@article {1224, title = {Common variants in the calcium-sensing receptor gene are associated with total serum calcium levels.}, journal = {Hum Mol Genet}, volume = {19}, year = {2010}, month = {2010 Nov 01}, pages = {4296-303}, abstract = {

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.

}, keywords = {Adult, Calcium, Female, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Receptors, Calcium-Sensing}, issn = {1460-2083}, doi = {10.1093/hmg/ddq342}, author = {O{\textquoteright}Seaghdha, Conall M and Yang, Qiong and Glazer, Nicole L and Leak, Tennille S and Dehghan, Abbas and Smith, Albert V and Kao, W H Linda and Lohman, Kurt and Hwang, Shih-Jen and Johnson, Andrew D and Hofman, Albert and Uitterlinden, Andr{\'e} G and Chen, Yii-Der Ida and Brown, Edward M and Siscovick, David S and Harris, Tamara B and Psaty, Bruce M and Coresh, Josef and Gudnason, Vilmundur and Witteman, Jacqueline C and Liu, Yong Mei and Kestenbaum, Bryan R and Fox, Caroline S and K{\"o}ttgen, Anna} } @article {1336, title = {Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD.}, journal = {PLoS Genet}, volume = {7}, year = {2011}, month = {2011 Sep}, pages = {e1002292}, abstract = {

Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR <60ml/min/1.73m(2) at follow-up) and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). SNPs at 11 of the 16 loci (UMOD, PRKAG2, ANXA9, DAB2, SHROOM3, DACH1, STC1, SLC34A1, ALMS1/NAT8, UBE2Q2, and GCKR) were associated with incident CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1). SNPs in UMOD (OR = 0.92, p = 0.04) and GCKR (OR = 0.93, p = 0.03) were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression.

}, keywords = {Adaptor Proteins, Signal Transducing, Adult, Aged, Chronic Disease, Creatinine, European Continental Ancestry Group, Female, Follow-Up Studies, Genetic Association Studies, Humans, Kidney Diseases, Kidney Failure, Chronic, Male, Middle Aged, Polymorphism, Single Nucleotide, Receptor, Epidermal Growth Factor, Uromodulin}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1002292}, author = {B{\"o}ger, Carsten A and Gorski, Mathias and Li, Man and Hoffmann, Michael M and Huang, Chunmei and Yang, Qiong and Teumer, Alexander and Krane, Vera and O{\textquoteright}Seaghdha, Conall M and Kutalik, Zolt{\'a}n and Wichmann, H-Erich and Haak, Thomas and Boes, Eva and Coassin, Stefan and Coresh, Josef and Kollerits, Barbara and Haun, Margot and Paulweber, Bernhard and K{\"o}ttgen, Anna and Li, Guo and Shlipak, Michael G and Powe, Neil and Hwang, Shih-Jen and Dehghan, Abbas and Rivadeneira, Fernando and Uitterlinden, Andre and Hofman, Albert and Beckmann, Jacques S and Kr{\"a}mer, Bernhard K and Witteman, Jacqueline and Bochud, Murielle and Siscovick, David and Rettig, Rainer and Kronenberg, Florian and Wanner, Christoph and Thadhani, Ravi I and Heid, Iris M and Fox, Caroline S and Kao, W H} } @article {1271, title = {CUBN is a gene locus for albuminuria.}, journal = {J Am Soc Nephrol}, volume = {22}, year = {2011}, month = {2011 Mar}, pages = {555-70}, abstract = {

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 {\texttimes} 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.

