@article {1107, title = {NRXN3 is a novel locus for waist circumference: a genome-wide association study from the CHARGE Consortium.}, journal = {PLoS Genet}, volume = {5}, year = {2009}, month = {2009 Jun}, pages = {e1000539}, abstract = {

Central abdominal fat is a strong risk factor for diabetes and cardiovascular disease. To identify common variants influencing central abdominal fat, we conducted a two-stage genome-wide association analysis for waist circumference (WC). In total, three loci reached genome-wide significance. In stage 1, 31,373 individuals of Caucasian descent from eight cohort studies confirmed the role of FTO and MC4R and identified one novel locus associated with WC in the neurexin 3 gene [NRXN3 (rs10146997, p = 6.4x10(-7))]. The association with NRXN3 was confirmed in stage 2 by combining stage 1 results with those from 38,641 participants in the GIANT consortium (p = 0.009 in GIANT only, p = 5.3x10(-8) for combined analysis, n = 70,014). Mean WC increase per copy of the G allele was 0.0498 z-score units (0.65 cm). This SNP was also associated with body mass index (BMI) [p = 7.4x10(-6), 0.024 z-score units (0.10 kg/m(2)) per copy of the G allele] and the risk of obesity (odds ratio 1.13, 95\% CI 1.07-1.19; p = 3.2x10(-5) per copy of the G allele). The NRXN3 gene has been previously implicated in addiction and reward behavior, lending further evidence that common forms of obesity may be a central nervous system-mediated disorder. Our findings establish that common variants in NRXN3 are associated with WC, BMI, and obesity.

}, keywords = {Aged, Body Mass Index, Cohort Studies, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Nerve Tissue Proteins, Obesity, Polymorphism, Single Nucleotide, Waist Circumference}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1000539}, author = {Heard-Costa, Nancy L and Zillikens, M Carola and Monda, Keri L and Johansson, Asa and Harris, Tamara B and Fu, Mao and Haritunians, Talin and Feitosa, Mary F and Aspelund, Thor and Eiriksdottir, Gudny and Garcia, Melissa and Launer, Lenore J and Smith, Albert V and Mitchell, Braxton D and McArdle, Patrick F and Shuldiner, Alan R and Bielinski, Suzette J and Boerwinkle, Eric and Brancati, Fred and Demerath, Ellen W and Pankow, James S and Arnold, Alice M and Chen, Yii-Der Ida and Glazer, Nicole L and McKnight, Barbara and Psaty, Bruce M and Rotter, Jerome I and Amin, Najaf and Campbell, Harry and Gyllensten, Ulf and Pattaro, Cristian and Pramstaller, Peter P and Rudan, Igor and Struchalin, Maksim and Vitart, Veronique and Gao, Xiaoyi and Kraja, Aldi and Province, Michael A and Zhang, Qunyuan and Atwood, Larry D and Dupuis, Jos{\'e}e and Hirschhorn, Joel N and Jaquish, Cashell E and O{\textquoteright}Donnell, Christopher J and Vasan, Ramachandran S and White, Charles C and Aulchenko, Yurii S and Estrada, Karol and Hofman, Albert and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Witteman, Jacqueline C M and Oostra, Ben A and Kaplan, Robert C and Gudnason, Vilmundur and O{\textquoteright}Connell, Jeffrey R and Borecki, Ingrid B and van Duijn, Cornelia M and Cupples, L Adrienne and Fox, Caroline S and North, Kari E} } @article {1237, title = {Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index.}, journal = {Nat Genet}, volume = {42}, year = {2010}, month = {2010 Nov}, pages = {937-48}, abstract = {

Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and \~{} 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 {\texttimes} 10$^{-}$$^{8}$), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.

}, keywords = {Body Height, Body Mass Index, Body Size, Body Weight, Chromosome Mapping, European Continental Ancestry Group, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Obesity, Polymorphism, Single Nucleotide}, issn = {1546-1718}, doi = {10.1038/ng.686}, author = {Speliotes, Elizabeth K and Willer, Cristen J and Berndt, Sonja I and Monda, Keri L and Thorleifsson, Gudmar and Jackson, Anne U and Lango Allen, Hana and Lindgren, Cecilia M and Luan, Jian{\textquoteright}an and M{\"a}gi, Reedik and Randall, Joshua C and Vedantam, Sailaja and Winkler, Thomas W and Qi, Lu and Workalemahu, Tsegaselassie and Heid, Iris M and Steinthorsdottir, Valgerdur and Stringham, Heather M and Weedon, Michael N and Wheeler, Eleanor and Wood, Andrew R and Ferreira, Teresa and Weyant, Robert J and Segr{\`e}, Ayellet V and Estrada, Karol and Liang, Liming and Nemesh, James and Park, Ju-Hyun and Gustafsson, Stefan and Kilpel{\"a}inen, Tuomas O and Yang, Jian and Bouatia-Naji, Nabila and Esko, T{\~o}nu and Feitosa, Mary F and Kutalik, Zolt{\'a}n and Mangino, Massimo and Raychaudhuri, Soumya and Scherag, Andre and Smith, Albert Vernon and Welch, Ryan and Zhao, Jing Hua and Aben, Katja K and Absher, Devin M and Amin, Najaf and Dixon, Anna L and Fisher, Eva and Glazer, Nicole L and Goddard, Michael E and Heard-Costa, Nancy L and Hoesel, Volker and Hottenga, Jouke-Jan and Johansson, Asa and Johnson, Toby and Ketkar, Shamika and Lamina, Claudia and Li, Shengxu and Moffatt, Miriam F and Myers, Richard H and Narisu, Narisu and Perry, John R B and Peters, Marjolein J and Preuss, Michael and Ripatti, Samuli and Rivadeneira, Fernando and Sandholt, Camilla and Scott, Laura J and Timpson, Nicholas J and Tyrer, Jonathan P and van Wingerden, Sophie and Watanabe, Richard M and White, Charles C and Wiklund, Fredrik and Barlassina, Christina and Chasman, Daniel I and Cooper, Matthew N and Jansson, John-Olov and Lawrence, Robert W and Pellikka, Niina and Prokopenko, Inga and Shi, Jianxin and Thiering, Elisabeth and Alavere, Helene and Alibrandi, Maria T S and Almgren, Peter and Arnold, Alice M and Aspelund, Thor and Atwood, Larry D and Balkau, Beverley and Balmforth, Anthony J and Bennett, Amanda J and Ben-Shlomo, Yoav and Bergman, Richard N and Bergmann, Sven and Biebermann, Heike and Blakemore, Alexandra I F and Boes, Tanja and Bonnycastle, Lori L and Bornstein, Stefan R and Brown, Morris J and Buchanan, Thomas A and Busonero, Fabio and Campbell, Harry