Using up to 24,047 European-American samples from the National Heart, Lung, and Blood Institute Candidate Gene Association Resource (CARe), we observed an excess of associations with BMI and height. In an independent replication panel the most strongly associated SNPs showed an 8.4-fold enrichment of associations at the nominal level, including three variants in previously identified loci and one in a locus (DENND1A) previously shown to be associated with polycystic ovary syndrome. Finally, using 1430 family trios, we showed that the transmissions from heterozygous parents to offspring of the derived alleles of rare (frequency <= 0.5\%) hcSNPs are not biased, particularly after adjusting for the rates of genotype missingness and error in the data. The lack of transmission bias ruled out an immediately and strongly deleterious effect due to the rare derived alleles, consistent with the observation that mice homozygous for the deletion of ultraconserved elements showed no overt phenotype. Our study also illustrated the importance of carefully modeling potential technical confounders when analyzing genotype data of rare variants.

}, keywords = {Alleles, Animals, Body Height, Body Mass Index, Child, Conserved Sequence, Dogs, Evolution, Molecular, Female, Genetic Fitness, Genetic Variation, Genome, Human, Genotype, Humans, Inheritance Patterns, Male, Mice, Pedigree, Phenotype, Polymorphism, Single Nucleotide, Rats, Reproduction, Young Adult}, issn = {1943-2631}, doi = {10.1534/genetics.112.141945}, author = {Chiang, Charleston W K and Liu, Ching-Ti and Lettre, Guillaume and Lange, Leslie A and Jorgensen, Neal W and Keating, Brendan J and Vedantam, Sailaja and Nock, Nora L and Franceschini, Nora and Reiner, Alex P and Demerath, Ellen W and Boerwinkle, Eric and Rotter, Jerome I and Wilson, James G and North, Kari E and Papanicolaou, George J and Cupples, L Adrienne and Murabito, Joanne M and Hirschhorn, Joel N} } @article {6078, title = {A meta-analysis identifies new loci associated with body mass index in individuals of African ancestry.}, journal = {Nat Genet}, volume = {45}, year = {2013}, month = {2013 Jun}, pages = {690-6}, abstract = {

Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one new locus at 5q33 (GALNT10, rs7708584, P = 3.4 {\texttimes} 10(-11)) and another at 7p15 when we included data from the GIANT consortium (MIR148A-NFE2L3, rs10261878, P = 1.2 {\texttimes} 10(-10)). We also found suggestive evidence of an association at a third locus at 6q16 in the African-ancestry sample (KLHL32, rs974417, P = 6.9 {\texttimes} 10(-8)). Thirty-two of the 36 previously established BMI variants showed directionally consistent effect estimates in our GWAS (binomial P = 9.7 {\texttimes} 10(-7)), five of which reached genome-wide significance. These findings provide strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations.

}, keywords = {African Americans, Body Mass Index, Case-Control Studies, Gene Frequency, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Obesity, Polymorphism, Single Nucleotide}, issn = {1546-1718}, doi = {10.1038/ng.2608}, author = {Monda, Keri L and Chen, Gary K and Taylor, Kira C and Palmer, Cameron and Edwards, Todd L and Lange, Leslie A and Ng, Maggie C Y and Adeyemo, Adebowale A and Allison, Matthew A and Bielak, Lawrence F and Chen, Guanjie and Graff, Mariaelisa and Irvin, Marguerite R and Rhie, Suhn K and Li, Guo and Liu, Yongmei and Liu, Youfang and Lu, Yingchang and Nalls, Michael A and Sun, Yan V and Wojczynski, Mary K and Yanek, Lisa R and Aldrich, Melinda C and Ademola, Adeyinka and Amos, Christopher I and Bandera, Elisa V and Bock, Cathryn H and Britton, Angela and Broeckel, Ulrich and Cai, Quiyin and Caporaso, Neil E and Carlson, Chris S and Carpten, John and Casey, Graham and Chen, Wei-Min and Chen, Fang and Chen, Yii-der I and Chiang, Charleston W K and Coetzee, Gerhard A and