}, keywords = {African Continental Ancestry Group, Albuminuria, European Continental Ancestry Group, Genetic Loci, Genetic Predisposition to Disease, Humans, Mutation, Missense, Receptors, Cell Surface}, issn = {1533-3450}, doi = {10.1681/ASN.2010060598}, author = {B{\"o}ger, Carsten A and Chen, Ming-Huei and Tin, Adrienne and Olden, Matthias and K{\"o}ttgen, Anna and de Boer, Ian H and Fuchsberger, Christian and O{\textquoteright}Seaghdha, Conall M and Pattaro, Cristian and Teumer, Alexander and Liu, Ching-Ti and Glazer, Nicole L and Li, Man and O{\textquoteright}Connell, Jeffrey R and Tanaka, Toshiko and Peralta, Carmen A and Kutalik, Zolt{\'a}n and Luan, Jian{\textquoteright}an and Zhao, Jing Hua and Hwang, Shih-Jen and Akylbekova, Ermeg and Kramer, Holly and van der Harst, Pim and Smith, Albert V and Lohman, Kurt and de Andrade, Mariza and Hayward, Caroline and Kollerits, Barbara and T{\"o}njes, Anke and Aspelund, Thor and Ingelsson, Erik and Eiriksdottir, Gudny and Launer, Lenore J and Harris, Tamara B and Shuldiner, Alan R and Mitchell, Braxton D and Arking, Dan E and Franceschini, Nora and Boerwinkle, Eric and Egan, Josephine and Hernandez, Dena and Reilly, Muredach and Townsend, Raymond R and Lumley, Thomas and Siscovick, David S and Psaty, Bruce M and Kestenbaum, Bryan and Haritunians, Talin and Bergmann, Sven and Vollenweider, Peter and Waeber, G{\'e}rard and Mooser, Vincent and Waterworth, Dawn and Johnson, Andrew D and Florez, Jose C and Meigs, James B and Lu, Xiaoning and Turner, Stephen T and Atkinson, Elizabeth J and Leak, Tennille S and Aasar{\o}d, Knut and Skorpen, Frank and Syv{\"a}nen, Ann-Christine and Illig, Thomas and Baumert, Jens and Koenig, Wolfgang and Kr{\"a}mer, Bernhard K and Devuyst, Olivier and Mychaleckyj, Josyf C and Minelli, Cosetta and Bakker, Stephan J L and Kedenko, Lyudmyla and Paulweber, Bernhard and Coassin, Stefan and Endlich, Karlhans and Kroemer, Heyo K and Biffar, Reiner and Stracke, Sylvia and V{\"o}lzke, Henry and Stumvoll, Michael and M{\"a}gi, Reedik and Campbell, Harry and Vitart, Veronique and Hastie, Nicholas D and Gudnason, Vilmundur and Kardia, Sharon L R and Liu, Yongmei and Polasek, Ozren and Curhan, Gary and Kronenberg, Florian and Prokopenko, Inga and Rudan, Igor and Arnl{\"o}v, Johan and Hallan, Stein and Navis, Gerjan and Parsa, Afshin and Ferrucci, Luigi and Coresh, Josef and Shlipak, Michael G and Bull, Shelley B and Paterson, Nicholas J and Wichmann, H-Erich and Wareham, Nicholas J and Loos, Ruth J F and Rotter, Jerome I and Pramstaller, Peter P and Cupples, L Adrienne and Beckmann, Jacques S and Yang, Qiong and Heid, Iris M and Rettig, Rainer and Dreisbach, Albert W and Bochud, Murielle and Fox, Caroline S and Kao, W H L} } @article {1377, title = {Genome-wide association and functional follow-up reveals new loci for kidney function.}, journal = {PLoS Genet}, volume = {8}, year = {2012}, month = {2012}, pages = {e1002584}, abstract = {

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.

