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1. Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations.

Author

Conall M O'Seaghdha, Hongsheng Wu, Qiong Yang, Karen Kapur, Idris Guessous, Annie Mercier Zuber, Anna Köttgen, Candice Stoudmann, Alexander Teumer, Zoltán Kutalik, Massimo Mangino, Abbas Dehghan, Weihua Zhang, Gudny Eiriksdottir, Guo Li, Toshiko Tanaka, Laura Portas, Lorna M Lopez, Caroline Hayward, Kurt Lohman, Koichi Matsuda, Sandosh Padmanabhan, Dmitri Firsov, Rossella Sorice, Sheila Ulivi, A Catharina Brockhaus, Marcus E Kleber, Anubha Mahajan, Florian D Ernst, Vilmundur Gudnason, Lenore J Launer, Aurelien Mace, Eric Boerwinckle, Dan E Arking, Chizu Tanikawa, Yusuke Nakamura, Morris J Brown, Jean-Michel Gaspoz, Jean-Marc Theler, David S Siscovick, Bruce M Psaty, Sven Bergmann, Peter Vollenweider, Veronique Vitart, Alan F Wright, Tatijana Zemunik, Mladen Boban, Ivana Kolcic, Pau Navarro, Edward M Brown, Karol Estrada, Jingzhong Ding, Tamara B Harris, Stefania Bandinelli, Dena Hernandez, Andrew B Singleton, Giorgia Girotto, Daniela Ruggiero, Adamo Pio d'Adamo, Antonietta Robino, Thomas Meitinger, Christa Meisinger, Gail Davies, John M Starr, John C Chambers, Bernhard O Boehm, Bernhard R Winkelmann, Jie Huang, Federico Murgia, Sarah H Wild, Harry Campbell, Andrew P Morris, Oscar H Franco, Albert Hofman, Andre G Uitterlinden, Fernando Rivadeneira, Uwe Völker, Anke Hannemann, Reiner Biffar, Wolfgang Hoffmann, So-Youn Shin, Pierre Lescuyer, Hughes Henry, Claudia Schurmann, SUNLIGHT Consortium, GEFOS Consortium, Patricia B Munroe, Paolo Gasparini, Nicola Pirastu, Marina Ciullo, Christian Gieger, Winfried März, Lars Lind, Tim D Spector, Albert V Smith, Igor Rudan, James F Wilson, Ozren Polasek, Ian J Deary, Mario Pirastu, Luigi Ferrucci, Yongmei Liu, Bryan Kestenbaum, Jaspal S Kooner, Jacqueline C M Witteman, Matthias Nauck, W H Linda Kao, Henri Wallaschofski, Olivier Bonny, Caroline S Fox, and Murielle Bochud

Subjects
Genetics, QH426-470
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.

Published
2013
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2. Genome-wide association and functional follow-up reveals new loci for kidney function.

