TY - JOUR T1 - Common genetic variants associate with serum phosphorus concentration. JF - J Am Soc Nephrol Y1 - 2010 A1 - Kestenbaum, Bryan A1 - Glazer, Nicole L A1 - Köttgen, Anna A1 - Felix, Janine F A1 - Hwang, Shih-Jen A1 - Liu, Yongmei A1 - Lohman, Kurt A1 - Kritchevsky, Stephen B A1 - Hausman, Dorothy B A1 - Petersen, Ann-Kristin A1 - Gieger, Christian A1 - Ried, Janina S A1 - Meitinger, Thomas A1 - Strom, Tim M A1 - Wichmann, H Erich A1 - Campbell, Harry A1 - Hayward, Caroline A1 - Rudan, Igor A1 - de Boer, Ian H A1 - Psaty, Bruce M A1 - Rice, Kenneth M A1 - Chen, Yii-Der Ida A1 - Li, Man A1 - Arking, Dan E A1 - Boerwinkle, Eric A1 - Coresh, Josef A1 - Yang, Qiong A1 - Levy, Daniel A1 - van Rooij, Frank J A A1 - Dehghan, Abbas A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Hofman, Albert A1 - van Duijn, Cornelia M A1 - Shlipak, Michael G A1 - Kao, W H Linda A1 - Witteman, Jacqueline C M A1 - Siscovick, David S A1 - Fox, Caroline S KW - Adult KW - Aged KW - European Continental Ancestry Group KW - Female KW - Fibroblast Growth Factors KW - Gene Frequency KW - Genetic Loci KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Kidney KW - Male KW - Middle Aged KW - Phosphorus KW - Polymorphism, Single Nucleotide KW - Receptors, Calcium-Sensing KW - Sex Factors KW - Sodium-Phosphate Cotransporter Proteins, Type IIa AB -

Phosphorus is an essential mineral that maintains cellular energy and mineralizes the skeleton. Because complex actions of ion transporters and regulatory hormones regulate serum phosphorus concentrations, genetic variation may determine interindividual variation in phosphorus metabolism. Here, we report a comprehensive genome-wide association study of serum phosphorus concentration. We evaluated 16,264 participants of European ancestry from the Cardiovascular Heath Study, Atherosclerosis Risk in Communities Study, Framingham Offspring Study, and the Rotterdam Study. We excluded participants with an estimated GFR <45 ml/min per 1.73 m(2) to focus on phosphorus metabolism under normal conditions. We imputed genotypes to approximately 2.5 million single-nucleotide polymorphisms in the HapMap and combined study-specific findings using meta-analysis. We tested top polymorphisms from discovery cohorts in a 5444-person replication sample. Polymorphisms in seven loci with minor allele frequencies 0.08 to 0.49 associate with serum phosphorus concentration (P = 3.5 x 10(-16) to 3.6 x 10(-7)). Three loci were near genes encoding the kidney-specific type IIa sodium phosphate co-transporter (SLC34A1), the calcium-sensing receptor (CASR), and fibroblast growth factor 23 (FGF23), proteins that contribute to phosphorus metabolism. We also identified genes encoding phosphatases, kinases, and phosphodiesterases that have yet-undetermined roles in phosphorus homeostasis. In the replication sample, five of seven top polymorphisms associate with serum phosphorous concentrations (P < 0.05 for each). In conclusion, common genetic variants associate with serum phosphorus in the general population. Further study of the loci identified in this study may help elucidate mechanisms of phosphorus regulation.

VL - 21 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20558539?dopt=Abstract ER - TY - JOUR T1 - Common variants in the calcium-sensing receptor gene are associated with total serum calcium levels. JF - Hum Mol Genet Y1 - 2010 A1 - O'Seaghdha, Conall M A1 - Yang, Qiong A1 - Glazer, Nicole L A1 - Leak, Tennille S A1 - Dehghan, Abbas A1 - Smith, Albert V A1 - Kao, W H Linda A1 - Lohman, Kurt A1 - Hwang, Shih-Jen A1 - Johnson, Andrew D A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Chen, Yii-Der Ida A1 - Brown, Edward M A1 - Siscovick, David S A1 - Harris, Tamara B A1 - Psaty, Bruce M A1 - Coresh, Josef A1 - Gudnason, Vilmundur A1 - Witteman, Jacqueline C A1 - Liu, Yong Mei A1 - Kestenbaum, Bryan R A1 - Fox, Caroline S A1 - Köttgen, Anna KW - Adult KW - Calcium KW - Female KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Receptors, Calcium-Sensing AB -

Serum calcium levels are tightly regulated. We performed genome-wide association studies (GWAS) in population-based studies participating in the CHARGE Consortium to uncover common genetic variations associated with total serum calcium levels. GWAS of serum calcium concentrations was performed in 20 611 individuals of European ancestry for ∼2.5 million genotyped and imputed single-nucleotide polymorphisms (SNPs). The SNP with the lowest P-value was rs17251221 (P = 2.4 * 10(-22), minor allele frequency 14%) in the calcium-sensing receptor gene (CASR). This lead SNP was associated with higher serum calcium levels [0.06 mg/dl (0.015 mmol/l) per copy of the minor G allele] and accounted for 0.54% of the variance in serum calcium concentrations. The identification of variation in CASR that influences serum calcium concentration confirms the results of earlier candidate gene studies. The G allele of rs17251221 was also associated with higher serum magnesium levels (P = 1.2 * 10(-3)), lower serum phosphate levels (P = 2.8 * 10(-7)) and lower bone mineral density at the lumbar spine (P = 0.038), but not the femoral neck. No additional genomic loci contained SNPs associated at genome-wide significance (P < 5 * 10(-8)). These associations resemble clinical characteristics of patients with familial hypocalciuric hypercalcemia, an autosomal-dominant disease arising from rare inactivating mutations in the CASR gene. We conclude that common genetic variation in the CASR gene is associated with similar but milder features in the general population.

VL - 19 IS - 21 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20705733?dopt=Abstract ER - TY - JOUR T1 - New loci associated with kidney function and chronic kidney disease. JF - Nat Genet Y1 - 2010 A1 - Köttgen, Anna A1 - Pattaro, Cristian A1 - Böger, Carsten A A1 - Fuchsberger, Christian A1 - Olden, Matthias A1 - Glazer, Nicole L A1 - Parsa, Afshin A1 - Gao, Xiaoyi A1 - Yang, Qiong A1 - Smith, Albert V A1 - O'Connell, Jeffrey R A1 - Li, Man A1 - Schmidt, Helena A1 - Tanaka, Toshiko A1 - Isaacs, Aaron A1 - Ketkar, Shamika A1 - Hwang, Shih-Jen A1 - Johnson, Andrew D A1 - Dehghan, Abbas A1 - Teumer, Alexander A1 - Paré, Guillaume A1 - Atkinson, Elizabeth J A1 - Zeller, Tanja A1 - Lohman, Kurt A1 - Cornelis, Marilyn C A1 - Probst-Hensch, Nicole M A1 - Kronenberg, Florian A1 - Tönjes, Anke A1 - Hayward, Caroline A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Launer, Lenore J A1 - Harris, Tamara B A1 - Rampersaud, Evadnie A1 - Mitchell, Braxton D A1 - Arking, Dan E A1 - Boerwinkle, Eric A1 - Struchalin, Maksim A1 - Cavalieri, Margherita A1 - Singleton, Andrew A1 - Giallauria, Francesco A1 - Metter, Jeffrey A1 - de Boer, Ian H A1 - Haritunians, Talin A1 - Lumley, Thomas A1 - Siscovick, David A1 - Psaty, Bruce M A1 - Zillikens, M Carola A1 - Oostra, Ben A A1 - Feitosa, Mary A1 - Province, Michael A1 - de Andrade, Mariza A1 - Turner, Stephen T A1 - Schillert, Arne A1 - Ziegler, Andreas A1 - Wild, Philipp S A1 - Schnabel, Renate B A1 - Wilde, Sandra A1 - Munzel, Thomas F A1 - Leak, Tennille S A1 - Illig, Thomas A1 - Klopp, Norman A1 - Meisinger, Christa A1 - Wichmann, H-Erich A1 - Koenig, Wolfgang A1 - Zgaga, Lina A1 - Zemunik, Tatijana A1 - Kolcic, Ivana A1 - Minelli, Cosetta A1 - Hu, Frank B A1 - Johansson, Asa A1 - Igl, Wilmar A1 - Zaboli, Ghazal A1 - Wild, Sarah H A1 - Wright, Alan F A1 - Campbell, Harry A1 - Ellinghaus, David A1 - Schreiber, Stefan A1 - Aulchenko, Yurii S A1 - Felix, Janine F A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Hofman, Albert A1 - Imboden, Medea A1 - Nitsch, Dorothea A1 - Brandstätter, Anita A1 - Kollerits, Barbara A1 - Kedenko, Lyudmyla A1 - Mägi, Reedik A1 - Stumvoll, Michael A1 - Kovacs, Peter A1 - Boban, Mladen A1 - Campbell, Susan A1 - Endlich, Karlhans A1 - Völzke, Henry A1 - Kroemer, Heyo K A1 - Nauck, Matthias A1 - Völker, Uwe A1 - Polasek, Ozren A1 - Vitart, Veronique A1 - Badola, Sunita A1 - Parker, Alexander N A1 - Ridker, Paul M A1 - Kardia, Sharon L R A1 - Blankenberg, Stefan A1 - Liu, Yongmei A1 - Curhan, Gary C A1 - Franke, Andre A1 - Rochat, Thierry A1 - Paulweber, Bernhard A1 - Prokopenko, Inga A1 - Wang, Wei A1 - Gudnason, Vilmundur A1 - Shuldiner, Alan R A1 - Coresh, Josef A1 - Schmidt, Reinhold A1 - Ferrucci, Luigi A1 - Shlipak, Michael G A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid A1 - Krämer, Bernhard K A1 - Rudan, Igor A1 - Gyllensten, Ulf A1 - Wilson, James F A1 - Witteman, Jacqueline C A1 - Pramstaller, Peter P A1 - Rettig, Rainer A1 - Hastie, Nick A1 - Chasman, Daniel I A1 - Kao, W H A1 - Heid, Iris M A1 - Fox, Caroline S KW - Cohort Studies KW - Creatinine KW - Cystatin C KW - Diet KW - Europe KW - Genetic Markers KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Kidney Failure, Chronic KW - Models, Genetic KW - Risk Factors AB -

Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m(2); n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide-significant loci (P < 5 x 10(-8)) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney.

VL - 42 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20383146?dopt=Abstract ER - TY - JOUR T1 - CUBN is a gene locus for albuminuria. JF - J Am Soc Nephrol Y1 - 2011 A1 - Böger, Carsten A A1 - Chen, Ming-Huei A1 - Tin, Adrienne A1 - Olden, Matthias A1 - Köttgen, Anna A1 - de Boer, Ian H A1 - Fuchsberger, Christian A1 - O'Seaghdha, Conall M A1 - Pattaro, Cristian A1 - Teumer, Alexander A1 - Liu, Ching-Ti A1 - Glazer, Nicole L A1 - Li, Man A1 - O'Connell, Jeffrey R A1 - Tanaka, Toshiko A1 - Peralta, Carmen A A1 - Kutalik, Zoltán A1 - Luan, Jian'an A1 - Zhao, Jing Hua A1 - Hwang, Shih-Jen A1 - Akylbekova, Ermeg A1 - Kramer, Holly A1 - van der Harst, Pim A1 - Smith, Albert V A1 - Lohman, Kurt A1 - de Andrade, Mariza A1 - Hayward, Caroline A1 - Kollerits, Barbara A1 - Tönjes, Anke A1 - Aspelund, Thor A1 - Ingelsson, Erik A1 - Eiriksdottir, Gudny A1 - Launer, Lenore J A1 - Harris, Tamara B A1 - Shuldiner, Alan R A1 - Mitchell, Braxton D A1 - Arking, Dan E A1 - Franceschini, Nora A1 - Boerwinkle, Eric A1 - Egan, Josephine A1 - Hernandez, Dena A1 - Reilly, Muredach A1 - Townsend, Raymond R A1 - Lumley, Thomas A1 - Siscovick, David S A1 - Psaty, Bruce M A1 - Kestenbaum, Bryan A1 - Haritunians, Talin A1 - Bergmann, Sven A1 - Vollenweider, Peter A1 - Waeber, Gérard A1 - Mooser, Vincent A1 - Waterworth, Dawn A1 - Johnson, Andrew D A1 - Florez, Jose C A1 - Meigs, James B A1 - Lu, Xiaoning A1 - Turner, Stephen T A1 - Atkinson, Elizabeth J A1 - Leak, Tennille S A1 - Aasarød, Knut A1 - Skorpen, Frank A1 - Syvänen, Ann-Christine A1 - Illig, Thomas A1 - Baumert, Jens A1 - Koenig, Wolfgang A1 - Krämer, Bernhard K A1 - Devuyst, Olivier A1 - Mychaleckyj, Josyf C A1 - Minelli, Cosetta A1 - Bakker, Stephan J L A1 - Kedenko, Lyudmyla A1 - Paulweber, Bernhard A1 - Coassin, Stefan A1 - Endlich, Karlhans A1 - Kroemer, Heyo K A1 - Biffar, Reiner A1 - Stracke, Sylvia A1 - Völzke, Henry A1 - Stumvoll, Michael A1 - Mägi, Reedik A1 - Campbell, Harry A1 - Vitart, Veronique A1 - Hastie, Nicholas D A1 - Gudnason, Vilmundur A1 - Kardia, Sharon L R A1 - Liu, Yongmei A1 - Polasek, Ozren A1 - Curhan, Gary A1 - Kronenberg, Florian A1 - Prokopenko, Inga A1 - Rudan, Igor A1 - Arnlöv, Johan A1 - Hallan, Stein A1 - Navis, Gerjan A1 - Parsa, Afshin A1 - Ferrucci, Luigi A1 - Coresh, Josef A1 - Shlipak, Michael G A1 - Bull, Shelley B A1 - Paterson, Nicholas J A1 - Wichmann, H-Erich A1 - Wareham, Nicholas J A1 - Loos, Ruth J F A1 - Rotter, Jerome I A1 - Pramstaller, Peter P A1 - Cupples, L Adrienne A1 - Beckmann, Jacques S A1 - Yang, Qiong A1 - Heid, Iris M A1 - Rettig, Rainer A1 - Dreisbach, Albert W A1 - Bochud, Murielle A1 - Fox, Caroline S A1 - Kao, W H L KW - African Continental Ancestry Group KW - Albuminuria KW - European Continental Ancestry Group KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Humans KW - Mutation, Missense KW - Receptors, Cell Surface AB -

Identification of genetic risk factors for albuminuria may alter strategies for early prevention of CKD progression, particularly among patients with diabetes. Little is known about the influence of common genetic variants on albuminuria in both general and diabetic populations. We performed a meta-analysis of data from 63,153 individuals of European ancestry with genotype information from genome-wide association studies (CKDGen Consortium) and from a large candidate gene study (CARe Consortium) to identify susceptibility loci for the quantitative trait urinary albumin-to-creatinine ratio (UACR) and the clinical diagnosis microalbuminuria. We identified an association between a missense variant (I2984V) in the CUBN gene, which encodes cubilin, and both UACR (P = 1.1 × 10(-11)) and microalbuminuria (P = 0.001). We observed similar associations among 6981 African Americans in the CARe Consortium. The associations between this variant and both UACR and microalbuminuria were significant in individuals of European ancestry regardless of diabetes status. Finally, this variant associated with a 41% increased risk for the development of persistent microalbuminuria during 20 years of follow-up among 1304 participants with type 1 diabetes in the prospective DCCT/EDIC Study. In summary, we identified a missense CUBN variant that associates with levels of albuminuria in both the general population and in individuals with diabetes.

VL - 22 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21355061?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function. JF - Nat Genet Y1 - 2011 A1 - Soler Artigas, Maria A1 - Loth, Daan W A1 - Wain, Louise V A1 - Gharib, Sina A A1 - Obeidat, Ma'en A1 - Tang, Wenbo A1 - Zhai, Guangju A1 - Zhao, Jing Hua A1 - Smith, Albert Vernon A1 - Huffman, Jennifer E A1 - Albrecht, Eva A1 - Jackson, Catherine M A1 - Evans, David M A1 - Cadby, Gemma A1 - Fornage, Myriam A1 - Manichaikul, Ani A1 - Lopez, Lorna M A1 - Johnson, Toby A1 - Aldrich, Melinda C A1 - Aspelund, Thor A1 - Barroso, Inês A1 - Campbell, Harry A1 - Cassano, Patricia A A1 - Couper, David J A1 - Eiriksdottir, Gudny A1 - Franceschini, Nora A1 - Garcia, Melissa A1 - Gieger, Christian A1 - Gislason, Gauti Kjartan A1 - Grkovic, Ivica A1 - Hammond, Christopher J A1 - Hancock, Dana B A1 - Harris, Tamara B A1 - Ramasamy, Adaikalavan A1 - Heckbert, Susan R A1 - Heliövaara, Markku A1 - Homuth, Georg A1 - Hysi, Pirro G A1 - James, Alan L A1 - Jankovic, Stipan A1 - Joubert, Bonnie R A1 - Karrasch, Stefan A1 - Klopp, Norman A1 - Koch, Beate A1 - Kritchevsky, Stephen B A1 - Launer, Lenore J A1 - Liu, Yongmei A1 - Loehr, Laura R A1 - Lohman, Kurt A1 - Loos, Ruth J F A1 - Lumley, Thomas A1 - Al Balushi, Khalid A A1 - Ang, Wei Q A1 - Barr, R Graham A1 - Beilby, John A1 - Blakey, John D A1 - Boban, Mladen A1 - Boraska, Vesna A1 - Brisman, Jonas A1 - Britton, John R A1 - Brusselle, Guy G A1 - Cooper, Cyrus A1 - Curjuric, Ivan A1 - Dahgam, Santosh A1 - Deary, Ian J A1 - Ebrahim, Shah A1 - Eijgelsheim, Mark A1 - Francks, Clyde A1 - Gaysina, Darya A1 - Granell, Raquel A1 - Gu, Xiangjun A1 - Hankinson, John L A1 - Hardy, Rebecca A1 - Harris, Sarah E A1 - Henderson, John A1 - Henry, Amanda A1 - Hingorani, Aroon D A1 - Hofman, Albert A1 - Holt, Patrick G A1 - Hui, Jennie A1 - Hunter, Michael L A1 - Imboden, Medea A1 - Jameson, Karen A A1 - Kerr, Shona M A1 - Kolcic, Ivana A1 - Kronenberg, Florian A1 - Liu, Jason Z A1 - Marchini, Jonathan A1 - McKeever, Tricia A1 - Morris, Andrew D A1 - Olin, Anna-Carin A1 - Porteous, David J A1 - Postma, Dirkje S A1 - Rich, Stephen S A1 - Ring, Susan M A1 - Rivadeneira, Fernando A1 - Rochat, Thierry A1 - Sayer, Avan Aihie A1 - Sayers, Ian A1 - Sly, Peter D A1 - Smith, George Davey A1 - Sood, Akshay A1 - Starr, John M A1 - Uitterlinden, André G A1 - Vonk, Judith M A1 - Wannamethee, S Goya A1 - Whincup, Peter H A1 - Wijmenga, Cisca A1 - Williams, O Dale A1 - Wong, Andrew A1 - Mangino, Massimo A1 - Marciante, Kristin D A1 - McArdle, Wendy L A1 - Meibohm, Bernd A1 - Morrison, Alanna C A1 - North, Kari E A1 - Omenaas, Ernst A1 - Palmer, Lyle J A1 - Pietiläinen, Kirsi H A1 - Pin, Isabelle A1 - Pola Sbreve Ek, Ozren A1 - Pouta, Anneli A1 - Psaty, Bruce M A1 - Hartikainen, Anna-Liisa A1 - Rantanen, Taina A1 - Ripatti, Samuli A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Rudnicka, Alicja R A1 - Schulz, Holger A1 - Shin, So-Youn A1 - Spector, Tim D A1 - Surakka, Ida A1 - Vitart, Veronique A1 - Völzke, Henry A1 - Wareham, Nicholas J A1 - Warrington, Nicole M A1 - Wichmann, H-Erich A1 - Wild, Sarah H A1 - Wilk, Jemma B A1 - Wjst, Matthias A1 - Wright, Alan F A1 - Zgaga, Lina A1 - Zemunik, Tatijana A1 - Pennell, Craig E A1 - Nyberg, Fredrik A1 - Kuh, Diana A1 - Holloway, John W A1 - Boezen, H Marike A1 - Lawlor, Debbie A A1 - Morris, Richard W A1 - Probst-Hensch, Nicole A1 - Kaprio, Jaakko A1 - Wilson, James F A1 - Hayward, Caroline A1 - Kähönen, Mika A1 - Heinrich, Joachim A1 - Musk, Arthur W A1 - Jarvis, Deborah L A1 - Gläser, Sven A1 - Jarvelin, Marjo-Riitta A1 - Ch Stricker, Bruno H A1 - Elliott, Paul A1 - O'Connor, George T A1 - Strachan, David P A1 - London, Stephanie J A1 - Hall, Ian P A1 - Gudnason, Vilmundur A1 - Tobin, Martin D KW - Child KW - European Continental Ancestry Group KW - Genome-Wide Association Study KW - Humans KW - Pulmonary Disease, Chronic Obstructive KW - Respiratory Function Tests AB -

Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.

