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

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.

%B Nat Genet %V 42 %P 376-84 %8 2010 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/20383146?dopt=Abstract %R 10.1038/ng.568 %0 Journal Article %J J Am Soc Nephrol %D 2011 %T CUBN is a gene locus for albuminuria. %A Böger, Carsten A %A Chen, Ming-Huei %A Tin, Adrienne %A Olden, Matthias %A Köttgen, Anna %A de Boer, Ian H %A Fuchsberger, Christian %A O'Seaghdha, Conall M %A Pattaro, Cristian %A Teumer, Alexander %A Liu, Ching-Ti %A Glazer, Nicole L %A Li, Man %A O'Connell, Jeffrey R %A Tanaka, Toshiko %A Peralta, Carmen A %A Kutalik, Zoltán %A Luan, Jian'an %A Zhao, Jing Hua %A Hwang, Shih-Jen %A Akylbekova, Ermeg %A Kramer, Holly %A van der Harst, Pim %A Smith, Albert V %A Lohman, Kurt %A de Andrade, Mariza %A Hayward, Caroline %A Kollerits, Barbara %A Tönjes, Anke %A Aspelund, Thor %A Ingelsson, Erik %A Eiriksdottir, Gudny %A Launer, Lenore J %A Harris, Tamara B %A Shuldiner, Alan R %A Mitchell, Braxton D %A Arking, Dan E %A Franceschini, Nora %A Boerwinkle, Eric %A Egan, Josephine %A Hernandez, Dena %A Reilly, Muredach %A Townsend, Raymond R %A Lumley, Thomas %A Siscovick, David S %A Psaty, Bruce M %A Kestenbaum, Bryan %A Haritunians, Talin %A Bergmann, Sven %A Vollenweider, Peter %A Waeber, Gérard %A Mooser, Vincent %A Waterworth, Dawn %A Johnson, Andrew D %A Florez, Jose C %A Meigs, James B %A Lu, Xiaoning %A Turner, Stephen T %A Atkinson, Elizabeth J %A Leak, Tennille S %A Aasarød, Knut %A Skorpen, Frank %A Syvänen, Ann-Christine %A Illig, Thomas %A Baumert, Jens %A Koenig, Wolfgang %A Krämer, Bernhard K %A Devuyst, Olivier %A Mychaleckyj, Josyf C %A Minelli, Cosetta %A Bakker, Stephan J L %A Kedenko, Lyudmyla %A Paulweber, Bernhard %A Coassin, Stefan %A Endlich, Karlhans %A Kroemer, Heyo K %A Biffar, Reiner %A Stracke, Sylvia %A Völzke, Henry %A Stumvoll, Michael %A Mägi, Reedik %A Campbell, Harry %A Vitart, Veronique %A Hastie, Nicholas D %A Gudnason, Vilmundur %A Kardia, Sharon L R %A Liu, Yongmei %A Polasek, Ozren %A Curhan, Gary %A Kronenberg, Florian %A Prokopenko, Inga %A Rudan, Igor %A Arnlöv, Johan %A Hallan, Stein %A Navis, Gerjan %A Parsa, Afshin %A Ferrucci, Luigi %A Coresh, Josef %A Shlipak, Michael G %A Bull, Shelley B %A Paterson, Nicholas J %A Wichmann, H-Erich %A Wareham, Nicholas J %A Loos, Ruth J F %A Rotter, Jerome I %A Pramstaller, Peter P %A Cupples, L Adrienne %A Beckmann, Jacques S %A Yang, Qiong %A Heid, Iris M %A Rettig, Rainer %A Dreisbach, Albert W %A Bochud, Murielle %A Fox, Caroline S %A Kao, W H L %K African Continental Ancestry Group %K Albuminuria %K European Continental Ancestry Group %K Genetic Loci %K Genetic Predisposition to Disease %K Humans %K Mutation, Missense %K Receptors, Cell Surface %X

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.