}, keywords = {African Americans, Aged, Animals, Caspase 9, Cyclin-Dependent Kinases, DEAD-box RNA Helicases, DNA Helicases, European Continental Ancestry Group, Female, Follow-Up Studies, Gene Knockdown Techniques, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Kidney, Kidney Failure, Chronic, Male, Middle Aged, Phosphoric Diester Hydrolases, Zebrafish}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1002584}, author = {Pattaro, Cristian and K{\"o}ttgen, Anna and Teumer, Alexander and Garnaas, Maija and B{\"o}ger, Carsten A and Fuchsberger, Christian and Olden, Matthias and Chen, Ming-Huei and Tin, Adrienne and Taliun, Daniel and Li, Man and Gao, Xiaoyi and Gorski, Mathias and Yang, Qiong and Hundertmark, Claudia and Foster, Meredith C and O{\textquoteright}Seaghdha, Conall M and Glazer, Nicole and Isaacs, Aaron and Liu, Ching-Ti and Smith, Albert V and O{\textquoteright}Connell, Jeffrey R and Struchalin, Maksim and Tanaka, Toshiko and Li, Guo and Johnson, Andrew D and Gierman, Hinco J and Feitosa, Mary and Hwang, Shih-Jen and Atkinson, Elizabeth J and Lohman, Kurt and Cornelis, Marilyn C and Johansson, Asa and T{\"o}njes, Anke and Dehghan, Abbas and Chouraki, Vincent and Holliday, Elizabeth G and Sorice, Rossella and Kutalik, Zolt{\'a}n and Lehtim{\"a}ki, Terho and Esko, T{\~o}nu and Deshmukh, Harshal and Ulivi, Sheila and Chu, Audrey Y and Murgia, Federico and Trompet, Stella and Imboden, Medea and Kollerits, Barbara and Pistis, Giorgio and Harris, Tamara B and Launer, Lenore J and Aspelund, Thor and Eiriksdottir, Gudny and Mitchell, Braxton D and Boerwinkle, Eric and Schmidt, Helena and Cavalieri, Margherita and Rao, Madhumathi and Hu, Frank B and Demirkan, Ayse and Oostra, Ben A and de Andrade, Mariza and Turner, Stephen T and Ding, Jingzhong and Andrews, Jeanette S and Freedman, Barry I and Koenig, Wolfgang and Illig, Thomas and D{\"o}ring, Angela and Wichmann, H-Erich and Kolcic, Ivana and Zemunik, Tatijana and Boban, Mladen and Minelli, Cosetta and Wheeler, Heather E and Igl, Wilmar and Zaboli, Ghazal and Wild, Sarah H and Wright, Alan F and Campbell, Harry and Ellinghaus, David and N{\"o}thlings, Ute and Jacobs, Gunnar and Biffar, Reiner and Endlich, Karlhans and Ernst, Florian and Homuth, Georg and Kroemer, Heyo K and Nauck, Matthias and Stracke, Sylvia and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Kovacs, Peter and Stumvoll, Michael and M{\"a}gi, Reedik and Hofman, Albert and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and Aulchenko, Yurii S and Polasek, Ozren and Hastie, Nick and Vitart, Veronique and Helmer, Catherine and Wang, Jie Jin and Ruggiero, Daniela and Bergmann, Sven and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and Nikopensius, Tiit and Province, Michael and Ketkar, Shamika and Colhoun, Helen and Doney, Alex and Robino, Antonietta and Giulianini, Franco and Kr{\"a}mer, Bernhard K and Portas, Laura and Ford, Ian and Buckley, Brendan M and Adam, Martin and Thun, Gian-Andri and Paulweber, Bernhard and Haun, Margot and Sala, Cinzia and Metzger, Marie and Mitchell, Paul and Ciullo, Marina and Kim, Stuart K and Vollenweider, Peter and Raitakari, Olli and Metspalu, Andres and Palmer, Colin and Gasparini, Paolo and Pirastu, Mario and Jukema, J Wouter and Probst-Hensch, Nicole M and Kronenberg, Florian and Toniolo, Daniela and Gudnason, Vilmundur and Shuldiner, Alan R and Coresh, Josef and Schmidt, Reinhold and Ferrucci, Luigi and Siscovick, David S and van Duijn, Cornelia M and Borecki, Ingrid and Kardia, Sharon L R and Liu, Yongmei and Curhan, Gary C and Rudan, Igor and Gyllensten, Ulf and Wilson, James F and Franke, Andre and Pramstaller, Peter P and Rettig, Rainer and Prokopenko, Inga and Witteman, Jacqueline C M and Hayward, Caroline and Ridker, Paul and Parsa, Afshin and Bochud, Murielle and Heid, Iris M and Goessling, Wolfram and Chasman, Daniel I and Kao, W H Linda and Fox, Caroline S} } @article {6288, title = {Common variants in Mendelian kidney disease genes and their association with renal function.}, journal = {J Am Soc Nephrol}, volume = {24}, year = {2013}, month = {2013 Dec}, pages = {2105-17}, abstract = {

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.