Author

Cristian Pattaro, Anna Köttgen, Alexander Teumer, Maija Garnaas, Carsten A Böger, Christian Fuchsberger, Matthias Olden, Ming-Huei Chen, Adrienne Tin, Daniel Taliun, Man Li, Xiaoyi Gao, Mathias Gorski, Qiong Yang, Claudia Hundertmark, Meredith C Foster, Conall M O'Seaghdha, Nicole Glazer, Aaron Isaacs, Ching-Ti Liu, Albert V Smith, Jeffrey R O'Connell, Maksim Struchalin, Toshiko Tanaka, Guo Li, Andrew D Johnson, Hinco J Gierman, Mary Feitosa, Shih-Jen Hwang, Elizabeth J Atkinson, Kurt Lohman, Marilyn C Cornelis, Åsa Johansson, Anke Tönjes, Abbas Dehghan, Vincent Chouraki, Elizabeth G Holliday, Rossella Sorice, Zoltan Kutalik, Terho Lehtimäki, Tõnu Esko, Harshal Deshmukh, Sheila Ulivi, Audrey Y Chu, Federico Murgia, Stella Trompet, Medea Imboden, Barbara Kollerits, Giorgio Pistis, CARDIoGRAM Consortium, ICBP Consortium, CARe Consortium, Wellcome Trust Case Control Consortium 2 (WTCCC2), Tamara B Harris, Lenore J Launer, Thor Aspelund, Gudny Eiriksdottir, Braxton D Mitchell, Eric Boerwinkle, Helena Schmidt, Margherita Cavalieri, Madhumathi Rao, Frank B Hu, Ayse Demirkan, Ben A Oostra, Mariza de Andrade, Stephen T Turner, Jingzhong Ding, Jeanette S Andrews, Barry I Freedman, Wolfgang Koenig, Thomas Illig, Angela Döring, H-Erich Wichmann, Ivana Kolcic, Tatijana Zemunik, Mladen Boban, Cosetta Minelli, Heather E Wheeler, Wilmar Igl, Ghazal Zaboli, Sarah H Wild, Alan F Wright, Harry Campbell, David Ellinghaus, Ute Nöthlings, Gunnar Jacobs, Reiner Biffar, Karlhans Endlich, Florian Ernst, Georg Homuth, Heyo K Kroemer, Matthias Nauck, Sylvia Stracke, Uwe Völker, Henry Völzke, Peter Kovacs, Michael Stumvoll, Reedik Mägi, Albert Hofman, Andre G Uitterlinden, Fernando Rivadeneira, Yurii S Aulchenko, Ozren Polasek, Nick Hastie, Veronique Vitart, Catherine Helmer, Jie Jin Wang, Daniela Ruggiero, Sven Bergmann, Mika Kähönen, Jorma Viikari, Tiit Nikopensius, Michael Province, Shamika Ketkar, Helen Colhoun, Alex Doney, Antonietta Robino, Franco Giulianini, Bernhard K Krämer, Laura Portas, Ian Ford, Brendan M Buckley, Martin Adam, Gian-Andri Thun, Bernhard Paulweber, Margot Haun, Cinzia Sala, Marie Metzger, Paul Mitchell, Marina Ciullo, Stuart K Kim, Peter Vollenweider, Olli Raitakari, Andres Metspalu, Colin Palmer, Paolo Gasparini, Mario Pirastu, J Wouter Jukema, Nicole M Probst-Hensch, Florian Kronenberg, Daniela Toniolo, Vilmundur Gudnason, Alan R Shuldiner, Josef Coresh, Reinhold Schmidt, Luigi Ferrucci, David S Siscovick, Cornelia M van Duijn, Ingrid Borecki, Sharon L R Kardia, Yongmei Liu, Gary C Curhan, Igor Rudan, Ulf Gyllensten, James F Wilson, Andre Franke, Peter P Pramstaller, Rainer Rettig, Inga Prokopenko, Jacqueline C M Witteman, Caroline Hayward, Paul Ridker, Afshin Parsa, Murielle Bochud, Iris M Heid, Wolfram Goessling, Daniel I Chasman, W H Linda Kao, and Caroline S Fox

Subjects
Genetics, QH426-470
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.

Published
2012
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3. Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD.

Author

Carsten A Böger, Mathias Gorski, Man Li, Michael M Hoffmann, Chunmei Huang, Qiong Yang, Alexander Teumer, Vera Krane, Conall M O'Seaghdha, Zoltán Kutalik, H-Erich Wichmann, Thomas Haak, Eva Boes, Stefan Coassin, Josef Coresh, Barbara Kollerits, Margot Haun, Bernhard Paulweber, Anna Köttgen, Guo Li, Michael G Shlipak, Neil Powe, Shih-Jen Hwang, Abbas Dehghan, Fernando Rivadeneira, André Uitterlinden, Albert Hofman, Jacques S Beckmann, Bernhard K Krämer, Jacqueline Witteman, Murielle Bochud, David Siscovick, Rainer Rettig, Florian Kronenberg, Christoph Wanner, Ravi I Thadhani, Iris M Heid, Caroline S Fox, W H Kao, and CKDGen Consortium

Subjects
Genetics, QH426-470
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

Published
2011
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4. Identification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in European ancestry individuals.