and Cappuccio, Francesco P and Cavalcanti-Proen{\c c}a, Christine and Chen, Yii-Der Ida and Chen, Chih-Mei and Chines, Peter S and Clarke, Robert and Coin, Lachlan and Connell, John and Day, Ian N M and den Heijer, Martin and Duan, Jubao and Ebrahim, Shah and Elliott, Paul and Elosua, Roberto and Eiriksdottir, Gudny and Erdos, Michael R and Eriksson, Johan G and Facheris, Maurizio F and Felix, Stephan B and Fischer-Posovszky, Pamela and Folsom, Aaron R and Friedrich, Nele and Freimer, Nelson B and Fu, Mao and Gaget, Stefan and Gejman, Pablo V and Geus, Eco J C and Gieger, Christian and Gjesing, Anette P and Goel, Anuj and Goyette, Philippe and Grallert, Harald and Gr{\"a}ssler, J{\"u}rgen and Greenawalt, Danielle M and Groves, Christopher J and Gudnason, Vilmundur and Guiducci, Candace and Hartikainen, Anna-Liisa and Hassanali, Neelam and Hall, Alistair S and Havulinna, Aki S and Hayward, Caroline and Heath, Andrew C and Hengstenberg, Christian and Hicks, Andrew A and Hinney, Anke and Hofman, Albert and Homuth, Georg and Hui, Jennie and Igl, Wilmar and Iribarren, Carlos and Isomaa, Bo and Jacobs, Kevin B and Jarick, Ivonne and Jewell, Elizabeth and John, Ulrich and J{\o}rgensen, Torben and Jousilahti, Pekka and Jula, Antti and Kaakinen, Marika and Kajantie, Eero and Kaplan, Lee M and Kathiresan, Sekar and Kettunen, Johannes and Kinnunen, Leena and Knowles, Joshua W and Kolcic, Ivana and K{\"o}nig, Inke R and Koskinen, Seppo and Kovacs, Peter and Kuusisto, Johanna and Kraft, Peter and Kval{\o}y, Kirsti and Laitinen, Jaana and Lantieri, Olivier and Lanzani, Chiara and Launer, Lenore J and Lecoeur, C{\'e}cile and Lehtim{\"a}ki, Terho and Lettre, Guillaume and Liu, Jianjun and Lokki, Marja-Liisa and Lorentzon, Mattias and Luben, Robert N and Ludwig, Barbara and Manunta, Paolo and Marek, Diana and Marre, Michel and Martin, Nicholas G and McArdle, Wendy L and McCarthy, Anne and McKnight, Barbara and Meitinger, Thomas and Melander, Olle and Meyre, David and Midthjell, Kristian and Montgomery, Grant W and Morken, Mario A and Morris, Andrew P and Mulic, Rosanda and Ngwa, Julius S and Nelis, Mari and Neville, Matt J and Nyholt, Dale R and O{\textquoteright}Donnell, Christopher J and O{\textquoteright}Rahilly, Stephen and Ong, Ken K and Oostra, Ben and Par{\'e}, Guillaume and Parker, Alex N and Perola, Markus and Pichler, Irene and Pietil{\"a}inen, Kirsi H and Platou, Carl G P and Polasek, Ozren and Pouta, Anneli and Rafelt, Suzanne and Raitakari, Olli and Rayner, Nigel W and Ridderstr{\r a}le, Martin and Rief, Winfried and Ruokonen, Aimo and Robertson, Neil R and Rzehak, Peter and Salomaa, Veikko and Sanders, Alan R and Sandhu, Manjinder S and Sanna, Serena and Saramies, Jouko and Savolainen, Markku J and Scherag, Susann and Schipf, Sabine and Schreiber, Stefan and Schunkert, Heribert and Silander, Kaisa and Sinisalo, Juha and Siscovick, David S and Smit, Jan H and Soranzo, Nicole and Sovio, Ulla and Stephens, Jonathan and Surakka, Ida and Swift, Amy J and Tammesoo, Mari-Liis and Tardif, Jean-Claude and Teder-Laving, Maris and Teslovich, Tanya M and Thompson, John R and Thomson, Brian and T{\"o}njes, Anke and Tuomi, Tiinamaija and van Meurs, Joyce B J and van Ommen, Gert-Jan and Vatin, Vincent and Viikari, Jorma and Visvikis-Siest, Sophie and Vitart, Veronique and Vogel, Carla I G and Voight, Benjamin F and Waite, Lindsay L and Wallaschofski, Henri and Walters, G Bragi and Widen, Elisabeth and Wiegand, Susanna and Wild, Sarah H and Willemsen, Gonneke and Witte, Daniel R and Witteman, Jacqueline C and Xu, Jianfeng and Zhang, Qunyuan and Zgaga, Lina and Ziegler, Andreas and Zitting, Paavo and Beilby, John P and Farooqi, I Sadaf and Hebebrand, Johannes and Huikuri, Heikki V and James, Alan L and K{\"a}h{\"o}nen, Mika and Levinson, Douglas F and Macciardi, Fabio and Nieminen, Markku S and Ohlsson, Claes and Palmer, Lyle J and Ridker, Paul M and Stumvoll, Michael and Beckmann, Jacques S and Boeing, Heiner and Boerwinkle, Eric and Boomsma, Dorret I and Caulfield, Mark J and Chanock, Stephen J and Collins, Francis S and Cupples, L Adrienne and Smith, George Davey and Erdmann, Jeanette and Froguel, Philippe and Gr{\"o}nberg, Henrik and Gyllensten, Ulf and Hall, Per and Hansen, Torben and Harris, Tamara B and Hattersley, Andrew T and Hayes, Richard B and Heinrich, Joachim and Hu, Frank B and Hveem, Kristian and Illig, Thomas and Jarvelin, Marjo-Riitta and Kaprio, Jaakko and Karpe, Fredrik and Khaw, Kay-Tee and Kiemeney, Lambertus A and Krude, Heiko and Laakso, Markku and Lawlor, Debbie A and Metspalu, Andres and Munroe, Patricia B and Ouwehand, Willem H and Pedersen, Oluf and Penninx, Brenda W and Peters, Annette and Pramstaller, Peter P and Quertermous, Thomas and Reinehr, Thomas and Rissanen, Aila and Rudan, Igor and Samani, Nilesh J and Schwarz, Peter E H and Shuldiner, Alan R and Spector, Timothy D and Tuomilehto, Jaakko and Uda, Manuela and Uitterlinden, Andre and Valle, Timo T and Wabitsch, Martin and Waeber, G{\'e}rard and Wareham, Nicholas J and Watkins, Hugh and Wilson, James F and Wright, Alan F and Zillikens, M Carola and Chatterjee, Nilanjan and McCarroll, Steven A and Purcell, Shaun and Schadt, Eric E and Visscher, Peter M and Assimes, Themistocles L and Borecki, Ingrid B and Deloukas, Panos and Fox, Caroline S and Groop, Leif C and Haritunians, Talin and Hunter, David J and Kaplan, Robert C and Mohlke, Karen L and O{\textquoteright}Connell, Jeffrey R and Peltonen, Leena and Schlessinger, David and Strachan, David P and van Duijn, Cornelia M and Wichmann, H-Erich and Frayling, Timothy M and Thorsteinsdottir, Unnur and Abecasis, Goncalo R and Barroso, In{\^e}s and Boehnke, Michael and Stefansson, Kari and North, Kari E and McCarthy, Mark I and Hirschhorn, Joel N and Ingelsson, Erik and Loos, Ruth J F} } @article {1234, title = {Hundreds of variants clustered in genomic loci and biological pathways affect human height.}, journal = {Nature}, volume = {467}, year = {2010}, month = {2010 Oct 14}, pages = {832-8}, abstract = {