VL - 43 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21946350?dopt=Abstract ER - TY - JOUR T1 - Association between chromosome 9p21 variants and the ankle-brachial index identified by a meta-analysis of 21 genome-wide association studies. JF - Circ Cardiovasc Genet Y1 - 2012 A1 - Murabito, Joanne M A1 - White, Charles C A1 - Kavousi, Maryam A1 - Sun, Yan V A1 - Feitosa, Mary F A1 - Nambi, Vijay A1 - Lamina, Claudia A1 - Schillert, Arne A1 - Coassin, Stefan A1 - Bis, Joshua C A1 - Broer, Linda A1 - Crawford, Dana C A1 - Franceschini, Nora A1 - Frikke-Schmidt, Ruth A1 - Haun, Margot A1 - Holewijn, Suzanne A1 - Huffman, Jennifer E A1 - Hwang, Shih-Jen A1 - Kiechl, Stefan A1 - Kollerits, Barbara A1 - Montasser, May E A1 - Nolte, Ilja M A1 - Rudock, Megan E A1 - Senft, Andrea A1 - Teumer, Alexander A1 - van der Harst, Pim A1 - Vitart, Veronique A1 - Waite, Lindsay L A1 - Wood, Andrew R A1 - Wassel, Christina L A1 - Absher, Devin M A1 - Allison, Matthew A A1 - Amin, Najaf A1 - Arnold, Alice A1 - Asselbergs, Folkert W A1 - Aulchenko, Yurii A1 - Bandinelli, Stefania A1 - Barbalic, Maja A1 - Boban, Mladen A1 - Brown-Gentry, Kristin A1 - Couper, David J A1 - Criqui, Michael H A1 - Dehghan, Abbas A1 - den Heijer, Martin A1 - Dieplinger, Benjamin A1 - Ding, Jingzhong A1 - Dörr, Marcus A1 - Espinola-Klein, Christine A1 - Felix, Stephan B A1 - Ferrucci, Luigi A1 - Folsom, Aaron R A1 - Fraedrich, Gustav A1 - Gibson, Quince A1 - Goodloe, Robert A1 - Gunjaca, Grgo A1 - Haltmayer, Meinhard A1 - Heiss, Gerardo A1 - Hofman, Albert A1 - Kieback, Arne A1 - Kiemeney, Lambertus A A1 - Kolcic, Ivana A1 - Kullo, Iftikhar J A1 - Kritchevsky, Stephen B A1 - Lackner, Karl J A1 - Li, Xiaohui A1 - Lieb, Wolfgang A1 - Lohman, Kurt A1 - Meisinger, Christa A1 - Melzer, David A1 - Mohler, Emile R A1 - Mudnic, Ivana A1 - Mueller, Thomas A1 - Navis, Gerjan A1 - Oberhollenzer, Friedrich A1 - Olin, Jeffrey W A1 - O'Connell, Jeff A1 - O'Donnell, Christopher J A1 - Palmas, Walter A1 - Penninx, Brenda W A1 - Petersmann, Astrid A1 - Polasek, Ozren A1 - Psaty, Bruce M A1 - Rantner, Barbara A1 - Rice, Ken A1 - Rivadeneira, Fernando A1 - Rotter, Jerome I A1 - Seldenrijk, Adrie A1 - Stadler, Marietta A1 - Summerer, Monika A1 - Tanaka, Toshiko A1 - Tybjaerg-Hansen, Anne A1 - Uitterlinden, André G A1 - van Gilst, Wiek H A1 - Vermeulen, Sita H A1 - Wild, Sarah H A1 - Wild, Philipp S A1 - Willeit, Johann A1 - Zeller, Tanja A1 - Zemunik, Tatijana A1 - Zgaga, Lina A1 - Assimes, Themistocles L A1 - Blankenberg, Stefan A1 - Boerwinkle, Eric A1 - Campbell, Harry A1 - Cooke, John P A1 - de Graaf, Jacqueline A1 - Herrington, David A1 - Kardia, Sharon L R A1 - Mitchell, Braxton D A1 - Murray, Anna A1 - Münzel, Thomas A1 - Newman, Anne B A1 - Oostra, Ben A A1 - Rudan, Igor A1 - Shuldiner, Alan R A1 - Snieder, Harold A1 - van Duijn, Cornelia M A1 - Völker, Uwe A1 - Wright, Alan F A1 - Wichmann, H-Erich A1 - Wilson, James F A1 - Witteman, Jacqueline C M A1 - Liu, Yongmei A1 - Hayward, Caroline A1 - Borecki, Ingrid B A1 - Ziegler, Andreas A1 - North, Kari E A1 - Cupples, L Adrienne A1 - Kronenberg, Florian KW - Adult KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Alleles KW - Ankle Brachial Index KW - Chromosomes, Human, Pair 9 KW - Cohort Studies KW - Cyclin-Dependent Kinase Inhibitor p15 KW - Female KW - Genome-Wide Association Study KW - Genotype KW - HapMap Project KW - Humans KW - Logistic Models KW - Male KW - Middle Aged KW - Peripheral Vascular Diseases KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Sex Factors AB -

BACKGROUND: Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts.

METHODS AND RESULTS: Continuous ABI and PAD (ABI ≤0.9) phenotypes adjusted for age and sex were examined. Each study conducted genotyping and imputed data to the ≈2.5 million single nucleotide polymorphisms (SNPs) in HapMap. Linear and logistic regression models were used to test each SNP for association with ABI and PAD using additive genetic models. Study-specific data were combined using fixed effects inverse variance weighted meta-analyses. There were a total of 41 692 participants of European ancestry (≈60% women, mean ABI 1.02 to 1.19), including 3409 participants with PAD and with genome-wide association study data available. In the discovery meta-analysis, rs10757269 on chromosome 9 near CDKN2B had the strongest association with ABI (β=-0.006, P=2.46×10(-8)). We sought replication of the 6 strongest SNP associations in 5 population-based studies and 3 clinical samples (n=16 717). The association for rs10757269 strengthened in the combined discovery and replication analysis (P=2.65×10(-9)). No other SNP associations for ABI or PAD achieved genome-wide significance. However, 2 previously reported candidate genes for PAD and 1 SNP associated with coronary artery disease were associated with ABI: DAB21P (rs13290547, P=3.6×10(-5)), CYBA (rs3794624, P=6.3×10(-5)), and rs1122608 (LDLR, P=0.0026).

CONCLUSIONS: Genome-wide association studies in more than 40 000 individuals identified 1 genome wide significant association on chromosome 9p21 with ABI. Two candidate genes for PAD and 1 SNP for coronary artery disease are associated with ABI.

VL - 5 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22199011?dopt=Abstract ER - TY - JOUR T1 - Genetic variants and associations of 25-hydroxyvitamin D concentrations with major clinical outcomes. JF - JAMA Y1 - 2012 A1 - Levin, Gregory P A1 - Robinson-Cohen, Cassianne A1 - de Boer, Ian H A1 - Houston, Denise K A1 - Lohman, Kurt A1 - Liu, Yongmei A1 - Kritchevsky, Stephen B A1 - Cauley, Jane A A1 - Tanaka, Toshiko A1 - Ferrucci, Luigi A1 - Bandinelli, Stefania A1 - Patel, Kushang V A1 - Hagström, Emil A1 - Michaëlsson, Karl A1 - Melhus, Håkan A1 - Wang, Thomas A1 - Wolf, Myles A1 - Psaty, Bruce M A1 - Siscovick, David A1 - Kestenbaum, Bryan KW - 25-Hydroxyvitamin D3 1-alpha-Hydroxylase KW - Aged KW - Chronic Disease KW - Cohort Studies KW - Female KW - Genetic Variation KW - Genotype KW - Hip Fractures KW - Humans KW - Low Density Lipoprotein Receptor-Related Protein-2 KW - Male KW - Meta-Analysis as Topic KW - Myocardial Infarction KW - Neoplasms KW - Polymorphism, Single Nucleotide KW - Receptors, Calcitriol KW - Receptors, Cell Surface KW - Risk KW - Steroid Hydroxylases KW - Vitamin D KW - Vitamin D3 24-Hydroxylase AB -

CONTEXT: Lower serum 25-hydroxyvitamin D concentrations are associated with greater risks of many chronic diseases across large, prospective community-based studies. Substrate 25-hydroxyvitamin D must be converted to 1,25-dihydroxyvitamin D for full biological activity, and complex metabolic pathways suggest that interindividual variability in vitamin D metabolism may alter the clinical consequences of measured serum 25-hydroxyvitamin D.

OBJECTIVE: To investigate whether common variation within genes encoding the vitamin D-binding protein, megalin, cubilin, CYP27B1, CYP24A1, and the vitamin D receptor (VDR) modify associations of low 25-hydroxyvitamin D with major clinical outcomes.

DESIGN, SETTING, AND PARTICIPANTS: Examination of 141 single-nucleotide polymorphisms in a discovery cohort of 1514 white participants (who were recruited from 4 US regions) from the community-based Cardiovascular Health Study. Participants had serum 25-hydroxyvitamin D measurements in 1992-1993 and were followed up for a median of 11 years (through 2006). Replication meta-analyses were conducted across the independent, community-based US Health, Aging, and Body Composition (n = 922; follow-up: 1998-1999 through 2005), Italian Invecchiare in Chianti (n = 835; follow-up: 1998-2000 through 2006), and Swedish Uppsala Longitudinal Study of Adult Men (n = 970; follow-up: 1991-1995 through 2008) cohort studies.

MAIN OUTCOME MEASURE: Composite outcome of incident hip facture, myocardial infarction, cancer, and mortality over long-term follow-up.

RESULTS: Interactions between 5 single-nucleotide polymorphisms and low 25-hydroxyvitamin D concentration were identified in the discovery phase and 1 involving a variant in the VDR gene replicated in independent meta-analysis. Among Cardiovascular Health Study participants, low 25-hydroxyvitamin D concentration was associated with hazard ratios for risk of the composite outcome of 1.40 (95% CI, 1.12-1.74) for those who had 1 minor allele at rs7968585 and 1.82 (95% CI, 1.31-2.54) for those with 2 minor alleles at rs7968585. In contrast, there was no evidence of an association (estimated hazard ratio, 0.93 [95% CI, 0.70-1.24]) among participants who had 0 minor alleles at this single-nucleotide polymorphism.

CONCLUSION: Known associations of low 25-hydroxyvitamin D with major health outcomes may vary according to common genetic differences in the vitamin D receptor.

VL - 308 IS - 18 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23150009?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association and functional follow-up reveals new loci for kidney function. JF - PLoS Genet Y1 - 2012 A1 - Pattaro, Cristian A1 - Köttgen, Anna A1 - Teumer, Alexander A1 - Garnaas, Maija A1 - Böger, Carsten A A1 - Fuchsberger, Christian A1 - Olden, Matthias A1 - Chen, Ming-Huei A1 - Tin, Adrienne A1 - Taliun, Daniel A1 - Li, Man A1 - Gao, Xiaoyi A1 - Gorski, Mathias A1 - Yang, Qiong A1 - Hundertmark, Claudia A1 - Foster, Meredith C A1 - O'Seaghdha, Conall M A1 - Glazer, Nicole A1 - Isaacs, Aaron A1 - Liu, Ching-Ti A1 - Smith, Albert V A1 - O'Connell, Jeffrey R A1 - Struchalin, Maksim A1 - Tanaka, Toshiko A1 - Li, Guo A1 - Johnson, Andrew D A1 - Gierman, Hinco J A1 - Feitosa, Mary A1 - Hwang, Shih-Jen A1 - Atkinson, Elizabeth J A1 - Lohman, Kurt A1 - Cornelis, Marilyn C A1 - Johansson, Asa A1 - Tönjes, Anke A1 - Dehghan, Abbas A1 - Chouraki, Vincent A1 - Holliday, Elizabeth G A1 - Sorice, Rossella A1 - Kutalik, Zoltán A1 - Lehtimäki, Terho A1 - Esko, Tõnu A1 - Deshmukh, Harshal A1 - Ulivi, Sheila A1 - Chu, Audrey Y A1 - Murgia, Federico A1 - Trompet, Stella A1 - Imboden, Medea A1 - Kollerits, Barbara A1 - Pistis, Giorgio A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Mitchell, Braxton D A1 - Boerwinkle, Eric A1 - Schmidt, Helena A1 - Cavalieri, Margherita A1 - Rao, Madhumathi A1 - Hu, Frank B A1 - Demirkan, Ayse A1 - Oostra, Ben A A1 - de Andrade, Mariza A1 - Turner, Stephen T A1 - Ding, Jingzhong A1 - Andrews, Jeanette S A1 - Freedman, Barry I A1 - Koenig, Wolfgang A1 - Illig, Thomas A1 - Döring, Angela A1 - Wichmann, H-Erich A1 - Kolcic, Ivana A1 - Zemunik, Tatijana A1 - Boban, Mladen A1 - Minelli, Cosetta A1 - Wheeler, Heather E A1 - Igl, Wilmar A1 - Zaboli, Ghazal A1 - Wild, Sarah H A1 - Wright, Alan F A1 - Campbell, Harry A1 - Ellinghaus, David A1 - Nöthlings, Ute A1 - Jacobs, Gunnar A1 - Biffar, Reiner A1 - Endlich, Karlhans A1 - Ernst, Florian A1 - Homuth, Georg A1 - Kroemer, Heyo K A1 - Nauck, Matthias A1 - Stracke, Sylvia A1 - Völker, Uwe A1 - Völzke, Henry A1 - Kovacs, Peter A1 - Stumvoll, Michael A1 - Mägi, Reedik A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Aulchenko, Yurii S A1 - Polasek, Ozren A1 - Hastie, Nick A1 - Vitart, Veronique A1 - Helmer, Catherine A1 - Wang, Jie Jin A1 - Ruggiero, Daniela A1 - Bergmann, Sven A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Nikopensius, Tiit A1 - Province, Michael A1 - Ketkar, Shamika A1 - Colhoun, Helen A1 - Doney, Alex A1 - Robino, Antonietta A1 - Giulianini, Franco A1 - Krämer, Bernhard K A1 - Portas, Laura A1 - Ford, Ian A1 - Buckley, Brendan M A1 - Adam, Martin A1 - Thun, Gian-Andri A1 - Paulweber, Bernhard A1 - Haun, Margot A1 - Sala, Cinzia A1 - Metzger, Marie A1 - Mitchell, Paul A1 - Ciullo, Marina A1 - Kim, Stuart K A1 - Vollenweider, Peter A1 - Raitakari, Olli A1 - Metspalu, Andres A1 - Palmer, Colin A1 - Gasparini, Paolo A1 - Pirastu, Mario A1 - Jukema, J Wouter A1 - Probst-Hensch, Nicole M A1 - Kronenberg, Florian A1 - Toniolo, Daniela A1 - Gudnason, Vilmundur A1 - Shuldiner, Alan R A1 - Coresh, Josef A1 - Schmidt, Reinhold A1 - Ferrucci, Luigi A1 - Siscovick, David S A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid A1 - Kardia, Sharon L R A1 - Liu, Yongmei A1 - Curhan, Gary C A1 - Rudan, Igor A1 - Gyllensten, Ulf A1 - Wilson, James F A1 - Franke, Andre A1 - Pramstaller, Peter P A1 - Rettig, Rainer A1 - Prokopenko, Inga A1 - Witteman, Jacqueline C M A1 - Hayward, Caroline A1 - Ridker, Paul A1 - Parsa, Afshin A1 - Bochud, Murielle A1 - Heid, Iris M A1 - Goessling, Wolfram A1 - Chasman, Daniel I A1 - Kao, W H Linda A1 - Fox, Caroline S KW - African Americans KW - Aged KW - Animals KW - Caspase 9 KW - Cyclin-Dependent Kinases KW - DEAD-box RNA Helicases KW - DNA Helicases KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Gene Knockdown Techniques KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Kidney Failure, Chronic KW - Male KW - Middle Aged KW - Phosphoric Diester Hydrolases KW - Zebrafish AB -

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.

VL - 8 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22479191?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation. JF - Blood Y1 - 2012 A1 - Huang, Jie A1 - Sabater-Lleal, Maria A1 - Asselbergs, Folkert W A1 - Tregouet, David A1 - Shin, So-Youn A1 - Ding, Jingzhong A1 - Baumert, Jens A1 - Oudot-Mellakh, Tiphaine A1 - Folkersen, Lasse A1 - Johnson, Andrew D A1 - Smith, Nicholas L A1 - Williams, Scott M A1 - Ikram, Mohammad A A1 - Kleber, Marcus E A1 - Becker, Diane M A1 - Truong, Vinh A1 - Mychaleckyj, Josyf C A1 - Tang, Weihong A1 - Yang, Qiong A1 - Sennblad, Bengt A1 - Moore, Jason H A1 - Williams, Frances M K A1 - Dehghan, Abbas A1 - Silbernagel, Günther A1 - Schrijvers, Elisabeth M C A1 - Smith, Shelly A1 - Karakas, Mahir A1 - Tofler, Geoffrey H A1 - Silveira, Angela A1 - Navis, Gerjan J A1 - Lohman, Kurt A1 - Chen, Ming-Huei A1 - Peters, Annette A1 - Goel, Anuj A1 - Hopewell, Jemma C A1 - Chambers, John C A1 - Saleheen, Danish A1 - Lundmark, Per A1 - Psaty, Bruce M A1 - Strawbridge, Rona J A1 - Boehm, Bernhard O A1 - Carter, Angela M A1 - Meisinger, Christa A1 - Peden, John F A1 - Bis, Joshua C A1 - McKnight, Barbara A1 - Ohrvik, John A1 - Taylor, Kent A1 - Franzosi, Maria Grazia A1 - Seedorf, Udo A1 - Collins, Rory A1 - Franco-Cereceda, Anders A1 - Syvänen, Ann-Christine A1 - Goodall, Alison H A1 - Yanek, Lisa R A1 - Cushman, Mary A1 - Müller-Nurasyid, Martina A1 - Folsom, Aaron R A1 - Basu, Saonli A1 - Matijevic, Nena A1 - van Gilst, Wiek H A1 - Kooner, Jaspal S A1 - Hofman, Albert A1 - Danesh, John A1 - Clarke, Robert A1 - Meigs, James B A1 - Kathiresan, Sekar A1 - Reilly, Muredach P A1 - Klopp, Norman A1 - Harris, Tamara B A1 - Winkelmann, Bernhard R A1 - Grant, Peter J A1 - Hillege, Hans L A1 - Watkins, Hugh A1 - Spector, Timothy D A1 - Becker, Lewis C A1 - Tracy, Russell P A1 - März, Winfried A1 - Uitterlinden, André G A1 - Eriksson, Per A1 - Cambien, Francois A1 - Morange, Pierre-Emmanuel A1 - Koenig, Wolfgang A1 - Soranzo, Nicole A1 - van der Harst, Pim A1 - Liu, Yongmei A1 - O'Donnell, Christopher J A1 - Hamsten, Anders KW - Adaptor Proteins, Signal Transducing KW - ARNTL Transcription Factors KW - ATPases Associated with Diverse Cellular Activities KW - Cell Line KW - Cell Line, Tumor KW - Cohort Studies KW - Coronary Artery Disease KW - Diabetes Mellitus, Type 2 KW - Gene Expression Profiling KW - Gene Expression Regulation KW - Gene Frequency KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - LIM Domain Proteins KW - Meta-Analysis as Topic KW - Monocytes KW - Mucin-3 KW - Plasminogen Activator Inhibitor 1 KW - Polymorphism, Single Nucleotide KW - PPAR gamma KW - Proteasome Endopeptidase Complex KW - RNA Interference KW - Transcription Factors AB -

We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P < 5 × 10(-8)) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P = 3.4 × 10(-10)); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 × 10(-8)); and chromosome 3p25.2 within PPARG (rs11128603, discovery P = 2.9 × 10(-8)). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (P < .05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1.