Author

Dan E Arking, M Juhani Junttila, Philippe Goyette, Adriana Huertas-Vazquez, Mark Eijgelsheim, Marieke T Blom, Christopher Newton-Cheh, Kyndaron Reinier, Carmen Teodorescu, Audrey Uy-Evanado, Naima Carter-Monroe, Kari S Kaikkonen, Marja-Leena Kortelainen, Gabrielle Boucher, Caroline Lagacé, Anna Moes, XiaoQing Zhao, Frank Kolodgie, Fernando Rivadeneira, Albert Hofman, Jacqueline C M Witteman, André G Uitterlinden, Roos F Marsman, Raha Pazoki, Abdennasser Bardai, Rudolph W Koster, Abbas Dehghan, Shih-Jen Hwang, Pallav Bhatnagar, Wendy Post, Gina Hilton, Ronald J Prineas, Man Li, Anna Köttgen, Georg Ehret, Eric Boerwinkle, Josef Coresh, W H Linda Kao, Bruce M Psaty, Gordon F Tomaselli, Nona Sotoodehnia, David S Siscovick, Greg L Burke, Eduardo Marbán, Peter M Spooner, L Adrienne Cupples, Jonathan Jui, Karen Gunson, Y Antero Kesäniemi, Arthur A M Wilde, Jean-Claude Tardif, Christopher J O'Donnell, Connie R Bezzina, Renu Virmani, Bruno H C H Stricker, Hanno L Tan, Christine M Albert, Aravinda Chakravarti, John D Rioux, Heikki V Huikuri, and Sumeet S Chugh

Subjects
Genetics, QH426-470
Abstract

Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000-300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10(-10)). The risk allele, while ancestral, has a frequency of ~1.4%, suggesting strong negative selection and increases risk for SCD by 1.92-fold per allele (95% CI 1.57-2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006).

Published
2011
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5. Genome-wide association studies of serum magnesium, potassium, and sodium concentrations identify six Loci influencing serum magnesium levels.

Author

Tamra E Meyer, Germaine C Verwoert, Shih-Jen Hwang, Nicole L Glazer, Albert V Smith, Frank J A van Rooij, Georg B Ehret, Eric Boerwinkle, Janine F Felix, Tennille S Leak, Tamara B Harris, Qiong Yang, Abbas Dehghan, Thor Aspelund, Ronit Katz, Georg Homuth, Thomas Kocher, Rainer Rettig, Janina S Ried, Christian Gieger, Hanna Prucha, Arne Pfeufer, Thomas Meitinger, Josef Coresh, Albert Hofman, Mark J Sarnak, Yii-Der Ida Chen, André G Uitterlinden, Aravinda Chakravarti, Bruce M Psaty, Cornelia M van Duijn, W H Linda Kao, Jacqueline C M Witteman, Vilmundur Gudnason, David S Siscovick, Caroline S Fox, Anna Köttgen, Genetic Factors for Osteoporosis Consortium, and Meta Analysis of Glucose and Insulin Related Traits Consortium

Subjects
Genetics, QH426-470
Abstract

Magnesium, potassium, and sodium, cations commonly measured in serum, are involved in many physiological processes including energy metabolism, nerve and muscle function, signal transduction, and fluid and blood pressure regulation. To evaluate the contribution of common genetic variation to normal physiologic variation in serum concentrations of these cations, we conducted genome-wide association studies of serum magnesium, potassium, and sodium concentrations using approximately 2.5 million genotyped and imputed common single nucleotide polymorphisms (SNPs) in 15,366 participants of European descent from the international CHARGE Consortium. Study-specific results were combined using fixed-effects inverse-variance weighted meta-analysis. SNPs demonstrating genome-wide significant (p

Published
2010
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6. Stratifying type 2 diabetes cases by BMI identifies genetic risk variants in LAMA1 and enrichment for risk variants in lean compared to obese cases