}, keywords = {Databases, Genetic, European Continental Ancestry Group, Gene Frequency, Genetic Variation, Genome-Wide Association Study, Humans, Kidney, Mendelian Randomization Analysis, Phenotype, Polymorphism, Single Nucleotide, Renal Insufficiency, Chronic}, issn = {1533-3450}, doi = {10.1681/ASN.2012100983}, author = {Parsa, Afshin and Fuchsberger, Christian and K{\"o}ttgen, Anna and O{\textquoteright}Seaghdha, Conall M and Pattaro, Cristian and de Andrade, Mariza and Chasman, Daniel I and Teumer, Alexander and Endlich, Karlhans and Olden, Matthias and Chen, Ming-Huei and Tin, Adrienne and Kim, Young J and Taliun, Daniel and Li, Man and Feitosa, Mary and Gorski, Mathias and Yang, Qiong and Hundertmark, Claudia and Foster, Meredith C and Glazer, Nicole and Isaacs, Aaron and Rao, Madhumathi and Smith, Albert V and O{\textquoteright}Connell, Jeffrey R and Struchalin, Maksim and Tanaka, Toshiko and Li, Guo and Hwang, Shih-Jen and Atkinson, Elizabeth J and Lohman, Kurt and Cornelis, Marilyn C and Johansson, Asa and T{\"o}njes, Anke and Dehghan, Abbas and Couraki, Vincent and Holliday, Elizabeth G and Sorice, Rossella and Kutalik, Zolt{\'a}n and Lehtim{\"a}ki, Terho and Esko, T{\~o}nu and Deshmukh, Harshal and Ulivi, Sheila and Chu, Audrey Y and Murgia, Federico and Trompet, Stella and Imboden, Medea and Kollerits, Barbara and Pistis, Giorgio and Harris, Tamara B and Launer, Lenore J and Aspelund, Thor and Eiriksdottir, Gudny and Mitchell, Braxton D and Boerwinkle, Eric and Schmidt, Helena and Hofer, Edith and Hu, Frank and Demirkan, Ayse and Oostra, Ben A and Turner, Stephen T and Ding, Jingzhong and Andrews, Jeanette S and Freedman, Barry I and Giulianini, Franco and Koenig, Wolfgang and Illig, Thomas and D{\"o}ring, Angela and Wichmann, H-Erich and Zgaga, Lina and Zemunik, Tatijana and Boban, Mladen and Minelli, Cosetta and Wheeler, Heather E and Igl, Wilmar and Zaboli, Ghazal and Wild, Sarah H and Wright, Alan F and Campbell, Harry and Ellinghaus, David and N{\"o}thlings, Ute and Jacobs, Gunnar and Biffar, Reiner and Ernst, Florian and Homuth, Georg and Kroemer, Heyo K and Nauck, Matthias and Stracke, Sylvia and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Kovacs, Peter and Stumvoll, Michael and M{\"a}gi, Reedik and Hofman, Albert and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and Aulchenko, Yurii S and Polasek, Ozren and Hastie, Nick and Vitart, Veronique and Helmer, Catherine and Wang, Jie Jin and Stengel, B{\'e}n{\'e}dicte and Ruggiero, Daniela and Bergmann, Sven and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and Nikopensius, Tiit and Province, Michael and Colhoun, Helen and Doney, Alex and Robino, Antonietta and Kr{\"a}mer, Bernhard K and Portas, Laura and Ford, Ian and Buckley, Brendan M and Adam, Martin and Thun, Gian-Andri and Paulweber, Bernhard and Haun, Margot and Sala, Cinzia and Mitchell, Paul and Ciullo, Marina and Vollenweider, Peter and Raitakari, Olli and Metspalu, Andres and Palmer, Colin and Gasparini, Paolo and Pirastu, Mario and Jukema, J Wouter and Probst-Hensch, Nicole M and Kronenberg, Florian and Toniolo, Daniela and Gudnason, Vilmundur and Shuldiner, Alan R and Coresh, Josef and Schmidt, Reinhold and Ferrucci, Luigi and van Duijn, Cornelia M and Borecki, Ingrid and Kardia, Sharon L R and Liu, Yongmei and Curhan, Gary C and Rudan, Igor and Gyllensten, Ulf and Wilson, James F and Franke, Andre and Pramstaller, Peter P and Rettig, Rainer and Prokopenko, Inga and Witteman, Jacqueline and Hayward, Caroline and Ridker, Paul M and Bochud, Murielle and Heid, Iris M and Siscovick, David S and Fox, Caroline S and Kao, W Linda and B{\"o}ger, Carsten A} } @article {6075, title = {Genome-wide association analyses identify 18 new loci associated with serum urate concentrations.}, journal = {Nat Genet}, volume = {45}, year = {2013}, month = {2013 Feb}, pages = {145-54}, abstract = {

Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.