VL - 120 IS - 24 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22990020?dopt=Abstract ER - TY - JOUR T1 - Genome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function. JF - PLoS Genet Y1 - 2012 A1 - Hancock, Dana B A1 - Soler Artigas, Maria A1 - Gharib, Sina A A1 - Henry, Amanda A1 - Manichaikul, Ani A1 - Ramasamy, Adaikalavan A1 - Loth, Daan W A1 - Imboden, Medea A1 - Koch, Beate A1 - McArdle, Wendy L A1 - Smith, Albert V A1 - Smolonska, Joanna A1 - Sood, Akshay A1 - Tang, Wenbo A1 - Wilk, Jemma B A1 - Zhai, Guangju A1 - Zhao, Jing Hua A1 - Aschard, Hugues A1 - Burkart, Kristin M A1 - Curjuric, Ivan A1 - Eijgelsheim, Mark A1 - Elliott, Paul A1 - Gu, Xiangjun A1 - Harris, Tamara B A1 - Janson, Christer A1 - Homuth, Georg A1 - Hysi, Pirro G A1 - Liu, Jason Z A1 - Loehr, Laura R A1 - Lohman, Kurt A1 - Loos, Ruth J F A1 - Manning, Alisa K A1 - Marciante, Kristin D A1 - Obeidat, Ma'en A1 - Postma, Dirkje S A1 - Aldrich, Melinda C A1 - Brusselle, Guy G A1 - Chen, Ting-Hsu A1 - Eiriksdottir, Gudny A1 - Franceschini, Nora A1 - Heinrich, Joachim A1 - Rotter, Jerome I A1 - Wijmenga, Cisca A1 - Williams, O Dale A1 - Bentley, Amy R A1 - Hofman, Albert A1 - Laurie, Cathy C A1 - Lumley, Thomas A1 - Morrison, Alanna C A1 - Joubert, Bonnie R A1 - Rivadeneira, Fernando A1 - Couper, David J A1 - Kritchevsky, Stephen B A1 - Liu, Yongmei A1 - Wjst, Matthias A1 - Wain, Louise V A1 - Vonk, Judith M A1 - Uitterlinden, André G A1 - Rochat, Thierry A1 - Rich, Stephen S A1 - Psaty, Bruce M A1 - O'Connor, George T A1 - North, Kari E A1 - Mirel, Daniel B A1 - Meibohm, Bernd A1 - Launer, Lenore J A1 - Khaw, Kay-Tee A1 - Hartikainen, Anna-Liisa A1 - Hammond, Christopher J A1 - Gläser, Sven A1 - Marchini, Jonathan A1 - Kraft, Peter A1 - Wareham, Nicholas J A1 - Völzke, Henry A1 - Stricker, Bruno H C A1 - Spector, Timothy D A1 - Probst-Hensch, Nicole M A1 - Jarvis, Deborah A1 - Jarvelin, Marjo-Riitta A1 - Heckbert, Susan R A1 - Gudnason, Vilmundur A1 - Boezen, H Marike A1 - Barr, R Graham A1 - Cassano, Patricia A A1 - Strachan, David P A1 - Fornage, Myriam A1 - Hall, Ian P A1 - Dupuis, Josée A1 - Tobin, Martin D A1 - London, Stephanie J KW - Forced Expiratory Volume KW - Gene Expression KW - Genome, Human KW - Genome-Wide Association Study KW - HLA-DQ Antigens KW - HLA-DQ beta-Chains KW - Humans KW - Lung KW - Nerve Tissue Proteins KW - Polymorphism, Single Nucleotide KW - Potassium Channels, Inwardly Rectifying KW - Pulmonary Disease, Chronic Obstructive KW - Receptors, Cell Surface KW - Smoking KW - SOX9 Transcription Factor KW - Vital Capacity AB -

Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV(1)), and its ratio to forced vital capacity (FEV(1)/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV(1) and FEV(1)/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P(JMA = )5.00×10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P(JMA = )4.35×10(-9)), and KCNJ2 and SOX9 (smallest P(JMA = )1.28×10(-8)) were associated with FEV(1)/FVC or FEV(1) in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.

VL - 8 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23284291?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis identifies six new susceptibility loci for atrial fibrillation. JF - Nat Genet Y1 - 2012 A1 - Ellinor, Patrick T A1 - Lunetta, Kathryn L A1 - Albert, Christine M A1 - Glazer, Nicole L A1 - Ritchie, Marylyn D A1 - Smith, Albert V A1 - Arking, Dan E A1 - Müller-Nurasyid, Martina A1 - Krijthe, Bouwe P A1 - Lubitz, Steven A A1 - Bis, Joshua C A1 - Chung, Mina K A1 - Dörr, Marcus A1 - Ozaki, Kouichi A1 - Roberts, Jason D A1 - Smith, J Gustav A1 - Pfeufer, Arne A1 - Sinner, Moritz F A1 - Lohman, Kurt A1 - Ding, Jingzhong A1 - Smith, Nicholas L A1 - Smith, Jonathan D A1 - Rienstra, Michiel A1 - Rice, Kenneth M A1 - Van Wagoner, David R A1 - Magnani, Jared W A1 - Wakili, Reza A1 - Clauss, Sebastian A1 - Rotter, Jerome I A1 - Steinbeck, Gerhard A1 - Launer, Lenore J A1 - Davies, Robert W A1 - Borkovich, Matthew A1 - Harris, Tamara B A1 - Lin, Honghuang A1 - Völker, Uwe A1 - Völzke, Henry A1 - Milan, David J A1 - Hofman, Albert A1 - Boerwinkle, Eric A1 - Chen, Lin Y A1 - Soliman, Elsayed Z A1 - Voight, Benjamin F A1 - Li, Guo A1 - Chakravarti, Aravinda A1 - Kubo, Michiaki A1 - Tedrow, Usha B A1 - Rose, Lynda M A1 - Ridker, Paul M A1 - Conen, David A1 - Tsunoda, Tatsuhiko A1 - Furukawa, Tetsushi A1 - Sotoodehnia, Nona A1 - Xu, Siyan A1 - Kamatani, Naoyuki A1 - Levy, Daniel A1 - Nakamura, Yusuke A1 - Parvez, Babar A1 - Mahida, Saagar A1 - Furie, Karen L A1 - Rosand, Jonathan A1 - Muhammad, Raafia A1 - Psaty, Bruce M A1 - Meitinger, Thomas A1 - Perz, Siegfried A1 - Wichmann, H-Erich A1 - Witteman, Jacqueline C M A1 - Kao, W H Linda A1 - Kathiresan, Sekar A1 - Roden, Dan M A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - McKnight, Barbara A1 - Sjögren, Marketa A1 - Newman, Anne B A1 - Liu, Yongmei A1 - Gollob, Michael H A1 - Melander, Olle A1 - Tanaka, Toshihiro A1 - Stricker, Bruno H Ch A1 - Felix, Stephan B A1 - Alonso, Alvaro A1 - Darbar, Dawood A1 - Barnard, John A1 - Chasman, Daniel I A1 - Heckbert, Susan R A1 - Benjamin, Emelia J A1 - Gudnason, Vilmundur A1 - Kääb, Stefan KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Asian Continental Ancestry Group KW - Atrial Fibrillation KW - Child KW - Child, Preschool KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Infant KW - Infant, Newborn KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Young Adult AB -

Atrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death. We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 10,030 subjects without atrial fibrillation (P < 5 × 10(-8)). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules.

VL - 44 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22544366?dopt=Abstract ER - TY - JOUR T1 - Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals. JF - PLoS Genet Y1 - 2012 A1 - Dastani, Zari A1 - Hivert, Marie-France A1 - Timpson, Nicholas A1 - Perry, John R B A1 - Yuan, Xin A1 - Scott, Robert A A1 - Henneman, Peter A1 - Heid, Iris M A1 - Kizer, Jorge R A1 - Lyytikäinen, Leo-Pekka A1 - Fuchsberger, Christian A1 - Tanaka, Toshiko A1 - Morris, Andrew P A1 - Small, Kerrin A1 - Isaacs, Aaron A1 - Beekman, Marian A1 - Coassin, Stefan A1 - Lohman, Kurt A1 - Qi, Lu A1 - Kanoni, Stavroula A1 - Pankow, James S A1 - Uh, Hae-Won A1 - Wu, Ying A1 - Bidulescu, Aurelian A1 - Rasmussen-Torvik, Laura J A1 - Greenwood, Celia M T A1 - Ladouceur, Martin A1 - Grimsby, Jonna A1 - Manning, Alisa K A1 - Liu, Ching-Ti A1 - Kooner, Jaspal A1 - Mooser, Vincent E A1 - Vollenweider, Peter A1 - Kapur, Karen A A1 - Chambers, John A1 - Wareham, Nicholas J A1 - Langenberg, Claudia A1 - Frants, Rune A1 - Willems-Vandijk, Ko A1 - Oostra, Ben A A1 - Willems, Sara M A1 - Lamina, Claudia A1 - Winkler, Thomas W A1 - Psaty, Bruce M A1 - Tracy, Russell P A1 - Brody, Jennifer A1 - Chen, Ida A1 - Viikari, Jorma A1 - Kähönen, Mika A1 - Pramstaller, Peter P A1 - Evans, David M A1 - St Pourcain, Beate A1 - Sattar, Naveed A1 - Wood, Andrew R A1 - Bandinelli, Stefania A1 - Carlson, Olga D A1 - Egan, Josephine M A1 - Böhringer, Stefan A1 - van Heemst, Diana A1 - Kedenko, Lyudmyla A1 - Kristiansson, Kati A1 - Nuotio, Marja-Liisa A1 - Loo, Britt-Marie A1 - Harris, Tamara A1 - Garcia, Melissa A1 - Kanaya, Alka A1 - Haun, Margot A1 - Klopp, Norman A1 - Wichmann, H-Erich A1 - Deloukas, Panos A1 - Katsareli, Efi A1 - Couper, David J A1 - Duncan, Bruce B A1 - Kloppenburg, Margreet A1 - Adair, Linda S A1 - Borja, Judith B A1 - Wilson, James G A1 - Musani, Solomon A1 - Guo, Xiuqing A1 - Johnson, Toby A1 - Semple, Robert A1 - Teslovich, Tanya M A1 - Allison, Matthew A A1 - Redline, Susan A1 - Buxbaum, Sarah G A1 - Mohlke, Karen L A1 - Meulenbelt, Ingrid A1 - Ballantyne, Christie M A1 - Dedoussis, George V A1 - Hu, Frank B A1 - Liu, Yongmei A1 - Paulweber, Bernhard A1 - Spector, Timothy D A1 - Slagboom, P Eline A1 - Ferrucci, Luigi A1 - Jula, Antti A1 - Perola, Markus A1 - Raitakari, Olli A1 - Florez, Jose C A1 - Salomaa, Veikko A1 - Eriksson, Johan G A1 - Frayling, Timothy M A1 - Hicks, Andrew A A1 - Lehtimäki, Terho A1 - Smith, George Davey A1 - Siscovick, David S A1 - Kronenberg, Florian A1 - van Duijn, Cornelia A1 - Loos, Ruth J F A1 - Waterworth, Dawn M A1 - Meigs, James B A1 - Dupuis, Josée A1 - Richards, J Brent A1 - Voight, Benjamin F A1 - Scott, Laura J A1 - Steinthorsdottir, Valgerdur A1 - Dina, Christian A1 - Welch, Ryan P A1 - Zeggini, Eleftheria A1 - Huth, Cornelia A1 - Aulchenko, Yurii S A1 - Thorleifsson, Gudmar A1 - McCulloch, Laura J A1 - Ferreira, Teresa A1 - Grallert, Harald A1 - Amin, Najaf A1 - Wu, Guanming A1 - Willer, Cristen J A1 - Raychaudhuri, Soumya A1 - McCarroll, Steve A A1 - Hofmann, Oliver M A1 - Segrè, Ayellet V A1 - van Hoek, Mandy A1 - Navarro, Pau A1 - Ardlie, Kristin A1 - Balkau, Beverley A1 - Benediktsson, Rafn A1 - Bennett, Amanda J A1 - Blagieva, Roza A1 - Boerwinkle, Eric A1 - Bonnycastle, Lori L A1 - Boström, Kristina Bengtsson A1 - Bravenboer, Bert A1 - Bumpstead, Suzannah A1 - Burtt, Noel P A1 - Charpentier, Guillaume A1 - Chines, Peter S A1 - Cornelis, Marilyn A1 - Crawford, Gabe A1 - Doney, Alex S F A1 - Elliott, Katherine S A1 - Elliott, Amanda L A1 - Erdos, Michael R A1 - Fox, Caroline S A1 - Franklin, Christopher S A1 - Ganser, Martha A1 - Gieger, Christian A1 - Grarup, Niels A1 - Green, Todd A1 - Griffin, Simon A1 - Groves, Christopher J A1 - Guiducci, Candace A1 - Hadjadj, Samy A1 - Hassanali, Neelam A1 - Herder, Christian A1 - Isomaa, Bo A1 - Jackson, Anne U A1 - Johnson, Paul R V A1 - Jørgensen, Torben A1 - Kao, Wen H L A1 - Kong, Augustine A1 - Kraft, Peter A1 - Kuusisto, Johanna A1 - Lauritzen, Torsten A1 - Li, Man A1 - Lieverse, Aloysius A1 - Lindgren, Cecilia M A1 - Lyssenko, Valeriya A1 - Marre, Michel A1 - Meitinger, Thomas A1 - Midthjell, Kristian A1 - Morken, Mario A A1 - Narisu, Narisu A1 - Nilsson, Peter A1 - Owen, Katharine R A1 - Payne, Felicity A1 - Petersen, Ann-Kristin A1 - Platou, Carl A1 - Proença, Christine A1 - Prokopenko, Inga A1 - Rathmann, Wolfgang A1 - Rayner, N William A1 - Robertson, Neil R A1 - Rocheleau, Ghislain A1 - Roden, Michael A1 - Sampson, Michael J A1 - Saxena, Richa A1 - Shields, Beverley M A1 - Shrader, Peter A1 - Sigurdsson, Gunnar A1 - Sparsø, Thomas A1 - Strassburger, Klaus A1 - Stringham, Heather M A1 - Sun, Qi A1 - Swift, Amy J A1 - Thorand, Barbara A1 - Tichet, Jean A1 - Tuomi, Tiinamaija A1 - van Dam, Rob M A1 - van Haeften, Timon W A1 - van Herpt, Thijs A1 - van Vliet-Ostaptchouk, Jana V A1 - Walters, G Bragi A1 - Weedon, Michael N A1 - Wijmenga, Cisca A1 - Witteman, Jacqueline A1 - Bergman, Richard N A1 - Cauchi, Stephane A1 - Collins, Francis S A1 - Gloyn, Anna L A1 - Gyllensten, Ulf A1 - Hansen, Torben A1 - Hide, Winston A A1 - Hitman, Graham A A1 - Hofman, Albert A1 - Hunter, David J A1 - Hveem, Kristian A1 - Laakso, Markku A1 - Morris, Andrew D A1 - Palmer, Colin N A A1 - Rudan, Igor A1 - Sijbrands, Eric A1 - Stein, Lincoln D A1 - Tuomilehto, Jaakko A1 - Uitterlinden, Andre A1 - Walker, Mark A1 - Watanabe, Richard M A1 - Abecasis, Goncalo R A1 - Boehm, Bernhard O A1 - Campbell, Harry A1 - Daly, Mark J A1 - Hattersley, Andrew T A1 - Pedersen, Oluf A1 - Barroso, Inês A1 - Groop, Leif A1 - Sladek, Rob A1 - Thorsteinsdottir, Unnur A1 - Wilson, James F A1 - Illig, Thomas A1 - Froguel, Philippe A1 - van Duijn, Cornelia M A1 - Stefansson, Kari A1 - Altshuler, David A1 - Boehnke, Michael A1 - McCarthy, Mark I A1 - Soranzo, Nicole A1 - Wheeler, Eleanor A1 - Glazer, Nicole L A1 - Bouatia-Naji, Nabila A1 - Mägi, Reedik A1 - Randall, Joshua A1 - Elliott, Paul A1 - Rybin, Denis A1 - Dehghan, Abbas A1 - Hottenga, Jouke Jan A1 - Song, Kijoung A1 - Goel, Anuj A1 - Lajunen, Taina A1 - Doney, Alex A1 - Cavalcanti-Proença, Christine A1 - Kumari, Meena A1 - Timpson, Nicholas J A1 - Zabena, Carina A1 - Ingelsson, Erik A1 - An, Ping A1 - O'Connell, Jeffrey A1 - Luan, Jian'an A1 - Elliott, Amanda A1 - McCarroll, Steven A A1 - Roccasecca, Rosa Maria A1 - Pattou, François A1 - Sethupathy, Praveen A1 - Ariyurek, Yavuz A1 - Barter, Philip A1 - Beilby, John P A1 - Ben-Shlomo, Yoav A1 - Bergmann, Sven A1 - Bochud, Murielle A1 - Bonnefond, Amélie A1 - Borch-Johnsen, Knut A1 - Böttcher, Yvonne A1 - Brunner, Eric A1 - Bumpstead, Suzannah J A1 - Chen, Yii-Der Ida A1 - Chines, Peter A1 - Clarke, Robert A1 - Coin, Lachlan J M A1 - Cooper, Matthew N A1 - Crisponi, Laura A1 - Day, Ian N M A1 - de Geus, Eco J C A1 - Delplanque, Jerome A1 - Fedson, Annette C A1 - Fischer-Rosinsky, Antje A1 - Forouhi, Nita G A1 - Franzosi, Maria Grazia A1 - Galan, Pilar A1 - Goodarzi, Mark O A1 - Graessler, Jürgen A1 - Grundy, Scott A1 - Gwilliam, Rhian A1 - Hallmans, Göran A1 - Hammond, Naomi A1 - Han, Xijing A1 - Hartikainen, Anna-Liisa A1 - Hayward, Caroline A1 - Heath, Simon C A1 - Hercberg, Serge A1 - Hillman, David R A1 - Hingorani, Aroon D A1 - Hui, Jennie A1 - Hung, Joe A1 - Kaakinen, Marika A1 - Kaprio, Jaakko A1 - Kesaniemi, Y Antero A1 - Kivimaki, Mika A1 - Knight, Beatrice A1 - Koskinen, Seppo A1 - Kovacs, Peter A1 - Kyvik, Kirsten Ohm A1 - Lathrop, G Mark A1 - Lawlor, Debbie A A1 - Le Bacquer, Olivier A1 - Lecoeur, Cécile A1 - Li, Yun A1 - Mahley, Robert A1 - Mangino, Massimo A1 - Martínez-Larrad, María Teresa A1 - McAteer, Jarred B A1 - McPherson, Ruth A1 - Meisinger, Christa A1 - Melzer, David A1 - Meyre, David A1 - Mitchell, Braxton D A1 - Mukherjee, Sutapa A1 - Naitza, Silvia A1 - Neville, Matthew J A1 - Orrù, Marco A1 - Pakyz, Ruth A1 - Paolisso, Giuseppe A1 - Pattaro, Cristian A1 - Pearson, Daniel A1 - Peden, John F A1 - Pedersen, Nancy L A1 - Pfeiffer, Andreas F H A1 - Pichler, Irene A1 - Polasek, Ozren A1 - Posthuma, Danielle A1 - Potter, Simon C A1 - Pouta, Anneli A1 - Province, Michael A A1 - Rayner, Nigel W A1 - Rice, Kenneth A1 - Ripatti, Samuli A1 - Rivadeneira, Fernando A1 - Rolandsson, Olov A1 - Sandbaek, Annelli A1 - Sandhu, Manjinder A1 - Sanna, Serena A1 - Sayer, Avan Aihie A1 - Scheet, Paul A1 - Seedorf, Udo A1 - Sharp, Stephen J A1 - Shields, Beverley A1 - Sigurðsson, Gunnar A1 - Sijbrands, Eric J G A1 - Silveira, Angela A1 - Simpson, Laila A1 - Singleton, Andrew A1 - Smith, Nicholas L A1 - Sovio, Ulla A1 - Swift, Amy A1 - Syddall, Holly A1 - Syvänen, Ann-Christine A1 - Tönjes, Anke A1 - Uitterlinden, André G A1 - van Dijk, Ko Willems A1 - Varma, Dhiraj A1 - Visvikis-Siest, Sophie A1 - Vitart, Veronique A1 - Vogelzangs, Nicole A1 - Waeber, Gérard A1 - Wagner, Peter J A1 - Walley, Andrew A1 - Ward, Kim L A1 - Watkins, Hugh A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Witteman, Jaqueline C M A1 - Yarnell, John W G A1 - Zelenika, Diana A1 - Zethelius, Björn A1 - Zhai, Guangju A1 - Zhao, Jing Hua A1 - Zillikens, M Carola A1 - Borecki, Ingrid B A1 - Meneton, Pierre A1 - Magnusson, Patrik K E A1 - Nathan, David M A1 - Williams, Gordon H A1 - Silander, Kaisa A1 - Bornstein, Stefan R A1 - Schwarz, Peter A1 - Spranger, Joachim A1 - Karpe, Fredrik A1 - Shuldiner, Alan R A1 - Cooper, Cyrus A1 - Serrano-Ríos, Manuel A1 - Lind, Lars A1 - Palmer, Lyle J A1 - Hu, Frank B A1 - Franks, Paul W A1 - Ebrahim, Shah A1 - Marmot, Michael A1 - Kao, W H Linda A1 - Pramstaller, Peter Paul A1 - Wright, Alan F A1 - Stumvoll, Michael A1 - Hamsten, Anders A1 - Buchanan, Thomas A A1 - Valle, Timo T A1 - Rotter, Jerome I A1 - Penninx, Brenda W J H A1 - Boomsma, Dorret I A1 - Cao, Antonio A1 - Scuteri, Angelo A1 - Schlessinger, David A1 - Uda, Manuela A1 - Ruokonen, Aimo A1 - Jarvelin, Marjo-Riitta A1 - Peltonen, Leena A1 - Mooser, Vincent A1 - Sladek, Robert A1 - Musunuru, Kiran A1 - Smith, Albert V A1 - Edmondson, Andrew C A1 - Stylianou, Ioannis M A1 - Koseki, Masahiro A1 - Pirruccello, James P A1 - Chasman, Daniel I A1 - Johansen, Christopher T A1 - Fouchier, Sigrid W A1 - Peloso, Gina M A1 - Barbalic, Maja A1 - Ricketts, Sally L A1 - Bis, Joshua C A1 - Feitosa, Mary F A1 - Orho-Melander, Marju A1 - Melander, Olle A1 - Li, Xiaohui A1 - Li, Mingyao A1 - Cho, Yoon Shin A1 - Go, Min Jin A1 - Kim, Young Jin A1 - Lee, Jong-Young A1 - Park, Taesung A1 - Kim, Kyunga A1 - Sim, Xueling A1 - Ong, Rick Twee-Hee A1 - Croteau-Chonka, Damien C A1 - Lange, Leslie A A1 - Smith, Joshua D A1 - Ziegler, Andreas A1 - Zhang, Weihua A1 - Zee, Robert Y L A1 - Whitfield, John B A1 - Thompson, John R A1 - Surakka, Ida A1 - Spector, Tim D A1 - Smit, Johannes H A1 - Sinisalo, Juha A1 - Scott, James A1 - Saharinen, Juha A1 - Sabatti, Chiara A1 - Rose, Lynda M A1 - Roberts, Robert A1 - Rieder, Mark A1 - Parker, Alex N A1 - Paré, Guillaume A1 - O'Donnell, Christopher J A1 - Nieminen, Markku S A1 - Nickerson, Deborah A A1 - Montgomery, Grant W A1 - McArdle, Wendy A1 - Masson, David A1 - Martin, Nicholas G A1 - Marroni, Fabio A1 - Lucas, Gavin A1 - Luben, Robert A1 - Lokki, Marja-Liisa A1 - Lettre, Guillaume A1 - Launer, Lenore J A1 - Lakatta, Edward G A1 - Laaksonen, Reijo A1 - Kyvik, Kirsten O A1 - König, Inke R A1 - Khaw, Kay-Tee A1 - Kaplan, Lee M A1 - Johansson, Asa A1 - Janssens, A Cecile J W A1 - Igl, Wilmar A1 - Hovingh, G Kees A1 - Hengstenberg, Christian A1 - Havulinna, Aki S A1 - Hastie, Nicholas D A1 - Harris, Tamara B A1 - Haritunians, Talin A1 - Hall, Alistair S A1 - Groop, Leif C A1 - Gonzalez, Elena A1 - Freimer, Nelson B A1 - Erdmann, Jeanette A1 - Ejebe, Kenechi G A1 - Döring, Angela A1 - Dominiczak, Anna F A1 - Demissie, Serkalem A1 - Deloukas, Panagiotis A1 - de Faire, Ulf A1 - Crawford, Gabriel A1 - Chen, Yii-der I A1 - Caulfield, Mark J A1 - Boekholdt, S Matthijs A1 - Assimes, Themistocles L A1 - Quertermous, Thomas A1 - Seielstad, Mark A1 - Wong, Tien Y A1 - Tai, E-Shyong A1 - Feranil, Alan B A1 - Kuzawa, Christopher W A1 - Taylor, Herman A A1 - Gabriel, Stacey B A1 - Holm, Hilma A1 - Gudnason, Vilmundur A1 - Krauss, Ronald M A1 - Ordovas, Jose M A1 - Munroe, Patricia B A1 - Kooner, Jaspal S A1 - Tall, Alan R A1 - Hegele, Robert A A1 - Kastelein, John J P A1 - Schadt, Eric E A1 - Strachan, David P A1 - Reilly, Muredach P A1 - Samani, Nilesh J A1 - Schunkert, Heribert A1 - Cupples, L Adrienne A1 - Sandhu, Manjinder S A1 - Ridker, Paul M A1 - Rader, Daniel J A1 - Kathiresan, Sekar KW - Adiponectin KW - African Americans KW - Asian Continental Ancestry Group KW - Cholesterol, HDL KW - Diabetes Mellitus, Type 2 KW - European Continental Ancestry Group KW - Female KW - Gene Expression KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Glucose Tolerance Test KW - Humans KW - Insulin Resistance KW - Male KW - Metabolic Networks and Pathways KW - Polymorphism, Single Nucleotide KW - Waist-Hip Ratio AB -

