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1.  Pleiotropic genes for metabolic syndrome and inflammation 
Molecular genetics and metabolism  2014;112(4):317-338.
Metabolic syndrome (MetS) has become a health and financial burden worldwide. The MetS definition captures clustering of risk factors that predict higher risk for diabetes mellitus and cardiovascular disease. Our study hypothesis is that additional to genes influencing individual MetS risk factors, genetic variants exist that influence MetS and inflammatory markers forming a predisposing MetS genetic network. To test this hypothesis a staged approach was undertaken. (a) We analyzed 17 metabolic and inflammatory traits in more than 85,500 participants from 14 large epidemiological studies within the Cross Consortia Pleiotropy Group. Individuals classified with MetS (NCEP definition), versus those without, showed on average significantly different levels for most inflammatory markers studied. (b) Paired average correlations between 8 metabolic traits and 9 inflammatory markers from the same studies as above, estimated with two methods, and factor analyses on large simulated data, helped in identifying 8 combinations of traits for follow-up in meta-analyses, out of 130,305 possible combinations between metabolic traits and inflammatory markers studied. (c) We performed correlated meta-analyses for 8 metabolic traits and 6 inflammatory markers by using existing GWAS published genetic summary results, with about 2.5 million SNPs from twelve predominantly largest GWAS consortia. These analyses yielded 130 unique SNPs/genes with pleiotropic associations (a SNP/gene associating at least one metabolic trait and one inflammatory marker). Of them twenty-five variants (seven loci newly reported) are proposed as MetS candidates. They map to genes MACF1, KIAA0754, GCKR, GRB14, COBLL1, LOC646736-IRS1, SLC39A8, NELFE, SKIV2L, STK19, TFAP2B, BAZ1B, BCL7B, TBL2, MLXIPL, LPL, TRIB1, ATXN2, HECTD4, PTPN11, ZNF664, PDXDC1, FTO, MC4R and TOMM40. Based on large data evidence, we conclude that inflammation is a feature of MetS and several gene variants show pleiotropic genetic associations across phenotypes and might explain a part of MetS correlated genetic architecture. These findings warrant further functional investigation.
doi:10.1016/j.ymgme.2014.04.007
PMCID: PMC4122618  PMID: 24981077
2.  Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility 
Wessel, Jennifer | Chu, Audrey Y. | Willems, Sara M. | Wang, Shuai | Yaghootkar, Hanieh | Brody, Jennifer A. | Dauriz, Marco | Hivert, Marie-France | Raghavan, Sridharan | Lipovich, Leonard | Hidalgo, Bertha | Fox, Keolu | Huffman, Jennifer E. | An, Ping | Lu, Yingchang | Rasmussen-Torvik, Laura J. | Grarup, Niels | Ehm, Margaret G. | Li, Li | Baldridge, Abigail S. | Stančáková, Alena | Abrol, Ravinder | Besse, Céline | Boland, Anne | Bork-Jensen, Jette | Fornage, Myriam | Freitag, Daniel F. | Garcia, Melissa E. | Guo, Xiuqing | Hara, Kazuo | Isaacs, Aaron | Jakobsdottir, Johanna | Lange, Leslie A. | Layton, Jill C. | Li, Man | Zhao, Jing Hua | Meidtner, Karina | Morrison, Alanna C. | Nalls, Mike A. | Peters, Marjolein J. | Sabater-Lleal, Maria | Schurmann, Claudia | Silveira, Angela | Smith, Albert V. | Southam, Lorraine | Stoiber, Marcus H. | Strawbridge, Rona J. | Taylor, Kent D. | Varga, Tibor V. | Allin, Kristine H. | Amin, Najaf | Aponte, Jennifer L. | Aung, Tin | Barbieri, Caterina | Bihlmeyer, Nathan A. | Boehnke, Michael | Bombieri, Cristina | Bowden, Donald W. | Burns, Sean M. | Chen, Yuning | Chen, Yii-Der I. | Cheng, Ching-Yu | Correa, Adolfo | Czajkowski, Jacek | Dehghan, Abbas | Ehret, Georg B. | Eiriksdottir, Gudny | Escher, Stefan A. | Farmaki, Aliki-Eleni | Frånberg, Mattias | Gambaro, Giovanni | Giulianini, Franco | III, William A. Goddard | Goel, Anuj | Gottesman, Omri | Grove, Megan L. | Gustafsson, Stefan | Hai, Yang | Hallmans, Göran | Heo, Jiyoung | Hoffmann, Per | Ikram, Mohammad K. | Jensen, Richard A. | Jørgensen, Marit E. | Jørgensen, Torben | Karaleftheri, Maria | Khor, Chiea C. | Kirkpatrick, Andrea | Kraja, Aldi T. | Kuusisto, Johanna | Lange, Ethan M. | Lee, I.T. | Lee, Wen-Jane | Leong, Aaron | Liao, Jiemin | Liu, Chunyu | Liu, Yongmei | Lindgren, Cecilia M. | Linneberg, Allan | Malerba, Giovanni | Mamakou, Vasiliki | Marouli, Eirini | Maruthur, Nisa M. | Matchan, Angela | McKean, Roberta | McLeod, Olga | Metcalf, Ginger A. | Mohlke, Karen L. | Muzny, Donna M. | Ntalla, Ioanna | Palmer, Nicholette D. | Pasko, Dorota | Peter, Andreas | Rayner, Nigel W. | Renström, Frida | Rice, Ken | Sala, Cinzia F. | Sennblad, Bengt | Serafetinidis, Ioannis | Smith, Jennifer A. | Soranzo, Nicole | Speliotes, Elizabeth K. | Stahl, Eli A. | Stirrups, Kathleen | Tentolouris, Nikos | Thanopoulou, Anastasia | Torres, Mina | Traglia, Michela | Tsafantakis, Emmanouil | Javad, Sundas | Yanek, Lisa R. | Zengini, Eleni | Becker, Diane M. | Bis, Joshua C. | Brown, James B. | Cupples, L. Adrienne | Hansen, Torben | Ingelsson, Erik | Karter, Andrew J. | Lorenzo, Carlos | Mathias, Rasika A. | Norris, Jill M. | Peloso, Gina M. | Sheu, Wayne H.-H. | Toniolo, Daniela | Vaidya, Dhananjay | Varma, Rohit | Wagenknecht, Lynne E. | Boeing, Heiner | Bottinger, Erwin P. | Dedoussis, George | Deloukas, Panos | Ferrannini, Ele | Franco, Oscar H. | Franks, Paul W. | Gibbs, Richard A. | Gudnason, Vilmundur | Hamsten, Anders | Harris, Tamara B. | Hattersley, Andrew T. | Hayward, Caroline | Hofman, Albert | Jansson, Jan-Håkan | Langenberg, Claudia | Launer, Lenore J. | Levy, Daniel | Oostra, Ben A. | O'Donnell, Christopher J. | O'Rahilly, Stephen | Padmanabhan, Sandosh | Pankow, James S. | Polasek, Ozren | Province, Michael A. | Rich, Stephen S. | Ridker, Paul M | Rudan, Igor | Schulze, Matthias B. | Smith, Blair H. | Uitterlinden, André G. | Walker, Mark | Watkins, Hugh | Wong, Tien Y. | Zeggini, Eleftheria | Scotland, Generation | Laakso, Markku | Borecki, Ingrid B. | Chasman, Daniel I. | Pedersen, Oluf | Psaty, Bruce M. | Tai, E. Shyong | van Duijn, Cornelia M. | Wareham, Nicholas J. | Waterworth, Dawn M. | Boerwinkle, Eric | Kao, WH Linda | Florez, Jose C. | Loos, Ruth J.F. | Wilson, James G. | Frayling, Timothy M. | Siscovick, David S. | Dupuis, Josée | Rotter, Jerome I. | Meigs, James B. | Scott, Robert A. | Goodarzi, Mark O.
Nature communications  2015;6:5897.
Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol L−1, p=3.4×10−12), T2D risk (OR[95%CI]=0.86[0.76-0.96], p=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose−1, p=0.048), but higher 2-h glucose (β=0.16±0.05 mmol L−1, p=4.3×10−4). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8×10−6) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol L−1, p=1.3×10−8). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
doi:10.1038/ncomms6897
PMCID: PMC4311266  PMID: 25631608
3.  Vitamin D and C-Reactive Protein: A Mendelian Randomization Study 
PLoS ONE  2015;10(7):e0131740.
Vitamin D deficiency is widely prevalent and has been associated with many diseases. It has been suggested that vitamin D has effects on the immune system and inhibits inflammation. The aim of our study was to investigate whether vitamin D has an inhibitory effect on systemic inflammation by assessing the association between serum levels of vitamin D and C-reactive protein. We studied the association between serum 25-hydroxyvitamin D and C-reactive protein through linear regression in 9,649 participants of the Rotterdam Study, an observational, prospective population-based cohort study. We used genetic variants related to vitamin D and CRP to compute a genetic risk score and perform bi-directional Mendelian randomization analysis. In linear regression adjusted for age, sex, cohort and other confounders, natural log-transformed CRP decreased with 0.06 (95% CI: -0.08, -0.03) unit per standard deviation increase in 25-hydroxyvitamin D. Bi-directional Mendelian randomization analyses showed no association between the vitamin D genetic risk score and lnCRP (Beta per SD = -0.018; p = 0.082) or the CRP genetic risk score and 25-hydroxyvitamin D (Beta per SD = 0.001; p = 0.998). In conclusion, higher levels of Vitamin D are associated with lower levels of C-reactive protein. In this study we did not find evidence for this to be the result of a causal relationship.
doi:10.1371/journal.pone.0131740
PMCID: PMC4492676  PMID: 26147588
4.  The Association between Metabolic Syndrome, Bone Mineral Density, Hip Bone Geometry and Fracture Risk: The Rotterdam Study 
PLoS ONE  2015;10(6):e0129116.