}, keywords = {Analysis of Variance, European Continental Ancestry Group, Gene Frequency, Genetic Loci, Genome-Wide Association Study, Glucose, Gout, Humans, Inhibins, Polymorphism, Single Nucleotide, Signal Transduction, Uric Acid}, issn = {1546-1718}, doi = {10.1038/ng.2500}, author = {K{\"o}ttgen, Anna and Albrecht, Eva and Teumer, Alexander and Vitart, Veronique and Krumsiek, Jan and Hundertmark, Claudia and Pistis, Giorgio and Ruggiero, Daniela and O{\textquoteright}Seaghdha, Conall M and Haller, Toomas and Yang, Qiong and Tanaka, Toshiko and Johnson, Andrew D and Kutalik, Zolt{\'a}n and Smith, Albert V and Shi, Julia and Struchalin, Maksim and Middelberg, Rita P S and Brown, Morris J and Gaffo, Angelo L and Pirastu, Nicola and Li, Guo and Hayward, Caroline and Zemunik, Tatijana and Huffman, Jennifer and Yengo, Loic and Zhao, Jing Hua and Demirkan, Ayse and Feitosa, Mary F and Liu, Xuan and Malerba, Giovanni and Lopez, Lorna M and van der Harst, Pim and Li, Xinzhong and Kleber, Marcus E and Hicks, Andrew A and Nolte, Ilja M and Johansson, Asa and Murgia, Federico and Wild, Sarah H and Bakker, Stephan J L and Peden, John F and Dehghan, Abbas and Steri, Maristella and Tenesa, Albert and Lagou, Vasiliki and Salo, Perttu and Mangino, Massimo and Rose, Lynda M and Lehtim{\"a}ki, Terho and Woodward, Owen M and Okada, Yukinori and Tin, Adrienne and M{\"u}ller, Christian and Oldmeadow, Christopher and Putku, Margus and Czamara, Darina and Kraft, Peter and Frogheri, Laura and Thun, Gian Andri and Grotevendt, Anne and Gislason, Gauti Kjartan and Harris, Tamara B and Launer, Lenore J and McArdle, Patrick and Shuldiner, Alan R and Boerwinkle, Eric and Coresh, Josef and Schmidt, Helena and Schallert, Michael and Martin, Nicholas G and Montgomery, Grant W and Kubo, Michiaki and Nakamura, Yusuke and Tanaka, Toshihiro and Munroe, Patricia B and Samani, Nilesh J and Jacobs, David R and Liu, Kiang and D{\textquoteright}Adamo, Pio and Ulivi, Sheila and Rotter, Jerome I and Psaty, Bruce M and Vollenweider, Peter and Waeber, G{\'e}rard and Campbell, Susan and Devuyst, Olivier and Navarro, Pau and Kolcic, Ivana and Hastie, Nicholas and Balkau, Beverley and Froguel, Philippe and Esko, T{\~o}nu and Salumets, Andres and Khaw, Kay Tee and Langenberg, Claudia and Wareham, Nicholas J and Isaacs, Aaron and Kraja, Aldi and Zhang, Qunyuan and Wild, Philipp S and Scott, Rodney J and Holliday, Elizabeth G and Org, Elin and Viigimaa, Margus and Bandinelli, Stefania and Metter, Jeffrey E and Lupo, Antonio and Trabetti, Elisabetta and Sorice, Rossella and D{\"o}ring, Angela and Lattka, Eva and Strauch, Konstantin and Theis, Fabian and Waldenberger, Melanie and Wichmann, H-Erich and Davies, Gail and Gow, Alan J and Bruinenberg, Marcel and Stolk, Ronald P and Kooner, Jaspal S and Zhang, Weihua and Winkelmann, Bernhard R and Boehm, Bernhard O and Lucae, Susanne and Penninx, Brenda W and Smit, Johannes H and Curhan, Gary and Mudgal, Poorva and Plenge, Robert M and Portas, Laura and Persico, Ivana and Kirin, Mirna and Wilson, James F and Mateo Leach, Irene and van Gilst, Wiek H and Goel, Anuj and Ongen, Halit and Hofman, Albert and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Imboden, Medea and von Eckardstein, Arnold and Cucca, Francesco and Nagaraja, Ramaiah and Piras, Maria Grazia and Nauck, Matthias and Schurmann, Claudia and Budde, Kathrin and Ernst, Florian and Farrington, Susan M and Theodoratou, Evropi and Prokopenko, Inga and Stumvoll, Michael and Jula, Antti and Perola, Markus and Salomaa, Veikko and Shin, So-Youn and Spector, Tim D and Sala, Cinzia and Ridker, Paul M and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and Hengstenberg, Christian and Nelson, Christopher P and Meschia, James F and Nalls, Michael A and Sharma, Pankaj and Singleton, Andrew B and Kamatani, Naoyuki and Zeller, Tanja and Burnier, Michel and Attia, John and Laan, Maris and Klopp, Norman and Hillege, Hans L and Kloiber, Stefan and Choi, Hyon and Pirastu, Mario and Tore, Silvia and Probst-Hensch, Nicole M and V{\"o}lzke, Henry and Gudnason, Vilmundur and Parsa, Afshin and Schmidt, Reinhold and Whitfield, John B and Fornage, Myriam and Gasparini, Paolo and Siscovick, David S and Polasek, Ozren and Campbell, Harry and Rudan, Igor and Bouatia-Naji, Nabila and Metspalu, Andres and Loos, Ruth J F and van Duijn, Cornelia M and Borecki, Ingrid B and Ferrucci, Luigi and Gambaro, Giovanni and Deary, Ian J and Wolffenbuttel, Bruce H R and Chambers, John C and M{\"a}rz, Winfried and Pramstaller, Peter P and Snieder, Harold and Gyllensten, Ulf and Wright, Alan F and Navis, Gerjan and Watkins, Hugh and Witteman, Jacqueline C M and Sanna, Serena and Schipf, Sabine and Dunlop, Malcolm G and T{\"o}njes, Anke and Ripatti, Samuli and Soranzo, Nicole and Toniolo, Daniela and Chasman, Daniel I and Raitakari, Olli and Kao, W H Linda and Ciullo, Marina and Fox, Caroline S and Caulfield, Mark and Bochud, Murielle and Gieger, Christian} } @article {6291, title = {Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations.}, journal = {PLoS Genet}, volume = {9}, year = {2013}, month = {2013}, pages = {e1003796}, abstract = {