Author

David Altschuler, Cornelia M. van Duijn, Igor Rudan, Denis Rybin, Yann Labrune, Francis S. Collins, Martha Ganser, Lu Qi, Michael Roden, Unnur Thorsteinsdottir, Inga Prokopenko, Albert Hofman, Guillaume Charpentier, Mark I. McCarthy, Robert Sladek, James F. Wilson, Stéphane Cauchi, Yurii S. Aulchenko, Christian Herder, Robert A. Scott, Man Li, Peter P. Pramstaller, Rafn Benediktsson, Frank B. Hu, Samy Hadjadj, Peter Almgren, Andrew D. Johnson, Beverley Balkau, Pau Navarro, Michael Boehnke, Michael N. Weedon, Leif Groop, John R. B. Perry, Lori L. Bonnycastle, Noël P. Burtt, Alisa K. Manning, Claudia Langenberg, W Rayner, Benjamin F. Voight, Wolfgang Rathmann, Timothy M. Frayling, Gunnar Sigurdsson, Eric Boerwinkle, James S. Pankow, Ben A. Oostra, Andrew D. Morris, Philippe Froguel, Linda Kao, Dan E. Arking, Kari Stefansson, Harry Campbell, Loic Yengo, Colin N. A. Palmer, Nicholas J. Wareham, James B. Meigs, Karen L. Mohlke, Gudmar Thorleifsson, Andrew T. Hattersley, Alan F. Wright, Laura J. Scott, Harald Grallert, Jaakko Tuomilehto, Najaf Amin, Christian Gieger, Thomas Illig, Anna Köttgen, Todd Green, Josée Dupuis, Sidonie Vivequin, Richard N. Bergman, Peter Kraft, André G. Uitterlinden, Valgerdur Steinthorsdottir, Andrew P. Morris, Ann-Kristin Petersen, Epidemiology, Dermatology, Clinical Genetics, and Internal Medicine

Subjects
Male, Cancer Research, Heredity, Epidemiology, PROTEIN, Type 2 diabetes, QH426-470, Overweight, MOUSE, Bioinformatics, DISEASE, GLUCOSE, Body Mass Index, Endocrinology, 0302 clinical medicine, Risk Factors, GENETICS & HEREDITY, Genetics (clinical), 2. Zero hunger, Molecular Epidemiology, 0303 health sciences, High Mobility Group Proteins, Middle Aged, INSULIN, 3. Good health, Phenotypes, DIFFERENTIATION, Genetic Epidemiology, Medicine, Female, medicine.symptom, Life Sciences & Biomedicine, Research Article, EXPRESSION, Asian Continental Ancestry Group, medicine.medical_specialty, SUSCEPTIBILITY LOCI, European Continental Ancestry Group, 030209 endocrinology & metabolism, DIAGRAM Consortium, Biology, Endocrinology and Diabetes, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, Asian People, SDG 3 - Good Health and Well-being, Internal medicine, GIANT Consortium, Genome-Wide Association Studies, Genetics, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, Obesity, GENOME-WIDE ASSOCIATION, Risk factor, Molecular Biology, Alleles, Ecology, Evolution, Behavior and Systematics, Aged, 030304 developmental biology, Diabetic Endocrinology, 0604 Genetics, Science & Technology, Complex Traits, Case-control study, Human Genetics, Odds ratio, Diabetes Mellitus Type 2, medicine.disease, MAGIC, Diabetes Mellitus, Type 2, Case-Control Studies, CELLS, Laminin, Body mass index, Developmental Biology, Genome-Wide Association Study
Abstract

Common diseases such as type 2 diabetes are phenotypically heterogeneous. Obesity is a major risk factor for type 2 diabetes, but patients vary appreciably in body mass index. We hypothesized that the genetic predisposition to the disease may be different in lean (BMI, Author Summary Individuals with Type 2 diabetes (T2D) can present with variable clinical characteristics. It is well known that obesity is a major risk factor for type 2 diabetes, yet patients can vary considerably—there are many lean diabetes patients and many overweight people without diabetes. We hypothesized that the genetic predisposition to the disease may be different in lean (BMI