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10\% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16\% of phenotypic variation (approximately 20\% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

}, keywords = {Body Height, Chromosomes, Human, Pair 3, Genetic Loci, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Metabolic Networks and Pathways, Multifactorial Inheritance, Phenotype, Polymorphism, Single Nucleotide}, issn = {1476-4687}, doi = {10.1038/nature09410}, author = {Lango Allen, Hana and Estrada, Karol and Lettre, Guillaume and Berndt, Sonja I and Weedon, Michael N and Rivadeneira, Fernando and Willer, Cristen J and Jackson, Anne U and Vedantam, Sailaja and Raychaudhuri, Soumya and Ferreira, Teresa and Wood, Andrew R and Weyant, Robert J and Segr{\`e}, Ayellet V and Speliotes, Elizabeth K and Wheeler, Eleanor and Soranzo, Nicole and Park, Ju-Hyun and Yang, Jian and Gudbjartsson, Daniel and Heard-Costa, Nancy L and Randall, Joshua C and Qi, Lu and Vernon Smith, Albert and M{\"a}gi, Reedik and Pastinen, Tomi and Liang, Liming and Heid, Iris M and Luan, Jian{\textquoteright}an and Thorleifsson, Gudmar and Winkler, Thomas W and Goddard, Michael E and Sin Lo, Ken and Palmer, Cameron and Workalemahu, Tsegaselassie and Aulchenko, Yurii S and Johansson, Asa and Zillikens, M Carola and Feitosa, Mary F and Esko, T{\~o}nu and Johnson, Toby and Ketkar, Shamika and Kraft, Peter and Mangino, Massimo and Prokopenko, Inga and Absher, Devin and Albrecht, Eva and Ernst, Florian and Glazer, Nicole L and Hayward, Caroline and Hottenga, Jouke-Jan and Jacobs, Kevin B and Knowles, Joshua W and Kutalik, Zolt{\'a}n and Monda, Keri L and Polasek, Ozren and Preuss, Michael and Rayner, Nigel W and Robertson, Neil R and Steinthorsdottir, Valgerdur and Tyrer, Jonathan P and Voight, Benjamin F and Wiklund, Fredrik and Xu, Jianfeng and Zhao, Jing Hua and Nyholt, Dale R and Pellikka, Niina and Perola, Markus and Perry, John R B and Surakka, Ida and Tammesoo, Mari-Liis and Altmaier, Elizabeth L and Amin, Najaf and Aspelund, Thor and Bhangale, Tushar and Boucher, Gabrielle and Chasman, Daniel I and Chen, Constance and Coin, Lachlan and Cooper, Matthew N and Dixon, Anna L and Gibson, Quince and Grundberg, Elin and Hao, Ke and Juhani Junttila, M and Kaplan, Lee M and Kettunen, Johannes and K{\"o}nig, Inke R and Kwan, Tony and Lawrence, Robert W and Levinson, Douglas F and Lorentzon, Mattias and McKnight, Barbara and Morris, Andrew P and M{\"u}ller, Martina and Suh Ngwa, Julius and Purcell, Shaun and Rafelt, Suzanne and Salem, Rany M and Salvi, Erika and Sanna, Serena and Shi, Jianxin and Sovio, Ulla and Thompson, John R and Turchin, Michael C and Vandenput, Liesbeth and Verlaan, Dominique J and Vitart, Veronique and White, Charles C and Ziegler, Andreas and Almgren, Peter and Balmforth, Anthony J and Campbell, Harry and Citterio, Lorena and De Grandi, Alessandro and Dominiczak, Anna and Duan, Jubao and Elliott, Paul and Elosua, Roberto and Eriksson, Johan G and Freimer, Nelson B and Geus, Eco J C and Glorioso, Nicola and Haiqing, Shen and Hartikainen, Anna-Liisa and Havulinna, Aki S and Hicks, Andrew A and Hui, Jennie and Igl, Wilmar and Illig, Thomas and Jula, Antti and Kajantie, Eero and Kilpel{\"a}inen, Tuomas O and Koiranen, Markku and Kolcic, Ivana and Koskinen, Seppo and Kovacs, Peter and Laitinen, Jaana and Liu, Jianjun and Lokki, Marja-Liisa and Marusic, Ana and Maschio, Andrea and Meitinger, Thomas and Mulas, Antonella and Par{\'e}, Guillaume and Parker, Alex N and Peden, John F and Petersmann, Astrid and Pichler, Irene and Pietil{\"a}inen, Kirsi H and Pouta, Anneli and Ridderstr{\r a}le, Martin and Rotter, Jerome I and Sambrook, Jennifer G and Sanders, Alan R and Schmidt, Carsten Oliver and Sinisalo, Juha and Smit, Jan H and Stringham, Heather M and Bragi Walters, G and Widen, Elisabeth and Wild, Sarah H and Willemsen, Gonneke and Zagato, Laura and Zgaga, Lina and Zitting, Paavo and Alavere, Helene and Farrall, Martin and McArdle, Wendy L and Nelis, Mari and Peters, Marjolein J and Ripatti, Samuli and van Meurs, Joyce B J and Aben, Katja K and Ardlie, Kristin G and Beckmann, Jacques S and Beilby, John P and Bergman, Richard N and Bergmann, Sven and Collins, Francis S and Cusi, Daniele and den Heijer, Martin and Eiriksdottir, Gudny and Gejman, Pablo V and Hall, Alistair S and Hamsten, Anders and Huikuri, Heikki V and Iribarren, Carlos and K{\"a}h{\"o}nen, Mika and Kaprio, Jaakko and Kathiresan, Sekar and Kiemeney, Lambertus and Kocher, Thomas and Launer, Lenore J and Lehtim{\"a}ki, Terho and Melander, Olle and Mosley, Tom H and Musk, Arthur W and Nieminen, Markku S and O{\textquoteright}Donnell, Christopher J and Ohlsson, Claes and Oostra, Ben and Palmer, Lyle J and Raitakari, Olli and Ridker, Paul M and Rioux, John D and Rissanen, Aila and Rivolta, Carlo and Schunkert, Heribert and Shuldiner, Alan R and Siscovick, David S and Stumvoll, Michael and T{\"o}njes, Anke and Tuomilehto, Jaakko and van Ommen, Gert-Jan and Viikari, Jorma and Heath, Andrew C and Martin, Nicholas G and Montgomery, Grant W and Province, Michael A and Kayser, Manfred and Arnold, Alice M and Atwood, Larry D and Boerwinkle, Eric and Chanock, Stephen J and Deloukas, Panos and Gieger, Christian and Gr{\"o}nberg, Henrik and Hall, Per and Hattersley, Andrew T and Hengstenberg, Christian and Hoffman, Wolfgang and Lathrop, G Mark and Salomaa, Veikko and Schreiber, Stefan and Uda, Manuela and Waterworth, Dawn and Wright, Alan F and Assimes, Themistocles L and Barroso, In{\^e}s and Hofman, Albert and Mohlke, Karen L and Boomsma, Dorret I and Caulfield, Mark J and Cupples, L Adrienne and Erdmann, Jeanette and Fox, Caroline S and Gudnason, Vilmundur and Gyllensten, Ulf and Harris, Tamara B and Hayes, Richard B and Jarvelin, Marjo-Riitta and Mooser, Vincent and Munroe, Patricia B and Ouwehand, Willem H and Penninx, Brenda W and Pramstaller, Peter P and Quertermous, Thomas and Rudan, Igor and Samani, Nilesh J and Spector, Timothy D and V{\"o}lzke, Henry and Watkins, Hugh and Wilson, James F and Groop, Leif C and Haritunians, Talin and Hu, Frank B and Kaplan, Robert C and Metspalu, Andres and North, Kari E and Schlessinger, David and Wareham, Nicholas J and Hunter, David J and O{\textquoteright}Connell, Jeffrey R and Strachan, David P and Wichmann, H-Erich and Borecki, Ingrid B and van Duijn, Cornelia M and Schadt, Eric E and Thorsteinsdottir, Unnur and Peltonen, Leena and Uitterlinden, Andr{\'e} G and Visscher, Peter M and Chatterjee, Nilanjan and Loos, Ruth J F and Boehnke, Michael and McCarthy, Mark I and Ingelsson, Erik and Lindgren, Cecilia M and Abecasis, Goncalo R and Stefansson, Kari and Frayling, Timothy M and Hirschhorn, Joel N} } @article {1236, title = {Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution.}, journal = {Nat Genet}, volume = {42}, year = {2010}, month = {2010 Nov}, pages = {949-60}, abstract = {

Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 {\texttimes} 10$^{-}$$^{9}$ to P = 1.8 {\texttimes} 10$^{-}$$^{4}$$^{0}$) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 {\texttimes} 10$^{-}${\textthreesuperior} to P = 1.2 {\texttimes} 10$^{-}${\textonesuperior}{\textthreesuperior}). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.