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

VL - 8 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22479202?dopt=Abstract ER - TY - JOUR T1 - Common variants in Mendelian kidney disease genes and their association with renal function. JF - J Am Soc Nephrol Y1 - 2013 A1 - Parsa, Afshin A1 - Fuchsberger, Christian A1 - Köttgen, Anna A1 - O'Seaghdha, Conall M A1 - Pattaro, Cristian A1 - de Andrade, Mariza A1 - Chasman, Daniel I A1 - Teumer, Alexander A1 - Endlich, Karlhans A1 - Olden, Matthias A1 - Chen, Ming-Huei A1 - Tin, Adrienne A1 - Kim, Young J A1 - Taliun, Daniel A1 - Li, Man A1 - Feitosa, Mary A1 - Gorski, Mathias A1 - Yang, Qiong A1 - Hundertmark, Claudia A1 - Foster, Meredith C A1 - Glazer, Nicole A1 - Isaacs, Aaron A1 - Rao, Madhumathi A1 - Smith, Albert V A1 - O'Connell, Jeffrey R A1 - Struchalin, Maksim A1 - Tanaka, Toshiko A1 - Li, Guo A1 - Hwang, Shih-Jen A1 - Atkinson, Elizabeth J A1 - Lohman, Kurt A1 - Cornelis, Marilyn C A1 - Johansson, Asa A1 - Tönjes, Anke A1 - Dehghan, Abbas A1 - Couraki, Vincent A1 - Holliday, Elizabeth G A1 - Sorice, Rossella A1 - Kutalik, Zoltán A1 - Lehtimäki, Terho A1 - Esko, Tõnu A1 - Deshmukh, Harshal A1 - Ulivi, Sheila A1 - Chu, Audrey Y A1 - Murgia, Federico A1 - Trompet, Stella A1 - Imboden, Medea A1 - Kollerits, Barbara A1 - Pistis, Giorgio A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Mitchell, Braxton D A1 - Boerwinkle, Eric A1 - Schmidt, Helena A1 - Hofer, Edith A1 - Hu, Frank A1 - Demirkan, Ayse A1 - Oostra, Ben A A1 - Turner, Stephen T A1 - Ding, Jingzhong A1 - Andrews, Jeanette S A1 - Freedman, Barry I A1 - Giulianini, Franco A1 - Koenig, Wolfgang A1 - Illig, Thomas A1 - Döring, Angela A1 - Wichmann, H-Erich A1 - Zgaga, Lina A1 - Zemunik, Tatijana A1 - Boban, Mladen A1 - Minelli, Cosetta A1 - Wheeler, Heather E A1 - Igl, Wilmar A1 - Zaboli, Ghazal A1 - Wild, Sarah H A1 - Wright, Alan F A1 - Campbell, Harry A1 - Ellinghaus, David A1 - Nöthlings, Ute A1 - Jacobs, Gunnar A1 - Biffar, Reiner A1 - Ernst, Florian A1 - Homuth, Georg A1 - Kroemer, Heyo K A1 - Nauck, Matthias A1 - Stracke, Sylvia A1 - Völker, Uwe A1 - Völzke, Henry A1 - Kovacs, Peter A1 - Stumvoll, Michael A1 - Mägi, Reedik A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Aulchenko, Yurii S A1 - Polasek, Ozren A1 - Hastie, Nick A1 - Vitart, Veronique A1 - Helmer, Catherine A1 - Wang, Jie Jin A1 - Stengel, Bénédicte A1 - Ruggiero, Daniela A1 - Bergmann, Sven A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Nikopensius, Tiit A1 - Province, Michael A1 - Colhoun, Helen A1 - Doney, Alex A1 - Robino, Antonietta A1 - Krämer, Bernhard K A1 - Portas, Laura A1 - Ford, Ian A1 - Buckley, Brendan M A1 - Adam, Martin A1 - Thun, Gian-Andri A1 - Paulweber, Bernhard A1 - Haun, Margot A1 - Sala, Cinzia A1 - Mitchell, Paul A1 - Ciullo, Marina A1 - Vollenweider, Peter A1 - Raitakari, Olli A1 - Metspalu, Andres A1 - Palmer, Colin A1 - Gasparini, Paolo A1 - Pirastu, Mario A1 - Jukema, J Wouter A1 - Probst-Hensch, Nicole M A1 - Kronenberg, Florian A1 - Toniolo, Daniela A1 - Gudnason, Vilmundur A1 - Shuldiner, Alan R A1 - Coresh, Josef A1 - Schmidt, Reinhold A1 - Ferrucci, Luigi A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid A1 - Kardia, Sharon L R A1 - Liu, Yongmei A1 - Curhan, Gary C A1 - Rudan, Igor A1 - Gyllensten, Ulf A1 - Wilson, James F A1 - Franke, Andre A1 - Pramstaller, Peter P A1 - Rettig, Rainer A1 - Prokopenko, Inga A1 - Witteman, Jacqueline A1 - Hayward, Caroline A1 - Ridker, Paul M A1 - Bochud, Murielle A1 - Heid, Iris M A1 - Siscovick, David S A1 - Fox, Caroline S A1 - Kao, W Linda A1 - Böger, Carsten A KW - Databases, Genetic KW - European Continental Ancestry Group KW - Gene Frequency KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Kidney KW - Mendelian Randomization Analysis KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Renal Insufficiency, Chronic AB -

Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.

VL - 24 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24029420?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association of body fat distribution in African ancestry populations suggests new loci. JF - PLoS Genet Y1 - 2013 A1 - Liu, Ching-Ti A1 - Monda, Keri L A1 - Taylor, Kira C A1 - Lange, Leslie A1 - Demerath, Ellen W A1 - Palmas, Walter A1 - Wojczynski, Mary K A1 - Ellis, Jaclyn C A1 - Vitolins, Mara Z A1 - Liu, Simin A1 - Papanicolaou, George J A1 - Irvin, Marguerite R A1 - Xue, Luting A1 - Griffin, Paula J A1 - Nalls, Michael A A1 - Adeyemo, Adebowale A1 - Liu, Jiankang A1 - Li, Guo A1 - Ruiz-Narvaez, Edward A A1 - Chen, Wei-Min A1 - Chen, Fang A1 - Henderson, Brian E A1 - Millikan, Robert C A1 - Ambrosone, Christine B A1 - Strom, Sara S A1 - Guo, Xiuqing A1 - Andrews, Jeanette S A1 - Sun, Yan V A1 - Mosley, Thomas H A1 - Yanek, Lisa R A1 - Shriner, Daniel A1 - Haritunians, Talin A1 - Rotter, Jerome I A1 - Speliotes, Elizabeth K A1 - Smith, Megan A1 - Rosenberg, Lynn A1 - Mychaleckyj, Josyf A1 - Nayak, Uma A1 - Spruill, Ida A1 - Garvey, W Timothy A1 - Pettaway, Curtis A1 - Nyante, Sarah A1 - Bandera, Elisa V A1 - Britton, Angela F A1 - Zonderman, Alan B A1 - Rasmussen-Torvik, Laura J A1 - Chen, Yii-Der Ida A1 - Ding, Jingzhong A1 - Lohman, Kurt A1 - Kritchevsky, Stephen B A1 - Zhao, Wei A1 - Peyser, Patricia A A1 - Kardia, Sharon L R A1 - Kabagambe, Edmond A1 - Broeckel, Ulrich A1 - Chen, Guanjie A1 - Zhou, Jie A1 - Wassertheil-Smoller, Sylvia A1 - Neuhouser, Marian L A1 - Rampersaud, Evadnie A1 - Psaty, Bruce A1 - Kooperberg, Charles A1 - Manson, JoAnn E A1 - Kuller, Lewis H A1 - Ochs-Balcom, Heather M A1 - Johnson, Karen C A1 - Sucheston, Lara A1 - Ordovas, Jose M A1 - Palmer, Julie R A1 - Haiman, Christopher A A1 - McKnight, Barbara A1 - Howard, Barbara V A1 - Becker, Diane M A1 - Bielak, Lawrence F A1 - Liu, Yongmei A1 - Allison, Matthew A A1 - Grant, Struan F A A1 - Burke, Gregory L A1 - Patel, Sanjay R A1 - Schreiner, Pamela J A1 - Borecki, Ingrid B A1 - Evans, Michele K A1 - Taylor, Herman A1 - Sale, Michèle M A1 - Howard, Virginia A1 - Carlson, Christopher S A1 - Rotimi, Charles N A1 - Cushman, Mary A1 - Harris, Tamara B A1 - Reiner, Alexander P A1 - Cupples, L Adrienne A1 - North, Kari E A1 - Fox, Caroline S KW - Adiposity KW - African Continental Ancestry Group KW - Body Fat Distribution KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Male KW - Obesity KW - Polymorphism, Single Nucleotide KW - Waist-Hip Ratio AB -

Central obesity, measured by waist circumference (WC) or waist-hip ratio (WHR), is a marker of body fat distribution. Although obesity disproportionately affects minority populations, few studies have conducted genome-wide association study (GWAS) of fat distribution among those of predominantly African ancestry (AA). We performed GWAS of WC and WHR, adjusted and unadjusted for BMI, in up to 33,591 and 27,350 AA individuals, respectively. We identified loci associated with fat distribution in AA individuals using meta-analyses of GWA results for WC and WHR (stage 1). Overall, 25 SNPs with single genomic control (GC)-corrected p-values<5.0 × 10(-6) were followed-up (stage 2) in AA with WC and with WHR. Additionally, we interrogated genomic regions of previously identified European ancestry (EA) WHR loci among AA. In joint analysis of association results including both Stage 1 and 2 cohorts, 2 SNPs demonstrated association, rs2075064 at LHX2, p = 2.24×10(-8) for WC-adjusted-for-BMI, and rs6931262 at RREB1, p = 2.48×10(-8) for WHR-adjusted-for-BMI. However, neither signal was genome-wide significant after double GC-correction (LHX2: p = 6.5 × 10(-8); RREB1: p = 5.7 × 10(-8)). Six of fourteen previously reported loci for waist in EA populations were significant (p<0.05 divided by the number of independent SNPs within the region) in AA studied here (TBX15-WARS2, GRB14, ADAMTS9, LY86, RSPO3, ITPR2-SSPN). Further, we observed associations with metabolic traits: rs13389219 at GRB14 associated with HDL-cholesterol, triglycerides, and fasting insulin, and rs13060013 at ADAMTS9 with HDL-cholesterol and fasting insulin. Finally, we observed nominal evidence for sexual dimorphism, with stronger results in AA women at the GRB14 locus (p for interaction = 0.02). In conclusion, we identified two suggestive loci associated with fat distribution in AA populations in addition to confirming 6 loci previously identified in populations of EA. These findings reinforce the concept that there are fat distribution loci that are independent of generalized adiposity.