Published
2012
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7. Genetic association for renal traits among participants of African ancestry reveals new loci for renal function

Author

Maija K. Garnaas, Tamara B. Harris, Josef Mychaleckjy, Michael F. Flessner, W. Linda Kao, Abdullah Kutlar, Thomas H. Mosley, Josef Coresh, Nora Franceschini, Ching-Ti Liu, Anna Köttgen, Daniel Shriner, Mike A. Nalls, Stephen T. Turner, Alan B. Zonderman, David S. Siscovick, Kirsten Bibbins-Domingo, Elizabeth J. Atkinson, Charles N. Rotimi, Sharon B. Wyatt, Carmen A. Peralta, Adebowale Adeyemo, Albert W. Dreisbach, Xiaoning Lu, Brad C. Astor, Ian H. de Boer, Raymond R. Townsend, Michael G. Shlipak, Adrienne Tin, Wolfram Goessling, Sharon L.R. Kardia, Man Li, Holly Kramer, Muredach P. Reilly, Mariza de Andrade, Michele K. Evans, Caroline S. Fox, Yongmei Liu, Jingzhong Ding, L. Adrienne Cupples, Ermeg L. Akylbekova, and Arnett, Donna K

Subjects
Male, Cancer Research, Kidney Disease, Heredity, 030232 urology & nephrology, Genome-wide association study, QH426-470, Kidney, Kidney Failure, 0302 clinical medicine, Chronic Kidney Disease, Chronic, Genetics (clinical), Zebrafish, African Continental Ancestry Group, Genetics, 0303 health sciences, Adaptor Proteins, Single Nucleotide, Blacks, Middle Aged, Phenotype, 3. Good health, Neoplasm Proteins, medicine.anatomical_structure, Nephrology, Gene Knockdown Techniques, KCNQ1 Potassium Channel, Medicine, Female, Glomerular Filtration Rate, Research Article, Adult, Renal and urogenital, Renal function, Black People, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Clinical Research, medicine, Genome-Wide Association Studies, SNP, Animals, Humans, Polymorphism, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Genetic Association Studies, 030304 developmental biology, Genetic association, Adaptor Proteins, Signal Transducing, Aged, Quantitative Traits, Complex Traits, CKDGen Consortium, Signal Transducing, Human Genetics, medicine.disease, Vesicular Transport, Adaptor Proteins, Vesicular Transport, Genetic Loci, Tubulointerstitial Disease, Genetics of Disease, Kidney Failure, Chronic, Kidney disease, Developmental Biology, Genome-Wide Association Study
Abstract

Chronic kidney disease (CKD) is an increasing global public health concern, particularly among populations of African ancestry. We performed an interrogation of known renal loci, genome-wide association (GWA), and IBC candidate-gene SNP association analyses in African Americans from the CARe Renal Consortium. In up to 8,110 participants, we performed meta-analyses of GWA and IBC array data for estimated glomerular filtration rate (eGFR), CKD (eGFR 30 mg/g) and interrogated the 250 kb flanking region around 24 SNPs previously identified in European Ancestry renal GWAS analyses. Findings were replicated in up to 4,358 African Americans. To assess function, individually identified genes were knocked down in zebrafish embryos by morpholino antisense oligonucleotides. Expression of kidney-specific genes was assessed by in situ hybridization, and glomerular filtration was evaluated by dextran clearance. Overall, 23 of 24 previously identified SNPs had direction-consistent associations with eGFR in African Americans, 2 of which achieved nominal significance (UMOD, PIP5K1B). Interrogation of the flanking regions uncovered 24 new index SNPs in African Americans, 12 of which were replicated (UMOD, ANXA9, GCKR, TFDP2, DAB2, VEGFA, ATXN2, GATM, SLC22A2, TMEM60, SLC6A13, and BCAS3). In addition, we identified 3 suggestive loci at DOK6 (p-value = 5.3×10−7) and FNDC1 (p-value = 3.0×10−7) for UACR, and KCNQ1 with eGFR (p = 3.6×10−6). Morpholino knockdown of kcnq1 in the zebrafish resulted in abnormal kidney development and filtration capacity. We identified several SNPs in association with eGFR in African Ancestry individuals, as well as 3 suggestive loci for UACR and eGFR. Functional genetic studies support a role for kcnq1 in glomerular development in zebrafish., Author Summary Chronic kidney disease (CKD) is an increasing global public health problem and disproportionately affects populations of African ancestry. Many studies have shown that genetic variants are associated with the development of CKD; however, similar studies are lacking in African ancestry populations. The CARe consortium consists of more than 8,000 individuals of African ancestry; genome-wide association analysis for renal-related phenotypes was conducted. In cross-ethnicity analyses, we found that 23 of 24 previously identified SNPs in European ancestry populations have the same effect direction in our samples of African ancestry. We also identified 3 suggestive genetic variants associated with measurement of kidney function. We then tested these genes in zebrafish knockdown models and demonstrated that kcnq1 is involved in kidney development in zebrafish. These results highlight the similarity of genetic variants across ethnicities and show that cross-species modeling in zebrafish is feasible for genes associated with chronic human disease.