The association between metabolic syndrome (MS) and bone health remains unclear. We aimed to study the association between MS and hip bone geometry (HBG), femoral neck bone mineral density (FN-BMD), and the risk of osteoporosis and incident fractures. Data of 2040 women and 1510 men participants in the third visit (1997–1999) of the Rotterdam Study (RSI-3), a prospective population based cohort, were available (mean follow-up 6.7 years). MS was defined according to the recent harmonized definition. HBG parameters were measured at the third round visit whereas FN-BMD was assessed at the third round and 5 years later. Incident fractures were identified from medical registry data. After correcting for age, body mass index (BMI), lifestyle factors and medication use, individuals with MS had lower bone width (β = -0.054, P = 0.003), lower cortical buckling ratio (β = -0.81, P = 0.003) and lower odds of having osteoporosis (odds ratio =0.56, P = 0.007) in women but not in men. Similarly, MS was associated with higher FN-BMD only in women (β = 0.028, P=0.001). In the analyses of MS components, the glucose component (unrelated to diabetes status) was positively associated with FN-BMD in both genders (β = 0.016, P = 0.01 for women and β = 0.022, P = 0.004 for men). In men, waist circumference was inversely associated with FN-BMD (β = -0.03, P = 0.004). No association was observed with fracture risk in either sex. In conclusion, women with MS had higher FN-BMD independent of BMI. The glucose component of MS was associated with high FN-BMD in both genders, highlighting the need to preserve glycemic control to prevent skeletal complications.
doi:10.1371/journal.pone.0129116
PMCID: PMC4466576  PMID: 26066649
5.  Tobacco smoking is associated with methylation of genes related to coronary artery disease 
Clinical Epigenetics  2015;7(1):54.
Background
Tobacco smoking, a risk factor for coronary artery disease (CAD), is known to modify DNA methylation. We hypothesized that tobacco smoking modifies methylation of the genes identified for CAD by genome-wide association study (GWAS).
Results
We selected genomic regions based on 150 single-nucleotide polymorphisms (SNPs) identified in the largest GWAS on CAD. We investigated the association between current smoking and the CpG sites within and near these CAD-related genes. Methylation was measured with the Illumina Human Methylation 450K array in whole blood of 724 Caucasian subjects from the Rotterdam Study, a Dutch population based cohort study.
A total of 3669 CpG sites within 169 CAD-related genes were studied for association with current compared to never smoking. Fifteen CpG sites were significantly associated after correction for multiple testing (Bonferroni-corrected p value <1.4 × 10−5). These sites were located in the genes TERT, SARS, GNGT2, SMG6, SKI, TOM1L2, SIPA1, MRAS, CDKN1A, LRRC2, FES and RPH3A. In 12 sites, current smoking was associated with a 1.2 to 2.4 % lower methylation compared to never smoking; and in three sites, it was associated with a 1.2 to 1.8 % higher methylation. The effect estimates were lower in 10 of the 15 CpG sites when comparing current to former smoking. One CpG site, cg05603985 (SKI), was found to be associated with expression of nearby CAD-related gene PRKCZ.
Conclusions
Our study suggests an effect of tobacco smoking on DNA methylation of CAD-related genes and thus provides novel insights in the pathways that link tobacco smoking to risk of CAD.
Electronic supplementary material
The online version of this article (doi:10.1186/s13148-015-0088-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s13148-015-0088-y
PMCID: PMC4443552  PMID: 26015811
DNA methylation; mRNA expression; Tobacco smoking; Coronary artery disease; White blood cells
6.  Genome-Wide Association Study for Circulating Tissue Plasminogen Activator (tPA) Levels and Functional Follow-up Implicates Endothelial STXBP5 and STX2 
Huang, Jie | Huffman, Jennifer E. | Yamkauchi, Munekazu | Trompet, Stella | Asselbergs, Folkert W. | Sabater-Lleal, Maria | Trégouët, David-Alexandre | Chen, Wei-Min | Smith, Nicholas L. | Kleber, Marcus E. | Shin, So-Youn | Becker, Diane M. | Tang, Weihong | Dehghan, Abbas | Johnson, Andrew D. | Truong, Vinh | Folkersen, Lasse | Yang, Qiong | Oudot-Mellakh, Tiphaine | Buckley, Brendan M. | Moore, Jason H. | Williams, Frances M.K. | Campbell, Harry | Silbernagel, Günther | Vitart, Veronique | Rudan, Igor | Tofler, Geoffrey H. | Navis, Gerjan J. | DeStefano, Anita | Wright, Alan F. | Chen, Ming-Huei | de Craen, Anton J.M. | Worrall, Bradford B. | Rudnicka, Alicja R. | Rumley, Ann | Bookman, Ebony B. | Psaty, Bruce M. | Chen, Fang | Keene, Keith L. | Franco, Oscar H. | Böhm, Bernhard O. | Uitterlinden, Andre G. | Carter, Angela M. | Jukema, J. Wouter | Sattar, Naveed | Bis, Joshua C. | Ikram, Mohammad A. | Sale, Michèle M. | McKnight, Barbara | Fornage, Myriam | Ford, Ian | Taylor, Kent | Slagboom, P. Eline | McArdle, Wendy L. | Hsu, Fang-Chi | Franco-Cereceda, Anders | Goodall, Alison H. | Yanek, Lisa R. | Furie, Karen L. | Cushman, Mary | Hofman, Albert | Witteman, Jacqueline CM. | Folsom, Aaron R. | Basu, Saonli | Matijevic, Nena | van Gilst, Wiek H. | Wilson, James F. | Westendorp, Rudi G.J. | Kathiresan, Sekar | Reilly, Muredach P. | Tracy, Russell P. | Polasek, Ozren | Winkelmann, Bernhard R. | Grant, Peter J. | Hillege, Hans L. | Cambien, Francois | Stott, David J. | Lowe, Gordon D. | Spector, Timothy D. | Meigs, James B. | Marz, Winfried | Eriksson, Per | Becker, Lewis C. | Morange, Pierre-Emmanuel | Soranzo, Nicole | Williams, Scott M. | Hayward, Caroline | van der Harst, Pim | Hamsten, Anders | Lowenstein, Charles J. | Strachan, David P. | O'Donnell, Christopher J.
Objective
Tissue plasminogen activator (tPA), a serine protease, catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for endogenous fibrinolysis. In some populations, elevated plasma levels of tPA have been associated with myocardial infarction and other cardiovascular diseases (CVD). We conducted a meta-analysis of genome-wide association studies (GWAS) to identify novel correlates of circulating levels of tPA.
Approach and Results
Fourteen cohort studies with tPA measures (N=26,929) contributed to the meta-analysis. Three loci were significantly associated with circulating tPA levels (P <5.0×10−8). The first locus is on 6q24.3, with the lead SNP (rs9399599, P=2.9×10−14) within STXBP5. The second locus is on 8p11.21. The lead SNP (rs3136739, P=1.3×10−9) is intronic to POLB and less than 200kb away from the tPA encoding gene PLAT. We identified a non-synonymous SNP (rs2020921) in modest LD with rs3136739 (r2 = 0.50) within exon 5 of PLAT (P=2.0×10−8). The third locus is on 12q24.33, with the lead SNP (rs7301826, P=1.0×10−9) within intron 7 of STX2. We further found evidence for association of lead SNPs in STXBP5 and STX2 with expression levels of the respective transcripts. In in vitro cell studies, silencing STXBP5 decreased release of tPA from vascular endothelial cells, while silencing of STX2 increased tPA release. Through an in-silico lookup, we found no associations of the three lead SNPs with coronary artery disease or stroke.
Conclusions
We identified three loci associated with circulating tPA levels, the PLAT region, STXBP5 and STX2. Our functional studies implicate a novel role for STXBP5 and STX2 in regulating tPA release.
doi:10.1161/ATVBAHA.113.302088
PMCID: PMC4009733  PMID: 24578379
tissue plasminogen activator; genome-wide association study; meta-analysis; cardiovascular disease risk; fibrinolysis; hemostasis
7.  Thyroid function and age-related macular degeneration: a prospective population-based cohort study - the Rotterdam Study 
BMC Medicine  2015;13:94.
Background
In animal models, lack of thyroid hormone is associated with cone photoreceptor preservation, while administration of high doses of active thyroid hormone leads to deterioration. The association between thyroid function and age-related macular degeneration (AMD) has not been investigated in the general population.
Methods
Participants of age ≥55 years from the Rotterdam Study with thyroid-stimulating hormone (TSH) and/or free thyroxine (FT4) measurements and AMD assessment were included. We conducted age- and sex-adjusted Cox proportional hazards models to explore the association of TSH or FT4 with AMD, in the full range and in those with TSH (0.4-4.0 mIU/L) and/or FT4 in normal range (11–25 pmol/L). Cox proportional hazards models were performed for the association of TSH or FT4 with retinal pigment alterations (RPA), as an early marker of retinal changes. Multivariable models additionally included cardiovascular risk factors and thyroid peroxidase antibodies positivity. We also performed stratification by age and sex. A bidirectional look-up in genome-wide association study (GWAS) data for thyroid parameters and AMD was performed. Single nucleotide polymorphisms (SNPs) that are significantly associated with both phenotypes were identified.
Results
We included 5,573 participants with a median follow-up of 6.9 years (interquartile range 4.4-10.8 years). During follow-up 805 people developed AMD. TSH levels were not associated with increased risk of AMD. Within normal range of FT4, participants in the highest FT4 quintile had a 1.34-fold increased risk of developing AMD, compared to individuals in the middle group (95% confidence interval [CI] 1.07-1.66). Higher FT4 values in the full range were associated with a higher risk of AMD (hazard ratio 1.04, CI, 1.01-1.06 per 1 pmol/L increase). Higher FT4 levels were similarly associated with a higher risk of RPA. Restricting analyses to euthyroid individuals, additional multivariable models, and stratification did not change estimates. We found a SNP (rs943080) in the VEGF-A gene, associated with AMD, to be significant in the TSH GWAS (P = 1.2 x 10−4). Adding this SNP to multivariable models did not change estimates.