VL - 9 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23966867?dopt=Abstract ER - TY - JOUR T1 - A meta-analysis identifies new loci associated with body mass index in individuals of African ancestry. JF - Nat Genet Y1 - 2013 A1 - Monda, Keri L A1 - Chen, Gary K A1 - Taylor, Kira C A1 - Palmer, Cameron A1 - Edwards, Todd L A1 - Lange, Leslie A A1 - Ng, Maggie C Y A1 - Adeyemo, Adebowale A A1 - Allison, Matthew A A1 - Bielak, Lawrence F A1 - Chen, Guanjie A1 - Graff, Mariaelisa A1 - Irvin, Marguerite R A1 - Rhie, Suhn K A1 - Li, Guo A1 - Liu, Yongmei A1 - Liu, Youfang A1 - Lu, Yingchang A1 - Nalls, Michael A A1 - Sun, Yan V A1 - Wojczynski, Mary K A1 - Yanek, Lisa R A1 - Aldrich, Melinda C A1 - Ademola, Adeyinka A1 - Amos, Christopher I A1 - Bandera, Elisa V A1 - Bock, Cathryn H A1 - Britton, Angela A1 - Broeckel, Ulrich A1 - Cai, Quiyin A1 - Caporaso, Neil E A1 - Carlson, Chris S A1 - Carpten, John A1 - Casey, Graham A1 - Chen, Wei-Min A1 - Chen, Fang A1 - Chen, Yii-der I A1 - Chiang, Charleston W K A1 - Coetzee, Gerhard A A1 - Demerath, Ellen A1 - Deming-Halverson, Sandra L A1 - Driver, Ryan W A1 - Dubbert, Patricia A1 - Feitosa, Mary F A1 - Feng, Ye A1 - Freedman, Barry I A1 - Gillanders, Elizabeth M A1 - Gottesman, Omri A1 - Guo, Xiuqing A1 - Haritunians, Talin A1 - Harris, Tamara A1 - Harris, Curtis C A1 - Hennis, Anselm J M A1 - Hernandez, Dena G A1 - McNeill, Lorna H A1 - Howard, Timothy D A1 - Howard, Barbara V A1 - Howard, Virginia J A1 - Johnson, Karen C A1 - Kang, Sun J A1 - Keating, Brendan J A1 - Kolb, Suzanne A1 - Kuller, Lewis H A1 - Kutlar, Abdullah A1 - Langefeld, Carl D A1 - Lettre, Guillaume A1 - Lohman, Kurt A1 - Lotay, Vaneet A1 - Lyon, Helen A1 - Manson, JoAnn E A1 - Maixner, William A1 - Meng, Yan A A1 - Monroe, Kristine R A1 - Morhason-Bello, Imran A1 - Murphy, Adam B A1 - Mychaleckyj, Josyf C A1 - Nadukuru, Rajiv A1 - Nathanson, Katherine L A1 - Nayak, Uma A1 - N'diaye, Amidou A1 - Nemesure, Barbara A1 - Wu, Suh-Yuh A1 - Leske, M Cristina A1 - Neslund-Dudas, Christine A1 - Neuhouser, Marian A1 - Nyante, Sarah A1 - Ochs-Balcom, Heather A1 - Ogunniyi, Adesola A1 - Ogundiran, Temidayo O A1 - Ojengbede, Oladosu A1 - Olopade, Olufunmilayo I A1 - Palmer, Julie R A1 - Ruiz-Narvaez, Edward A A1 - Palmer, Nicholette D A1 - Press, Michael F A1 - Rampersaud, Evandine A1 - Rasmussen-Torvik, Laura J A1 - Rodriguez-Gil, Jorge L A1 - Salako, Babatunde A1 - Schadt, Eric E A1 - Schwartz, Ann G A1 - Shriner, Daniel A A1 - Siscovick, David A1 - Smith, Shad B A1 - Wassertheil-Smoller, Sylvia A1 - Speliotes, Elizabeth K A1 - Spitz, Margaret R A1 - Sucheston, Lara A1 - Taylor, Herman A1 - Tayo, Bamidele O A1 - Tucker, Margaret A A1 - Van Den Berg, David J A1 - Edwards, Digna R Velez A1 - Wang, Zhaoming A1 - Wiencke, John K A1 - Winkler, Thomas W A1 - Witte, John S A1 - Wrensch, Margaret A1 - Wu, Xifeng A1 - Yang, James J A1 - Levin, Albert M A1 - Young, Taylor R A1 - Zakai, Neil A A1 - Cushman, Mary A1 - Zanetti, Krista A A1 - Zhao, Jing Hua A1 - Zhao, Wei A1 - Zheng, Yonglan A1 - Zhou, Jie A1 - Ziegler, Regina G A1 - Zmuda, Joseph M A1 - Fernandes, Jyotika K A1 - Gilkeson, Gary S A1 - Kamen, Diane L A1 - Hunt, Kelly J A1 - Spruill, Ida J A1 - Ambrosone, Christine B A1 - Ambs, Stefan A1 - Arnett, Donna K A1 - Atwood, Larry A1 - Becker, Diane M A1 - Berndt, Sonja I A1 - Bernstein, Leslie A1 - Blot, William J A1 - Borecki, Ingrid B A1 - Bottinger, Erwin P A1 - Bowden, Donald W A1 - Burke, Gregory A1 - Chanock, Stephen J A1 - Cooper, Richard S A1 - Ding, Jingzhong A1 - Duggan, David A1 - Evans, Michele K A1 - Fox, Caroline A1 - Garvey, W Timothy A1 - Bradfield, Jonathan P A1 - Hakonarson, Hakon A1 - Grant, Struan F A A1 - Hsing, Ann A1 - Chu, Lisa A1 - Hu, Jennifer J A1 - Huo, Dezheng A1 - Ingles, Sue A A1 - John, Esther M A1 - Jordan, Joanne M A1 - Kabagambe, Edmond K A1 - Kardia, Sharon L R A1 - Kittles, Rick A A1 - Goodman, Phyllis J A1 - Klein, Eric A A1 - Kolonel, Laurence N A1 - Le Marchand, Loïc A1 - Liu, Simin A1 - McKnight, Barbara A1 - Millikan, Robert C A1 - Mosley, Thomas H A1 - Padhukasahasram, Badri A1 - Williams, L Keoki A1 - Patel, Sanjay R A1 - Peters, Ulrike A1 - Pettaway, Curtis A A1 - Peyser, Patricia A A1 - Psaty, Bruce M A1 - Redline, Susan A1 - Rotimi, Charles N A1 - Rybicki, Benjamin A A1 - Sale, Michèle M A1 - Schreiner, Pamela J A1 - Signorello, Lisa B A1 - Singleton, Andrew B A1 - Stanford, Janet L A1 - Strom, Sara S A1 - Thun, Michael J A1 - Vitolins, Mara A1 - Zheng, Wei A1 - Moore, Jason H A1 - Williams, Scott M A1 - Ketkar, Shamika A1 - Zhu, Xiaofeng A1 - Zonderman, Alan B A1 - Kooperberg, Charles A1 - Papanicolaou, George J A1 - Henderson, Brian E A1 - Reiner, Alex P A1 - Hirschhorn, Joel N A1 - Loos, Ruth J F A1 - North, Kari E A1 - Haiman, Christopher A KW - African Americans KW - Body Mass Index KW - Case-Control Studies KW - Gene Frequency KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Linkage Disequilibrium KW - Obesity KW - Polymorphism, Single Nucleotide AB -

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 × 10(-11)) and another at 7p15 when we included data from the GIANT consortium (MIR148A-NFE2L3, rs10261878, P = 1.2 × 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 × 10(-8)). Thirty-two of the 36 previously established BMI variants showed directionally consistent effect estimates in our GWAS (binomial P = 9.7 × 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.

VL - 45 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23583978?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations. JF - PLoS Genet Y1 - 2013 A1 - O'Seaghdha, Conall M A1 - Wu, Hongsheng A1 - Yang, Qiong A1 - Kapur, Karen A1 - Guessous, Idris A1 - Zuber, Annie Mercier A1 - Köttgen, Anna A1 - Stoudmann, Candice A1 - Teumer, Alexander A1 - Kutalik, Zoltán A1 - Mangino, Massimo A1 - Dehghan, Abbas A1 - Zhang, Weihua A1 - Eiriksdottir, Gudny A1 - Li, Guo A1 - Tanaka, Toshiko A1 - Portas, Laura A1 - Lopez, Lorna M A1 - Hayward, Caroline A1 - Lohman, Kurt A1 - Matsuda, Koichi A1 - Padmanabhan, Sandosh A1 - Firsov, Dmitri A1 - Sorice, Rossella A1 - Ulivi, Sheila A1 - Brockhaus, A Catharina A1 - Kleber, Marcus E A1 - Mahajan, Anubha A1 - Ernst, Florian D A1 - Gudnason, Vilmundur A1 - Launer, Lenore J A1 - Mace, Aurelien A1 - Boerwinckle, Eric A1 - Arking, Dan E A1 - Tanikawa, Chizu A1 - Nakamura, Yusuke A1 - Brown, Morris J A1 - Gaspoz, Jean-Michel A1 - Theler, Jean-Marc A1 - Siscovick, David S A1 - Psaty, Bruce M A1 - Bergmann, Sven A1 - Vollenweider, Peter A1 - Vitart, Veronique A1 - Wright, Alan F A1 - Zemunik, Tatijana A1 - Boban, Mladen A1 - Kolcic, Ivana A1 - Navarro, Pau A1 - Brown, Edward M A1 - Estrada, Karol A1 - Ding, Jingzhong A1 - Harris, Tamara B A1 - Bandinelli, Stefania A1 - Hernandez, Dena A1 - Singleton, Andrew B A1 - Girotto, Giorgia A1 - Ruggiero, Daniela A1 - d'Adamo, Adamo Pio A1 - Robino, Antonietta A1 - Meitinger, Thomas A1 - Meisinger, Christa A1 - Davies, Gail A1 - Starr, John M A1 - Chambers, John C A1 - Boehm, Bernhard O A1 - Winkelmann, Bernhard R A1 - Huang, Jie A1 - Murgia, Federico A1 - Wild, Sarah H A1 - Campbell, Harry A1 - Morris, Andrew P A1 - Franco, Oscar H A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Völker, Uwe A1 - Hannemann, Anke A1 - Biffar, Reiner A1 - Hoffmann, Wolfgang A1 - Shin, So-Youn A1 - Lescuyer, Pierre A1 - Henry, Hughes A1 - Schurmann, Claudia A1 - Munroe, Patricia B A1 - Gasparini, Paolo A1 - Pirastu, Nicola A1 - Ciullo, Marina A1 - Gieger, Christian A1 - März, Winfried A1 - Lind, Lars A1 - Spector, Tim D A1 - Smith, Albert V A1 - Rudan, Igor A1 - Wilson, James F A1 - Polasek, Ozren A1 - Deary, Ian J A1 - Pirastu, Mario A1 - Ferrucci, Luigi A1 - Liu, Yongmei A1 - Kestenbaum, Bryan A1 - Kooner, Jaspal S A1 - Witteman, Jacqueline C M A1 - Nauck, Matthias A1 - Kao, W H Linda A1 - Wallaschofski, Henri A1 - Bonny, Olivier A1 - Fox, Caroline S A1 - Bochud, Murielle KW - Animals KW - Bone and Bones KW - Bone Density KW - Calcium KW - European Continental Ancestry Group KW - Gene Expression Regulation KW - Genome-Wide Association Study KW - Homeostasis KW - Humans KW - Kidney KW - Mice KW - Polymorphism, Single Nucleotide AB -

Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤ 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.

VL - 9 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24068962?dopt=Abstract ER - TY - JOUR T1 - Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks. JF - Am J Hum Genet Y1 - 2014 A1 - Peloso, Gina M A1 - Auer, Paul L A1 - Bis, Joshua C A1 - Voorman, Arend A1 - Morrison, Alanna C A1 - Stitziel, Nathan O A1 - Brody, Jennifer A A1 - Khetarpal, Sumeet A A1 - Crosby, Jacy R A1 - Fornage, Myriam A1 - Isaacs, Aaron A1 - Jakobsdottir, Johanna A1 - Feitosa, Mary F A1 - Davies, Gail A1 - Huffman, Jennifer E A1 - Manichaikul, Ani A1 - Davis, Brian A1 - Lohman, Kurt A1 - Joon, Aron Y A1 - Smith, Albert V A1 - Grove, Megan L A1 - Zanoni, Paolo A1 - Redon, Valeska A1 - Demissie, Serkalem A1 - Lawson, Kim A1 - Peters, Ulrike A1 - Carlson, Christopher A1 - Jackson, Rebecca D A1 - Ryckman, Kelli K A1 - Mackey, Rachel H A1 - Robinson, Jennifer G A1 - Siscovick, David S A1 - Schreiner, Pamela J A1 - Mychaleckyj, Josyf C A1 - Pankow, James S A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Harris, Tamara B A1 - Taylor, Kent D A1 - Stafford, Jeanette M A1 - Reynolds, Lindsay M A1 - Marioni, Riccardo E A1 - Dehghan, Abbas A1 - Franco, Oscar H A1 - Patel, Aniruddh P A1 - Lu, Yingchang A1 - Hindy, George A1 - Gottesman, Omri A1 - Bottinger, Erwin P A1 - Melander, Olle A1 - Orho-Melander, Marju A1 - Loos, Ruth J F A1 - Duga, Stefano A1 - Merlini, Piera Angelica A1 - Farrall, Martin A1 - Goel, Anuj A1 - Asselta, Rosanna A1 - Girelli, Domenico A1 - Martinelli, Nicola A1 - Shah, Svati H A1 - Kraus, William E A1 - Li, Mingyao A1 - Rader, Daniel J A1 - Reilly, Muredach P A1 - McPherson, Ruth A1 - Watkins, Hugh A1 - Ardissino, Diego A1 - Zhang, Qunyuan A1 - Wang, Judy A1 - Tsai, Michael Y A1 - Taylor, Herman A A1 - Correa, Adolfo A1 - Griswold, Michael E A1 - Lange, Leslie A A1 - Starr, John M A1 - Rudan, Igor A1 - Eiriksdottir, Gudny A1 - Launer, Lenore J A1 - Ordovas, Jose M A1 - Levy, Daniel A1 - Chen, Y-D Ida A1 - Reiner, Alexander P A1 - Hayward, Caroline A1 - Polasek, Ozren A1 - Deary, Ian J A1 - Borecki, Ingrid B A1 - Liu, Yongmei A1 - Gudnason, Vilmundur A1 - Wilson, James G A1 - van Duijn, Cornelia M A1 - Kooperberg, Charles A1 - Rich, Stephen S A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - O'Donnell, Christopher J A1 - Rice, Kenneth A1 - Boerwinkle, Eric A1 - Kathiresan, Sekar A1 - Cupples, L Adrienne KW - 1-Alkyl-2-acetylglycerophosphocholine Esterase KW - Adult KW - African Continental Ancestry Group KW - Aged KW - Alleles KW - Animals KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Cohort Studies KW - Coronary Disease KW - European Continental Ancestry Group KW - Female KW - Gene Frequency KW - Genetic Association Studies KW - Genetic Code KW - Genetic Variation KW - Humans KW - Linear Models KW - Male KW - Mice KW - Mice, Inbred C57BL KW - Microtubule-Associated Proteins KW - Middle Aged KW - Phenotype KW - Sequence Analysis, DNA KW - Subtilisins KW - Triglycerides AB -

Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121*], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.

VL - 94 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24507774?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association analysis identifies six new loci associated with forced vital capacity. JF - Nat Genet Y1 - 2014 A1 - Loth, Daan W A1 - Soler Artigas, Maria A1 - Gharib, Sina A A1 - Wain, Louise V A1 - Franceschini, Nora A1 - Koch, Beate A1 - Pottinger, Tess D A1 - Smith, Albert Vernon A1 - Duan, Qing A1 - Oldmeadow, Chris A1 - Lee, Mi Kyeong A1 - Strachan, David P A1 - James, Alan L A1 - Huffman, Jennifer E A1 - Vitart, Veronique A1 - Ramasamy, Adaikalavan A1 - Wareham, Nicholas J A1 - Kaprio, Jaakko A1 - Wang, Xin-Qun A1 - Trochet, Holly A1 - Kähönen, Mika A1 - Flexeder, Claudia A1 - Albrecht, Eva A1 - Lopez, Lorna M A1 - de Jong, Kim A1 - Thyagarajan, Bharat A1 - Alves, Alexessander Couto A1 - Enroth, Stefan A1 - Omenaas, Ernst A1 - Joshi, Peter K A1 - Fall, Tove A1 - Viñuela, Ana A1 - Launer, Lenore J A1 - Loehr, Laura R A1 - Fornage, Myriam A1 - Li, Guo A1 - Wilk, Jemma B A1 - Tang, Wenbo A1 - Manichaikul, Ani A1 - Lahousse, Lies A1 - Harris, Tamara B A1 - North, Kari E A1 - Rudnicka, Alicja R A1 - Hui, Jennie A1 - Gu, Xiangjun A1 - Lumley, Thomas A1 - Wright, Alan F A1 - Hastie, Nicholas D A1 - Campbell, Susan A1 - Kumar, Rajesh A1 - Pin, Isabelle A1 - Scott, Robert A A1 - Pietiläinen, Kirsi H A1 - Surakka, Ida A1 - Liu, Yongmei A1 - Holliday, Elizabeth G A1 - Schulz, Holger A1 - Heinrich, Joachim A1 - Davies, Gail A1 - Vonk, Judith M A1 - Wojczynski, Mary A1 - Pouta, Anneli A1 - Johansson, Asa A1 - Wild, Sarah H A1 - Ingelsson, Erik A1 - Rivadeneira, Fernando A1 - Völzke, Henry A1 - Hysi, Pirro G A1 - Eiriksdottir, Gudny A1 - Morrison, Alanna C A1 - Rotter, Jerome I A1 - Gao, Wei A1 - Postma, Dirkje S A1 - White, Wendy B A1 - Rich, Stephen S A1 - Hofman, Albert A1 - Aspelund, Thor A1 - Couper, David A1 - Smith, Lewis J A1 - Psaty, Bruce M A1 - Lohman, Kurt A1 - Burchard, Esteban G A1 - Uitterlinden, André G A1 - Garcia, Melissa A1 - Joubert, Bonnie R A1 - McArdle, Wendy L A1 - Musk, A Bill A1 - Hansel, Nadia A1 - Heckbert, Susan R A1 - Zgaga, Lina A1 - van Meurs, Joyce B J A1 - Navarro, Pau A1 - Rudan, Igor A1 - Oh, Yeon-Mok A1 - Redline, Susan A1 - Jarvis, Deborah L A1 - Zhao, Jing Hua A1 - Rantanen, Taina A1 - O'Connor, George T A1 - Ripatti, Samuli A1 - Scott, Rodney J A1 - Karrasch, Stefan A1 - Grallert, Harald A1 - Gaddis, Nathan C A1 - Starr, John M A1 - Wijmenga, Cisca A1 - Minster, Ryan L A1 - Lederer, David J A1 - Pekkanen, Juha A1 - Gyllensten, Ulf A1 - Campbell, Harry A1 - Morris, Andrew P A1 - Gläser, Sven A1 - Hammond, Christopher J A1 - Burkart, Kristin M A1 - Beilby, John A1 - Kritchevsky, Stephen B A1 - Gudnason, Vilmundur A1 - Hancock, Dana B A1 - Williams, O Dale A1 - Polasek, Ozren A1 - Zemunik, Tatijana A1 - Kolcic, Ivana A1 - Petrini, Marcy F A1 - Wjst, Matthias A1 - Kim, Woo Jin A1 - Porteous, David J A1 - Scotland, Generation A1 - Smith, Blair H A1 - Viljanen, Anne A1 - Heliövaara, Markku A1 - Attia, John R A1 - Sayers, Ian A1 - Hampel, Regina A1 - Gieger, Christian A1 - Deary, Ian J A1 - Boezen, H Marike A1 - Newman, Anne A1 - Jarvelin, Marjo-Riitta A1 - Wilson, James F A1 - Lind, Lars A1 - Stricker, Bruno H A1 - Teumer, Alexander A1 - Spector, Timothy D A1 - Melén, Erik A1 - Peters, Marjolein J A1 - Lange, Leslie A A1 - Barr, R Graham A1 - Bracke, Ken R A1 - Verhamme, Fien M A1 - Sung, Joohon A1 - Hiemstra, Pieter S A1 - Cassano, Patricia A A1 - Sood, Akshay A1 - Hayward, Caroline A1 - Dupuis, Josée A1 - Hall, Ian P A1 - Brusselle, Guy G A1 - Tobin, Martin D A1 - London, Stephanie J KW - Cohort Studies KW - Databases, Genetic KW - Follow-Up Studies KW - Forced Expiratory Volume KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Lung Diseases KW - Meta-Analysis as Topic KW - Polymorphism, Single Nucleotide KW - Prognosis KW - Quantitative Trait Loci KW - Respiratory Function Tests KW - Spirometry KW - Vital Capacity AB -

Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.