}, keywords = {Adipose Tissue, Age Factors, Chromosome Mapping, Female, Genome, Human, Genome-Wide Association Study, Humans, Male, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Sex Characteristics, Waist-Hip Ratio}, issn = {1546-1718}, doi = {10.1038/ng.685}, author = {Heid, Iris M and Jackson, Anne U and Randall, Joshua C and Winkler, Thomas W and Qi, Lu and Steinthorsdottir, Valgerdur and Thorleifsson, Gudmar and Zillikens, M Carola and Speliotes, Elizabeth K and M{\"a}gi, Reedik and Workalemahu, Tsegaselassie and White, Charles C and Bouatia-Naji, Nabila and Harris, Tamara B and Berndt, Sonja I and Ingelsson, Erik and Willer, Cristen J and Weedon, Michael N and Luan, Jian{\textquoteright}an and Vedantam, Sailaja and Esko, T{\~o}nu and Kilpel{\"a}inen, Tuomas O and Kutalik, Zolt{\'a}n and Li, Shengxu and Monda, Keri L and Dixon, Anna L and Holmes, Christopher C and Kaplan, Lee M and Liang, Liming and Min, Josine L and Moffatt, Miriam F and Molony, Cliona and Nicholson, George and Schadt, Eric E and Zondervan, Krina T and Feitosa, Mary F and Ferreira, Teresa and Lango Allen, Hana and Weyant, Robert J and Wheeler, Eleanor and Wood, Andrew R and Estrada, Karol and Goddard, Michael E and Lettre, Guillaume and Mangino, Massimo and Nyholt, Dale R and Purcell, Shaun and Smith, Albert Vernon and Visscher, Peter M and Yang, Jian and McCarroll, Steven A and Nemesh, James and Voight, Benjamin F and Absher, Devin and Amin, Najaf and Aspelund, Thor and Coin, Lachlan and Glazer, Nicole L and Hayward, Caroline and Heard-Costa, Nancy L and Hottenga, Jouke-Jan and Johansson, Asa and Johnson, Toby and Kaakinen, Marika and Kapur, Karen and Ketkar, Shamika and Knowles, Joshua W and Kraft, Peter and Kraja, Aldi T and Lamina, Claudia and Leitzmann, Michael F and McKnight, Barbara and Morris, Andrew P and Ong, Ken K and Perry, John R B and Peters, Marjolein J and Polasek, Ozren and Prokopenko, Inga and Rayner, Nigel W and Ripatti, Samuli and Rivadeneira, Fernando and Robertson, Neil R and Sanna, Serena and Sovio, Ulla and Surakka, Ida and Teumer, Alexander and van Wingerden, Sophie and Vitart, Veronique and Zhao, Jing Hua and Cavalcanti-Proen{\c c}a, Christine and Chines, Peter S and Fisher, Eva and Kulzer, Jennifer R and Lecoeur, C{\'e}cile and Narisu, Narisu and Sandholt, Camilla and Scott, Laura J and Silander, Kaisa and Stark, Klaus and Tammesoo, Mari-Liis and Teslovich, Tanya M and Timpson, Nicholas John and Watanabe, Richard M and Welch, Ryan and Chasman, Daniel I and Cooper, Matthew N and Jansson, John-Olov and Kettunen, Johannes and Lawrence, Robert W and Pellikka, Niina and Perola, Markus and Vandenput, Liesbeth and Alavere, Helene and Almgren, Peter and Atwood, Larry D and Bennett, Amanda J and Biffar, Reiner and Bonnycastle, Lori L and Bornstein, Stefan R and Buchanan, Thomas A and Campbell, Harry and Day, Ian N M and Dei, Mariano and D{\"o}rr, Marcus and Elliott, Paul and Erdos, Michael R and Eriksson, Johan G and Freimer, Nelson B and Fu, Mao and Gaget, Stefan and Geus, Eco J C and Gjesing, Anette P and Grallert, Harald and Gr{\"a}ssler, J{\"u}rgen and Groves, Christopher J and Guiducci, Candace and Hartikainen, Anna-Liisa and Hassanali, Neelam and Havulinna, Aki S and Herzig, Karl-Heinz and Hicks, Andrew A and Hui, Jennie and Igl, Wilmar and Jousilahti, Pekka and Jula, Antti and Kajantie, Eero and Kinnunen, Leena and Kolcic, Ivana and Koskinen, Seppo and Kovacs, Peter and Kroemer, Heyo K and Krzelj, Vjekoslav and Kuusisto, Johanna and Kvaloy, Kirsti and Laitinen, Jaana and Lantieri, Olivier and Lathrop, G Mark and Lokki, Marja-Liisa and Luben, Robert N and Ludwig, Barbara and McArdle, Wendy L and McCarthy, Anne and Morken, Mario A and Nelis, Mari and Neville, Matt J and Par{\'e}, Guillaume and Parker, Alex N and Peden, John F and Pichler, Irene and Pietil{\"a}inen, Kirsi H and Platou, Carl G P and Pouta, Anneli and Ridderstr{\r a}le, Martin and Samani, Nilesh J and Saramies, Jouko and Sinisalo, Juha and Smit, Jan H and Strawbridge, Rona J and Stringham, Heather M and Swift, Amy J and Teder-Laving, Maris and Thomson, Brian and Usala, Gianluca and van Meurs, Joyce B J and van Ommen, Gert-Jan and Vatin, Vincent and Volpato, Claudia B and Wallaschofski, Henri and Walters, G Bragi and Widen, Elisabeth and Wild, Sarah H and Willemsen, Gonneke and Witte, Daniel R and Zgaga, Lina and Zitting, Paavo and Beilby, John P and James, Alan L and K{\"a}h{\"o}nen, Mika and Lehtim{\"a}ki, Terho and Nieminen, Markku S and Ohlsson, Claes and Palmer, Lyle J and Raitakari, Olli and Ridker, Paul M and Stumvoll, Michael and T{\"o}njes, Anke and Viikari, Jorma and Balkau, Beverley and Ben-Shlomo, Yoav and Bergman, Richard N and Boeing, Heiner and Smith, George Davey and Ebrahim, Shah and Froguel, Philippe and Hansen, Torben and Hengstenberg, Christian and Hveem, Kristian and Isomaa, Bo and J{\o}rgensen, Torben and Karpe, Fredrik and Khaw, Kay-Tee and Laakso, Markku and Lawlor, Debbie A and Marre, Michel and Meitinger, Thomas and Metspalu, Andres and Midthjell, Kristian and Pedersen, Oluf and Salomaa, Veikko and Schwarz, Peter E H and Tuomi, Tiinamaija and Tuomilehto, Jaakko and Valle, Timo T and Wareham, Nicholas J and Arnold, Alice M and Beckmann, Jacques S and Bergmann, Sven and Boerwinkle, Eric and Boomsma, Dorret I and Caulfield, Mark J and Collins, Francis S and Eiriksdottir, Gudny and Gudnason, Vilmundur and Gyllensten, Ulf and Hamsten, Anders and Hattersley, Andrew T and Hofman, Albert and Hu, Frank B and Illig, Thomas and Iribarren, Carlos and Jarvelin, Marjo-Riitta and Kao, W H Linda and Kaprio, Jaakko and Launer, Lenore J and Munroe, Patricia B and Oostra, Ben and Penninx, Brenda W and Pramstaller, Peter P and Psaty, Bruce M and Quertermous, Thomas and Rissanen, Aila and Rudan, Igor and Shuldiner, Alan R and Soranzo, Nicole and Spector, Timothy D and Syv{\"a}nen, Ann-Christine and Uda, Manuela and Uitterlinden, Andre and V{\"o}lzke, Henry and Vollenweider, Peter and Wilson, James F and Witteman, Jacqueline C and Wright, Alan F and Abecasis, Goncalo R and Boehnke, Michael and Borecki, Ingrid B and Deloukas, Panos and Frayling, Timothy M and Groop, Leif C and Haritunians, Talin and Hunter, David J and Kaplan, Robert C and North, Kari E and O{\textquoteright}Connell, Jeffrey R and Peltonen, Leena and Schlessinger, David and Strachan, David P and Hirschhorn, Joel N and Assimes, Themistocles L and Wichmann, H-Erich and Thorsteinsdottir, Unnur and van Duijn, Cornelia M and Stefansson, Kari and Cupples, L Adrienne and Loos, Ruth J F and Barroso, In{\^e}s and McCarthy, Mark I and Fox, Caroline S and Mohlke, Karen L and Lindgren, Cecilia M} } @article {6175, title = {FTO genotype is associated with phenotypic variability of body mass index.}, journal = {Nature}, volume = {490}, year = {2012}, month = {2012 Oct 11}, pages = {267-72}, abstract = {

There is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using \~{}170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7\%, corresponding to a difference of \~{}0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI, possibly mediated by DNA methylation. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.

}, keywords = {Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Body Height, Body Mass Index, Co-Repressor Proteins, Female, Genetic Variation, Genome-Wide Association Study, Humans, Male, Nerve Tissue Proteins, Phenotype, Polymorphism, Single Nucleotide, Proteins, Repressor Proteins}, issn = {1476-4687}, doi = {10.1038/nature11401}, author = {Yang, Jian and Loos, Ruth J F and Powell, Joseph E and Medland, Sarah E and Speliotes, Elizabeth K and Chasman, Daniel I and Rose, Lynda M and Thorleifsson, Gudmar and Steinthorsdottir, Valgerdur and M{\"a}gi, Reedik and Waite, Lindsay and Smith, Albert Vernon and Yerges-Armstrong, Laura M and Monda, Keri L and Hadley, David and Mahajan, Anubha and Li, Guo and Kapur, Karen and Vitart, Veronique and Huffman, Jennifer E and Wang, Sophie R and Palmer, Cameron and Esko, T{\~o}nu and Fischer, Krista and Zhao, Jing Hua and Demirkan, Ayse and Isaacs, Aaron and Feitosa, Mary F and Luan, Jian{\textquoteright}an and Heard-Costa, Nancy L and White, Charles and Jackson, Anne U and Preuss, Michael and Ziegler, Andreas and Eriksson, Joel and Kutalik, Zolt{\'a}n and Frau, Francesca and Nolte, Ilja M and van Vliet-Ostaptchouk, Jana V and Hottenga, Jouke-Jan and Jacobs, Kevin B and Verweij, Niek and Goel, Anuj and Medina-G{\'o}mez, Carolina and Estrada, Karol and Bragg-Gresham, Jennifer Lynn and Sanna, Serena and Sidore, Carlo and Tyrer, Jonathan and Teumer, Alexander and Prokopenko, Inga and Mangino, Massimo and Lindgren, Cecilia M and Assimes, Themistocles L and Shuldiner, Alan R and Hui, Jennie and Beilby, John P and McArdle, Wendy L and Hall, Per and Haritunians, Talin and Zgaga, Lina and Kolcic, Ivana and Polasek, Ozren and Zemunik, Tatijana and Oostra, Ben A and Junttila, M Juhani and Gr{\"o}nberg, Henrik and Schreiber, Stefan and Peters, Annette and Hicks, Andrew A and Stephens, Jonathan and Foad, Nicola S and Laitinen, Jaana and Pouta, Anneli and Kaakinen, Marika and Willemsen, Gonneke and Vink, Jacqueline M and Wild, Sarah H and Navis, Gerjan and Asselbergs, Folkert W and Homuth, Georg and John, Ulrich and Iribarren, Carlos and Harris, Tamara and Launer, Lenore and Gudnason, Vilmundur and O{\textquoteright}Connell, Jeffrey R and Boerwinkle, Eric and Cadby, Gemma and Palmer, Lyle J and James, Alan L and Musk, Arthur W and Ingelsson, Erik and Psaty, Bruce M and Beckmann, Jacques S and Waeber, G{\'e}rard and Vollenweider, Peter and Hayward, Caroline and Wright, Alan F and Rudan, Igor and Groop, Leif C and Metspalu, Andres and Khaw, Kay Tee and van Duijn, Cornelia M and Borecki, Ingrid B and Province, Michael A and Wareham, Nicholas J and Tardif, Jean-Claude and Huikuri, Heikki V and Cupples, L Adrienne and Atwood, Larry D and Fox, Caroline S and Boehnke, Michael and Collins, Francis S and Mohlke, Karen L and Erdmann, Jeanette and Schunkert, Heribert and Hengstenberg, Christian and Stark, Klaus and Lorentzon, Mattias and Ohlsson, Claes and Cusi, Daniele and Staessen, Jan A and van der Klauw, Melanie M and Pramstaller, Peter P and Kathiresan, Sekar and Jolley, Jennifer D and Ripatti, Samuli and Jarvelin, Marjo-Riitta and de Geus, Eco J C and Boomsma, Dorret I and Penninx, Brenda and Wilson, James F and Campbell, Harry and Chanock, Stephen J and van der Harst, Pim and Hamsten, Anders and Watkins, Hugh and Hofman, Albert and Witteman, Jacqueline C and Zillikens, M Carola and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and Zillikens, M Carola and Kiemeney, Lambertus A and Vermeulen, Sita H and Abecasis, Goncalo R and Schlessinger, David and Schipf, Sabine and Stumvoll, Michael and T{\"o}njes, Anke and Spector, Tim D and North, Kari E and Lettre, Guillaume and McCarthy, Mark I and Berndt, Sonja I and Heath, Andrew C and Madden, Pamela A F and Nyholt, Dale R and Montgomery, Grant W and Martin, Nicholas G and McKnight, Barbara and Strachan, David P and Hill, William G and Snieder, Harold and Ridker, Paul M and Thorsteinsdottir, Unnur and Stefansson, Kari and Frayling, Timothy M and Hirschhorn, Joel N and Goddard, Michael E and Visscher, Peter M} } @article {6152, title = {Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture.}, journal = {Nat Genet}, volume = {45}, year = {2013}, month = {2013 May}, pages = {501-12}, abstract = {

Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.