Conclusions
Higher FT4 values are associated with increased risk of AMD - even in euthyroid individuals - and increased risk of RPA. Our data suggest an important role of thyroid hormone in pathways leading to AMD.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-015-0329-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s12916-015-0329-0
PMCID: PMC4407352  PMID: 25903050
Thyroid hormone; Thyroid function; AMD; Age-related macular degeneration
8.  Modulation of Genetic Associations with Serum Urate Levels by Body-Mass-Index in Humans 
Huffman, Jennifer E. | Albrecht, Eva | Teumer, Alexander | Mangino, Massimo | Kapur, Karen | Johnson, Toby | Kutalik, Zoltán | Pirastu, Nicola | Pistis, Giorgio | Lopez, Lorna M. | Haller, Toomas | Salo, Perttu | Goel, Anuj | Li, Man | Tanaka, Toshiko | Dehghan, Abbas | Ruggiero, Daniela | Malerba, Giovanni | Smith, Albert V. | Nolte, Ilja M. | Portas, Laura | Phipps-Green, Amanda | Boteva, Lora | Navarro, Pau | Johansson, Asa | Hicks, Andrew A. | Polasek, Ozren | Esko, Tõnu | Peden, John F. | Harris, Sarah E. | Murgia, Federico | Wild, Sarah H. | Tenesa, Albert | Tin, Adrienne | Mihailov, Evelin | Grotevendt, Anne | Gislason, Gauti K. | Coresh, Josef | D'Adamo, Pio | Ulivi, Sheila | Vollenweider, Peter | Waeber, Gerard | Campbell, Susan | Kolcic, Ivana | Fisher, Krista | Viigimaa, Margus | Metter, Jeffrey E. | Masciullo, Corrado | Trabetti, Elisabetta | Bombieri, Cristina | Sorice, Rossella | Döring, Angela | Reischl, Eva | Strauch, Konstantin | Hofman, Albert | Uitterlinden, Andre G. | Waldenberger, Melanie | Wichmann, H-Erich | Davies, Gail | Gow, Alan J. | Dalbeth, Nicola | Stamp, Lisa | Smit, Johannes H. | Kirin, Mirna | Nagaraja, Ramaiah | Nauck, Matthias | Schurmann, Claudia | Budde, Kathrin | Farrington, Susan M. | Theodoratou, Evropi | Jula, Antti | Salomaa, Veikko | Sala, Cinzia | Hengstenberg, Christian | Burnier, Michel | Mägi, Reedik | Klopp, Norman | Kloiber, Stefan | Schipf, Sabine | Ripatti, Samuli | Cabras, Stefano | Soranzo, Nicole | Homuth, Georg | Nutile, Teresa | Munroe, Patricia B. | Hastie, Nicholas | Campbell, Harry | Rudan, Igor | Cabrera, Claudia | Haley, Chris | Franco, Oscar H. | Merriman, Tony R. | Gudnason, Vilmundur | Pirastu, Mario | Penninx, Brenda W. | Snieder, Harold | Metspalu, Andres | Ciullo, Marina | Pramstaller, Peter P. | van Duijn, Cornelia M. | Ferrucci, Luigi | Gambaro, Giovanni | Deary, Ian J. | Dunlop, Malcolm G. | Wilson, James F. | Gasparini, Paolo | Gyllensten, Ulf | Spector, Tim D. | Wright, Alan F. | Hayward, Caroline | Watkins, Hugh | Perola, Markus | Bochud, Murielle | Kao, W. H. Linda | Caulfield, Mark | Toniolo, Daniela | Völzke, Henry | Gieger, Christian | Köttgen, Anna | Vitart, Veronique
PLoS ONE  2015;10(3):e0119752.
We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, Pinter= 2.6 x 10-8). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDARADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10-8), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10-8), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10-4). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.
doi:10.1371/journal.pone.0119752
PMCID: PMC4374966  PMID: 25811787
9.  A Meta-analysis of Gene Expression Signatures of Blood Pressure and Hypertension 
PLoS Genetics  2015;11(3):e1005035.
Genome-wide association studies (GWAS) have uncovered numerous genetic variants (SNPs) that are associated with blood pressure (BP). Genetic variants may lead to BP changes by acting on intermediate molecular phenotypes such as coded protein sequence or gene expression, which in turn affect BP variability. Therefore, characterizing genes whose expression is associated with BP may reveal cellular processes involved in BP regulation and uncover how transcripts mediate genetic and environmental effects on BP variability. A meta-analysis of results from six studies of global gene expression profiles of BP and hypertension in whole blood was performed in 7017 individuals who were not receiving antihypertensive drug treatment. We identified 34 genes that were differentially expressed in relation to BP (Bonferroni-corrected p<0.05). Among these genes, FOS and PTGS2 have been previously reported to be involved in BP-related processes; the others are novel. The top BP signature genes in aggregate explain 5%–9% of inter-individual variance in BP. Of note, rs3184504 in SH2B3, which was also reported in GWAS to be associated with BP, was found to be a trans regulator of the expression of 6 of the transcripts we found to be associated with BP (FOS, MYADM, PP1R15A, TAGAP, S100A10, and FGBP2). Gene set enrichment analysis suggested that the BP-related global gene expression changes include genes involved in inflammatory response and apoptosis pathways. Our study provides new insights into molecular mechanisms underlying BP regulation, and suggests novel transcriptomic markers for the treatment and prevention of hypertension.
Author Summary
The focus of blood pressure (BP) GWAS has been the identification of common DNA sequence variants associated with the phenotype; this approach provides only one dimension of molecular information about BP. While it is a critical dimension, analyzing DNA variation alone is not sufficient for achieving an understanding of the multidimensional complexity of BP physiology. The top loci identified by GWAS explain only about 1 percent of inter-individual BP variability. In this study, we performed a meta-analysis of gene expression profiles in relation to BP and hypertension in 7017 individuals from six studies. We identified 34 differentially expressed genes for BP, and discovered that the top BP signature genes explain 5%–9% of BP variability. We further linked BP gene expression signature genes with BP GWAS results by integrating expression associated SNPs (eSNPs) and discovered that one of the top BP loci from GWAS, rs3184504 in SH2B3, is a trans regulator of expression of 6 of the top 34 BP signature genes. Our study, in conjunction with prior GWAS, provides a deeper understanding of the molecular and genetic basis of BP regulation, and identifies several potential targets and pathways for the treatment and prevention of hypertension and its sequelae.
doi:10.1371/journal.pgen.1005035
PMCID: PMC4365001  PMID: 25785607
10.  Pleiotropy among Common Genetic Loci Identified for Cardiometabolic Disorders and C-Reactive Protein 
PLoS ONE  2015;10(3):e0118859.
Pleiotropic genetic variants have independent effects on different phenotypes. C-reactive protein (CRP) is associated with several cardiometabolic phenotypes. Shared genetic backgrounds may partially underlie these associations. We conducted a genome-wide analysis to identify the shared genetic background of inflammation and cardiometabolic phenotypes using published genome-wide association studies (GWAS). We also evaluated whether the pleiotropic effects of such loci were biological or mediated in nature. First, we examined whether 283 common variants identified for 10 cardiometabolic phenotypes in GWAS are associated with CRP level. Second, we tested whether 18 variants identified for serum CRP are associated with 10 cardiometabolic phenotypes. We used a Bonferroni corrected p-value of 1.1×10-04 (0.05/463) as a threshold of significance. We evaluated the independent pleiotropic effect on both phenotypes using individual level data from the Women Genome Health Study. Evaluating the genetic overlap between inflammation and cardiometabolic phenotypes, we found 13 pleiotropic regions. Additional analyses showed that 6 regions (APOC1, HNF1A, IL6R, PPP1R3B, HNF4A and IL1F10) appeared to have a pleiotropic effect on CRP independent of the effects on the cardiometabolic phenotypes. These included loci where individuals carrying the risk allele for CRP encounter higher lipid levels and risk of type 2 diabetes. In addition, 5 regions (GCKR, PABPC4, BCL7B, FTO and TMEM18) had an effect on CRP largely mediated through the cardiometabolic phenotypes. In conclusion, our results show genetic pleiotropy among inflammation and cardiometabolic phenotypes. In addition to reverse causation, our data suggests that pleiotropic genetic variants partially underlie the association between CRP and cardiometabolic phenotypes.
doi:10.1371/journal.pone.0118859
PMCID: PMC4358943  PMID: 25768928
11.  Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility 
Wessel, Jennifer | Chu, Audrey Y | Willems, Sara M | Wang, Shuai | Yaghootkar, Hanieh | Brody, Jennifer A | Dauriz, Marco | Hivert, Marie-France | Raghavan, Sridharan | Lipovich, Leonard | Hidalgo, Bertha | Fox, Keolu | Huffman, Jennifer E | An, Ping | Lu, Yingchang | Rasmussen-Torvik, Laura J | Grarup, Niels | Ehm, Margaret G | Li, Li | Baldridge, Abigail S | Stančáková, Alena | Abrol, Ravinder | Besse, Céline | Boland, Anne | Bork-Jensen, Jette | Fornage, Myriam | Freitag, Daniel F | Garcia, Melissa E | Guo, Xiuqing | Hara, Kazuo | Isaacs, Aaron | Jakobsdottir, Johanna | Lange, Leslie A | Layton, Jill C | Li, Man | Hua Zhao, Jing | Meidtner, Karina | Morrison, Alanna C | Nalls, Mike A | Peters, Marjolein J | Sabater-Lleal, Maria | Schurmann, Claudia | Silveira, Angela | Smith, Albert V | Southam, Lorraine | Stoiber, Marcus H | Strawbridge, Rona J | Taylor, Kent D | Varga, Tibor V | Allin, Kristine H | Amin, Najaf | Aponte, Jennifer L | Aung, Tin | Barbieri, Caterina | Bihlmeyer, Nathan A | Boehnke, Michael | Bombieri, Cristina | Bowden, Donald W | Burns, Sean M | Chen, Yuning | Chen, Yii-DerI | Cheng, Ching-Yu | Correa, Adolfo | Czajkowski, Jacek | Dehghan, Abbas | Ehret, Georg B | Eiriksdottir, Gudny | Escher, Stefan A | Farmaki, Aliki-Eleni | Frånberg, Mattias | Gambaro, Giovanni | Giulianini, Franco | Goddard, William A | Goel, Anuj | Gottesman, Omri | Grove, Megan L | Gustafsson, Stefan | Hai, Yang | Hallmans, Göran | Heo, Jiyoung | Hoffmann, Per | Ikram, Mohammad K | Jensen, Richard A | Jørgensen, Marit E | Jørgensen, Torben | Karaleftheri, Maria | Khor, Chiea C | Kirkpatrick, Andrea | Kraja, Aldi T | Kuusisto, Johanna | Lange, Ethan M | Lee, I T | Lee, Wen-Jane | Leong, Aaron | Liao, Jiemin | Liu, Chunyu | Liu, Yongmei | Lindgren, Cecilia M | Linneberg, Allan | Malerba, Giovanni | Mamakou, Vasiliki | Marouli, Eirini | Maruthur, Nisa M | Matchan, Angela | McKean-Cowdin, Roberta | McLeod, Olga | Metcalf, Ginger A | Mohlke, Karen L | Muzny, Donna M | Ntalla, Ioanna | Palmer, Nicholette D | Pasko, Dorota | Peter, Andreas | Rayner, Nigel W | Renström, Frida | Rice, Ken | Sala, Cinzia F | Sennblad, Bengt | Serafetinidis, Ioannis | Smith, Jennifer A | Soranzo, Nicole | Speliotes, Elizabeth K | Stahl, Eli A | Stirrups, Kathleen | Tentolouris, Nikos | Thanopoulou, Anastasia | Torres, Mina | Traglia, Michela | Tsafantakis, Emmanouil | Javad, Sundas | Yanek, Lisa R | Zengini, Eleni | Becker, Diane M | Bis, Joshua C | Brown, James B | Adrienne Cupples, L | Hansen, Torben | Ingelsson, Erik | Karter, Andrew J | Lorenzo, Carlos | Mathias, Rasika A | Norris, Jill M | Peloso, Gina M | Sheu, Wayne H.-H. | Toniolo, Daniela | Vaidya, Dhananjay | Varma, Rohit | Wagenknecht, Lynne E | Boeing, Heiner | Bottinger, Erwin P | Dedoussis, George | Deloukas, Panos | Ferrannini, Ele | Franco, Oscar H | Franks, Paul W | Gibbs, Richard A | Gudnason, Vilmundur | Hamsten, Anders | Harris, Tamara B | Hattersley, Andrew T | Hayward, Caroline | Hofman, Albert | Jansson, Jan-Håkan | Langenberg, Claudia | Launer, Lenore J | Levy, Daniel | Oostra, Ben A | O'Donnell, Christopher J | O'Rahilly, Stephen | Padmanabhan, Sandosh | Pankow, James S | Polasek, Ozren | Province, Michael A | Rich, Stephen S | Ridker, Paul M | Rudan, Igor | Schulze, Matthias B | Smith, Blair H | Uitterlinden, André G | Walker, Mark | Watkins, Hugh | Wong, Tien Y | Zeggini, Eleftheria | Laakso, Markku | Borecki, Ingrid B | Chasman, Daniel I | Pedersen, Oluf | Psaty, Bruce M | Shyong Tai, E | van Duijn, Cornelia M | Wareham, Nicholas J | Waterworth, Dawn M | Boerwinkle, Eric | Linda Kao, W H | Florez, Jose C | Loos, Ruth J.F. | Wilson, James G | Frayling, Timothy M | Siscovick, David S | Dupuis, Josée | Rotter, Jerome I | Meigs, James B | Scott, Robert A | Goodarzi, Mark O
Nature Communications  2015;6:5897.
Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=−0.09±0.01 mmol l−1, P=3.4 × 10−12), T2D risk (OR[95%CI]=0.86[0.76–0.96], P=0.010), early insulin secretion (β=−0.07±0.035 pmolinsulin mmolglucose−1, P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l−1, P=4.3 × 10−4). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10−6) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l−1, P=1.3 × 10−8). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
Both rare and common variants contribute to the aetiology of complex traits such as type 2 diabetes (T2D). Here, the authors examine the effect of coding variation on glycaemic traits and T2D, and identify low-frequency variation in GLP1R significantly associated with these traits.
doi:10.1038/ncomms6897
PMCID: PMC4311266  PMID: 25631608
12.  No Evidence for Genome-Wide Interactions on Plasma Fibrinogen by Smoking, Alcohol Consumption and Body Mass Index: Results from Meta-Analyses of 80,607 Subjects 
Baumert, Jens | Huang, Jie | McKnight, Barbara | Sabater-Lleal, Maria | Steri, Maristella | Chu, Audrey Y. | Trompet, Stella | Lopez, Lorna M. | Fornage, Myriam | Teumer, Alexander | Tang, Weihong | Rudnicka, Alicja R. | Mälarstig, Anders | Hottenga, Jouke-Jan | Kavousi, Maryam | Lahti, Jari | Tanaka, Toshiko | Hayward, Caroline | Huffman, Jennifer E. | Morange, Pierre-Emmanuel | Rose, Lynda M. | Basu, Saonli | Rumley, Ann | Stott, David J. | Buckley, Brendan M. | de Craen, Anton J. M. | Sanna, Serena | Masala, Marco | Biffar, Reiner | Homuth, Georg | Silveira, Angela | Sennblad, Bengt | Goel, Anuj | Watkins, Hugh | Müller-Nurasyid, Martina | Rückerl, Regina | Taylor, Kent | Chen, Ming-Huei | de Geus, Eco J. C. | Hofman, Albert | Witteman, Jacqueline C. M. | de Maat, Moniek P. M. | Palotie, Aarno | Davies, Gail | Siscovick, David S. | Kolcic, Ivana | Wild, Sarah H. | Song, Jaejoon | McArdle, Wendy L. | Ford, Ian | Sattar, Naveed | Schlessinger, David | Grotevendt, Anne | Franzosi, Maria Grazia | Illig, Thomas | Waldenberger, Melanie | Lumley, Thomas | Tofler, Geoffrey H. | Willemsen, Gonneke | Uitterlinden, André G. | Rivadeneira, Fernando | Räikkönen, Katri | Chasman, Daniel I. | Folsom, Aaron R. | Lowe, Gordon D. | Westendorp, Rudi G. J. | Slagboom, P. Eline | Cucca, Francesco | Wallaschofski, Henri | Strawbridge, Rona J. | Seedorf, Udo | Koenig, Wolfgang | Bis, Joshua C. | Mukamal, Kenneth J. | van Dongen, Jenny | Widen, Elisabeth | Franco, Oscar H. | Starr, John M. | Liu, Kiang | Ferrucci, Luigi | Polasek, Ozren | Wilson, James F. | Oudot-Mellakh, Tiphaine | Campbell, Harry | Navarro, Pau | Bandinelli, Stefania | Eriksson, Johan | Boomsma, Dorret I. | Dehghan, Abbas | Clarke, Robert | Hamsten, Anders | Boerwinkle, Eric | Jukema, J. Wouter | Naitza, Silvia | Ridker, Paul M. | Völzke, Henry | Deary, Ian J. | Reiner, Alexander P. | Trégouët, David-Alexandre | O'Donnell, Christopher J. | Strachan, David P. | Peters, Annette | Smith, Nicholas L.
PLoS ONE  2014;9(12):e111156.
Plasma fibrinogen is an acute phase protein playing an important role in the blood coagulation cascade having strong associations with smoking, alcohol consumption and body mass index (BMI). Genome-wide association studies (GWAS) have identified a variety of gene regions associated with elevated plasma fibrinogen concentrations. However, little is yet known about how associations between environmental factors and fibrinogen might be modified by genetic variation. Therefore, we conducted large-scale meta-analyses of genome-wide interaction studies to identify possible interactions of genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentration. The present study included 80,607 subjects of European ancestry from 22 studies. Genome-wide interaction analyses were performed separately in each study for about 2.6 million single nucleotide polymorphisms (SNPs) across the 22 autosomal chromosomes. For each SNP and risk factor, we performed a linear regression under an additive genetic model including an interaction term between SNP and risk factor. Interaction estimates were meta-analysed using a fixed-effects model. No genome-wide significant interaction with smoking status, alcohol consumption or BMI was observed in the meta-analyses. The most suggestive interaction was found for smoking and rs10519203, located in the LOC123688 region on chromosome 15, with a p value of 6.2×10−8. This large genome-wide interaction study including 80,607 participants found no strong evidence of interaction between genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentrations. Further studies are needed to yield deeper insight in the interplay between environmental factors and gene variants on the regulation of fibrinogen concentrations.
doi:10.1371/journal.pone.0111156
PMCID: PMC4281156  PMID: 25551457
13.  Prospective Associations of Coronary Heart Disease Loci in African Americans Using the MetaboChip: The PAGE Study 
PLoS ONE  2014;9(12):e113203.
Background
Coronary heart disease (CHD) is a leading cause of morbidity and mortality in African Americans. However, there is a paucity of studies assessing genetic determinants of CHD in African Americans. We examined the association of published variants in CHD loci with incident CHD, attempted to fine map these loci, and characterize novel variants influencing CHD risk in African Americans.
Methods and Results
Up to 8,201 African Americans (including 546 first CHD events) were genotyped using the MetaboChip array in the Atherosclerosis Risk in Communities (ARIC) study and Women's Health Initiative (WHI). We tested associations using Cox proportional hazard models in sex- and study-stratified analyses and combined results using meta-analysis. Among 44 validated CHD loci available in the array, we replicated and fine-mapped the SORT1 locus, and showed same direction of effects as reported in studies of individuals of European ancestry for SNPs in 22 additional published loci. We also identified a SNP achieving array wide significance (MYC: rs2070583, allele frequency 0.02, P = 8.1×10−8), but the association did not replicate in an additional 8,059 African Americans (577 events) from the WHI, HealthABC and GeneSTAR studies, and in a meta-analysis of 5 cohort studies of European ancestry (24,024 individuals including 1,570 cases of MI and 2,406 cases of CHD) from the CHARGE Consortium.
Conclusions
Our findings suggest that some CHD loci previously identified in individuals of European ancestry may be relevant to incident CHD in African Americans.
doi:10.1371/journal.pone.0113203
PMCID: PMC4277270  PMID: 25542012
14.  A Multi-Ethnic Meta-Analysis of Genome-Wide Association Studies in Over 100,000 Subjects Identifies 23 Fibrinogen-Associated Loci but no Strong Evidence of a Causal Association between Circulating Fibrinogen and Cardiovascular Disease 
Sabater-Lleal, Maria | Huang, Jie | Chasman, Daniel | Naitza, Silvia | Dehghan, Abbas | Johnson, Andrew D | Teumer, Alexander | Reiner, Alex P | Folkersen, Lasse | Basu, Saonli | Rudnicka, Alicja R | Trompet, Stella | Mälarstig, Anders | Baumert, Jens | Bis, Joshua C. | Guo, Xiuqing | Hottenga, Jouke J | Shin, So-Youn | Lopez, Lorna M | Lahti, Jari | Tanaka, Toshiko | Yanek, Lisa R | Oudot-Mellakh, Tiphaine | Wilson, James F | Navarro, Pau | Huffman, Jennifer E | Zemunik, Tatijana | Redline, Susan | Mehra, Reena | Pulanic, Drazen | Rudan, Igor | Wright, Alan F | Kolcic, Ivana | Polasek, Ozren | Wild, Sarah H | Campbell, Harry | Curb, J David | Wallace, Robert | Liu, Simin | Eaton, Charles B. | Becker, Diane M. | Becker, Lewis C. | Bandinelli, Stefania | Räikkönen, Katri | Widen, Elisabeth | Palotie, Aarno | Fornage, Myriam | Green, David | Gross, Myron | Davies, Gail | Harris, Sarah E | Liewald, David C | Starr, John M | Williams, Frances M.K. | Grant, P.J. | Spector, Timothy D. | Strawbridge, Rona J | Silveira, Angela | Sennblad, Bengt | Rivadeneira, Fernando | Uitterlinden, Andre G | Franco, Oscar H | Hofman, Albert | van Dongen, Jenny | Willemsen, G | Boomsma, Dorret I | Yao, Jie | Jenny, Nancy Swords | Haritunians, Talin | McKnight, Barbara | Lumley, Thomas | Taylor, Kent D | Rotter, Jerome I | Psaty, Bruce M | Peters, Annette | Gieger, Christian | Illig, Thomas | Grotevendt, Anne | Homuth, Georg | Völzke, Henry | Kocher, Thomas | Goel, Anuj | Franzosi, Maria Grazia | Seedorf, Udo | Clarke, Robert | Steri, Maristella | Tarasov, Kirill V | Sanna, Serena | Schlessinger, David | Stott, David J | Sattar, Naveed | Buckley, Brendan M | Rumley, Ann | Lowe, Gordon D | McArdle, Wendy L | Chen, Ming-Huei | Tofler, Geoffrey H | Song, Jaejoon | Boerwinkle, Eric | Folsom, Aaron R. | Rose, Lynda M. | Franco-Cereceda, Anders | Teichert, Martina | Ikram, M Arfan | Mosley, Thomas H | Bevan, Steve | Dichgans, Martin | Rothwell, Peter M. | Sudlow, Cathie L M | Hopewell, Jemma C. | Chambers, John C. | Saleheen, Danish | Kooner, Jaspal S. | Danesh, John | Nelson, Christopher P | Erdmann, Jeanette | Reilly, Muredach P. | Kathiresan, Sekar | Schunkert, Heribert | Morange, Pierre-Emmanuel | Ferrucci, Luigi | Eriksson, Johan G | Jacobs, David | Deary, Ian J | Soranzo, Nicole | Witteman, Jacqueline CM | de Geus, Eco JC | Tracy, Russell P. | Hayward, Caroline | Koenig, Wolfgang | Cucca, Francesco | Jukema, J Wouter | Eriksson, Per | Seshadri, Sudha | Markus, Hugh S. | Watkins, Hugh | Samani, Nilesh J | Wallaschofski, Henri | Smith, Nicholas L. | Tregouet, David | Ridker, Paul M. | Tang, Weihong | Strachan, David P. | Hamsten, Anders | O’Donnell, Christopher J.