VL - 46 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24929828?dopt=Abstract ER - TY - JOUR T1 - Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function. JF - PLoS One Y1 - 2014 A1 - Tang, Wenbo A1 - Kowgier, Matthew A1 - Loth, Daan W A1 - Soler Artigas, Maria A1 - Joubert, Bonnie R A1 - Hodge, Emily A1 - Gharib, Sina A A1 - Smith, Albert V A1 - Ruczinski, Ingo A1 - Gudnason, Vilmundur A1 - Mathias, Rasika A A1 - Harris, Tamara B A1 - Hansel, Nadia N A1 - Launer, Lenore J A1 - Barnes, Kathleen C A1 - Hansen, Joyanna G A1 - Albrecht, Eva A1 - Aldrich, Melinda C A1 - Allerhand, Michael A1 - Barr, R Graham A1 - Brusselle, Guy G A1 - Couper, David J A1 - Curjuric, Ivan A1 - Davies, Gail A1 - Deary, Ian J A1 - Dupuis, Josée A1 - Fall, Tove A1 - Foy, Millennia A1 - Franceschini, Nora A1 - Gao, Wei A1 - Gläser, Sven A1 - Gu, Xiangjun A1 - Hancock, Dana B A1 - Heinrich, Joachim A1 - Hofman, Albert A1 - Imboden, Medea A1 - Ingelsson, Erik A1 - James, Alan A1 - Karrasch, Stefan A1 - Koch, Beate A1 - Kritchevsky, Stephen B A1 - Kumar, Ashish A1 - Lahousse, Lies A1 - Li, Guo A1 - Lind, Lars A1 - Lindgren, Cecilia A1 - Liu, Yongmei A1 - Lohman, Kurt A1 - Lumley, Thomas A1 - McArdle, Wendy L A1 - Meibohm, Bernd A1 - Morris, Andrew P A1 - Morrison, Alanna C A1 - Musk, Bill A1 - North, Kari E A1 - Palmer, Lyle J A1 - Probst-Hensch, Nicole M A1 - Psaty, Bruce M A1 - Rivadeneira, Fernando A1 - Rotter, Jerome I A1 - Schulz, Holger A1 - Smith, Lewis J A1 - Sood, Akshay A1 - Starr, John M A1 - Strachan, David P A1 - Teumer, Alexander A1 - Uitterlinden, André G A1 - Völzke, Henry A1 - Voorman, Arend A1 - Wain, Louise V A1 - Wells, Martin T A1 - Wilk, Jemma B A1 - Williams, O Dale A1 - Heckbert, Susan R A1 - Stricker, Bruno H A1 - London, Stephanie J A1 - Fornage, Myriam A1 - Tobin, Martin D A1 - O'Connor, George T A1 - Hall, Ian P A1 - Cassano, Patricia A KW - Adult KW - Chromosomes, Human, Pair 11 KW - Female KW - Gene Expression Regulation KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Longitudinal Studies KW - Male KW - Respiration AB -

BACKGROUND: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.

METHODS: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis.

RESULTS: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively.

CONCLUSIONS: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.

VL - 9 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24983941?dopt=Abstract ER - TY - JOUR T1 - An Empirical Comparison of Joint and Stratified Frameworks for Studying G × E Interactions: Systolic Blood Pressure and Smoking in the CHARGE Gene-Lifestyle Interactions Working Group. JF - Genet Epidemiol Y1 - 2016 A1 - Sung, Yun Ju A1 - Winkler, Thomas W A1 - Manning, Alisa K A1 - Aschard, Hugues A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Smith, Albert V A1 - Boerwinkle, Eric A1 - Brown, Michael R A1 - Morrison, Alanna C A1 - Fornage, Myriam A1 - Lin, Li-An A1 - Richard, Melissa A1 - Bartz, Traci M A1 - Psaty, Bruce M A1 - Hayward, Caroline A1 - Polasek, Ozren A1 - Marten, Jonathan A1 - Rudan, Igor A1 - Feitosa, Mary F A1 - Kraja, Aldi T A1 - Province, Michael A A1 - Deng, Xuan A1 - Fisher, Virginia A A1 - Zhou, Yanhua A1 - Bielak, Lawrence F A1 - Smith, Jennifer A1 - Huffman, Jennifer E A1 - Padmanabhan, Sandosh A1 - Smith, Blair H A1 - Ding, Jingzhong A1 - Liu, Yongmei A1 - Lohman, Kurt A1 - Bouchard, Claude A1 - Rankinen, Tuomo A1 - Rice, Treva K A1 - Arnett, Donna A1 - Schwander, Karen A1 - Guo, Xiuqing A1 - Palmas, Walter A1 - Rotter, Jerome I A1 - Alfred, Tamuno A1 - Bottinger, Erwin P A1 - Loos, Ruth J F A1 - Amin, Najaf A1 - Franco, Oscar H A1 - van Duijn, Cornelia M A1 - Vojinovic, Dina A1 - Chasman, Daniel I A1 - Ridker, Paul M A1 - Rose, Lynda M A1 - Kardia, Sharon A1 - Zhu, Xiaofeng A1 - Rice, Kenneth A1 - Borecki, Ingrid B A1 - Rao, Dabeeru C A1 - Gauderman, W James A1 - Cupples, L Adrienne AB -

Studying gene-environment (G × E) interactions is important, as they extend our knowledge of the genetic architecture of complex traits and may help to identify novel variants not detected via analysis of main effects alone. The main statistical framework for studying G × E interactions uses a single regression model that includes both the genetic main and G × E interaction effects (the "joint" framework). The alternative "stratified" framework combines results from genetic main-effect analyses carried out separately within the exposed and unexposed groups. Although there have been several investigations using theory and simulation, an empirical comparison of the two frameworks is lacking. Here, we compare the two frameworks using results from genome-wide association studies of systolic blood pressure for 3.2 million low frequency and 6.5 million common variants across 20 cohorts of European ancestry, comprising 79,731 individuals. Our cohorts have sample sizes ranging from 456 to 22,983 and include both family-based and population-based samples. In cohort-specific analyses, the two frameworks provided similar inference for population-based cohorts. The agreement was reduced for family-based cohorts. In meta-analyses, agreement between the two frameworks was less than that observed in cohort-specific analyses, despite the increased sample size. In meta-analyses, agreement depended on (1) the minor allele frequency, (2) inclusion of family-based cohorts in meta-analysis, and (3) filtering scheme. The stratified framework appears to approximate the joint framework well only for common variants in population-based cohorts. We conclude that the joint framework is the preferred approach and should be used to control false positives when dealing with low-frequency variants and/or family-based cohorts.

VL - 40 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27230302?dopt=Abstract ER - TY - JOUR T1 - Epigenetic Signatures of Cigarette Smoking. JF - Circ Cardiovasc Genet Y1 - 2016 A1 - Joehanes, Roby A1 - Just, Allan C A1 - Marioni, Riccardo E A1 - Pilling, Luke C A1 - Reynolds, Lindsay M A1 - Mandaviya, Pooja R A1 - Guan, Weihua A1 - Xu, Tao A1 - Elks, Cathy E A1 - Aslibekyan, Stella A1 - Moreno-Macias, Hortensia A1 - Smith, Jennifer A A1 - Brody, Jennifer A A1 - Dhingra, Radhika A1 - Yousefi, Paul A1 - Pankow, James S A1 - Kunze, Sonja A1 - Shah, Sonia H A1 - McRae, Allan F A1 - Lohman, Kurt A1 - Sha, Jin A1 - Absher, Devin M A1 - Ferrucci, Luigi A1 - Zhao, Wei A1 - Demerath, Ellen W A1 - Bressler, Jan A1 - Grove, Megan L A1 - Huan, Tianxiao A1 - Liu, Chunyu A1 - Mendelson, Michael M A1 - Yao, Chen A1 - Kiel, Douglas P A1 - Peters, Annette A1 - Wang-Sattler, Rui A1 - Visscher, Peter M A1 - Wray, Naomi R A1 - Starr, John M A1 - Ding, Jingzhong A1 - Rodriguez, Carlos J A1 - Wareham, Nicholas J A1 - Irvin, Marguerite R A1 - Zhi, Degui A1 - Barrdahl, Myrto A1 - Vineis, Paolo A1 - Ambatipudi, Srikant A1 - Uitterlinden, André G A1 - Hofman, Albert A1 - Schwartz, Joel A1 - Colicino, Elena A1 - Hou, Lifang A1 - Vokonas, Pantel S A1 - Hernandez, Dena G A1 - Singleton, Andrew B A1 - Bandinelli, Stefania A1 - Turner, Stephen T A1 - Ware, Erin B A1 - Smith, Alicia K A1 - Klengel, Torsten A1 - Binder, Elisabeth B A1 - Psaty, Bruce M A1 - Taylor, Kent D A1 - Gharib, Sina A A1 - Swenson, Brenton R A1 - Liang, Liming A1 - DeMeo, Dawn L A1 - O'Connor, George T A1 - Herceg, Zdenko A1 - Ressler, Kerry J A1 - Conneely, Karen N A1 - Sotoodehnia, Nona A1 - Kardia, Sharon L R A1 - Melzer, David A1 - Baccarelli, Andrea A A1 - van Meurs, Joyce B J A1 - Romieu, Isabelle A1 - Arnett, Donna K A1 - Ong, Ken K A1 - Liu, Yongmei A1 - Waldenberger, Melanie A1 - Deary, Ian J A1 - Fornage, Myriam A1 - Levy, Daniel A1 - London, Stephanie J AB -

BACKGROUND: DNA methylation leaves a long-term signature of smoking exposure and is one potential mechanism by which tobacco exposure predisposes to adverse health outcomes, such as cancers, osteoporosis, lung, and cardiovascular disorders.

METHODS AND RESULTS: To comprehensively determine the association between cigarette smoking and DNA methylation, we conducted a meta-analysis of genome-wide DNA methylation assessed using the Illumina BeadChip 450K array on 15 907 blood-derived DNA samples from participants in 16 cohorts (including 2433 current, 6518 former, and 6956 never smokers). Comparing current versus never smokers, 2623 cytosine-phosphate-guanine sites (CpGs), annotated to 1405 genes, were statistically significantly differentially methylated at Bonferroni threshold of P<1×10(-7) (18 760 CpGs at false discovery rate <0.05). Genes annotated to these CpGs were enriched for associations with several smoking-related traits in genome-wide studies including pulmonary function, cancers, inflammatory diseases, and heart disease. Comparing former versus never smokers, 185 of the CpGs that differed between current and never smokers were significant P<1×10(-7) (2623 CpGs at false discovery rate <0.05), indicating a pattern of persistent altered methylation, with attenuation, after smoking cessation. Transcriptomic integration identified effects on gene expression at many differentially methylated CpGs.

CONCLUSIONS: Cigarette smoking has a broad impact on genome-wide methylation that, at many loci, persists many years after smoking cessation. Many of the differentially methylated genes were novel genes with respect to biological effects of smoking and might represent therapeutic targets for prevention or treatment of tobacco-related diseases. Methylation at these sites could also serve as sensitive and stable biomarkers of lifetime exposure to tobacco smoke.

VL - 9 IS - 5 ER - TY - JOUR T1 - Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium. JF - PLoS One Y1 - 2016 A1 - Dehghan, Abbas A1 - Bis, Joshua C A1 - White, Charles C A1 - Smith, Albert Vernon A1 - Morrison, Alanna C A1 - Cupples, L Adrienne A1 - Trompet, Stella A1 - Chasman, Daniel I A1 - Lumley, Thomas A1 - Völker, Uwe A1 - Buckley, Brendan M A1 - Ding, Jingzhong A1 - Jensen, Majken K A1 - Folsom, Aaron R A1 - Kritchevsky, Stephen B A1 - Girman, Cynthia J A1 - Ford, Ian A1 - Dörr, Marcus A1 - Salomaa, Veikko A1 - Uitterlinden, André G A1 - Eiriksdottir, Gudny A1 - Vasan, Ramachandran S A1 - Franceschini, Nora A1 - Carty, Cara L A1 - Virtamo, Jarmo A1 - Demissie, Serkalem A1 - Amouyel, Philippe A1 - Arveiler, Dominique A1 - Heckbert, Susan R A1 - Ferrieres, Jean A1 - Ducimetiere, Pierre A1 - Smith, Nicholas L A1 - Wang, Ying A A1 - Siscovick, David S A1 - Rice, Kenneth M A1 - Wiklund, Per-Gunnar A1 - Taylor, Kent D A1 - Evans, Alun A1 - Kee, Frank A1 - Rotter, Jerome I A1 - Karvanen, Juha A1 - Kuulasmaa, Kari A1 - Heiss, Gerardo A1 - Kraft, Peter A1 - Launer, Lenore J A1 - Hofman, Albert A1 - Markus, Marcello R P A1 - Rose, Lynda M A1 - Silander, Kaisa A1 - Wagner, Peter A1 - Benjamin, Emelia J A1 - Lohman, Kurt A1 - Stott, David J A1 - Rivadeneira, Fernando A1 - Harris, Tamara B A1 - Levy, Daniel A1 - Liu, Yongmei A1 - Rimm, Eric B A1 - Jukema, J Wouter A1 - Völzke, Henry A1 - Ridker, Paul M A1 - Blankenberg, Stefan A1 - Franco, Oscar H A1 - Gudnason, Vilmundur A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - O'Donnell, Christopher J KW - Aged KW - Cohort Studies KW - Cooperative Behavior KW - Coronary Artery Disease KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Myocardial Infarction KW - Polymorphism, Single Nucleotide KW - Prospective Studies AB -

BACKGROUND: Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting.

METHODS: We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5×10-6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up.

RESULTS: In Stage I 15 loci passed the threshold of 5×10-6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8×10-3) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2×10-9). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2×10-3).

CONCLUSIONS: QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.

VL - 11 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26950853?dopt=Abstract ER - TY - JOUR T1 - GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium. JF - Aging Cell Y1 - 2016 A1 - Matteini, Amy M A1 - Tanaka, Toshiko A1 - Karasik, David A1 - Atzmon, Gil A1 - Chou, Wen-Chi A1 - Eicher, John D A1 - Johnson, Andrew D A1 - Arnold, Alice M A1 - Callisaya, Michele L A1 - Davies, Gail A1 - Evans, Daniel S A1 - Holtfreter, Birte A1 - Lohman, Kurt A1 - Lunetta, Kathryn L A1 - Mangino, Massimo A1 - Smith, Albert V A1 - Smith, Jennifer A A1 - Teumer, Alexander A1 - Yu, Lei A1 - Arking, Dan E A1 - Buchman, Aron S A1 - Chibinik, Lori B A1 - De Jager, Philip L A1 - Evans, Denis A A1 - Faul, Jessica D A1 - Garcia, Melissa E A1 - Gillham-Nasenya, Irina A1 - Gudnason, Vilmundur A1 - Hofman, Albert A1 - Hsu, Yi-Hsiang A1 - Ittermann, Till A1 - Lahousse, Lies A1 - Liewald, David C A1 - Liu, Yongmei A1 - Lopez, Lorna A1 - Rivadeneira, Fernando A1 - Rotter, Jerome I A1 - Siggeirsdottir, Kristin A1 - Starr, John M A1 - Thomson, Russell A1 - Tranah, Gregory J A1 - Uitterlinden, André G A1 - Völker, Uwe A1 - Völzke, Henry A1 - Weir, David R A1 - Yaffe, Kristine A1 - Zhao, Wei A1 - Zhuang, Wei Vivian A1 - Zmuda, Joseph M A1 - Bennett, David A A1 - Cummings, Steven R A1 - Deary, Ian J A1 - Ferrucci, Luigi A1 - Harris, Tamara B A1 - Kardia, Sharon L R A1 - Kocher, Thomas A1 - Kritchevsky, Stephen B A1 - Psaty, Bruce M A1 - Seshadri, Sudha A1 - Spector, Timothy D A1 - Srikanth, Velandai K A1 - Windham, B Gwen A1 - Zillikens, M Carola A1 - Newman, Anne B A1 - Walston, Jeremy D A1 - Kiel, Douglas P A1 - Murabito, Joanne M AB -

Decline in muscle strength with aging is an important predictor of health trajectory in the elderly. Several factors, including genetics, are proposed contributors to variability in muscle strength. To identify genetic contributors to muscle strength, a meta-analysis of genomewide association studies of handgrip was conducted. Grip strength was measured using a handheld dynamometer in 27 581 individuals of European descent over 65 years of age from 14 cohort studies. Genomewide association analysis was conducted on ~2.7 million imputed and genotyped variants (SNPs). Replication of the most significant findings was conducted using data from 6393 individuals from three cohorts. GWAS of lower body strength was also characterized in a subset of cohorts. Two genomewide significant (P-value< 5 × 10(-8) ) and 39 suggestive (P-value< 5 × 10(-5) ) associations were observed from meta-analysis of the discovery cohorts. After meta-analysis with replication cohorts, genomewide significant association was observed for rs752045 on chromosome 8 (β = 0.47, SE = 0.08, P-value = 5.20 × 10(-10) ). This SNP is mapped to an intergenic region and is located within an accessible chromatin region (DNase hypersensitivity site) in skeletal muscle myotubes differentiated from the human skeletal muscle myoblasts cell line. This locus alters a binding motif of the CCAAT/enhancer-binding protein-β (CEBPB) that is implicated in muscle repair mechanisms. GWAS of lower body strength did not yield significant results. A common genetic variant in a chromosomal region that regulates myotube differentiation and muscle repair may contribute to variability in grip strength in the elderly. Further studies are needed to uncover the mechanisms that link this genetic variant with muscle strength.