Demerath, Ellen and Deming-Halverson, Sandra L and Driver, Ryan W and Dubbert, Patricia and Feitosa, Mary F and Feng, Ye and Freedman, Barry I and Gillanders, Elizabeth M and Gottesman, Omri and Guo, Xiuqing and Haritunians, Talin and Harris, Tamara and Harris, Curtis C and Hennis, Anselm J M and Hernandez, Dena G and McNeill, Lorna H and Howard, Timothy D and Howard, Barbara V and Howard, Virginia J and Johnson, Karen C and Kang, Sun J and Keating, Brendan J and Kolb, Suzanne and Kuller, Lewis H and Kutlar, Abdullah and Langefeld, Carl D and Lettre, Guillaume and Lohman, Kurt and Lotay, Vaneet and Lyon, Helen and Manson, JoAnn E and Maixner, William and Meng, Yan A and Monroe, Kristine R and Morhason-Bello, Imran and Murphy, Adam B and Mychaleckyj, Josyf C and Nadukuru, Rajiv and Nathanson, Katherine L and Nayak, Uma and N{\textquoteright}diaye, Amidou and Nemesure, Barbara and Wu, Suh-Yuh and Leske, M Cristina and Neslund-Dudas, Christine and Neuhouser, Marian and Nyante, Sarah and Ochs-Balcom, Heather and Ogunniyi, Adesola and Ogundiran, Temidayo O and Ojengbede, Oladosu and Olopade, Olufunmilayo I and Palmer, Julie R and Ruiz-Narvaez, Edward A and Palmer, Nicholette D and Press, Michael F and Rampersaud, Evandine and Rasmussen-Torvik, Laura J and Rodriguez-Gil, Jorge L and Salako, Babatunde and Schadt, Eric E and Schwartz, Ann G and Shriner, Daniel A and Siscovick, David and Smith, Shad B and Wassertheil-Smoller, Sylvia and Speliotes, Elizabeth K and Spitz, Margaret R and Sucheston, Lara and Taylor, Herman and Tayo, Bamidele O and Tucker, Margaret A and Van Den Berg, David J and Edwards, Digna R Velez and Wang, Zhaoming and Wiencke, John K and Winkler, Thomas W and Witte, John S and Wrensch, Margaret and Wu, Xifeng and Yang, James J and Levin, Albert M and Young, Taylor R and Zakai, Neil A and Cushman, Mary and Zanetti, Krista A and Zhao, Jing Hua and Zhao, Wei and Zheng, Yonglan and Zhou, Jie and Ziegler, Regina G and Zmuda, Joseph M and Fernandes, Jyotika K and Gilkeson, Gary S and Kamen, Diane L and Hunt, Kelly J and Spruill, Ida J and Ambrosone, Christine B and Ambs, Stefan and Arnett, Donna K and Atwood, Larry and Becker, Diane M and Berndt, Sonja I and Bernstein, Leslie and Blot, William J and Borecki, Ingrid B and Bottinger, Erwin P and Bowden, Donald W and Burke, Gregory and Chanock, Stephen J and Cooper, Richard S and Ding, Jingzhong and Duggan, David and Evans, Michele K and Fox, Caroline and Garvey, W Timothy and Bradfield, Jonathan P and Hakonarson, Hakon and Grant, Struan F A and Hsing, Ann and Chu, Lisa and Hu, Jennifer J and Huo, Dezheng and Ingles, Sue A and John, Esther M and Jordan, Joanne M and Kabagambe, Edmond K and Kardia, Sharon L R and Kittles, Rick A and Goodman, Phyllis J and Klein, Eric A and Kolonel, Laurence N and Le Marchand, Lo{\"\i}c and Liu, Simin and McKnight, Barbara and Millikan, Robert C and Mosley, Thomas H and Padhukasahasram, Badri and Williams, L Keoki and Patel, Sanjay R and Peters, Ulrike and Pettaway, Curtis A and Peyser, Patricia A and Psaty, Bruce M and Redline, Susan and Rotimi, Charles N and Rybicki, Benjamin A and Sale, Mich{\`e}le M and Schreiner, Pamela J and Signorello, Lisa B and Singleton, Andrew B and Stanford, Janet L and Strom, Sara S and Thun, Michael J and Vitolins, Mara and Zheng, Wei and Moore, Jason H and Williams, Scott M and Ketkar, Shamika and Zhu, Xiaofeng and Zonderman, Alan B and Kooperberg, Charles and Papanicolaou, George J and Henderson, Brian E and Reiner, Alex P and Hirschhorn, Joel N and Loos, Ruth J F and North, Kari E and Haiman, Christopher A} } @article {8570, title = {A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape.}, journal = {Nat Commun}, volume = {7}, year = {2016}, month = {2016 11 23}, pages = {13357}, abstract = {

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99\% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.