Circulation  2013;128(12):10.1161/CIRCULATIONAHA.113.002251.
Background
Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease (CVD), range from 34 to 50%. Genetic variants so far identified by genome-wide association (GWA) studies only explain a small proportion (< 2%) of its variation.
Methods and Results
We conducted a meta-analysis of 28 GWA studies, including more than 90,000 subjects of European ancestry, the first GWA meta-analysis of fibrinogen levels in 7 African Americans studies totaling 8,289 samples, and a GWA study in Hispanic-Americans totaling 1,366 samples. Evaluation for association of SNPs with clinical outcomes included a total of 40,695 cases and 85,582 controls for coronary artery disease (CAD), 4,752 cases and 24,030 controls for stroke, and 3,208 cases and 46,167 controls for venous thromboembolism (VTE). Overall, we identified 24 genome-wide significant (P<5×10−8) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the three structural fibrinogen genes and pathways related to inflammation, adipocytokines and thyrotrophin-releasing hormone signaling. Whereas lead SNPs in a few loci were significantly associated with CAD, the combined effect of all 24 fibrinogen-associated lead SNPs was not significant for CAD, stroke or VTE.
Conclusion
We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and CAD, stroke or VTE.
doi:10.1161/CIRCULATIONAHA.113.002251
PMCID: PMC3842025  PMID: 23969696
Fibrinogen; cardiovascular disease; genome-wide association study
15.  Overlap Between Common Genetic Polymorphisms Underpinning Kidney Traits and Cardiovascular Disease Phenotypes: The CKDGen Consortium 
Background
Chronic kidney disease is associated with cardiovascular disease. We tested for evidence of a shared genetic basis to these traits.
Study Design
We conducted two targeted analyses. First, we examined whether known single nucleotide polymorphisms (SNPs) underpinning kidney traits were associated with a series of vascular phenotypes. Additionally, we tested whether vascular SNPs were associated with markers of kidney damage. Significance was set to 1.5 × 10-4 (0.05/325 tests).
Setting & Participants
Vascular outcomes were analyzed in participants from the AortaGen (20,634), CARDIoGRAM (86,995), CHARGE Eye (15,358), CHARGE IMT (31,181), ICBP (69,395) and NeuroCHARGE (12,385) consortia. Tests for kidney outcomes were conducted in up to 67,093 participants from the CKDGen consortium.
Predictor
We used 19 kidney SNPs and 64 vascular SNPs.
Outcomes & Measurements
Vascular outcomes tested were blood pressure, coronary artery disease, carotid intima-media thickness, pulse wave velocity, retinal venular caliber and brain white matter lesions. Kidney outcomes were estimated glomerular filtration rate and albuminuria.
Results
In general, we found that kidney disease variants were not associated with vascular phenotypes (127 of 133 tests were non-significant). The one exception was rs653178 near SH2B3 (SH2B adaptor protein 3), which showed direction-consistent association with systolic (p=9.3E-10) and diastolic (p=1.6E-14) blood pressure and coronary artery disease (p=2.2E-6), all previously reported. Similarly, the 64 SNPs associated with vascular phenotypes were not associated with kidney phenotypes (187 of 192 tests were non-significant), with the exception of 2 high-correlated SNPs at the SH2B3 locus (p=1.06E-07 and p=7.05E-08).
Limitations
Combined effect size of the SNPs for kidney and vascular outcomes may be too low to detect shared genetic associations.
Conclusions
Overall, although we confirmed one locus (SH2B3) as associated with both kidney and cardiovascular disease, our primary findings suggest that there is little overlap between kidney and cardiovascular disease risk variants in the overall population. The reciprocal risks of kidney and cardiovascular disease may not be genetically mediated, but rather a function of the disease milieu itself.
doi:10.1053/j.ajkd.2012.12.024
PMCID: PMC3660426  PMID: 23474010
16.  High Bone Mineral Density and Fracture Risk in Type 2 Diabetes as Skeletal Complications of Inadequate Glucose Control 
Diabetes Care  2013;36(6):1619-1628.
OBJECTIVE
Individuals with type 2 diabetes have increased fracture risk despite higher bone mineral density (BMD). Our aim was to examine the influence of glucose control on skeletal complications.
RESEARCH DESIGN AND METHODS
Data of 4,135 participants of the Rotterdam Study, a prospective population-based cohort, were available (mean follow-up 12.2 years). At baseline, 420 participants with type 2 diabetes were classified by glucose control (according to HbA1c calculated from fructosamine), resulting in three comparison groups: adequately controlled diabetes (ACD; n = 203; HbA1c <7.5%), inadequately controlled diabetes (ICD; n = 217; HbA1c ≥7.5%), and no diabetes (n = 3,715). Models adjusted for sex, age, height, and weight (and femoral neck BMD) were used to test for differences in bone parameters and fracture risk (hazard ratio [HR] [95% CI]).
RESULTS
The ICD group had 1.1–5.6% higher BMD, 4.6–5.6% thicker cortices, and −1.2 to −1.8% narrower femoral necks than ACD and ND, respectively. Participants with ICD had 47–62% higher fracture risk than individuals without diabetes (HR 1.47 [1.12–1.92]) and ACD (1.62 [1.09–2.40]), whereas those with ACD had a risk similar to those without diabetes (0.91 [0.67–1.23]).
CONCLUSIONS
Poor glycemic control in type 2 diabetes is associated with fracture risk, high BMD, and thicker femoral cortices in narrower bones. We postulate that fragility in apparently “strong” bones in ICD can result from microcrack accumulation and/or cortical porosity, reflecting impaired bone repair.
doi:10.2337/dc12-1188
PMCID: PMC3661786  PMID: 23315602
17.  Genetic variation associated with circulating monocyte count in the eMERGE Network 
Human Molecular Genetics  2013;22(10):2119-2127.
With white blood cell count emerging as an important risk factor for chronic inflammatory diseases, genetic associations of differential leukocyte types, specifically monocyte count, are providing novel candidate genes and pathways to further investigate. Circulating monocytes play a critical role in vascular diseases such as in the formation of atherosclerotic plaque. We performed a joint and ancestry-stratified genome-wide association analyses to identify variants specifically associated with monocyte count in 11 014 subjects in the electronic Medical Records and Genomics Network. In the joint and European ancestry samples, we identified novel associations in the chromosome 16 interferon regulatory factor 8 (IRF8) gene (P-value = 2.78×10(−16), β = −0.22). Other monocyte associations include novel missense variants in the chemokine-binding protein 2 (CCBP2) gene (P-value = 1.88×10(−7), β = 0.30) and a region of replication found in ribophorin I (RPN1) (P-value = 2.63×10(−16), β = −0.23) on chromosome 3. The CCBP2 and RPN1 region is located near GATA binding protein2 gene that has been previously shown to be associated with coronary heart disease. On chromosome 9, we found a novel association in the prostaglandin reductase 1 gene (P-value = 2.29×10(−7), β = 0.16), which is downstream from lysophosphatidic acid receptor 1. This region has previously been shown to be associated with monocyte count. We also replicated monocyte associations of genome-wide significance (P-value = 5.68×10(−17), β = −0.23) at the integrin, alpha 4 gene on chromosome 2. The novel IRF8 results and further replications provide supporting evidence of genetic regions associated with monocyte count.