VL - 15 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27325353?dopt=Abstract ER - TY - JOUR T1 - SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function. JF - J Am Soc Nephrol Y1 - 2016 A1 - Li, Man A1 - Li, Yong A1 - Weeks, Olivia A1 - Mijatovic, Vladan A1 - Teumer, Alexander A1 - Huffman, Jennifer E A1 - Tromp, Gerard A1 - Fuchsberger, Christian A1 - Gorski, Mathias A1 - Lyytikäinen, Leo-Pekka A1 - Nutile, Teresa A1 - Sedaghat, Sanaz A1 - Sorice, Rossella A1 - Tin, Adrienne A1 - Yang, Qiong A1 - Ahluwalia, Tarunveer S A1 - Arking, Dan E A1 - Bihlmeyer, Nathan A A1 - Böger, Carsten A A1 - Carroll, Robert J A1 - Chasman, Daniel I A1 - Cornelis, Marilyn C A1 - Dehghan, Abbas A1 - Faul, Jessica D A1 - Feitosa, Mary F A1 - Gambaro, Giovanni A1 - Gasparini, Paolo A1 - Giulianini, Franco A1 - Heid, Iris A1 - Huang, Jinyan A1 - Imboden, Medea A1 - Jackson, Anne U A1 - Jeff, Janina A1 - Jhun, Min A A1 - Katz, Ronit A1 - Kifley, Annette A1 - Kilpeläinen, Tuomas O A1 - Kumar, Ashish A1 - Laakso, Markku A1 - Li-Gao, Ruifang A1 - Lohman, Kurt A1 - Lu, Yingchang A1 - Mägi, Reedik A1 - Malerba, Giovanni A1 - Mihailov, Evelin A1 - Mohlke, Karen L A1 - Mook-Kanamori, Dennis O A1 - Robino, Antonietta A1 - Ruderfer, Douglas A1 - Salvi, Erika A1 - Schick, Ursula M A1 - Schulz, Christina-Alexandra A1 - Smith, Albert V A1 - Smith, Jennifer A A1 - Traglia, Michela A1 - Yerges-Armstrong, Laura M A1 - Zhao, Wei A1 - Goodarzi, Mark O A1 - Kraja, Aldi T A1 - Liu, Chunyu A1 - Wessel, Jennifer A1 - Boerwinkle, Eric A1 - Borecki, Ingrid B A1 - Bork-Jensen, Jette A1 - Bottinger, Erwin P A1 - Braga, Daniele A1 - Brandslund, Ivan A1 - Brody, Jennifer A A1 - Campbell, Archie A1 - Carey, David J A1 - Christensen, Cramer A1 - Coresh, Josef A1 - Crook, Errol A1 - Curhan, Gary C A1 - Cusi, Daniele A1 - de Boer, Ian H A1 - de Vries, Aiko P J A1 - Denny, Joshua C A1 - Devuyst, Olivier A1 - Dreisbach, Albert W A1 - Endlich, Karlhans A1 - Esko, Tõnu A1 - Franco, Oscar H A1 - Fulop, Tibor A1 - Gerhard, Glenn S A1 - Glümer, Charlotte A1 - Gottesman, Omri A1 - Grarup, Niels A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Hocking, Lynne A1 - Hofman, Albert A1 - Hu, Frank B A1 - Husemoen, Lise Lotte N A1 - Jackson, Rebecca D A1 - Jørgensen, Torben A1 - Jørgensen, Marit E A1 - Kähönen, Mika A1 - Kardia, Sharon L R A1 - König, Wolfgang A1 - Kooperberg, Charles A1 - Kriebel, Jennifer A1 - Launer, Lenore J A1 - Lauritzen, Torsten A1 - Lehtimäki, Terho A1 - Levy, Daniel A1 - Linksted, Pamela A1 - Linneberg, Allan A1 - Liu, Yongmei A1 - Loos, Ruth J F A1 - Lupo, Antonio A1 - Meisinger, Christine A1 - Melander, Olle A1 - Metspalu, Andres A1 - Mitchell, Paul A1 - Nauck, Matthias A1 - Nürnberg, Peter A1 - Orho-Melander, Marju A1 - Parsa, Afshin A1 - Pedersen, Oluf A1 - Peters, Annette A1 - Peters, Ulrike A1 - Polasek, Ozren A1 - Porteous, David A1 - Probst-Hensch, Nicole M A1 - Psaty, Bruce M A1 - Qi, Lu A1 - Raitakari, Olli T A1 - Reiner, Alex P A1 - Rettig, Rainer A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Rossouw, Jacques E A1 - Schmidt, Frank A1 - Siscovick, David A1 - Soranzo, Nicole A1 - Strauch, Konstantin A1 - Toniolo, Daniela A1 - Turner, Stephen T A1 - Uitterlinden, André G A1 - Ulivi, Sheila A1 - Velayutham, Dinesh A1 - Völker, Uwe A1 - Völzke, Henry A1 - Waldenberger, Melanie A1 - Wang, Jie Jin A1 - Weir, David R A1 - Witte, Daniel A1 - Kuivaniemi, Helena A1 - Fox, Caroline S A1 - Franceschini, Nora A1 - Goessling, Wolfram A1 - Köttgen, Anna A1 - Chu, Audrey Y AB -

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1<3.7×10(-7)), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 (P=5.4×10(-8) by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.

ER - TY - JOUR T1 - Meta-analysis of exome array data identifies six novel genetic loci for lung function. JF - Wellcome Open Res Y1 - 2018 A1 - Jackson, Victoria E A1 - Latourelle, Jeanne C A1 - Wain, Louise V A1 - Smith, Albert V A1 - Grove, Megan L A1 - Bartz, Traci M A1 - Obeidat, Ma'en A1 - Province, Michael A A1 - Gao, Wei A1 - Qaiser, Beenish A1 - Porteous, David J A1 - Cassano, Patricia A A1 - Ahluwalia, Tarunveer S A1 - Grarup, Niels A1 - Li, Jin A1 - Altmaier, Elisabeth A1 - Marten, Jonathan A1 - Harris, Sarah E A1 - Manichaikul, Ani A1 - Pottinger, Tess D A1 - Li-Gao, Ruifang A1 - Lind-Thomsen, Allan A1 - Mahajan, Anubha A1 - Lahousse, Lies A1 - Imboden, Medea A1 - Teumer, Alexander A1 - Prins, Bram A1 - Lyytikäinen, Leo-Pekka A1 - Eiriksdottir, Gudny A1 - Franceschini, Nora A1 - Sitlani, Colleen M A1 - Brody, Jennifer A A1 - Bossé, Yohan A1 - Timens, Wim A1 - Kraja, Aldi A1 - Loukola, Anu A1 - Tang, Wenbo A1 - Liu, Yongmei A1 - Bork-Jensen, Jette A1 - Justesen, Johanne M A1 - Linneberg, Allan A1 - Lange, Leslie A A1 - Rawal, Rajesh A1 - Karrasch, Stefan A1 - Huffman, Jennifer E A1 - Smith, Blair H A1 - Davies, Gail A1 - Burkart, Kristin M A1 - Mychaleckyj, Josyf C A1 - Bonten, Tobias N A1 - Enroth, Stefan A1 - Lind, Lars A1 - Brusselle, Guy G A1 - Kumar, Ashish A1 - Stubbe, Beate A1 - Kähönen, Mika A1 - Wyss, Annah B A1 - Psaty, Bruce M A1 - Heckbert, Susan R A1 - Hao, Ke A1 - Rantanen, Taina A1 - Kritchevsky, Stephen B A1 - Lohman, Kurt A1 - Skaaby, Tea A1 - Pisinger, Charlotta A1 - Hansen, Torben A1 - Schulz, Holger A1 - Polasek, Ozren A1 - Campbell, Archie A1 - Starr, John M A1 - Rich, Stephen S A1 - Mook-Kanamori, Dennis O A1 - Johansson, Asa A1 - Ingelsson, Erik A1 - Uitterlinden, André G A1 - Weiss, Stefan A1 - Raitakari, Olli T A1 - Gudnason, Vilmundur A1 - North, Kari E A1 - Gharib, Sina A A1 - Sin, Don D A1 - Taylor, Kent D A1 - O'Connor, George T A1 - Kaprio, Jaakko A1 - Harris, Tamara B A1 - Pederson, Oluf A1 - Vestergaard, Henrik A1 - Wilson, James G A1 - Strauch, Konstantin A1 - Hayward, Caroline A1 - Kerr, Shona A1 - Deary, Ian J A1 - Barr, R Graham A1 - de Mutsert, Renée A1 - Gyllensten, Ulf A1 - Morris, Andrew P A1 - Ikram, M Arfan A1 - Probst-Hensch, Nicole A1 - Gläser, Sven A1 - Zeggini, Eleftheria A1 - Lehtimäki, Terho A1 - Strachan, David P A1 - Dupuis, Josée A1 - Morrison, Alanna C A1 - Hall, Ian P A1 - Tobin, Martin D A1 - London, Stephanie J AB -

Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV ), forced vital capacity (FVC) and the ratio of FEV to FVC (FEV /FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. We identified significant (P<2·8x10 ) associations with six SNPs: a nonsynonymous variant in , which is predicted to be damaging, three intronic SNPs ( and ) and two intergenic SNPs near to and Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including and . Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.

VL - 3 ER - TY - JOUR T1 - Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function. JF - Nat Commun Y1 - 2018 A1 - Wyss, Annah B A1 - Sofer, Tamar A1 - Lee, Mi Kyeong A1 - Terzikhan, Natalie A1 - Nguyen, Jennifer N A1 - Lahousse, Lies A1 - Latourelle, Jeanne C A1 - Smith, Albert Vernon A1 - Bartz, Traci M A1 - Feitosa, Mary F A1 - Gao, Wei A1 - Ahluwalia, Tarunveer S A1 - Tang, Wenbo A1 - Oldmeadow, Christopher A1 - Duan, Qing A1 - de Jong, Kim A1 - Wojczynski, Mary K A1 - Wang, Xin-Qun A1 - Noordam, Raymond A1 - Hartwig, Fernando Pires A1 - Jackson, Victoria E A1 - Wang, Tianyuan A1 - Obeidat, Ma'en A1 - Hobbs, Brian D A1 - Huan, Tianxiao A1 - Gui, Hongsheng A1 - Parker, Margaret M A1 - Hu, Donglei A1 - Mogil, Lauren S A1 - Kichaev, Gleb A1 - Jin, Jianping A1 - Graff, Mariaelisa A1 - Harris, Tamara B A1 - Kalhan, Ravi A1 - Heckbert, Susan R A1 - Paternoster, Lavinia A1 - Burkart, Kristin M A1 - Liu, Yongmei A1 - Holliday, Elizabeth G A1 - Wilson, James G A1 - Vonk, Judith M A1 - Sanders, Jason L A1 - Barr, R Graham A1 - de Mutsert, Renée A1 - Menezes, Ana Maria Baptista A1 - Adams, Hieab H H A1 - van den Berge, Maarten A1 - Joehanes, Roby A1 - Levin, Albert M A1 - Liberto, Jennifer A1 - Launer, Lenore J A1 - Morrison, Alanna C A1 - Sitlani, Colleen M A1 - Celedón, Juan C A1 - Kritchevsky, Stephen B A1 - Scott, Rodney J A1 - Christensen, Kaare A1 - Rotter, Jerome I A1 - Bonten, Tobias N A1 - Wehrmeister, Fernando César A1 - Bossé, Yohan A1 - Xiao, Shujie A1 - Oh, Sam A1 - Franceschini, Nora A1 - Brody, Jennifer A A1 - Kaplan, Robert C A1 - Lohman, Kurt A1 - McEvoy, Mark A1 - Province, Michael A A1 - Rosendaal, Frits R A1 - Taylor, Kent D A1 - Nickle, David C A1 - Williams, L Keoki A1 - Burchard, Esteban G A1 - Wheeler, Heather E A1 - Sin, Don D A1 - Gudnason, Vilmundur A1 - North, Kari E A1 - Fornage, Myriam A1 - Psaty, Bruce M A1 - Myers, Richard H A1 - O'Connor, George A1 - Hansen, Torben A1 - Laurie, Cathy C A1 - Cassano, Patricia A A1 - Sung, Joohon A1 - Kim, Woo Jin A1 - Attia, John R A1 - Lange, Leslie A1 - Boezen, H Marike A1 - Thyagarajan, Bharat A1 - Rich, Stephen S A1 - Mook-Kanamori, Dennis O A1 - Horta, Bernardo Lessa A1 - Uitterlinden, André G A1 - Im, Hae Kyung A1 - Cho, Michael H A1 - Brusselle, Guy G A1 - Gharib, Sina A A1 - Dupuis, Josée A1 - Manichaikul, Ani A1 - London, Stephanie J AB -

Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci.

VL - 9 IS - 1 ER - TY - JOUR T1 - Whole Blood DNA Methylation Signatures of Diet Are Associated With Cardiovascular Disease Risk Factors and All-Cause Mortality. JF - Circ Genom Precis Med Y1 - 2020 A1 - Ma, Jiantao A1 - Rebholz, Casey M A1 - Braun, Kim V E A1 - Reynolds, Lindsay M A1 - Aslibekyan, Stella A1 - Xia, Rui A1 - Biligowda, Niranjan G A1 - Huan, Tianxiao A1 - Liu, Chunyu A1 - Mendelson, Michael M A1 - Joehanes, Roby A1 - Hu, Emily A A1 - Vitolins, Mara Z A1 - Wood, Alexis C A1 - Lohman, Kurt A1 - Ochoa-Rosales, Carolina A1 - van Meurs, Joyce A1 - Uitterlinden, Andre A1 - Liu, Yongmei A1 - Elhadad, Mohamed A A1 - Heier, Margit A1 - Waldenberger, Melanie A1 - Peters, Annette A1 - Colicino, Elena A1 - Whitsel, Eric A A1 - Baldassari, Antoine A1 - Gharib, Sina A A1 - Sotoodehnia, Nona A1 - Brody, Jennifer A A1 - Sitlani, Colleen M A1 - Tanaka, Toshiko A1 - Hill, W David A1 - Corley, Janie A1 - Deary, Ian J A1 - Zhang, Yan A1 - Schöttker, Ben A1 - Brenner, Hermann A1 - Walker, Maura E A1 - Ye, Shumao A1 - Nguyen, Steve A1 - Pankow, Jim A1 - Demerath, Ellen W A1 - Zheng, Yinan A1 - Hou, Lifang A1 - Liang, Liming A1 - Lichtenstein, Alice H A1 - Hu, Frank B A1 - Fornage, Myriam A1 - Voortman, Trudy A1 - Levy, Daniel AB -

BACKGROUND: DNA methylation patterns associated with habitual diet have not been well studied.

METHODS: Diet quality was characterized using a Mediterranean-style diet score and the Alternative Healthy Eating Index score. We conducted ethnicity-specific and trans-ethnic epigenome-wide association analyses for diet quality and leukocyte-derived DNA methylation at over 400 000 CpGs (cytosine-guanine dinucleotides) in 5 population-based cohorts including 6662 European ancestry, 2702 African ancestry, and 360 Hispanic ancestry participants. For diet-associated CpGs identified in epigenome-wide analyses, we conducted Mendelian randomization (MR) analysis to examine their relations to cardiovascular disease risk factors and examined their longitudinal associations with all-cause mortality.

RESULTS: We identified 30 CpGs associated with either Mediterranean-style diet score or Alternative Healthy Eating Index, or both, in European ancestry participants. Among these CpGs, 12 CpGs were significantly associated with all-cause mortality (Bonferroni corrected <1.6×10). Hypermethylation of cg18181703 () was associated with higher scores of both Mediterranean-style diet score and Alternative Healthy Eating Index and lower risk for all-cause mortality (=5.7×10). Ten additional diet-associated CpGs were nominally associated with all-cause mortality (<0.05). MR analysis revealed 8 putatively causal associations for 6 CpGs with 4 cardiovascular disease risk factors (body mass index, triglycerides, high-density lipoprotein cholesterol concentrations, and type 2 diabetes mellitus; Bonferroni corrected MR <4.5×10). For example, hypermethylation of cg11250194 () was associated with lower triglyceride concentrations (MR, =1.5×10).and hypermethylation of cg02079413 (; ) was associated with body mass index (corrected MR, =1×10).

CONCLUSIONS: Habitual diet quality was associated with differential peripheral leukocyte DNA methylation levels of 30 CpGs, most of which were also associated with multiple health outcomes, in European ancestry individuals. These findings demonstrate that integrative genomic analysis of dietary information may reveal molecular targets for disease prevention and treatment.

VL - 13 IS - 4 ER - TY - JOUR T1 - Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry. JF - Am J Hum Genet Y1 - 2021 A1 - Graff, Mariaelisa A1 - Justice, Anne E A1 - Young, Kristin L A1 - Marouli, Eirini A1 - Zhang, Xinruo A1 - Fine, Rebecca S A1 - Lim, Elise A1 - Buchanan, Victoria A1 - Rand, Kristin A1 - Feitosa, Mary F A1 - Wojczynski, Mary K A1 - Yanek, Lisa R A1 - Shao, Yaming A1 - Rohde, Rebecca A1 - Adeyemo, Adebowale A A1 - Aldrich, Melinda C A1 - Allison, Matthew A A1 - Ambrosone, Christine B A1 - Ambs, Stefan A1 - Amos, Christopher A1 - Arnett, Donna K A1 - Atwood, Larry A1 - Bandera, Elisa V A1 - Bartz, Traci A1 - Becker, Diane M A1 - Berndt, Sonja I A1 - Bernstein, Leslie A1 - Bielak, Lawrence F A1 - Blot, William J A1 - Bottinger, Erwin P A1 - Bowden, Donald W A1 - Bradfield, Jonathan P A1 - Brody, Jennifer A A1 - Broeckel, Ulrich A1 - Burke, Gregory A1 - Cade, Brian E A1 - Cai, Qiuyin A1 - Caporaso, Neil A1 - Carlson, Chris A1 - Carpten, John A1 - Casey, Graham A1 - Chanock, Stephen J A1 - Chen, Guanjie A1 - Chen, Minhui A1 - Chen, Yii-der I A1 - Chen, Wei-Min A1 - Chesi, Alessandra A1 - Chiang, Charleston W K A1 - Chu, Lisa A1 - Coetzee, Gerry A A1 - Conti, David V A1 - Cooper, Richard S A1 - Cushman, Mary A1 - Demerath, Ellen A1 - Deming, Sandra L A1 - Dimitrov, Latchezar A1 - Ding, Jingzhong A1 - Diver, W Ryan A1 - Duan, Qing A1 - Evans, Michele K A1 - Falusi, Adeyinka G A1 - Faul, Jessica D A1 - Fornage, Myriam A1 - Fox, Caroline A1 - Freedman, Barry I A1 - Garcia, Melissa A1 - Gillanders, Elizabeth M A1 - Goodman, Phyllis A1 - Gottesman, Omri A1 - Grant, Struan F A A1 - Guo, Xiuqing A1 - Hakonarson, Hakon A1 - Haritunians, Talin A1 - Harris, Tamara B A1 - Harris, Curtis C A1 - Henderson, Brian E A1 - Hennis, Anselm A1 - Hernandez, Dena G A1 - Hirschhorn, Joel N A1 - McNeill, Lorna Haughton A1 - Howard, Timothy D A1 - Howard, Barbara A1 - Hsing, Ann W A1 - Hsu, Yu-Han H A1 - Hu, Jennifer J A1 - Huff, Chad D A1 - Huo, Dezheng A1 - Ingles, Sue A A1 - Irvin, Marguerite R A1 - John, Esther M A1 - Johnson, Karen C A1 - Jordan, Joanne M A1 - Kabagambe, Edmond K A1 - Kang, Sun J A1 - Kardia, Sharon L A1 - Keating, Brendan J A1 - Kittles, Rick A A1 - Klein, Eric A A1 - Kolb, Suzanne A1 - Kolonel, Laurence N A1 - Kooperberg, Charles A1 - Kuller, Lewis A1 - Kutlar, Abdullah A1 - Lange, Leslie A1 - Langefeld, Carl D A1 - Le Marchand, Loïc A1 - Leonard, Hampton A1 - Lettre, Guillaume A1 - Levin, Albert M A1 - Li, Yun A1 - Li, Jin A1 - Liu, Yongmei A1 - Liu, Youfang A1 - Liu, Simin A1 - Lohman, Kurt A1 - Lotay, Vaneet A1 - Lu, Yingchang A1 - Maixner, William A1 - Manson, JoAnn E A1 - McKnight, Barbara A1 - Meng, Yan A1 - Monda, Keri L A1 - Monroe, Kris A1 - Moore, Jason H A1 - Mosley, Thomas H A1 - Mudgal, Poorva A1 - Murphy, Adam B A1 - Nadukuru, Rajiv A1 - Nalls, Mike A A1 - Nathanson, Katherine L A1 - Nayak, Uma A1 - N'diaye, Amidou A1 - Nemesure, Barbara A1 - Neslund-Dudas, Christine A1 - Neuhouser, Marian L A1 - Nyante, Sarah A1 - Ochs-Balcom, Heather A1 - Ogundiran, Temidayo O A1 - Ogunniyi, Adesola A1 - Ojengbede, Oladosu A1 - Okut, Hayrettin A1 - Olopade, Olufunmilayo I A1 - Olshan, Andrew A1 - Padhukasahasram, Badri A1 - Palmer, Julie A1 - Palmer, Cameron D A1 - Palmer, Nicholette D A1 - Papanicolaou, George A1 - Patel, Sanjay R A1 - Pettaway, Curtis A A1 - Peyser, Patricia A A1 - Press, Michael F A1 - Rao, D C A1 - Rasmussen-Torvik, Laura J A1 - Redline, Susan A1 - Reiner, Alex P A1 - Rhie, Suhn K A1 - Rodriguez-Gil, Jorge L A1 - Rotimi, Charles N A1 - Rotter, Jerome I A1 - Ruiz-Narvaez, Edward A A1 - Rybicki, Benjamin A A1 - Salako, Babatunde A1 - Sale, Michèle M A1 - Sanderson, Maureen A1 - Schadt, Eric A1 - Schreiner, Pamela J A1 - Schurmann, Claudia A1 - Schwartz, Ann G A1 - Shriner, Daniel A A1 - Signorello, Lisa B A1 - Singleton, Andrew B A1 - Siscovick, David S A1 - Smith, Jennifer A A1 - Smith, Shad A1 - Speliotes, Elizabeth A1 - Spitz, Margaret A1 - Stanford, Janet L A1 - Stevens, Victoria L A1 - Stram, Alex A1 - Strom, Sara S A1 - Sucheston, Lara A1 - Sun, Yan V A1 - Tajuddin, Salman M A1 - Taylor, Herman A1 - Taylor, Kira A1 - Tayo, Bamidele O A1 - Thun, Michael J A1 - Tucker, Margaret A A1 - Vaidya, Dhananjay A1 - Van Den Berg, David J A1 - Vedantam, Sailaja A1 - Vitolins, Mara A1 - Wang, Zhaoming A1 - Ware, Erin B A1 - Wassertheil-Smoller, Sylvia A1 - Weir, David R A1 - Wiencke, John K A1 - Williams, Scott M A1 - Williams, L Keoki A1 - Wilson, James G A1 - Witte, John S A1 - Wrensch, Margaret A1 - Wu, Xifeng A1 - Yao, Jie A1 - Zakai, Neil A1 - Zanetti, Krista A1 - Zemel, Babette S A1 - Zhao, Wei A1 - Zhao, Jing Hua A1 - Zheng, Wei A1 - Zhi, Degui A1 - Zhou, Jie A1 - Zhu, Xiaofeng A1 - Ziegler, Regina G A1 - Zmuda, Joe A1 - Zonderman, Alan B A1 - Psaty, Bruce M A1 - Borecki, Ingrid B A1 - Cupples, L Adrienne A1 - Liu, Ching-Ti A1 - Haiman, Christopher A A1 - Loos, Ruth A1 - Ng, Maggie C Y A1 - North, Kari E AB -