}, keywords = {Anthropometry, Body Height, Body Mass Index, Case-Control Studies, European Continental Ancestry Group, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Meta-Analysis as Topic, Obesity, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Waist-Hip Ratio}, issn = {1546-1718}, doi = {10.1038/ng.2606}, author = {Berndt, Sonja I and Gustafsson, Stefan and M{\"a}gi, Reedik and Ganna, Andrea and Wheeler, Eleanor and Feitosa, Mary F and Justice, Anne E and Monda, Keri L and Croteau-Chonka, Damien C and Day, Felix R and Esko, T{\~o}nu and Fall, Tove and Ferreira, Teresa and Gentilini, Davide and Jackson, Anne U and Luan, Jian{\textquoteright}an and Randall, Joshua C and Vedantam, Sailaja and Willer, Cristen J and Winkler, Thomas W and Wood, Andrew R and Workalemahu, Tsegaselassie and Hu, Yi-Juan and Lee, Sang Hong and Liang, Liming and Lin, Dan-Yu and Min, Josine L and Neale, Benjamin M and Thorleifsson, Gudmar and Yang, Jian and Albrecht, Eva and Amin, Najaf and Bragg-Gresham, Jennifer L and Cadby, Gemma and den Heijer, Martin and Eklund, Niina and Fischer, Krista and Goel, Anuj and Hottenga, Jouke-Jan and Huffman, Jennifer E and Jarick, Ivonne and Johansson, Asa and Johnson, Toby and Kanoni, Stavroula and Kleber, Marcus E and K{\"o}nig, Inke R and Kristiansson, Kati and Kutalik, Zolt{\'a}n and Lamina, Claudia and Lecoeur, C{\'e}cile and Li, Guo and Mangino, Massimo and McArdle, Wendy L and Medina-G{\'o}mez, Carolina and M{\"u}ller-Nurasyid, Martina and Ngwa, Julius S and Nolte, Ilja M and Paternoster, Lavinia and Pechlivanis, Sonali and Perola, Markus and Peters, Marjolein J and Preuss, Michael and Rose, Lynda M and Shi, Jianxin and Shungin, Dmitry and Smith, Albert Vernon and Strawbridge, Rona J and Surakka, Ida and Teumer, Alexander and Trip, Mieke D and Tyrer, Jonathan and van Vliet-Ostaptchouk, Jana V and Vandenput, Liesbeth and Waite, Lindsay L and Zhao, Jing Hua and Absher, Devin and Asselbergs, Folkert W and Atalay, Mustafa and Attwood, Antony P and Balmforth, Anthony J and Basart, Hanneke and Beilby, John and Bonnycastle, Lori L and Brambilla, Paolo and Bruinenberg, Marcel and Campbell, Harry and Chasman, Daniel I and Chines, Peter S and Collins, Francis S and Connell, John M and Cookson, William O and de Faire, Ulf and de Vegt, Femmie and Dei, Mariano and Dimitriou, Maria and Edkins, Sarah and Estrada, Karol and Evans, David M and Farrall, Martin and Ferrario, Marco M and Ferrieres, Jean and Franke, Lude and Frau, Francesca and Gejman, Pablo V and Grallert, Harald and Gr{\"o}nberg, Henrik and Gudnason, Vilmundur and Hall, Alistair S and Hall, Per and Hartikainen, Anna-Liisa and Hayward, Caroline and Heard-Costa, Nancy L and Heath, Andrew C and Hebebrand, Johannes and Homuth, Georg and Hu, Frank B and Hunt, Sarah E and Hypp{\"o}nen, Elina and Iribarren, Carlos and Jacobs, Kevin B and Jansson, John-Olov and Jula, Antti and K{\"a}h{\"o}nen, Mika and Kathiresan, Sekar and Kee, Frank and Khaw, Kay-Tee and Kivimaki, Mika and Koenig, Wolfgang and Kraja, Aldi T and Kumari, Meena and Kuulasmaa, Kari and Kuusisto, Johanna and Laitinen, Jaana H and Lakka, Timo A and Langenberg, Claudia and Launer, Lenore J and Lind, Lars and Lindstr{\"o}m, Jaana and Liu, Jianjun and Liuzzi, Antonio and Lokki, Marja-Liisa and Lorentzon, Mattias and Madden, Pamela A and Magnusson, Patrik K and Manunta, Paolo and Marek, Diana and M{\"a}rz, Winfried and Mateo Leach, Irene and McKnight, Barbara and Medland, Sarah E and Mihailov, Evelin and Milani, Lili and Montgomery, Grant W and Mooser, Vincent and M{\"u}hleisen, Thomas W and Munroe, Patricia B and Musk, Arthur W and Narisu, Narisu and Navis, Gerjan and Nicholson, George and Nohr, Ellen A and Ong, Ken K and Oostra, Ben A and Palmer, Colin N A and Palotie, Aarno and Peden, John F and Pedersen, Nancy and Peters, Annette and Polasek, Ozren and Pouta, Anneli and Pramstaller, Peter P and Prokopenko, Inga and P{\"u}tter, Carolin and Radhakrishnan, Aparna and Raitakari, Olli and Rendon, Augusto and Rivadeneira, Fernando and Rudan, Igor and Saaristo, Timo E and Sambrook, Jennifer G and Sanders, Alan R and Sanna, Serena and Saramies, Jouko and Schipf, Sabine and Schreiber, Stefan and Schunkert, Heribert and Shin, So-Youn and Signorini, Stefano and Sinisalo, Juha and Skrobek, Boris and Soranzo, Nicole and Stan{\v c}{\'a}kov{\'a}, Alena and Stark, Klaus and Stephens, Jonathan C and Stirrups, Kathleen and Stolk, Ronald P and Stumvoll, Michael and Swift, Amy J and Theodoraki, Eirini V and Thorand, Barbara and Tr{\'e}gou{\"e}t, David-Alexandre and Tremoli, Elena and van der Klauw, Melanie M and van Meurs, Joyce B J and Vermeulen, Sita H and Viikari, Jorma and Virtamo, Jarmo and Vitart, Veronique and Waeber, G{\'e}rard and Wang, Zhaoming and Widen, Elisabeth and Wild, Sarah H and Willemsen, Gonneke and Winkelmann, Bernhard R and Witteman, Jacqueline C M and Wolffenbuttel, Bruce H R and Wong, Andrew and Wright, Alan F and Zillikens, M Carola and Amouyel, Philippe and Boehm, Bernhard O and Boerwinkle, Eric and Boomsma, Dorret I and Caulfield, Mark J and Chanock, Stephen J and Cupples, L Adrienne and Cusi, Daniele and Dedoussis, George V and Erdmann, Jeanette and Eriksson, Johan G and Franks, Paul W and Froguel, Philippe and Gieger, Christian and Gyllensten, Ulf and Hamsten, Anders and Harris, Tamara B and Hengstenberg, Christian and Hicks, Andrew A and Hingorani, Aroon and Hinney, Anke and Hofman, Albert and Hovingh, Kees G and Hveem, Kristian and Illig, Thomas and Jarvelin, Marjo-Riitta and J{\"o}ckel, Karl-Heinz and Keinanen-Kiukaanniemi, Sirkka M and Kiemeney, Lambertus A and Kuh, Diana and Laakso, Markku and Lehtim{\"a}ki, Terho and Levinson, Douglas F and Martin, Nicholas G and Metspalu, Andres and Morris, Andrew D and Nieminen, Markku S and Nj{\o}lstad, Inger and Ohlsson, Claes and Oldehinkel, Albertine J and Ouwehand, Willem H and Palmer, Lyle J and Penninx, Brenda and Power, Chris and Province, Michael A and Psaty, Bruce M and Qi, Lu and Rauramaa, Rainer and Ridker, Paul M and Ripatti, Samuli and Salomaa, Veikko and Samani, Nilesh J and Snieder, Harold and S{\o}rensen, Thorkild I A and Spector, Timothy D and Stefansson, Kari and T{\"o}njes, Anke and Tuomilehto, Jaakko and Uitterlinden, Andr{\'e} G and Uusitupa, Matti and van der Harst, Pim and Vollenweider, Peter and Wallaschofski, Henri and Wareham, Nicholas J and Watkins, Hugh and Wichmann, H-Erich and Wilson, James F and Abecasis, Goncalo R and Assimes, Themistocles L and Barroso, In{\^e}s and Boehnke, Michael and Borecki, Ingrid B and Deloukas, Panos and Fox, Caroline S and Frayling, Timothy and Groop, Leif C and Haritunian, Talin and Heid, Iris M and Hunter, David and Kaplan, Robert C and Karpe, Fredrik and Moffatt, Miriam F and Mohlke, Karen L and O{\textquoteright}Connell, Jeffrey R and Pawitan, Yudi and Schadt, Eric E and Schlessinger, David and Steinthorsdottir, Valgerdur and Strachan, David P and Thorsteinsdottir, Unnur and van Duijn, Cornelia M and Visscher, Peter M and Di Blasio, Anna Maria and Hirschhorn, Joel N and Lindgren, Cecilia M and Morris, Andrew P and Meyre, David and Scherag, Andre and McCarthy, Mark I and Speliotes, Elizabeth K and North, Kari E and Loos, Ruth J F and Ingelsson, Erik} } @article {6028, title = {Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits.}, journal = {PLoS Genet}, volume = {9}, year = {2013}, month = {2013 Jun}, pages = {e1003500}, abstract = {

Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5\%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5{\texttimes}10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.