%B J Am Soc Nephrol %V 22 %P 555-70 %8 2011 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/21355061?dopt=Abstract %R 10.1681/ASN.2010060598 %0 Journal Article %J PLoS Genet %D 2012 %T Genome-wide association and functional follow-up reveals new loci for kidney function. %A Pattaro, Cristian %A Köttgen, Anna %A Teumer, Alexander %A Garnaas, Maija %A Böger, Carsten A %A Fuchsberger, Christian %A Olden, Matthias %A Chen, Ming-Huei %A Tin, Adrienne %A Taliun, Daniel %A Li, Man %A Gao, Xiaoyi %A Gorski, Mathias %A Yang, Qiong %A Hundertmark, Claudia %A Foster, Meredith C %A O'Seaghdha, Conall M %A Glazer, Nicole %A Isaacs, Aaron %A Liu, Ching-Ti %A Smith, Albert V %A O'Connell, Jeffrey R %A Struchalin, Maksim %A Tanaka, Toshiko %A Li, Guo %A Johnson, Andrew D %A Gierman, Hinco J %A Feitosa, Mary %A Hwang, Shih-Jen %A Atkinson, Elizabeth J %A Lohman, Kurt %A Cornelis, Marilyn C %A Johansson, Asa %A Tönjes, Anke %A Dehghan, Abbas %A Chouraki, Vincent %A Holliday, Elizabeth G %A Sorice, Rossella %A Kutalik, Zoltán %A Lehtimäki, Terho %A Esko, Tõnu %A Deshmukh, Harshal %A Ulivi, Sheila %A Chu, Audrey Y %A Murgia, Federico %A Trompet, Stella %A Imboden, Medea %A Kollerits, Barbara %A Pistis, Giorgio %A Harris, Tamara B %A Launer, Lenore J %A Aspelund, Thor %A Eiriksdottir, Gudny %A Mitchell, Braxton D %A Boerwinkle, Eric %A Schmidt, Helena %A Cavalieri, Margherita %A Rao, Madhumathi %A Hu, Frank B %A Demirkan, Ayse %A Oostra, Ben A %A de Andrade, Mariza %A Turner, Stephen T %A Ding, Jingzhong %A Andrews, Jeanette S %A Freedman, Barry I %A Koenig, Wolfgang %A Illig, Thomas %A Döring, Angela %A Wichmann, H-Erich %A Kolcic, Ivana %A Zemunik, Tatijana %A Boban, Mladen %A Minelli, Cosetta %A Wheeler, Heather E %A Igl, Wilmar %A Zaboli, Ghazal %A Wild, Sarah H %A Wright, Alan F %A Campbell, Harry %A Ellinghaus, David %A Nöthlings, Ute %A Jacobs, Gunnar %A Biffar, Reiner %A Endlich, Karlhans %A Ernst, Florian %A Homuth, Georg %A Kroemer, Heyo K %A Nauck, Matthias %A Stracke, Sylvia %A Völker, Uwe %A Völzke, Henry %A Kovacs, Peter %A Stumvoll, Michael %A Mägi, Reedik %A Hofman, Albert %A Uitterlinden, André G %A Rivadeneira, Fernando %A Aulchenko, Yurii S %A Polasek, Ozren %A Hastie, Nick %A Vitart, Veronique %A Helmer, Catherine %A Wang, Jie Jin %A Ruggiero, Daniela %A Bergmann, Sven %A Kähönen, Mika %A Viikari, Jorma %A Nikopensius, Tiit %A Province, Michael %A Ketkar, Shamika %A Colhoun, Helen %A Doney, Alex %A Robino, Antonietta %A Giulianini, Franco %A Krämer, Bernhard K %A Portas, Laura %A Ford, Ian %A Buckley, Brendan M %A Adam, Martin %A Thun, Gian-Andri %A Paulweber, Bernhard %A Haun, Margot %A Sala, Cinzia %A Metzger, Marie %A Mitchell, Paul %A Ciullo, Marina %A Kim, Stuart K %A Vollenweider, Peter %A Raitakari, Olli %A Metspalu, Andres %A Palmer, Colin %A Gasparini, Paolo %A Pirastu, Mario %A Jukema, J Wouter %A Probst-Hensch, Nicole M %A Kronenberg, Florian %A Toniolo, Daniela %A Gudnason, Vilmundur %A Shuldiner, Alan R %A Coresh, Josef %A Schmidt, Reinhold %A Ferrucci, Luigi %A Siscovick, David S %A van Duijn, Cornelia M %A Borecki, Ingrid %A Kardia, Sharon L R %A Liu, Yongmei %A Curhan, Gary C %A Rudan, Igor %A Gyllensten, Ulf %A Wilson, James F %A Franke, Andre %A Pramstaller, Peter P %A Rettig, Rainer %A Prokopenko, Inga %A Witteman, Jacqueline C M %A Hayward, Caroline %A Ridker, Paul %A Parsa, Afshin %A Bochud, Murielle %A Heid, Iris M %A Goessling, Wolfram %A Chasman, Daniel I %A Kao, W H Linda %A Fox, Caroline S %K African Americans %K Aged %K Animals %K Caspase 9 %K Cyclin-Dependent Kinases %K DEAD-box RNA Helicases %K DNA Helicases %K European Continental Ancestry Group %K Female %K Follow-Up Studies %K Gene Knockdown Techniques %K Genome-Wide Association Study %K Glomerular Filtration Rate %K Humans %K Kidney %K Kidney Failure, Chronic %K Male %K Middle Aged %K Phosphoric Diester Hydrolases %K Zebrafish %X

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.