doi:10.1093/hmg/ddt010
PMCID: PMC3633369  PMID: 23314186
18.  Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function 
Chasman, Daniel I. | Fuchsberger, Christian | Pattaro, Cristian | Teumer, Alexander | Böger, Carsten A. | Endlich, Karlhans | Olden, Matthias | Chen, Ming-Huei | Tin, Adrienne | Taliun, Daniel | Li, Man | Gao, Xiaoyi | Gorski, Mathias | Yang, Qiong | Hundertmark, Claudia | Foster, Meredith C. | O'Seaghdha, Conall M. | Glazer, Nicole | Isaacs, Aaron | Liu, Ching-Ti | Smith, Albert V. | O'Connell, Jeffrey R. | Struchalin, Maksim | Tanaka, Toshiko | Li, Guo | Johnson, Andrew D. | Gierman, Hinco J. | Feitosa, Mary F. | Hwang, Shih-Jen | Atkinson, Elizabeth J. | Lohman, Kurt | Cornelis, Marilyn C. | Johansson, Åsa | Tönjes, Anke | Dehghan, Abbas | Lambert, Jean-Charles | Holliday, Elizabeth G. | Sorice, Rossella | Kutalik, Zoltan | Lehtimäki, Terho | Esko, Tõnu | Deshmukh, Harshal | Ulivi, Sheila | Chu, Audrey Y. | Murgia, Federico | Trompet, Stella | Imboden, Medea | Coassin, Stefan | Pistis, Giorgio | Harris, Tamara B. | Launer, Lenore J. | Aspelund, Thor | Eiriksdottir, Gudny | Mitchell, Braxton D. | Boerwinkle, Eric | Schmidt, Helena | Cavalieri, Margherita | Rao, Madhumathi | Hu, Frank | Demirkan, Ayse | Oostra, Ben A. | de Andrade, Mariza | Turner, Stephen T. | Ding, Jingzhong | Andrews, Jeanette S. | Freedman, Barry I. | Giulianini, Franco | Koenig, Wolfgang | Illig, Thomas | Meisinger, Christa | Gieger, Christian | Zgaga, Lina | Zemunik, Tatijana | Boban, Mladen | Minelli, Cosetta | Wheeler, Heather E. | Igl, Wilmar | Zaboli, Ghazal | Wild, Sarah H. | Wright, Alan F. | Campbell, Harry | Ellinghaus, David | Nöthlings, Ute | Jacobs, Gunnar | Biffar, Reiner | Ernst, Florian | Homuth, Georg | Kroemer, Heyo K. | Nauck, Matthias | Stracke, Sylvia | Völker, Uwe | Völzke, Henry | Kovacs, Peter | Stumvoll, Michael | Mägi, Reedik | Hofman, Albert | Uitterlinden, Andre G. | Rivadeneira, Fernando | Aulchenko, Yurii S. | Polasek, Ozren | Hastie, Nick | Vitart, Veronique | Helmer, Catherine | Wang, Jie Jin | Stengel, Bénédicte | Ruggiero, Daniela | Bergmann, Sven | Kähönen, Mika | Viikari, Jorma | Nikopensius, Tiit | Province, Michael | Ketkar, Shamika | Colhoun, Helen | Doney, Alex | Robino, Antonietta | Krämer, Bernhard K. | Portas, Laura | Ford, Ian | Buckley, Brendan M. | Adam, Martin | Thun, Gian-Andri | Paulweber, Bernhard | Haun, Margot | Sala, Cinzia | Mitchell, Paul | Ciullo, Marina | Kim, Stuart K. | Vollenweider, Peter | Raitakari, Olli | Metspalu, Andres | Palmer, Colin | Gasparini, Paolo | Pirastu, Mario | Jukema, J. Wouter | Probst-Hensch, Nicole M. | Kronenberg, Florian | Toniolo, Daniela | Gudnason, Vilmundur | Shuldiner, Alan R. | Coresh, Josef | Schmidt, Reinhold | Ferrucci, Luigi | Siscovick, David S. | van Duijn, Cornelia M. | Borecki, Ingrid B. | Kardia, Sharon L.R. | Liu, Yongmei | Curhan, Gary C. | Rudan, Igor | Gyllensten, Ulf | Wilson, James F. | Franke, Andre | Pramstaller, Peter P. | Rettig, Rainer | Prokopenko, Inga | Witteman, Jacqueline | Hayward, Caroline | Ridker, Paul M | Parsa, Afshin | Bochud, Murielle | Heid, Iris M. | Kao, W.H. Linda | Fox, Caroline S. | Köttgen, Anna
Human Molecular Genetics  2012;21(24):5329-5343.
In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10−9) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10−4–2.2 × 10−7. Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.
doi:10.1093/hmg/dds369
PMCID: PMC3607468  PMID: 22962313
19.  Secretory Phospholipase A2-IIA and Cardiovascular Disease 
Holmes, Michael V. | Simon, Tabassome | Exeter, Holly J. | Folkersen, Lasse | Asselbergs, Folkert W. | Guardiola, Montse | Cooper, Jackie A. | Palmen, Jutta | Hubacek, Jaroslav A. | Carruthers, Kathryn F. | Horne, Benjamin D. | Brunisholz, Kimberly D. | Mega, Jessica L. | van Iperen, Erik P.A. | Li, Mingyao | Leusink, Maarten | Trompet, Stella | Verschuren, Jeffrey J.W. | Hovingh, G. Kees | Dehghan, Abbas | Nelson, Christopher P. | Kotti, Salma | Danchin, Nicolas | Scholz, Markus | Haase, Christiane L. | Rothenbacher, Dietrich | Swerdlow, Daniel I. | Kuchenbaecker, Karoline B. | Staines-Urias, Eleonora | Goel, Anuj | van 't Hooft, Ferdinand | Gertow, Karl | de Faire, Ulf | Panayiotou, Andrie G. | Tremoli, Elena | Baldassarre, Damiano | Veglia, Fabrizio | Holdt, Lesca M. | Beutner, Frank | Gansevoort, Ron T. | Navis, Gerjan J. | Mateo Leach, Irene | Breitling, Lutz P. | Brenner, Hermann | Thiery, Joachim | Dallmeier, Dhayana | Franco-Cereceda, Anders | Boer, Jolanda M.A. | Stephens, Jeffrey W. | Hofker, Marten H. | Tedgui, Alain | Hofman, Albert | Uitterlinden, André G. | Adamkova, Vera | Pitha, Jan | Onland-Moret, N. Charlotte | Cramer, Maarten J. | Nathoe, Hendrik M. | Spiering, Wilko | Klungel, Olaf H. | Kumari, Meena | Whincup, Peter H. | Morrow, David A. | Braund, Peter S. | Hall, Alistair S. | Olsson, Anders G. | Doevendans, Pieter A. | Trip, Mieke D. | Tobin, Martin D. | Hamsten, Anders | Watkins, Hugh | Koenig, Wolfgang | Nicolaides, Andrew N. | Teupser, Daniel | Day, Ian N.M. | Carlquist, John F. | Gaunt, Tom R. | Ford, Ian | Sattar, Naveed | Tsimikas, Sotirios | Schwartz, Gregory G. | Lawlor, Debbie A. | Morris, Richard W. | Sandhu, Manjinder S. | Poledne, Rudolf | Maitland-van der Zee, Anke H. | Khaw, Kay-Tee | Keating, Brendan J. | van der Harst, Pim | Price, Jackie F. | Mehta, Shamir R. | Yusuf, Salim | Witteman, Jaqueline C.M. | Franco, Oscar H. | Jukema, J. Wouter | de Knijff, Peter | Tybjaerg-Hansen, Anne | Rader, Daniel J. | Farrall, Martin | Samani, Nilesh J. | Kivimaki, Mika | Fox, Keith A.A. | Humphries, Steve E. | Anderson, Jeffrey L. | Boekholdt, S. Matthijs | Palmer, Tom M. | Eriksson, Per | Paré, Guillaume | Hingorani, Aroon D. | Sabatine, Marc S. | Mallat, Ziad | Casas, Juan P. | Talmud, Philippa J.
Objectives
This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease.
Background
Higher circulating levels of sPLA2-IIA mass or sPLA2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy.
Methods
We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2-IIA isoenzyme, as an instrumental variable.
Results
PLA2G2A rs11573156 C allele associated with lower circulating sPLA2-IIA mass (38% to 44%) and sPLA2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA2-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE.
Conclusions
Reducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.
doi:10.1016/j.jacc.2013.06.044
PMCID: PMC3826105  PMID: 23916927
cardiovascular diseases; drug development; epidemiology; genetics; Mendelian randomization; ACS, acute coronary syndrome(s); CI, confidence interval; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; MVE, major vascular events; OR, odds ratio; RCT, randomized clinical trial; SNP, single-nucleotide polymorphism; sPLA2, secretory phospholipase A2
20.  Serum Uric Acid and Chronic Kidney Disease: The Role of Hypertension 
PLoS ONE  2013;8(11):e76827.
Background
There are inconsistent findings on the role of hyperuricemia as an independent risk factor for chronic kidney disease (CKD). Hypertension has been implicated as a factor influencing the association between serum uric acid and CKD. In this population-based study we investigated the association between serum uric acid and decline in renal function and tested whether hypertension moderates this association.
Methods
We included 2601 subjects aged 55 years and over from the Rotterdam Study. Serum uric acid and estimated glomerular filtration rate (eGFR) were assessed at baseline. After average 6.5 years of follow-up, second eGFR was assessed. CKD was defined as eGFR<60 ml/min/1.73 m2. All associations were corrected for socio-demographic and cardiovascular factors.
Results
Each unit (mg/dL) increase in serum uric acid was associated with 0.19 ml/min per 1.73 m2 faster annual decline in eGFR. While the association between serum uric acid and incidence of CKD was not significant in our study population (Hazard Ratio: 1.12, 95% confidence interval [CI]: 0.98–1.28), incorporating our results in a meta-analysis with eleven published studies revealed a significant association (Relative Risk: 1.18, 95%CI: 1.15–1.22). In the stratified analyses, we observed that the associations of serum uric acid with eGFR decline and incident CKD were stronger in hypertensive subjects (P for interaction = 0.046 and 0.024, respectively).
Conclusions
Our findings suggest that hyperuricemia is independently associated with a decline in renal function. Stronger association in hypertensive individuals may indicate that hypertension mediates the association between serum uric acid and CKD.
doi:10.1371/journal.pone.0076827
PMCID: PMC3827035  PMID: 24265674
21.  Mining the Human Phenome Using Allelic Scores That Index Biological Intermediates 
PLoS Genetics  2013;9(10):e1003919.
It is common practice in genome-wide association studies (GWAS) to focus on the relationship between disease risk and genetic variants one marker at a time. When relevant genes are identified it is often possible to implicate biological intermediates and pathways likely to be involved in disease aetiology. However, single genetic variants typically explain small amounts of disease risk. Our idea is to construct allelic scores that explain greater proportions of the variance in biological intermediates, and subsequently use these scores to data mine GWAS. To investigate the approach's properties, we indexed three biological intermediates where the results of large GWAS meta-analyses were available: body mass index, C-reactive protein and low density lipoprotein levels. We generated allelic scores in the Avon Longitudinal Study of Parents and Children, and in publicly available data from the first Wellcome Trust Case Control Consortium. We compared the explanatory ability of allelic scores in terms of their capacity to proxy for the intermediate of interest, and the extent to which they associated with disease. We found that allelic scores derived from known variants and allelic scores derived from hundreds of thousands of genetic markers explained significant portions of the variance in biological intermediates of interest, and many of these scores showed expected correlations with disease. Genome-wide allelic scores however tended to lack specificity suggesting that they should be used with caution and perhaps only to proxy biological intermediates for which there are no known individual variants. Power calculations confirm the feasibility of extending our strategy to the analysis of tens of thousands of molecular phenotypes in large genome-wide meta-analyses. We conclude that our method represents a simple way in which potentially tens of thousands of molecular phenotypes could be screened for causal relationships with disease without having to expensively measure these variables in individual disease collections.