}, keywords = {Anthropometry, Body Size, Genome-Wide Association Study, Genotype, Humans, Models, Genetic, Principal Component Analysis}, issn = {2041-1723}, doi = {10.1038/ncomms13357}, author = {Ried, Janina S and Jeff M, Janina and Chu, Audrey Y and Bragg-Gresham, Jennifer L and van Dongen, Jenny and Huffman, Jennifer E and Ahluwalia, Tarunveer S and Cadby, Gemma and Eklund, Niina and Eriksson, Joel and Esko, T{\~o}nu and Feitosa, Mary F and Goel, Anuj and Gorski, Mathias and Hayward, Caroline and Heard-Costa, Nancy L and Jackson, Anne U and Jokinen, Eero and Kanoni, Stavroula and Kristiansson, Kati and Kutalik, Zolt{\'a}n and Lahti, Jari and Luan, Jian{\textquoteright}an and M{\"a}gi, Reedik and Mahajan, Anubha and Mangino, Massimo and Medina-G{\'o}mez, Carolina and Monda, Keri L and Nolte, Ilja M and Perusse, Louis and Prokopenko, Inga and Qi, Lu and Rose, Lynda M and Salvi, Erika and Smith, Megan T and Snieder, Harold and Stan{\v c}{\'a}kov{\'a}, Alena and Ju Sung, Yun and Tachmazidou, Ioanna and Teumer, Alexander and Thorleifsson, Gudmar and van der Harst, Pim and Walker, Ryan W and Wang, Sophie R and Wild, Sarah H and Willems, Sara M and Wong, Andrew and Zhang, Weihua and Albrecht, Eva and Couto Alves, Alexessander and Bakker, Stephan J L and Barlassina, Cristina and Bartz, Traci M and Beilby, John and Bellis, Claire and Bergman, Richard N and Bergmann, Sven and Blangero, John and Bl{\"u}her, Matthias and Boerwinkle, Eric and Bonnycastle, Lori L and Bornstein, Stefan R and Bruinenberg, Marcel and Campbell, Harry and Chen, Yii-Der Ida and Chiang, Charleston W K and Chines, Peter S and Collins, Francis S and Cucca, Fracensco and Cupples, L Adrienne and D{\textquoteright}Avila, Francesca and de Geus, Eco J C and Dedoussis, George and Dimitriou, Maria and D{\"o}ring, Angela and Eriksson, Johan G and Farmaki, Aliki-Eleni and Farrall, Martin and Ferreira, Teresa and Fischer, Krista and Forouhi, Nita G and Friedrich, Nele and Gjesing, Anette Prior and Glorioso, Nicola and Graff, Mariaelisa and Grallert, Harald and Grarup, Niels and Gr{\"a}{\ss}ler, J{\"u}rgen and Grewal, Jagvir and Hamsten, Anders and Harder, Marie Neergaard and Hartman, Catharina A and Hassinen, Maija and Hastie, Nicholas and Hattersley, Andrew Tym and Havulinna, Aki S and Heli{\"o}vaara, Markku and Hillege, Hans and Hofman, Albert and Holmen, Oddgeir and Homuth, Georg and Hottenga, Jouke-Jan and Hui, Jennie and Husemoen, Lise Lotte and Hysi, Pirro G and Isaacs, Aaron and Ittermann, Till and Jalilzadeh, Shapour and James, Alan L and J{\o}rgensen, Torben and Jousilahti, Pekka and Jula, Antti and Marie Justesen, Johanne and Justice, Anne E and K{\"a}h{\"o}nen, Mika and Karaleftheri, Maria and Tee Khaw, Kay and Keinanen-Kiukaanniemi, Sirkka M and Kinnunen, Leena and Knekt, Paul B and Koistinen, Heikki A and Kolcic, Ivana and Kooner, Ishminder K and Koskinen, Seppo and Kovacs, Peter and Kyriakou, Theodosios and Laitinen, Tomi and Langenberg, Claudia and Lewin, Alexandra M and Lichtner, Peter and Lindgren, Cecilia M and Lindstr{\"o}m, Jaana and Linneberg, Allan and