%B PLoS Genet %V 8 %P e1002584 %8 2012 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/22479191?dopt=Abstract %R 10.1371/journal.pgen.1002584 %0 Journal Article %J J Am Soc Nephrol %D 2013 %T Common variants in Mendelian kidney disease genes and their association with renal function. %A Parsa, Afshin %A Fuchsberger, Christian %A Köttgen, Anna %A O'Seaghdha, Conall M %A Pattaro, Cristian %A de Andrade, Mariza %A Chasman, Daniel I %A Teumer, Alexander %A Endlich, Karlhans %A Olden, Matthias %A Chen, Ming-Huei %A Tin, Adrienne %A Kim, Young J %A Taliun, Daniel %A Li, Man %A Feitosa, Mary %A Gorski, Mathias %A Yang, Qiong %A Hundertmark, Claudia %A Foster, Meredith C %A Glazer, Nicole %A Isaacs, Aaron %A Rao, Madhumathi %A Smith, Albert V %A O'Connell, Jeffrey R %A Struchalin, Maksim %A Tanaka, Toshiko %A Li, Guo %A Hwang, Shih-Jen %A Atkinson, Elizabeth J %A Lohman, Kurt %A Cornelis, Marilyn C %A Johansson, Asa %A Tönjes, Anke %A Dehghan, Abbas %A Couraki, Vincent %A Holliday, Elizabeth G %A Sorice, Rossella %A Kutalik, Zoltán %A Lehtimäki, Terho %A Esko, Tõnu %A Deshmukh, Harshal %A Ulivi, Sheila %A Chu, Audrey Y %A Murgia, Federico %A Trompet, Stella %A Imboden, Medea %A Kollerits, Barbara %A Pistis, Giorgio %A Harris, Tamara B %A Launer, Lenore J %A Aspelund, Thor %A Eiriksdottir, Gudny %A Mitchell, Braxton D %A Boerwinkle, Eric %A Schmidt, Helena %A Hofer, Edith %A Hu, Frank %A Demirkan, Ayse %A Oostra, Ben A %A Turner, Stephen T %A Ding, Jingzhong %A Andrews, Jeanette S %A Freedman, Barry I %A Giulianini, Franco %A Koenig, Wolfgang %A Illig, Thomas %A Döring, Angela %A Wichmann, H-Erich %A Zgaga, Lina %A Zemunik, Tatijana %A Boban, Mladen %A Minelli, Cosetta %A Wheeler, Heather E %A Igl, Wilmar %A Zaboli, Ghazal %A Wild, Sarah H %A Wright, Alan F %A Campbell, Harry %A Ellinghaus, David %A Nöthlings, Ute %A Jacobs, Gunnar %A Biffar, Reiner %A Ernst, Florian %A Homuth, Georg %A Kroemer, Heyo K %A Nauck, Matthias %A Stracke, Sylvia %A Völker, Uwe %A Völzke, Henry %A Kovacs, Peter %A Stumvoll, Michael %A Mägi, Reedik %A Hofman, Albert %A Uitterlinden, André G %A Rivadeneira, Fernando %A Aulchenko, Yurii S %A Polasek, Ozren %A Hastie, Nick %A Vitart, Veronique %A Helmer, Catherine %A Wang, Jie Jin %A Stengel, Bénédicte %A Ruggiero, Daniela %A Bergmann, Sven %A Kähönen, Mika %A Viikari, Jorma %A Nikopensius, Tiit %A Province, Michael %A Colhoun, Helen %A Doney, Alex %A Robino, Antonietta %A Krämer, Bernhard K %A Portas, Laura %A Ford, Ian %A Buckley, Brendan M %A Adam, Martin %A Thun, Gian-Andri %A Paulweber, Bernhard %A Haun, Margot %A Sala, Cinzia %A Mitchell, Paul %A Ciullo, Marina %A Vollenweider, Peter %A Raitakari, Olli %A Metspalu, Andres %A Palmer, Colin %A Gasparini, Paolo %A Pirastu, Mario %A Jukema, J Wouter %A Probst-Hensch, Nicole M %A Kronenberg, Florian %A Toniolo, Daniela %A Gudnason, Vilmundur %A Shuldiner, Alan R %A Coresh, Josef %A Schmidt, Reinhold %A Ferrucci, Luigi %A van Duijn, Cornelia M %A Borecki, Ingrid %A Kardia, Sharon L R %A Liu, Yongmei %A Curhan, Gary C %A Rudan, Igor %A Gyllensten, Ulf %A Wilson, James F %A Franke, Andre %A Pramstaller, Peter P %A Rettig, Rainer %A Prokopenko, Inga %A Witteman, Jacqueline %A Hayward, Caroline %A Ridker, Paul M %A Bochud, Murielle %A Heid, Iris M %A Siscovick, David S %A Fox, Caroline S %A Kao, W Linda %A Böger, Carsten A %K Databases, Genetic %K European Continental Ancestry Group %K Gene Frequency %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Kidney %K Mendelian Randomization Analysis %K Phenotype %K Polymorphism, Single Nucleotide %K Renal Insufficiency, Chronic %X

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.