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.

VL - 108 IS - 4 ER - TY - JOUR T1 - Meta-analyses identify DNA methylation associated with kidney function and damage. JF - Nat Commun Y1 - 2021 A1 - Schlosser, Pascal A1 - Tin, Adrienne A1 - Matias-Garcia, Pamela R A1 - Thio, Chris H L A1 - Joehanes, Roby A1 - Liu, Hongbo A1 - Weihs, Antoine A1 - Yu, Zhi A1 - Hoppmann, Anselm A1 - Grundner-Culemann, Franziska A1 - Min, Josine L A1 - Adeyemo, Adebowale A A1 - Agyemang, Charles A1 - Arnlöv, Johan A1 - Aziz, Nasir A A1 - Baccarelli, Andrea A1 - Bochud, Murielle A1 - Brenner, Hermann A1 - Breteler, Monique M B A1 - Carmeli, Cristian A1 - Chaker, Layal A1 - Chambers, John C A1 - Cole, Shelley A A1 - Coresh, Josef A1 - Corre, Tanguy A1 - Correa, Adolfo A1 - Cox, Simon R A1 - de Klein, Niek A1 - Delgado, Graciela E A1 - Domingo-Relloso, Arce A1 - Eckardt, Kai-Uwe A1 - Ekici, Arif B A1 - Endlich, Karlhans A1 - Evans, Kathryn L A1 - Floyd, James S A1 - Fornage, Myriam A1 - Franke, Lude A1 - Fraszczyk, Eliza A1 - Gao, Xu A1 - Gào, Xīn A1 - Ghanbari, Mohsen A1 - Ghasemi, Sahar A1 - Gieger, Christian A1 - Greenland, Philip A1 - Grove, Megan L A1 - Harris, Sarah E A1 - Hemani, Gibran A1 - Henneman, Peter A1 - Herder, Christian A1 - Horvath, Steve A1 - Hou, Lifang A1 - Hurme, Mikko A A1 - Hwang, Shih-Jen A1 - Jarvelin, Marjo-Riitta A1 - Kardia, Sharon L R A1 - Kasela, Silva A1 - Kleber, Marcus E A1 - Koenig, Wolfgang A1 - Kooner, Jaspal S A1 - Kramer, Holly A1 - Kronenberg, Florian A1 - Kuhnel, Brigitte A1 - Lehtimäki, Terho A1 - Lind, Lars A1 - Liu, Dan A1 - Liu, Yongmei A1 - Lloyd-Jones, Donald M A1 - Lohman, Kurt A1 - Lorkowski, Stefan A1 - Lu, Ake T A1 - Marioni, Riccardo E A1 - März, Winfried A1 - McCartney, Daniel L A1 - Meeks, Karlijn A C A1 - Milani, Lili A1 - Mishra, Pashupati P A1 - Nauck, Matthias A1 - Navas-Acien, Ana A1 - Nowak, Christoph A1 - Peters, Annette A1 - Prokisch, Holger A1 - Psaty, Bruce M A1 - Raitakari, Olli T A1 - Ratliff, Scott M A1 - Reiner, Alex P A1 - Rosas, Sylvia E A1 - Schöttker, Ben A1 - Schwartz, Joel A1 - Sedaghat, Sanaz A1 - Smith, Jennifer A A1 - Sotoodehnia, Nona A1 - Stocker, Hannah R A1 - Stringhini, Silvia A1 - Sundström, Johan A1 - Swenson, Brenton R A1 - Tellez-Plaza, Maria A1 - van Meurs, Joyce B J A1 - van Vliet-Ostaptchouk, Jana V A1 - Venema, Andrea A1 - Verweij, Niek A1 - Walker, Rosie M A1 - Wielscher, Matthias A1 - Winkelmann, Juliane A1 - Wolffenbuttel, Bruce H R A1 - Zhao, Wei A1 - Zheng, Yinan A1 - Loh, Marie A1 - Snieder, Harold A1 - Levy, Daniel A1 - Waldenberger, Melanie A1 - Susztak, Katalin A1 - Köttgen, Anna A1 - Teumer, Alexander KW - Adult KW - Aged KW - CpG Islands KW - DNA Methylation KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Interferon Regulatory Factors KW - Kidney KW - Kidney Function Tests KW - LIM Domain Proteins KW - Male KW - Membrane Proteins KW - Middle Aged KW - Renal Insufficiency, Chronic KW - Transcription Factors AB -

Chronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. To extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated glomerular filtration rate (n = 33,605) and urinary albumin-to-creatinine ratio (n = 15,068) and detected 69 and seven CpG sites where DNA methylation was associated with the respective trait. The majority of these findings showed directionally consistent associations with the respective clinical outcomes chronic kidney disease and moderately increased albuminuria. Associations of DNA methylation with kidney function, such as CpGs at JAZF1, PELI1 and CHD2 were validated in kidney tissue. Methylation at PHRF1, LDB2, CSRNP1 and IRF5 indicated causal effects on kidney function. Enrichment analyses revealed pathways related to hemostasis and blood cell migration for estimated glomerular filtration rate, and immune cell activation and response for urinary albumin-to-creatinineratio-associated CpGs.

VL - 12 IS - 1 ER - TY - JOUR T1 - Multi-Ancestry Genome-wide Association Study Accounting for Gene-Psychosocial Factor Interactions Identifies Novel Loci for Blood Pressure Traits. JF - HGG Adv Y1 - 2021 A1 - Sun, Daokun A1 - Richard, Melissa A1 - Musani, Solomon K A1 - Sung, Yun Ju A1 - Winkler, Thomas W A1 - Schwander, Karen A1 - Chai, Jin Fang A1 - Guo, Xiuqing A1 - Kilpeläinen, Tuomas O A1 - Vojinovic, Dina A1 - Aschard, Hugues A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Brown, Michael R A1 - Chitrala, Kumaraswamy A1 - Hartwig, Fernando P A1 - Horimoto, Andrea R V R A1 - Liu, Yongmei A1 - Manning, Alisa K A1 - Noordam, Raymond A1 - Smith, Albert V A1 - Harris, Sarah E A1 - Kuhnel, Brigitte A1 - Lyytikäinen, Leo-Pekka A1 - Nolte, Ilja M A1 - Rauramaa, Rainer A1 - van der Most, Peter J A1 - Wang, Rujia A1 - Ware, Erin B A1 - Weiss, Stefan A1 - Wen, Wanqing A1 - Yanek, Lisa R A1 - Arking, Dan E A1 - Arnett, Donna K A1 - Barac, Ana A1 - Boerwinkle, Eric A1 - Broeckel, Ulrich A1 - Chakravarti, Aravinda A1 - Chen, Yii-Der Ida A1 - Cupples, L Adrienne A1 - Davigulus, Martha L A1 - de Las Fuentes, Lisa A1 - de Mutsert, Renée A1 - de Vries, Paul S A1 - Delaney, Joseph A C A1 - Roux, Ana V Diez A1 - Dörr, Marcus A1 - Faul, Jessica D A1 - Fretts, Amanda M A1 - Gallo, Linda C A1 - Grabe, Hans Jörgen A1 - Gu, C Charles A1 - Harris, Tamara B A1 - Hartman, Catharina C A A1 - Heikkinen, Sami A1 - Ikram, M Arfan A1 - Isasi, Carmen A1 - Johnson, W Craig A1 - Jonas, Jost Bruno A1 - Kaplan, Robert C A1 - Komulainen, Pirjo A1 - Krieger, Jose E A1 - Levy, Daniel A1 - Liu, Jianjun A1 - Lohman, Kurt A1 - Luik, Annemarie I A1 - Martin, Lisa W A1 - Meitinger, Thomas A1 - Milaneschi, Yuri A1 - O'Connell, Jeff R A1 - Palmas, Walter R A1 - Peters, Annette A1 - Peyser, Patricia A A1 - Pulkki-Råback, Laura A1 - Raffel, Leslie J A1 - Reiner, Alex P A1 - Rice, Kenneth A1 - Robinson, Jennifer G A1 - Rosendaal, Frits R A1 - Schmidt, Carsten Oliver A1 - Schreiner, Pamela J A1 - Schwettmann, Lars A1 - Shikany, James M A1 - Shu, Xiao-Ou A1 - Sidney, Stephen A1 - Sims, Mario A1 - Smith, Jennifer A A1 - Sotoodehnia, Nona A1 - Strauch, Konstantin A1 - Tai, E Shyong A1 - Taylor, Kent A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Waldenberger, Melanie A1 - Wee, Hwee-Lin A1 - Wei, Wen-Bin A1 - Wilson, Gregory A1 - Xuan, Deng A1 - Yao, Jie A1 - Zeng, Donglin A1 - Zhao, Wei A1 - Zhu, Xiaofeng A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Deary, Ian J A1 - Gieger, Christian A1 - Lakka, Timo A A1 - Lehtimäki, Terho A1 - North, Kari E A1 - Oldehinkel, Albertine J A1 - Penninx, Brenda W J H A1 - Snieder, Harold A1 - Wang, Ya-Xing A1 - Weir, David R A1 - Zheng, Wei A1 - Evans, Michele K A1 - Gauderman, W James A1 - Gudnason, Vilmundur A1 - Horta, Bernardo L A1 - Liu, Ching-Ti A1 - Mook-Kanamori, Dennis O A1 - Morrison, Alanna C A1 - Pereira, Alexandre C A1 - Psaty, Bruce M A1 - Amin, Najaf A1 - Fox, Ervin R A1 - Kooperberg, Charles A1 - Sim, Xueling A1 - Bierut, Laura A1 - Rotter, Jerome I A1 - Kardia, Sharon L R A1 - Franceschini, Nora A1 - Rao, Dabeeru C A1 - Fornage, Myriam AB -

Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from 5 ancestry groups. In the combined meta-analyses of Stages 1 and 2, we identified 59 loci (p value <5e-8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel loci supports a major role for genes implicated in the immune response (), synaptic function and neurotransmission (), as well as genes previously implicated in neuropsychiatric or stress-related disorders (). These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations.

VL - 2 IS - 1 ER - TY - JOUR T1 - Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci. JF - Front Genet Y1 - 2023 A1 - de Las Fuentes, Lisa A1 - Schwander, Karen L A1 - Brown, Michael R A1 - Bentley, Amy R A1 - Winkler, Thomas W A1 - Sung, Yun Ju A1 - Munroe, Patricia B A1 - Miller, Clint L A1 - Aschard, Hugo A1 - Aslibekyan, Stella A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Chai, Jin Fang A1 - Cheng, Ching-Yu A1 - Dorajoo, Rajkumar A1 - Feitosa, Mary F A1 - Guo, Xiuqing A1 - Hartwig, Fernando P A1 - Horimoto, Andrea A1 - Kolcic, Ivana A1 - Lim, Elise A1 - Liu, Yongmei A1 - Manning, Alisa K A1 - Marten, Jonathan A1 - Musani, Solomon K A1 - Noordam, Raymond A1 - Padmanabhan, Sandosh A1 - Rankinen, Tuomo A1 - Richard, Melissa A A1 - Ridker, Paul M A1 - Smith, Albert V A1 - Vojinovic, Dina A1 - Zonderman, Alan B A1 - Alver, Maris A1 - Boissel, Mathilde A1 - Christensen, Kaare A1 - Freedman, Barry I A1 - Gao, Chuan A1 - Giulianini, Franco A1 - Harris, Sarah E A1 - He, Meian A1 - Hsu, Fang-Chi A1 - Kuhnel, Brigitte A1 - Laguzzi, Federica A1 - Li, Xiaoyin A1 - Lyytikäinen, Leo-Pekka A1 - Nolte, Ilja M A1 - Poveda, Alaitz A1 - Rauramaa, Rainer A1 - Riaz, Muhammad A1 - Robino, Antonietta A1 - Sofer, Tamar A1 - Takeuchi, Fumihiko A1 - Tayo, Bamidele O A1 - van der Most, Peter J A1 - Verweij, Niek A1 - Ware, Erin B A1 - Weiss, Stefan A1 - Wen, Wanqing A1 - Yanek, Lisa R A1 - Zhan, Yiqiang A1 - Amin, Najaf A1 - Arking, Dan E A1 - Ballantyne, Christie A1 - Boerwinkle, Eric A1 - Brody, Jennifer A A1 - Broeckel, Ulrich A1 - Campbell, Archie A1 - Canouil, Mickaël A1 - Chai, Xiaoran A1 - Chen, Yii-Der Ida A1 - Chen, Xu A1 - Chitrala, Kumaraswamy Naidu A1 - Concas, Maria Pina A1 - de Faire, Ulf A1 - de Mutsert, Renée A1 - de Silva, H Janaka A1 - de Vries, Paul S A1 - Do, Ahn A1 - Faul, Jessica D A1 - Fisher, Virginia A1 - Floyd, James S A1 - Forrester, Terrence A1 - Friedlander, Yechiel A1 - Girotto, Giorgia A1 - Gu, C Charles A1 - Hallmans, Göran A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Homuth, Georg A1 - Hunt, Steven A1 - Ikram, M Arfan A1 - Jacobs, David R A1 - Kavousi, Maryam A1 - Khor, Chiea Chuen A1 - Kilpeläinen, Tuomas O A1 - Koh, Woon-Puay A1 - Komulainen, Pirjo A1 - Langefeld, Carl D A1 - Liang, Jingjing A1 - Liu, Kiang A1 - Liu, Jianjun A1 - Lohman, Kurt A1 - Mägi, Reedik A1 - Manichaikul, Ani W A1 - McKenzie, Colin A A1 - Meitinger, Thomas A1 - Milaneschi, Yuri A1 - Nauck, Matthias A1 - Nelson, Christopher P A1 - O'Connell, Jeffrey R A1 - Palmer, Nicholette D A1 - Pereira, Alexandre C A1 - Perls, Thomas A1 - Peters, Annette A1 - Polasek, Ozren A1 - Raitakari, Olli T A1 - Rice, Kenneth A1 - Rice, Treva K A1 - Rich, Stephen S A1 - Sabanayagam, Charumathi A1 - Schreiner, Pamela J A1 - Shu, Xiao-Ou A1 - Sidney, Stephen A1 - Sims, Mario A1 - Smith, Jennifer A A1 - Starr, John M A1 - Strauch, Konstantin A1 - Tai, E Shyong A1 - Taylor, Kent D A1 - Tsai, Michael Y A1 - Uitterlinden, André G A1 - van Heemst, Diana A1 - Waldenberger, Melanie A1 - Wang, Ya-Xing A1 - Wei, Wen-Bin A1 - Wilson, Gregory A1 - Xuan, Deng A1 - Yao, Jie A1 - Yu, Caizheng A1 - Yuan, Jian-Min A1 - Zhao, Wei A1 - Becker, Diane M A1 - Bonnefond, Amélie A1 - Bowden, Donald W A1 - Cooper, Richard S A1 - Deary, Ian J A1 - Divers, Jasmin A1 - Esko, Tõnu A1 - Franks, Paul W A1 - Froguel, Philippe A1 - Gieger, Christian A1 - Jonas, Jost B A1 - Kato, Norihiro A1 - Lakka, Timo A A1 - Leander, Karin A1 - Lehtimäki, Terho A1 - Magnusson, Patrik K E A1 - North, Kari E A1 - Ntalla, Ioanna A1 - Penninx, Brenda A1 - Samani, Nilesh J A1 - Snieder, Harold A1 - Spedicati, Beatrice A1 - van der Harst, Pim A1 - Völzke, Henry A1 - Wagenknecht, Lynne E A1 - Weir, David R A1 - Wojczynski, Mary K A1 - Wu, Tangchun A1 - Zheng, Wei A1 - Zhu, Xiaofeng A1 - Bouchard, Claude A1 - Chasman, Daniel I A1 - Evans, Michele K A1 - Fox, Ervin R A1 - Gudnason, Vilmundur A1 - Hayward, Caroline A1 - Horta, Bernardo L A1 - Kardia, Sharon L R A1 - Krieger, Jose Eduardo A1 - Mook-Kanamori, Dennis O A1 - Peyser, Patricia A A1 - Province, Michael M A1 - Psaty, Bruce M A1 - Rudan, Igor A1 - Sim, Xueling A1 - Smith, Blair H A1 - van Dam, Rob M A1 - van Duijn, Cornelia M A1 - Wong, Tien Yin A1 - Arnett, Donna K A1 - Rao, Dabeeru C A1 - Gauderman, James A1 - Liu, Ching-Ti A1 - Morrison, Alanna C A1 - Rotter, Jerome I A1 - Fornage, Myriam AB -

Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: "Some College" (yes/no, for any education beyond high school) and "Graduated College" (yes/no, for completing a 4-year college degree). Genome-wide significant ( < 5 × 10) and suggestive ( < 1 × 10) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals). In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (), brain (), and liver () biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue. Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.

VL - 14 ER -