Published
2011

8. Genome-wide association studies of serum magnesium, potassium, and sodium concentrations identify six Loci influencing serum magnesium levels

Author

Aravinda Chakravarti, Albert Hofman, Thomas Meitinger, Frank J. A. van Rooij, Ronit Katz, Georg Homuth, Mark J. Sarnak, Thomas Kocher, Yii-Der Ida Chen, David S. Siscovick, Tamara B. Harris, Vilmundur Gudnason, Qiong Yang, Anna Köttgen, Albert V. Smith, Bruce M. Psaty, Shih-Jen Hwang, Jacqueline C. M. Witteman, Eric Boerwinkle, Janina S. Ried, Hanna Prucha, Caroline S. Fox, Nicole L. Glazer, Cornelia M. van Duijn, André G. Uitterlinden, Arne Pfeufer, Christian Gieger, Abbas Dehghan, Josef Coresh, Georg Ehret, Janine F. Felix, Rainer Rettig, Thor Aspelund, W. H. Linda Kao, Tamra E. Meyer, Tennille S. Leak, Germaine C. Verwoert, Internal Medicine, and Epidemiology

Subjects
Adult, Male, Cancer Research, medicine.medical_specialty, lcsh:QH426-470, Cardiovascular Disorders, Magnesium transporter, Sodium, Potassium, Public Health and Epidemiology, Blood sugar, chemistry.chemical_element, Single-nucleotide polymorphism, Genome-wide association study, 030204 cardiovascular system & hematology, Biology, Polymorphism, Single Nucleotide, White People, Hypomagnesemia, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Genetics, medicine, Humans, Magnesium, Genetics and Genomics/Genomics, Molecular Biology, Genetics (clinical), Ecology, Evolution, Behavior and Systematics, Aged, 030304 developmental biology, 0303 health sciences, Physiology/Genomics, Middle Aged, medicine.disease, lcsh:Genetics, Endocrinology, Biochemistry, chemistry, Physiology/Renal, Fluid, and Electrolyte Physiology, Female, Research Article, Genome-Wide Association Study
Abstract