}, keywords = {Anthropometry, Body Height, Body Mass Index, Body Weight, Body Weights and Measures, Female, Genetic Loci, Genome, Human, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide, Sex Characteristics, Waist Circumference, Waist-Hip Ratio}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1003500}, author = {Randall, Joshua C and Winkler, Thomas W and Kutalik, Zolt{\'a}n and Berndt, Sonja I and Jackson, Anne U and Monda, Keri L and Kilpel{\"a}inen, Tuomas O and Esko, T{\~o}nu and M{\"a}gi, Reedik and Li, Shengxu and Workalemahu, Tsegaselassie and Feitosa, Mary F and Croteau-Chonka, Damien C and Day, Felix R and Fall, Tove and Ferreira, Teresa and Gustafsson, Stefan and Locke, Adam E and Mathieson, Iain and Scherag, Andre and Vedantam, Sailaja and Wood, Andrew R and Liang, Liming and Steinthorsdottir, Valgerdur and Thorleifsson, Gudmar and Dermitzakis, Emmanouil T and Dimas, Antigone S and Karpe, Fredrik and Min, Josine L and Nicholson, George and Clegg, Deborah J and Person, Thomas and Krohn, Jon P and Bauer, Sabrina and Buechler, Christa and Eisinger, Kristina and Bonnefond, Am{\'e}lie and Froguel, Philippe and Hottenga, Jouke-Jan and Prokopenko, Inga and Waite, Lindsay L and Harris, Tamara B and Smith, Albert Vernon and Shuldiner, Alan R and McArdle, Wendy L and Caulfield, Mark J and Munroe, Patricia B and Gr{\"o}nberg, Henrik and Chen, Yii-Der Ida and Li, Guo and Beckmann, Jacques S and Johnson, Toby and Thorsteinsdottir, Unnur and Teder-Laving, Maris and Khaw, Kay-Tee and Wareham, Nicholas J and Zhao, Jing Hua and Amin, Najaf and Oostra, Ben A and Kraja, Aldi T and Province, Michael A and Cupples, L Adrienne and Heard-Costa, Nancy L and Kaprio, Jaakko and Ripatti, Samuli and Surakka, Ida and Collins, Francis S and Saramies, Jouko and Tuomilehto, Jaakko and Jula, Antti and Salomaa, Veikko and Erdmann, Jeanette and Hengstenberg, Christian and Loley, Christina and Schunkert, Heribert and Lamina, Claudia and Wichmann, H Erich and Albrecht, Eva and Gieger, Christian and Hicks, Andrew A and Johansson, Asa and Pramstaller, Peter P and Kathiresan, Sekar and Speliotes, Elizabeth K and Penninx, Brenda and Hartikainen, Anna-Liisa and Jarvelin, Marjo-Riitta and Gyllensten, Ulf and Boomsma, Dorret I and Campbell, Harry and Wilson, James F and Chanock, Stephen J and Farrall, Martin and Goel, Anuj and Medina-G{\'o}mez, Carolina and Rivadeneira, Fernando and Estrada, Karol and Uitterlinden, Andr{\'e} G and Hofman, Albert and Zillikens, M Carola and den Heijer, Martin and Kiemeney, Lambertus A and Maschio, Andrea and Hall, Per and Tyrer, Jonathan and Teumer, Alexander and V{\"o}lzke, Henry and Kovacs, Peter and T{\"o}njes, Anke and Mangino, Massimo and Spector, Tim D and Hayward, Caroline and Rudan, Igor and Hall, Alistair S and Samani, Nilesh J and Attwood, Antony Paul and Sambrook, Jennifer G and Hung, Joseph and Palmer, Lyle J and Lokki, Marja-Liisa and Sinisalo, Juha and Boucher, Gabrielle and Huikuri, Heikki and Lorentzon, Mattias and Ohlsson, Claes and Eklund, Niina and Eriksson, Johan G and Barlassina, Cristina and Rivolta, Carlo and Nolte, Ilja M and Snieder, Harold and van der Klauw, Melanie M and van Vliet-Ostaptchouk, Jana V and Gejman, Pablo V and Shi, Jianxin and Jacobs, Kevin B and Wang, Zhaoming and Bakker, Stephan J L and Mateo Leach, Irene and Navis, Gerjan and van der Harst, Pim and Martin, Nicholas G and Medland, Sarah E and Montgomery, Grant W and Yang, Jian and Chasman, Daniel I and Ridker, Paul M and Rose, Lynda M and Lehtim{\"a}ki, Terho and Raitakari, Olli and Absher, Devin and Iribarren, Carlos and Basart, Hanneke and Hovingh, Kees G and Hypp{\"o}nen, Elina and Power, Chris and Anderson, Denise and Beilby, John P and Hui, Jennie and Jolley, Jennifer and Sager, Hendrik and Bornstein, Stefan R and Schwarz, Peter E H and Kristiansson, Kati and Perola, Markus and Lindstr{\"o}m, Jaana and Swift, Amy J and Uusitupa, Matti and Atalay, Mustafa and Lakka, Timo A and Rauramaa, Rainer and Bolton, Jennifer L and Fowkes, Gerry and Fraser, Ross M and Price, Jackie F and Fischer, Krista and Krjut{\r a} Kov, Kaarel and Metspalu, Andres and Mihailov, Evelin and Langenberg, Claudia and Luan, Jian{\textquoteright}an and Ong, Ken K and Chines, Peter S and Keinanen-Kiukaanniemi, Sirkka M and Saaristo, Timo E and Edkins, Sarah and Franks, Paul W and Hallmans, G{\"o}ran and Shungin, Dmitry and Morris, Andrew David and Palmer, Colin N A and Erbel, Raimund and Moebus, Susanne and N{\"o}then, Markus M and Pechlivanis, Sonali and Hveem, Kristian and Narisu, Narisu and Hamsten, Anders and Humphries, Steve E and Strawbridge, Rona J and Tremoli, Elena and Grallert, Harald and Thorand, Barbara and Illig, Thomas and Koenig, Wolfgang and M{\"u}ller-Nurasyid, Martina and Peters, Annette and Boehm, Bernhard O and Kleber, Marcus E and M{\"a}rz, Winfried and Winkelmann, Bernhard R and Kuusisto, Johanna and Laakso, Markku and Arveiler, Dominique and Cesana, Giancarlo and Kuulasmaa, Kari and Virtamo, Jarmo and Yarnell, John W G and Kuh, Diana and Wong, Andrew and Lind, Lars and de Faire, Ulf and Gigante, Bruna and Magnusson, Patrik K E and Pedersen, Nancy L and Dedoussis, George and Dimitriou, Maria and Kolovou, Genovefa and Kanoni, Stavroula and Stirrups, Kathleen and Bonnycastle, Lori L and Nj{\o}lstad, Inger and Wilsgaard, Tom and Ganna, Andrea and Rehnberg, Emil and Hingorani, Aroon and Kivimaki, Mika and Kumari, Meena and Assimes, Themistocles L and Barroso, In{\^e}s and Boehnke, Michael and Borecki, Ingrid B and Deloukas, Panos and Fox, Caroline S and Frayling, Timothy and Groop, Leif C and Haritunians, Talin and Hunter, David and Ingelsson, Erik and Kaplan, Robert and Mohlke, Karen L and O{\textquoteright}Connell, Jeffrey R and Schlessinger, David and Strachan, David P and Stefansson, Kari and van Duijn, Cornelia M and Abecasis, Goncalo R and McCarthy, Mark I and Hirschhorn, Joel N and Qi, Lu and Loos, Ruth J F and Lindgren, Cecilia M and North, Kari E and Heid, Iris M} } @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} } @article {8774, title = {Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes.}, journal = {Nat Commun}, volume = {12}, year = {2021}, month = {2021 06 09}, pages = {3505}, abstract = {

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1\% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60\% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias.