Lorbeer, Roberto and Lorentzon, Mattias and Luben, Robert and Lyssenko, Valeriya and M{\"a}nnist{\"o}, Satu and Manunta, Paolo and Leach, Irene Mateo and McArdle, Wendy L and McKnight, Barbara and Mohlke, Karen L and Mihailov, Evelin and Milani, Lili and Mills, Rebecca and Montasser, May E and Morris, Andrew P and M{\"u}ller, Gabriele and Musk, Arthur W and Narisu, Narisu and Ong, Ken K and Oostra, Ben A and Osmond, Clive and Palotie, Aarno and Pankow, James S and Paternoster, Lavinia and Penninx, Brenda W and Pichler, Irene and Pilia, Maria G and Polasek, Ozren and Pramstaller, Peter P and Raitakari, Olli T and Rankinen, Tuomo and Rao, D C and Rayner, Nigel W and Ribel-Madsen, Rasmus and Rice, Treva K and Richards, Marcus and Ridker, Paul M and Rivadeneira, Fernando and Ryan, Kathy A and Sanna, Serena and Sarzynski, Mark A and Scholtens, Salome and Scott, Robert A and Sebert, Sylvain and Southam, Lorraine and Spars{\o}, Thomas Hempel and Steinthorsdottir, Valgerdur and Stirrups, Kathleen and Stolk, Ronald P and Strauch, Konstantin and Stringham, Heather M and Swertz, Morris A and Swift, Amy J and T{\"o}njes, Anke and Tsafantakis, Emmanouil and van der Most, Peter J and van Vliet-Ostaptchouk, Jana V and Vandenput, Liesbeth and Vartiainen, Erkki and Venturini, Cristina and Verweij, Niek and Viikari, Jorma S and Vitart, Veronique and Vohl, Marie-Claude and Vonk, Judith M and Waeber, G{\'e}rard and Widen, Elisabeth and Willemsen, Gonneke and Wilsgaard, Tom and Winkler, Thomas W and Wright, Alan F and Yerges-Armstrong, Laura M and Hua Zhao, Jing and Zillikens, M Carola and Boomsma, Dorret I and Bouchard, Claude and Chambers, John C and Chasman, Daniel I and Cusi, Daniele and Gansevoort, Ron T and Gieger, Christian and Hansen, Torben and Hicks, Andrew A and Hu, Frank and Hveem, Kristian and Jarvelin, Marjo-Riitta and Kajantie, Eero and Kooner, Jaspal S and Kuh, Diana and Kuusisto, Johanna and Laakso, Markku and Lakka, Timo A and Lehtim{\"a}ki, Terho and Metspalu, Andres and Nj{\o}lstad, Inger and Ohlsson, Claes and Oldehinkel, Albertine J and Palmer, Lyle J and Pedersen, Oluf and Perola, Markus and Peters, Annette and Psaty, Bruce M and Puolijoki, Hannu and Rauramaa, Rainer and Rudan, Igor and Salomaa, Veikko and Schwarz, Peter E H and Shudiner, Alan R and Smit, Jan H and S{\o}rensen, Thorkild I A and Spector, Timothy D and Stefansson, Kari and Stumvoll, Michael and Tremblay, Angelo and Tuomilehto, Jaakko and Uitterlinden, Andr{\'e} G and Uusitupa, Matti and V{\"o}lker, Uwe and Vollenweider, Peter and Wareham, Nicholas J and Watkins, Hugh and Wilson, James F and Zeggini, Eleftheria and Abecasis, Goncalo R and Boehnke, Michael and Borecki, Ingrid B and Deloukas, Panos and van Duijn, Cornelia M and Fox, Caroline and Groop, Leif C and Heid, Iris M and Hunter, David J and Kaplan, Robert C and McCarthy, Mark I and North, Kari E and O{\textquoteright}Connell, Jeffrey R and Schlessinger, David and Thorsteinsdottir, Unnur and Strachan, David P and Frayling, Timothy and Hirschhorn, Joel N and M{\"u}ller-Nurasyid, Martina and Loos, Ruth J F} }