Magnesium, potassium, and sodium, cations commonly measured in serum, are involved in many physiological processes including energy metabolism, nerve and muscle function, signal transduction, and fluid and blood pressure regulation. To evaluate the contribution of common genetic variation to normal physiologic variation in serum concentrations of these cations, we conducted genome-wide association studies of serum magnesium, potassium, and sodium concentrations using ∼2.5 million genotyped and imputed common single nucleotide polymorphisms (SNPs) in 15,366 participants of European descent from the international CHARGE Consortium. Study-specific results were combined using fixed-effects inverse-variance weighted meta-analysis. SNPs demonstrating genome-wide significant (p, Author Summary Magnesium, potassium, and sodium are involved in important physiological processes. To better understand how common genetic variation may contribute to inter-individual differences in serum concentrations of these electrolytes, we evaluated single nucleotide polymorphisms (SNPs) across the genome in association with serum magnesium, potassium, and sodium levels in 15,366 participants of European descent from the CHARGE Consortium. We then verified the associations in an additional 8,463 study participants. Six different genomic regions contain variants that are reproducibly associated with serum magnesium levels, and only one of the regions had been previously known to influence serum magnesium concentrations in humans. The identified SNPs also show association with clinically defined hypomagnesemia, and some of them with traits that have been linked to serum magnesium levels, including kidney function, fasting glucose, and bone mineral density. We further provide evidence for a physiological role of magnesium transporters in humans which have previously only been studied in model systems. None of the SNPs evaluated in our study are significantly associated with serum levels of sodium or potassium. Additional studies are needed to investigate the underlying molecular mechanisms in order to help us understand the contribution of these newly identified regions to magnesium homeostasis.

Published
2010

9. Genetic association for renal traits among participants of African ancestry reveals new loci for renal function.

Author

Ching-Ti Liu, Maija K Garnaas, Adrienne Tin, Anna Kottgen, Nora Franceschini, Carmen A Peralta, Ian H de Boer, Xiaoning Lu, Elizabeth Atkinson, Jingzhong Ding, Michael Nalls, Daniel Shriner, Josef Coresh, Abdullah Kutlar, Kirsten Bibbins-Domingo, David Siscovick, Ermeg Akylbekova, Sharon Wyatt, Brad Astor, Josef Mychaleckjy, Man Li, Muredach P Reilly, Raymond R Townsend, Adebowale Adeyemo, Alan B Zonderman, Mariza de Andrade, Stephen T Turner, Thomas H Mosley, Tamara B Harris, CKDGen Consortium, Charles N Rotimi, Yongmei Liu, Sharon L R Kardia, Michele K Evans, Michael G Shlipak, Holly Kramer, Michael F Flessner, Albert W Dreisbach, Wolfram Goessling, L Adrienne Cupples, W Linda Kao, and Caroline S Fox

Subjects
Genetics, QH426-470
Abstract

Chronic kidney disease (CKD) is an increasing global public health concern, particularly among populations of African ancestry. We performed an interrogation of known renal loci, genome-wide association (GWA), and IBC candidate-gene SNP association analyses in African Americans from the CARe Renal Consortium. In up to 8,110 participants, we performed meta-analyses of GWA and IBC array data for estimated glomerular filtration rate (eGFR), CKD (eGFR 30 mg/g) and interrogated the 250 kb flanking region around 24 SNPs previously identified in European Ancestry renal GWAS analyses. Findings were replicated in up to 4,358 African Americans. To assess function, individually identified genes were knocked down in zebrafish embryos by morpholino antisense oligonucleotides. Expression of kidney-specific genes was assessed by in situ hybridization, and glomerular filtration was evaluated by dextran clearance. Overall, 23 of 24 previously identified SNPs had direction-consistent associations with eGFR in African Americans, 2 of which achieved nominal significance (UMOD, PIP5K1B). Interrogation of the flanking regions uncovered 24 new index SNPs in African Americans, 12 of which were replicated (UMOD, ANXA9, GCKR, TFDP2, DAB2, VEGFA, ATXN2, GATM, SLC22A2, TMEM60, SLC6A13, and BCAS3). In addition, we identified 3 suggestive loci at DOK6 (p-value = 5.3×10(-7)) and FNDC1 (p-value = 3.0×10(-7)) for UACR, and KCNQ1 with eGFR (p = 3.6×10(-6)). Morpholino knockdown of kcnq1 in the zebrafish resulted in abnormal kidney development and filtration capacity. We identified several SNPs in association with eGFR in African Ancestry individuals, as well as 3 suggestive loci for UACR and eGFR. Functional genetic studies support a role for kcnq1 in glomerular development in zebrafish.

Published
2011
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