}, keywords = {Adult, Biological Variation, Population, Biomarkers, Diabetes Mellitus, Type 2, Dyslipidemias, Exome, Genetic Predisposition to Disease, Genotype, Humans, Multifactorial Inheritance, Penetrance, Risk Assessment}, issn = {2041-1723}, doi = {10.1038/s41467-021-23556-4}, author = {Goodrich, Julia K and Singer-Berk, Moriel and Son, Rachel and Sveden, Abigail and Wood, Jordan and England, Eleina and Cole, Joanne B and Weisburd, Ben and Watts, Nick and Caulkins, Lizz and Dornbos, Peter and Koesterer, Ryan and Zappala, Zachary and Zhang, Haichen and Maloney, Kristin A and Dahl, Andy and Aguilar-Salinas, Carlos A and Atzmon, Gil and Barajas-Olmos, Francisco and Barzilai, Nir and Blangero, John and Boerwinkle, Eric and Bonnycastle, Lori L and Bottinger, Erwin and Bowden, Donald W and Centeno-Cruz, Federico and Chambers, John C and Chami, Nathalie and Chan, Edmund and Chan, Juliana and Cheng, Ching-Yu and Cho, Yoon Shin and Contreras-Cubas, Cecilia and C{\'o}rdova, Emilio and Correa, Adolfo and DeFronzo, Ralph A and Duggirala, Ravindranath and Dupuis, Jos{\'e}e and Garay-Sevilla, Ma Eugenia and Garc{\'\i}a-Ortiz, Humberto and Gieger, Christian and Glaser, Benjamin and Gonz{\'a}lez-Villalpando, Clicerio and Gonzalez, Ma Elena and Grarup, Niels and Groop, Leif and Gross, Myron and Haiman, Christopher and Han, Sohee and Hanis, Craig L and Hansen, Torben and Heard-Costa, Nancy L and Henderson, Brian E and Hernandez, Juan Manuel Malacara and Hwang, Mi Yeong and Islas-Andrade, Sergio and J{\o}rgensen, Marit E and Kang, Hyun Min and Kim, Bong-Jo and Kim, Young Jin and Koistinen, Heikki A and Kooner, Jaspal Singh and Kuusisto, Johanna and Kwak, Soo-Heon and Laakso, Markku and Lange, Leslie and Lee, Jong-Young and Lee, Juyoung and Lehman, Donna M and Linneberg, Allan and Liu, Jianjun and Loos, Ruth J F and Lyssenko, Valeriya and Ma, Ronald C W and Mart{\'\i}nez-Hern{\'a}ndez, Ang{\'e}lica and Meigs, James B and Meitinger, Thomas and Mendoza-Caamal, Elvia and Mohlke, Karen L and Morris, Andrew D and Morrison, Alanna C and Ng, Maggie C Y and Nilsson, Peter M and O{\textquoteright}Donnell, Christopher J and Orozco, Lorena and Palmer, Colin N A and Park, Kyong Soo and Post, Wendy S and Pedersen, Oluf and Preuss, Michael and Psaty, Bruce M and Reiner, Alexander P and Revilla-Monsalve, Cristina and Rich, Stephen S and Rotter, Jerome I and Saleheen, Danish and Schurmann, Claudia and Sim, Xueling and Sladek, Rob and Small, Kerrin S and So, Wing Yee and Spector, Timothy D and Strauch, Konstantin and Strom, Tim M and Tai, E Shyong and Tam, Claudia H T and Teo, Yik Ying and Thameem, Farook and Tomlinson, Brian and Tracy, Russell P and Tuomi, Tiinamaija and Tuomilehto, Jaakko and Tusi{\'e}-Luna, Teresa and van Dam, Rob M and Vasan, Ramachandran S and Wilson, James G and Witte, Daniel R and Wong, Tien-Yin and Burtt, Noel P and Zaitlen, Noah and McCarthy, Mark I and Boehnke, Michael and Pollin, Toni I and Flannick, Jason and Mercader, Josep M and O{\textquoteright}Donnell-Luria, Anne and Baxter, Samantha and Florez, Jose C and MacArthur, Daniel G and Udler, Miriam S} } @article {9246, title = {Correlations between complex human phenotypes vary by genetic background, gender, and environment.}, journal = {Cell Rep Med}, volume = {3}, year = {2022}, month = {2022 Dec 20}, pages = {100844}, abstract = {

We develop a closed-form Haseman-Elston estimator for genetic and environmental correlation coefficients between complex phenotypes, which we term HEc, that is as precise as GCTA yet \~{}20{\texttimes} faster. We estimate genetic and environmental correlations between over 7,000 phenotype pairs in subgroups from the Trans-Omics in Precision Medicine (TOPMed) program. We demonstrate substantial differences in both heritabilities and genetic correlations for multiple phenotypes and phenotype pairs between individuals of self-reported Black, Hispanic/Latino, and White backgrounds. We similarly observe differences in many of the genetic and environmental correlations between genders. To estimate the contribution of genetics to the observed phenotypic correlation, we introduce "fractional genetic correlation" as the fraction of phenotypic correlation explained by genetics. Finally, we quantify the enrichment of correlations between phenotypic domains, each of which is comprised of multiple phenotypes. Altogether, we demonstrate that the observed correlations between complex human phenotypes depend on the genetic background of the individuals, their gender, and their environment.

}, keywords = {Female, Genetic Background, Humans, Male, Phenotype}, issn = {2666-3791}, doi = {10.1016/j.xcrm.2022.100844}, author = {Elgart, Michael and Goodman, Matthew O and Isasi, Carmen and Chen, Han and Morrison, Alanna C and de Vries, Paul S and Xu, Huichun and Manichaikul, Ani W and Guo, Xiuqing and Franceschini, Nora and Psaty, Bruce M and Rich, Stephen S and Rotter, Jerome I and Lloyd-Jones, Donald M and Fornage, Myriam and Correa, Adolfo and Heard-Costa, Nancy L and Vasan, Ramachandran S and Hernandez, Ryan and Kaplan, Robert C and Redline, Susan and Sofer, Tamar} } @article {8975, title = {Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes.}, journal = {Am J Hum Genet}, volume = {109}, year = {2022}, month = {2022 01 06}, pages = {81-96}, abstract = {

Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1\%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.

}, keywords = {Alleles, Blood Glucose, Case-Control Studies, Computational Biology, Databases, Genetic, Diabetes Mellitus, Type 2, Exome, Genetic Predisposition to Disease, Genetic Variation, Genetics, Population, Genome-Wide Association Study, Humans, Lipid Metabolism, Lipids, Liver, Molecular Sequence Annotation, Multifactorial Inheritance, Open Reading Frames, Phenotype, Polymorphism, Single Nucleotide}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.11.021}, author = {Hindy, George and Dornbos, Peter and Chaffin, Mark D and Liu, Dajiang J and Wang, Minxian and Selvaraj, Margaret Sunitha and Zhang, David and Park, Joseph and Aguilar-Salinas, Carlos A and Antonacci-Fulton, Lucinda and Ardissino, Diego and Arnett, Donna K and Aslibekyan, Stella and Atzmon, Gil and Ballantyne, Christie M and Barajas-Olmos, Francisco and Barzilai, Nir and Becker, Lewis C and Bielak, Lawrence F and Bis, Joshua C and Blangero, John and Boerwinkle, Eric and Bonnycastle, Lori L and Bottinger, Erwin and Bowden, Donald W and Bown, Matthew J and Brody, Jennifer A and Broome, Jai G and Burtt, Noel P and Cade, Brian E and Centeno-Cruz, Federico and Chan, Edmund and Chang, Yi-Cheng and Chen, Yii-der I and Cheng, Ching-Yu and Choi, Won Jung and Chowdhury, Rajiv and Contreras-Cubas, Cecilia and C{\'o}rdova, Emilio J and Correa, Adolfo and Cupples, L Adrienne and Curran, Joanne E and Danesh, John and de Vries, Paul S and DeFronzo, Ralph A and Doddapaneni, Harsha and Duggirala, Ravindranath and Dutcher, Susan K and Ellinor, Patrick T and Emery, Leslie S and Florez, Jose C and Fornage, Myriam and Freedman, Barry I and Fuster, Valentin and Garay-Sevilla, Ma Eugenia and Garc{\'\i}a-Ortiz, Humberto and Germer, Soren and Gibbs, Richard A and Gieger, Christian and Glaser, Benjamin and Gonzalez, Clicerio and Gonzalez-Villalpando, Maria Elena and Graff, Mariaelisa and Graham, Sarah E and Grarup, Niels and Groop, Leif C and Guo, Xiuqing and Gupta, Namrata and Han, Sohee and Hanis, Craig L and Hansen, Torben and He, Jiang and Heard-Costa, Nancy L and Hung, Yi-Jen and Hwang, Mi Yeong and Irvin, Marguerite R and Islas-Andrade, Sergio and Jarvik, Gail P and Kang, Hyun Min and Kardia, Sharon L R and Kelly, Tanika and Kenny, Eimear E and Khan, Alyna T and Kim, Bong-Jo and Kim, Ryan W and Kim, Young Jin and Koistinen, Heikki A and Kooperberg, Charles and Kuusisto, Johanna and Kwak, Soo Heon and Laakso, Markku and Lange, Leslie A and Lee, Jiwon and Lee, Juyoung and Lee, Seonwook and Lehman, Donna M and Lemaitre, Rozenn N and Linneberg, Allan and Liu, Jianjun and Loos, Ruth J F and Lubitz, Steven A and Lyssenko, Valeriya and Ma, Ronald C W and Martin, Lisa Warsinger and Mart{\'\i}nez-Hern{\'a}ndez, Ang{\'e}lica and Mathias, Rasika A and McGarvey, Stephen T and McPherson, Ruth and Meigs, James B and Meitinger, Thomas and Melander, Olle and Mendoza-Caamal, Elvia and Metcalf, Ginger A and Mi, Xuenan and Mohlke, Karen L and Montasser, May E and Moon, Jee-Young and Moreno-Macias, Hortensia and Morrison, Alanna C and Muzny, Donna M and Nelson, Sarah C and Nilsson, Peter M and O{\textquoteright}Connell, Jeffrey R and Orho-Melander, Marju and Orozco, Lorena and Palmer, Colin N A and Palmer, Nicholette D and Park, Cheol Joo and Park, Kyong Soo and Pedersen, Oluf and Peralta, Juan M and Peyser, Patricia A and Post, Wendy S and Preuss, Michael and Psaty, Bruce M and Qi, Qibin and Rao, D C and Redline, Susan and Reiner, Alexander P and Revilla-Monsalve, Cristina and Rich, Stephen S and Samani, Nilesh and Schunkert, Heribert and Schurmann, Claudia and Seo, Daekwan and Seo, Jeong-Sun and Sim, Xueling and Sladek, Rob and Small, Kerrin S and So, Wing Yee and Stilp, Adrienne M and Tai, E Shyong and Tam, Claudia H T and Taylor, Kent D and Teo, Yik Ying and Thameem, Farook and Tomlinson, Brian and Tsai, Michael Y and Tuomi, Tiinamaija and Tuomilehto, Jaakko and Tusi{\'e}-Luna, Teresa and Udler, Miriam S and van Dam, Rob M and Vasan, Ramachandran S and Viaud Martinez, Karine A and Wang, Fei Fei and Wang, Xuzhi and Watkins, Hugh and Weeks, Daniel E and Wilson, James G and Witte, Daniel R and Wong, Tien-Yin and Yanek, Lisa R and Kathiresan, Sekar and Rader, Daniel J and Rotter, Jerome I and Boehnke, Michael and McCarthy, Mark I and Willer, Cristen J and Natarajan, Pradeep and Flannick, Jason A and Khera, Amit V and Peloso, Gina M} } @article {9388, title = {Association of Severe Hypercholesterolemia and Familial Hypercholesterolemia Genotype With Risk of Coronary Heart Disease.}, journal = {Circulation}, volume = {147}, year = {2023}, month = {2023 May 16}, pages = {1556-1559}, keywords = {Coronary Disease, Genotype, Humans, Hypercholesterolemia, Hyperlipoproteinemia Type II}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.123.064168}, author = {Zhang, Yiyi and Dron, Jacqueline S and Bellows, Brandon K and Khera, Amit V and Liu, Junxiu and Balte, Pallavi P and Oelsner, Elizabeth C and Amr, Sami Samir and Lebo, Matthew S and Nagy, Anna and Peloso, Gina M and Natarajan, Pradeep and Rotter, Jerome I and Willer, Cristen and Boerwinkle, Eric and Ballantyne, Christie M and Lutsey, Pamela L and Fornage, Myriam and Lloyd-Jones, Donald M and Hou, Lifang and Psaty, Bruce M and Bis, Joshua C and Floyd, James S and Vasan, Ramachandran S and Heard-Costa, Nancy L and Carson, April P and Hall, Michael E and Rich, Stephen S and Guo, Xiuqing and Kazi, Dhruv S and de Ferranti, Sarah D and Moran, Andrew E} } @article {9787, title = {Rare variant contribution to the heritability of coronary artery disease.}, journal = {Nat Commun}, volume = {15}, year = {2024}, month = {2024 Oct 09}, pages = {8741}, abstract = {

Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3\% assuming a prevalence of 8.2\%. Ultra-rare (minor allele frequency <= 0.1\%) variants with low linkage disequilibrium (LD) score contribute ~50\% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin atlas of the human coronary; and iv) annotation principal components representing a wide range of functional processes. We observe marked enrichment of CAD heritability for most functional annotations. These results reveal the predominant role of ultra-rare variants in low LD on the heritability of CAD. Moreover, they highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk.

}, keywords = {Case-Control Studies, Coronary Artery Disease, Female, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Male, Middle Aged, Polymorphism, Single Nucleotide, White People, Whole Genome Sequencing}, issn = {2041-1723}, doi = {10.1038/s41467-024-52939-6}, author = {Rocheleau, Ghislain and Clarke, Shoa L and Auguste, Ga{\"e}lle and Hasbani, Natalie R and Morrison, Alanna C and Heath, Adam S and Bielak, Lawrence F and Iyer, Kruthika R and Young, Erica P and Stitziel, Nathan O and Jun, Goo and Laurie, Cecelia and Broome, Jai G and Khan, Alyna T and Arnett, Donna K and Becker, Lewis C and Bis, Joshua C and Boerwinkle, Eric and Bowden, Donald W and Carson, April P and Ellinor, Patrick T and Fornage, Myriam and Franceschini, Nora and Freedman, Barry I and Heard-Costa, Nancy L and Hou, Lifang and Chen, Yii-Der Ida and Kenny, Eimear E and Kooperberg, Charles and Kral, Brian G and Loos, Ruth J F and Lutz, Sharon M and Manson, JoAnn E and Martin, Lisa W and Mitchell, Braxton D and Nassir, Rami and Palmer, Nicholette D and Post, Wendy S and Preuss, Michael H and Psaty, Bruce M and Raffield, Laura M and Regan, Elizabeth A and Rich, Stephen S and Smith, Jennifer A and Taylor, Kent D and Yanek, Lisa R and Young, Kendra A and Hilliard, Austin T and Tcheandjieu, Catherine and Peyser, Patricia A and Vasan, Ramachandran S and Rotter, Jerome I and Miller, Clint L and Assimes, Themistocles L and de Vries, Paul S and Do, Ron} } @article {9899, title = {A statistical framework for multi-trait rare variant analysis in large-scale whole-genome sequencing studies.}, journal = {Nat Comput Sci}, volume = {5}, year = {2025}, month = {2025 Feb}, pages = {125-143}, abstract = {

Large-scale whole-genome sequencing (WGS) studies have improved our understanding of the contributions of coding and noncoding rare variants to complex human traits. Leveraging association effect sizes across multiple traits in WGS rare variant association analysis can improve statistical power over single-trait analysis, and also detect pleiotropic genes and regions. Existing multi-trait methods have limited ability to perform rare variant analysis of large-scale WGS data. We propose MultiSTAAR, a statistical framework and computationally scalable analytical pipeline for functionally informed multi-trait rare variant analysis in large-scale WGS studies. MultiSTAAR accounts for relatedness, population structure and correlation among phenotypes by jointly analyzing multiple traits, and further empowers rare variant association analysis by incorporating multiple functional annotations. We applied MultiSTAAR to jointly analyze three lipid traits in 61,838 multi-ethnic samples from the Trans-Omics for Precision Medicine (TOPMed) Program. We discovered and replicated new associations with lipid traits missed by single-trait analysis.

}, keywords = {Genetic Variation, Genome, Human, Genome-Wide Association Study, Humans, Lipids, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Whole Genome Sequencing}, issn = {2662-8457}, doi = {10.1038/s43588-024-00764-8}, author = {Li, Xihao and Chen, Han and Selvaraj, Margaret Sunitha and Van Buren, Eric and Zhou, Hufeng and Wang, Yuxuan and Sun, Ryan and McCaw, Zachary R and Yu, Zhi and Jiang, Min-Zhi and DiCorpo, Daniel and Gaynor, Sheila M and Dey, Rounak and Arnett, Donna K and Benjamin, Emelia J and Bis, Joshua C and Blangero, John and Boerwinkle, Eric and Bowden, Donald W and Brody, Jennifer A and Cade, Brian E and Carson, April P and Carlson, Jenna C and Chami, Nathalie and Chen, Yii-Der Ida and Curran, Joanne E and de Vries, Paul S and Fornage, Myriam and Franceschini, Nora and Freedman, Barry I and Gu, Charles and Heard-Costa, Nancy L and He, Jiang and Hou, Lifang and Hung, Yi-Jen and Irvin, Marguerite R and Kaplan, Robert C and Kardia, Sharon L R and Kelly, Tanika N and Konigsberg, Iain and Kooperberg, Charles and Kral, Brian G and Li, Changwei and Li, Yun and Lin, Honghuang and Liu, Ching-Ti and Loos, Ruth J F and Mahaney, Michael C and Martin, Lisa W and Mathias, Rasika A and Mitchell, Braxton D and Montasser, May E and Morrison, Alanna C and Naseri, Take and North, Kari E and Palmer, Nicholette D and Peyser, Patricia A and Psaty, Bruce M and Redline, Susan and Reiner, Alexander P and Rich, Stephen S and Sitlani, Colleen M and Smith, Jennifer A and Taylor, Kent D and Tiwari, Hemant K and Vasan, Ramachandran S and Viali, Satupa{\textquoteright}itea and Wang, Zhe and Wessel, Jennifer and Yanek, Lisa R and Yu, Bing and Dupuis, Jos{\'e}e and Meigs, James B and Auer, Paul L and Raffield, Laura M and Manning, Alisa K and Rice, Kenneth M and Rotter, Jerome I and Peloso, Gina M and Natarajan, Pradeep and Li, Zilin and Liu, Zhonghua and Lin, Xihong} }