%B J Am Soc Nephrol %V 24 %P 2105-17 %8 2013 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/24029420?dopt=Abstract %R 10.1681/ASN.2012100983 %0 Journal Article %J Circ Cardiovasc Genet %D 2015 %T Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI. %A Verhaaren, Benjamin F J %A Debette, Stephanie %A Bis, Joshua C %A Smith, Jennifer A %A Ikram, M Kamran %A Adams, Hieab H %A Beecham, Ashley H %A Rajan, Kumar B %A Lopez, Lorna M %A Barral, Sandra %A van Buchem, Mark A %A van der Grond, Jeroen %A Smith, Albert V %A Hegenscheid, Katrin %A Aggarwal, Neelum T %A de Andrade, Mariza %A Atkinson, Elizabeth J %A Beekman, Marian %A Beiser, Alexa S %A Blanton, Susan H %A Boerwinkle, Eric %A Brickman, Adam M %A Bryan, R Nick %A Chauhan, Ganesh %A Chen, Christopher P L H %A Chouraki, Vincent %A de Craen, Anton J M %A Crivello, Fabrice %A Deary, Ian J %A Deelen, Joris %A De Jager, Philip L %A Dufouil, Carole %A Elkind, Mitchell S V %A Evans, Denis A %A Freudenberger, Paul %A Gottesman, Rebecca F %A Guðnason, Vilmundur %A Habes, Mohamad %A Heckbert, Susan R %A Heiss, Gerardo %A Hilal, Saima %A Hofer, Edith %A Hofman, Albert %A Ibrahim-Verbaas, Carla A %A Knopman, David S %A Lewis, Cora E %A Liao, Jiemin %A Liewald, David C M %A Luciano, Michelle %A van der Lugt, Aad %A Martinez, Oliver O %A Mayeux, Richard %A Mazoyer, Bernard %A Nalls, Mike %A Nauck, Matthias %A Niessen, Wiro J %A Oostra, Ben A %A Psaty, Bruce M %A Rice, Kenneth M %A Rotter, Jerome I %A von Sarnowski, Bettina %A Schmidt, Helena %A Schreiner, Pamela J %A Schuur, Maaike %A Sidney, Stephen S %A Sigurdsson, Sigurdur %A Slagboom, P Eline %A Stott, David J M %A van Swieten, John C %A Teumer, Alexander %A Töglhofer, Anna Maria %A Traylor, Matthew %A Trompet, Stella %A Turner, Stephen T %A Tzourio, Christophe %A Uh, Hae-Won %A Uitterlinden, André G %A Vernooij, Meike W %A Wang, Jing J %A Wong, Tien Y %A Wardlaw, Joanna M %A Windham, B Gwen %A Wittfeld, Katharina %A Wolf, Christiane %A Wright, Clinton B %A Yang, Qiong %A Zhao, Wei %A Zijdenbos, Alex %A Jukema, J Wouter %A Sacco, Ralph L %A Kardia, Sharon L R %A Amouyel, Philippe %A Mosley, Thomas H %A Longstreth, W T %A DeCarli, Charles C %A van Duijn, Cornelia M %A Schmidt, Reinhold %A Launer, Lenore J %A Grabe, Hans J %A Seshadri, Sudha S %A Ikram, M Arfan %A Fornage, Myriam %K Aged %K Aged, 80 and over %K Chromosomes, Human %K Continental Population Groups %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Male %K Meta-Analysis as Topic %K Middle Aged %K Models, Genetic %K Stroke %K White Matter %X

BACKGROUND: The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies.

METHODS AND RESULTS: We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10(-19)) and identified novel loci on chr10q24 (P=1.6×10(-9)) and chr2p21 (P=4.4×10(-8)). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10(-8)) and chr2p16 (P=1.5×10(-8)). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16).

CONCLUSIONS: We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.

%B Circ Cardiovasc Genet %V 8 %P 398-409 %8 2015 Apr %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/25663218?dopt=Abstract %R 10.1161/CIRCGENETICS.114.000858