Author Summary
The standard approach in genome-wide association studies is to analyse the relationship between genetic variants and disease one marker at a time. Significant associations between markers and disease are then used as evidence to implicate biological intermediates and pathways likely to be involved in disease aetiology. However, single genetic variants typically only explain small amounts of disease risk. Our idea is to construct allelic scores that explain greater proportions of the variance in biological intermediates than single markers, and then use these scores to data mine genome-wide association studies. We show how allelic scores derived from known variants as well as allelic scores derived from hundreds of thousands of genetic markers across the genome explain significant portions of the variance in body mass index, levels of C-reactive protein, and LDLc cholesterol, and many of these scores show expected correlations with disease. Power calculations confirm the feasibility of scaling our strategy to the analysis of tens of thousands of molecular phenotypes in large genome-wide meta-analyses. Our method represents a simple way in which tens of thousands of molecular phenotypes could be screened for potential causal relationships with disease.
doi:10.1371/journal.pgen.1003919
PMCID: PMC3814299  PMID: 24204319
22.  Meta-Analysis of Genome-Wide Association Studies Identifies Six New Loci for Serum Calcium Concentrations 
O'Seaghdha, Conall M. | Wu, Hongsheng | Yang, Qiong | Kapur, Karen | Guessous, Idris | Zuber, Annie Mercier | Köttgen, Anna | Stoudmann, Candice | Teumer, Alexander | Kutalik, Zoltán | Mangino, Massimo | Dehghan, Abbas | Zhang, Weihua | Eiriksdottir, Gudny | Li, Guo | Tanaka, Toshiko | Portas, Laura | Lopez, Lorna M. | Hayward, Caroline | Lohman, Kurt | Matsuda, Koichi | Padmanabhan, Sandosh | Firsov, Dmitri | Sorice, Rossella | Ulivi, Sheila | Brockhaus, A. Catharina | Kleber, Marcus E. | Mahajan, Anubha | Ernst, Florian D. | Gudnason, Vilmundur | Launer, Lenore J. | Mace, Aurelien | Boerwinckle, Eric | Arking, Dan E. | Tanikawa, Chizu | Nakamura, Yusuke | Brown, Morris J. | Gaspoz, Jean-Michel | Theler, Jean-Marc | Siscovick, David S. | Psaty, Bruce M. | Bergmann, Sven | Vollenweider, Peter | Vitart, Veronique | Wright, Alan F. | Zemunik, Tatijana | Boban, Mladen | Kolcic, Ivana | Navarro, Pau | Brown, Edward M. | Estrada, Karol | Ding, Jingzhong | Harris, Tamara B. | Bandinelli, Stefania | Hernandez, Dena | Singleton, Andrew B. | Girotto, Giorgia | Ruggiero, Daniela | d'Adamo, Adamo Pio | Robino, Antonietta | Meitinger, Thomas | Meisinger, Christa | Davies, Gail | Starr, John M. | Chambers, John C. | Boehm, Bernhard O. | Winkelmann, Bernhard R. | Huang, Jie | Murgia, Federico | Wild, Sarah H. | Campbell, Harry | Morris, Andrew P. | Franco, Oscar H. | Hofman, Albert | Uitterlinden, Andre G. | Rivadeneira, Fernando | Völker, Uwe | Hannemann, Anke | Biffar, Reiner | Hoffmann, Wolfgang | Shin, So–Youn | Lescuyer, Pierre | Henry, Hughes | Schurmann, Claudia | Munroe, Patricia B. | Gasparini, Paolo | Pirastu, Nicola | Ciullo, Marina | Gieger, Christian | März, Winfried | Lind, Lars | Spector, Tim D. | Smith, Albert V. | Rudan, Igor | Wilson, James F. | Polasek, Ozren | Deary, Ian J. | Pirastu, Mario | Ferrucci, Luigi | Liu, Yongmei | Kestenbaum, Bryan | Kooner, Jaspal S. | Witteman, Jacqueline C. M. | Nauck, Matthias | Kao, W. H. Linda | Wallaschofski, Henri | Bonny, Olivier | Fox, Caroline S. | Bochud, Murielle
PLoS Genetics  2013;9(9):e1003796.
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.
Author Summary
Calcium is vital to many biological processes and its serum concentration is tightly regulated. Family studies have shown that serum calcium is under strong genetic control. 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. We identified seven loci (six new regions) as being robustly associated with serum calcium. Three loci implicate regions involved in rare monogenic diseases including disturbances of serum calcium levels. Several of the newly identified loci harbor genes linked to the hormonal control of serum calcium. In mice experiments, we characterized the expression of these genes in gut, kidney, and bone, and explored the influence of dietary calcium intake on the expression of these genes in these organs. Our results shed new light on the genetics of calcium homeostasis and suggest a role for dietary calcium intake in bone-specific gene expression.
doi:10.1371/journal.pgen.1003796
PMCID: PMC3778004  PMID: 24068962
23.  Common genetic variation at the IL1RL1 locus regulates IL-33/ST2 signaling  
The Journal of Clinical Investigation  2013;123(10):4208-4218.
The suppression of tumorigenicity 2/IL-33 (ST2/IL-33) pathway has been implicated in several immune and inflammatory diseases. ST2 is produced as 2 isoforms. The membrane-bound isoform (ST2L) induces an immune response when bound to its ligand, IL-33. The other isoform is a soluble protein (sST2) that is thought to be a decoy receptor for IL-33 signaling. Elevated sST2 levels in serum are associated with an increased risk for cardiovascular disease. We investigated the determinants of sST2 plasma concentrations in 2,991 Framingham Offspring Cohort participants. While clinical and environmental factors explained some variation in sST2 levels, much of the variation in sST2 production was driven by genetic factors. In a genome-wide association study (GWAS), multiple SNPs within IL1RL1 (the gene encoding ST2) demonstrated associations with sST2 concentrations. Five missense variants of IL1RL1 correlated with higher sST2 levels in the GWAS and mapped to the intracellular domain of ST2, which is absent in sST2. In a cell culture model, IL1RL1 missense variants increased sST2 expression by inducing IL-33 expression and enhancing IL-33 responsiveness (via ST2L). Our data suggest that genetic variation in IL1RL1 can result in increased levels of sST2 and alter immune and inflammatory signaling through the ST2/IL-33 pathway.
doi:10.1172/JCI67119
PMCID: PMC3784527  PMID: 23999434
24.  Genome-wide association analyses identify 18 new loci associated with serum urate concentrations 
Köttgen, Anna | Albrecht, Eva | Teumer, Alexander | Vitart, Veronique | Krumsiek, Jan | Hundertmark, Claudia | Pistis, Giorgio | Ruggiero, Daniela | O’Seaghdha, Conall M | Haller, Toomas | Yang, Qiong | Tanaka, Toshiko | Johnson, Andrew D | Kutalik, Zoltán | Smith, Albert V | Shi, Julia | Struchalin, Maksim | Middelberg, Rita P S | Brown, Morris J | Gaffo, Angelo L | Pirastu, Nicola | Li, Guo | Hayward, Caroline | Zemunik, Tatijana | Huffman, Jennifer | Yengo, Loic | Zhao, Jing Hua | Demirkan, Ayse | Feitosa, Mary F | Liu, Xuan | Malerba, Giovanni | Lopez, Lorna M | van der Harst, Pim | Li, Xinzhong | Kleber, Marcus E | Hicks, Andrew A | Nolte, Ilja M | Johansson, Asa | Murgia, Federico | Wild, Sarah H | Bakker, Stephan J L | Peden, John F | Dehghan, Abbas | Steri, Maristella | Tenesa, Albert | Lagou, Vasiliki | Salo, Perttu | Mangino, Massimo | Rose, Lynda M | Lehtimäki, Terho | Woodward, Owen M | Okada, Yukinori | Tin, Adrienne | Müller, Christian | Oldmeadow, Christopher | Putku, Margus | Czamara, Darina | Kraft, Peter | Frogheri, Laura | Thun, Gian Andri | Grotevendt, Anne | Gislason, Gauti Kjartan | Harris, Tamara B | Launer, Lenore J | McArdle, Patrick | Shuldiner, Alan R | Boerwinkle, Eric | Coresh, Josef | Schmidt, Helena | Schallert, Michael | Martin, Nicholas G | Montgomery, Grant W | Kubo, Michiaki | Nakamura, Yusuke | Tanaka, Toshihiro | Munroe, Patricia B | Samani, Nilesh J | Jacobs, David R | Liu, Kiang | D’Adamo, Pio | Ulivi, Sheila | Rotter, Jerome I | Psaty, Bruce M | Vollenweider, Peter | Waeber, Gerard | Campbell, Susan | Devuyst, Olivier | Navarro, Pau | Kolcic, Ivana | Hastie, Nicholas | Balkau, Beverley | Froguel, Philippe | Esko, Tõnu | Salumets, Andres | Khaw, Kay Tee | Langenberg, Claudia | Wareham, Nicholas J | Isaacs, Aaron | Kraja, Aldi | Zhang, Qunyuan | Wild, Philipp S | Scott, Rodney J | Holliday, Elizabeth G | Org, Elin | Viigimaa, Margus | Bandinelli, Stefania | Metter, Jeffrey E | Lupo, Antonio | Trabetti, Elisabetta | Sorice, Rossella | Döring, Angela | Lattka, Eva | Strauch, Konstantin | Theis, Fabian | Waldenberger, Melanie | Wichmann, H-Erich | Davies, Gail | Gow, Alan J | Bruinenberg, Marcel | Study, LifeLines Cohort | Stolk, Ronald P | Kooner, Jaspal S | Zhang, Weihua | Winkelmann, Bernhard R | Boehm, Bernhard O | Lucae, Susanne | Penninx, Brenda W | Smit, Johannes H | Curhan, Gary | Mudgal, Poorva | Plenge, Robert M | Portas, Laura | Persico, Ivana | Kirin, Mirna | Wilson, James F | Leach, Irene Mateo | van Gilst, Wiek H | Goel, Anuj | Ongen, Halit | Hofman, Albert | Rivadeneira, Fernando | Uitterlinden, Andre G | Imboden, Medea | von Eckardstein, Arnold | Cucca, Francesco | Nagaraja, Ramaiah | Piras, Maria Grazia | Nauck, Matthias | Schurmann, Claudia | Budde, Kathrin | Ernst, Florian | Farrington, Susan M | Theodoratou, Evropi | Prokopenko, Inga | Stumvoll, Michael | Jula, Antti | Perola, Markus | Salomaa, Veikko | Shin, So-Youn | Spector, Tim D | Sala, Cinzia | Ridker, Paul M | Kähönen, Mika | Viikari, Jorma | Hengstenberg, Christian | Nelson, Christopher P | Consortium, CARDIoGRAM | Consortium, DIAGRAM | Consortium, ICBP | Consortium, MAGIC | Meschia, James F | Nalls, Michael A | Sharma, Pankaj | Singleton, Andrew B | Kamatani, Naoyuki | Zeller, Tanja | Burnier, Michel | Attia, John | Laan, Maris | Klopp, Norman | Hillege, Hans L | Kloiber, Stefan | Choi, Hyon | Pirastu, Mario | Tore, Silvia | Probst-Hensch, Nicole M | Völzke, Henry | Gudnason, Vilmundur | Parsa, Afshin | Schmidt, Reinhold | Whitfield, John B | Fornage, Myriam | Gasparini, Paolo | Siscovick, David S | Polašek, Ozren | Campbell, Harry | Rudan, Igor | Bouatia-Naji, Nabila | Metspalu, Andres | Loos, Ruth J F | van Duijn, Cornelia M | Borecki, Ingrid B | Ferrucci, Luigi | Gambaro, Giovanni | Deary, Ian J | Wolffenbuttel, Bruce H R | Chambers, John C | März, Winfried | Pramstaller, Peter P | Snieder, Harold | Gyllensten, Ulf | Wright, Alan F | Navis, Gerjan | Watkins, Hugh | Witteman, Jacqueline C M | Sanna, Serena | Schipf, Sabine | Dunlop, Malcolm G | Tönjes, Anke | Ripatti, Samuli | Soranzo, Nicole | Toniolo, Daniela | Chasman, Daniel I | Raitakari, Olli | Kao, W H Linda | Ciullo, Marina | Fox, Caroline S | Caulfield, Mark | Bochud, Murielle | Gieger, Christian
Nature genetics  2012;45(2):145-154.