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.

}, keywords = {Animals, Bone and Bones, Bone Density, Calcium, European Continental Ancestry Group, Gene Expression Regulation, Genome-Wide Association Study, Homeostasis, Humans, Kidney, Mice, Polymorphism, Single Nucleotide}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1003796}, author = {O{\textquoteright}Seaghdha, Conall M and Wu, Hongsheng and Yang, Qiong and Kapur, Karen and Guessous, Idris and Zuber, Annie Mercier and K{\"o}ttgen, Anna and Stoudmann, Candice and Teumer, Alexander and Kutalik, Zolt{\'a}n and Mangino, Massimo and Dehghan, Abbas and Zhang, Weihua and Eiriksdottir, Gudny and Li, Guo and Tanaka, Toshiko and Portas, Laura and Lopez, Lorna M and Hayward, Caroline and Lohman, Kurt and Matsuda, Koichi and Padmanabhan, Sandosh and Firsov, Dmitri and Sorice, Rossella and Ulivi, Sheila and Brockhaus, A Catharina and Kleber, Marcus E and Mahajan, Anubha and Ernst, Florian D and Gudnason, Vilmundur and Launer, Lenore J and Mace, Aurelien and Boerwinckle, Eric and Arking, Dan E and Tanikawa, Chizu and Nakamura, Yusuke and Brown, Morris J and Gaspoz, Jean-Michel and Theler, Jean-Marc and Siscovick, David S and Psaty, Bruce M and Bergmann, Sven and Vollenweider, Peter and Vitart, Veronique and Wright, Alan F and Zemunik, Tatijana and Boban, Mladen and Kolcic, Ivana and Navarro, Pau and Brown, Edward M and Estrada, Karol and Ding, Jingzhong and Harris, Tamara B and Bandinelli, Stefania and Hernandez, Dena and Singleton, Andrew B and Girotto, Giorgia and Ruggiero, Daniela and d{\textquoteright}Adamo, Adamo Pio and Robino, Antonietta and Meitinger, Thomas and Meisinger, Christa and Davies, Gail and Starr, John M and Chambers, John C and Boehm, Bernhard O and Winkelmann, Bernhard R and Huang, Jie and Murgia, Federico and Wild, Sarah H and Campbell, Harry and Morris, Andrew P and Franco, Oscar H and Hofman, Albert and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and V{\"o}lker, Uwe and Hannemann, Anke and Biffar, Reiner and Hoffmann, Wolfgang and Shin, So-Youn and Lescuyer, Pierre and Henry, Hughes and Schurmann, Claudia and Munroe, Patricia B and Gasparini, Paolo and Pirastu, Nicola and Ciullo, Marina and Gieger, Christian and M{\"a}rz, Winfried and Lind, Lars and Spector, Tim D and Smith, Albert V and Rudan, Igor and Wilson, James F and Polasek, Ozren and Deary, Ian J and Pirastu, Mario and Ferrucci, Luigi and Liu, Yongmei and Kestenbaum, Bryan and Kooner, Jaspal S and Witteman, Jacqueline C M and Nauck, Matthias and Kao, W H Linda and Wallaschofski, Henri and Bonny, Olivier and Fox, Caroline S and Bochud, Murielle} } @article {6587, title = {Association of a cystatin C gene variant with cystatin C levels, CKD, and risk of incident cardiovascular disease and mortality.}, journal = {Am J Kidney Dis}, volume = {63}, year = {2014}, month = {2014 Jan}, pages = {16-22}, abstract = {