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.
doi:10.1038/ng.2500
PMCID: PMC3663712  PMID: 23263486
25.  The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis 
Fall, Tove | Hägg, Sara | Mägi, Reedik | Ploner, Alexander | Fischer, Krista | Horikoshi, Momoko | Sarin, Antti-Pekka | Thorleifsson, Gudmar | Ladenvall, Claes | Kals, Mart | Kuningas, Maris | Draisma, Harmen H. M. | Ried, Janina S. | van Zuydam, Natalie R. | Huikari, Ville | Mangino, Massimo | Sonestedt, Emily | Benyamin, Beben | Nelson, Christopher P. | Rivera, Natalia V. | Kristiansson, Kati | Shen, Huei-yi | Havulinna, Aki S. | Dehghan, Abbas | Donnelly, Louise A. | Kaakinen, Marika | Nuotio, Marja-Liisa | Robertson, Neil | de Bruijn, Renée F. A. G. | Ikram, M. Arfan | Amin, Najaf | Balmforth, Anthony J. | Braund, Peter S. | Doney, Alexander S. F. | Döring, Angela | Elliott, Paul | Esko, Tõnu | Franco, Oscar H. | Gretarsdottir, Solveig | Hartikainen, Anna-Liisa | Heikkilä, Kauko | Herzig, Karl-Heinz | Holm, Hilma | Hottenga, Jouke Jan | Hyppönen, Elina | Illig, Thomas | Isaacs, Aaron | Isomaa, Bo | Karssen, Lennart C. | Kettunen, Johannes | Koenig, Wolfgang | Kuulasmaa, Kari | Laatikainen, Tiina | Laitinen, Jaana | Lindgren, Cecilia | Lyssenko, Valeriya | Läärä, Esa | Rayner, Nigel W. | Männistö, Satu | Pouta, Anneli | Rathmann, Wolfgang | Rivadeneira, Fernando | Ruokonen, Aimo | Savolainen, Markku J. | Sijbrands, Eric J. G. | Small, Kerrin S. | Smit, Jan H. | Steinthorsdottir, Valgerdur | Syvänen, Ann-Christine | Taanila, Anja | Tobin, Martin D. | Uitterlinden, Andre G. | Willems, Sara M. | Willemsen, Gonneke | Witteman, Jacqueline | Perola, Markus | Evans, Alun | Ferrières, Jean | Virtamo, Jarmo | Kee, Frank | Tregouet, David-Alexandre | Arveiler, Dominique | Amouyel, Philippe | Ferrario, Marco M. | Brambilla, Paolo | Hall, Alistair S. | Heath, Andrew C. | Madden, Pamela A. F. | Martin, Nicholas G. | Montgomery, Grant W. | Whitfield, John B. | Jula, Antti | Knekt, Paul | Oostra, Ben | van Duijn, Cornelia M. | Penninx, Brenda W. J. H. | Davey Smith, George | Kaprio, Jaakko | Samani, Nilesh J. | Gieger, Christian | Peters, Annette | Wichmann, H.-Erich | Boomsma, Dorret I. | de Geus, Eco J. C. | Tuomi, TiinaMaija | Power, Chris | Hammond, Christopher J. | Spector, Tim D. | Lind, Lars | Orho-Melander, Marju | Palmer, Colin Neil Alexander | Morris, Andrew D. | Groop, Leif | Järvelin, Marjo-Riitta | Salomaa, Veikko | Vartiainen, Erkki | Hofman, Albert | Ripatti, Samuli | Metspalu, Andres | Thorsteinsdottir, Unnur | Stefansson, Kari | Pedersen, Nancy L. | McCarthy, Mark I. | Ingelsson, Erik | Prokopenko, Inga
PLoS Medicine  2013;10(6):e1001474.
In this study, Prokopenko and colleagues provide novel evidence for causal relationship between adiposity and heart failure and increased liver enzymes using a Mendelian randomization study design.
Please see later in the article for the Editors' Summary
Background
The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach.
Methods and Findings
We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses.
Age- and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n = 198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI–trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03–1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1–1.4; all p<0.05). For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p<0.05). The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (p = 0.001).
Conclusions
We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.
Please see later in the article for the Editors' Summary
Editors' Summary
Cardiovascular disease (CVD)—disease that affects the heart and/or the blood vessels—is a major cause of illness and death worldwide. In the US, for example, coronary heart disease—a CVD in which narrowing of the heart's blood vessels by fatty deposits slows the blood supply to the heart and may eventually cause a heart attack—is the leading cause of death, and stroke—a CVD in which the brain's blood supply is interrupted—is the fourth leading cause of death. Globally, both the incidence of CVD (the number of new cases in a population every year) and its prevalence (the proportion of the population with CVD) are increasing, particularly in low- and middle-income countries. This increasing burden of CVD is occurring in parallel with a global increase in the incidence and prevalence of obesity—having an unhealthy amount of body fat (adiposity)—and of metabolic diseases—conditions such as diabetes in which metabolism (the processes that the body uses to make energy from food) is disrupted, with resulting high blood sugar and damage to the blood vessels.
Why Was This Study Done?
Epidemiological studies—investigations that record the patterns and causes of disease in populations—have reported an association between adiposity (indicated by an increased body mass index [BMI], which is calculated by dividing body weight in kilograms by height in meters squared) and cardiometabolic traits such as coronary heart disease, stroke, heart failure (a condition in which the heart is incapable of pumping sufficient amounts of blood around the body), diabetes, high blood pressure (hypertension), and high blood cholesterol (dyslipidemia). However, observational studies cannot prove that adiposity causes any particular cardiometabolic trait because overweight individuals may share other characteristics (confounding factors) that are the real causes of both obesity and the cardiometabolic disease. Moreover, it is possible that having CVD or a metabolic disease causes obesity (reverse causation). For example, individuals with heart failure cannot do much exercise, so heart failure may cause obesity rather than vice versa. Here, the researchers use “Mendelian randomization” to examine whether adiposity is causally related to various cardiometabolic traits. Because gene variants are inherited randomly, they are not prone to confounding and are free from reverse causation. It is known that a genetic variant (rs9939609) within the genome region that encodes the fat-mass- and obesity-associated gene (FTO) is associated with increased BMI. Thus, an investigation of the associations between rs9939609 and cardiometabolic traits can indicate whether obesity is causally related to these traits.
What Did the Researchers Do and Find?
The researchers analyzed the association between rs9939609 (the “instrumental variable,” or IV) and BMI, between rs9939609 and 24 cardiometabolic traits, and between BMI and the same traits using genetic and health data collected in 36 population-based studies of nearly 200,000 individuals of European descent. They then quantified the strength of the causal association between BMI and the cardiometabolic traits by calculating “IV estimators.” Higher BMI showed a causal relationship with heart failure, metabolic syndrome (a combination of medical disorders that increases the risk of developing CVD), type 2 diabetes, dyslipidemia, hypertension, increased blood levels of liver enzymes (an indicator of liver damage; some metabolic disorders involve liver damage), and several other cardiometabolic traits. All the IV estimators were similar to the BMI–cardiovascular trait associations (observational estimates) derived from the same individuals, with the exception of diabetes, where the causal estimate was higher than the observational estimate, probably because the observational estimate is based on a single BMI measurement, whereas the causal estimate considers lifetime changes in BMI.
What Do These Findings Mean?
Like all Mendelian randomization studies, the reliability of the causal associations reported here depends on several assumptions made by the researchers. Nevertheless, these findings provide support for many previously suspected and biologically plausible causal relationships, such as that between adiposity and hypertension. They also provide new insights into the causal effect of obesity on liver enzyme levels and on heart failure. In the latter case, these findings suggest that a one-unit increase in BMI might increase the incidence of heart failure by 17%. In the US, this corresponds to 113,000 additional cases of heart failure for every unit increase in BMI at the population level. Although additional studies are needed to confirm and extend these findings, these results suggest that global efforts to reduce the burden of obesity will likely also reduce the occurrence of CVD and metabolic disorders.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001474.
The American Heart Association provides information on all aspects of cardiovascular disease and tips on keeping the heart healthy, including weight management (in several languages); its website includes personal stories about stroke and heart attacks
The US Centers for Disease Control and Prevention has information on heart disease, stroke, and all aspects of overweight and obesity (in English and Spanish)
The UK National Health Service Choices website provides information about cardiovascular disease and obesity, including a personal story about losing weight
The World Health Organization provides information on obesity (in several languages)
The International Obesity Taskforce provides information about the global obesity epidemic
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
MedlinePlus provides links to other sources of information on heart disease, on vascular disease, on obesity, and on metabolic disorders (in English and Spanish)
The International Association for the Study of Obesity provides maps and information about obesity worldwide
The International Diabetes Federation has a web page that describes types, complications, and risk factors of diabetes
doi:10.1371/journal.pmed.1001474
PMCID: PMC3692470  PMID: 23824655

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