BACKGROUND: Carriers of the T allele of the single-nucleotide polymorphism rs13038305 tend to have lower cystatin C levels and higher cystatin C-based estimated glomerular filtration rate (eGFRcys). Adjusting for this genetic effect on cystatin C concentrations may improve GFR estimation, reclassify cases of chronic kidney disease (CKD), and strengthen risk estimates for cardiovascular disease (CVD) and mortality.

STUDY DESIGN: Observational.

SETTING \& POPULATION: 4 population-based cohorts: Atherosclerosis Risk in Communities (ARIC), Cardiovascular Health (CHS), Framingham Heart (FHS), and Health, Aging, and Body Composition (Health ABC) studies.

PREDICTORS: We estimated the association of rs13038305 with eGFRcys and serum creatinine-based eGFR (eGFRcr) and performed longitudinal analyses of the associations of eGFRcys with mortality and cardiovascular events following adjustment for rs13038305.

OUTCOMES: We assessed reclassification by genotype-adjusted eGFRcys across CKD categories: <45, 45-59, 60-89, and >= 90 mL/min/1.73 m(2). We compared mortality and CVD outcomes in those reclassified to a worse eGFRcys category with those unaffected. Results were combined using fixed-effect inverse-variance meta-analysis.

RESULTS: In 14,645 participants, each copy of the T allele of rs13038305 (frequency, 21\%) was associated with a 6.4\% lower cystatin C concentration, 5.5-mL/min/1.73 m(2) higher eGFRcys, and 36\% [95\% CI, 29\%-41\%] lower odds of CKD. Associations with CVD (HR, 1.17; 95\% CI, 1.14-1.20) and mortality (HR, 1.22; 95\% CI, 1.19-1.24) per 10-mL/min/1.73 m(2) lower eGFRcys were similar with or without rs13038305 adjustment. 1,134 (7.7\%) participants were reclassified to a worse CKD category following rs13038305 adjustment, and rates of CVD and mortality were higher in individuals who were reclassified. However, the overall net reclassification index was not significant for either outcome, at 0.009 (95\% CI, -0.003 to 0.022) for mortality and 0.014 (95\% CI, 0.0 to 0.028) for CVD.

LIMITATIONS: rs13038305 explains only a small proportion of cystatin C variation.

CONCLUSIONS: Statistical adjustment can correct a genetic bias in GFR estimates based on cystatin C in carriers of the T allele of rs13038305 and result in changes in disease classification. However, on a population level, the effects on overall reclassification of CKD status are modest.

}, keywords = {Aged, Bias, Biomarkers, Cardiovascular Diseases, Creatinine, Cystatin C, Female, Genetic Variation, Glomerular Filtration Rate, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Renal Insufficiency, Chronic, Risk Assessment, Risk Factors, Severity of Illness Index, Statistics as Topic, Survival Rate}, issn = {1523-6838}, doi = {10.1053/j.ajkd.2013.06.015}, author = {O{\textquoteright}Seaghdha, Conall M and Tin, Adrienne and Yang, Qiong and Katz, Ronit and Liu, Yongmei and Harris, Tamara and Astor, Brad and Coresh, Josef and Fox, Caroline S and Kao, W H Linda and Shlipak, Michael G} }