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1.  MicroRNAs in cardiovascular disease: an introduction for clinicians 
Heart  2015;101(12):921-928.
MicroRNAs (miRNAs) are small, non-coding, RNA molecules approximately 22 nucleotides in length which act as post-transcriptional regulators of gene expression. Individual miRNAs have been shown to regulate the expression of multiple genes. Conversely, the expression of individual genes can be regulated by multiple miRNAs. Consequently, since their discovery just over 20 years ago, miRNAs have been identified as key regulators of complex biological processes linked to multiple cardiovascular pathologies, including left ventricular hypertrophy, ischaemic heart disease, heart failure, hypertension and arrhythmias. Furthermore, since the finding that miRNAs are present in the circulation, they have been investigated as novel biomarkers, especially in the context of acute myocardial infarction (AMI) and heart failure. While there is little convincing evidence that miRNAs can outperform traditional biomarkers, such as cardiac troponins, in the diagnosis of AMI, there is potential for miRNAs to complement existing risk prediction models and act as valuable markers of post-AMI prognosis. Encouragingly, the concept of miRNA-based therapeutics is developing, with synthetic antagonists of miRNAs (antagomiRs) currently in phase II trials for the treatment of chronic hepatitis C virus infection. In the cardiovascular field, promising preclinical studies suggest that they could be useful in treating disorders ranging from heart failure to dyslipidaemia, although several challenges related to specificity and targeted delivery remain to be overcome. Through this review, we provide clinicians with a brief overview of the ever-expanding world of miRNAs.
doi:10.1136/heartjnl-2013-305402
PMCID: PMC4484262  PMID: 25814653
2.  Variants near TERC are associated with mean telomere length. 
Nature genetics  2010;42(3):197-199.
We conducted genome-wide association analyses of mean leukocyte telomere length in 2,917 subjects and follow-up replication analyses in 9,492 and identified a locus on 3q26 encompassing the telomerase RNA component TERC, with compelling evidence for association (rs12696304, combined P value 3.72×10−14). Each copy of the minor allele of rs12696304 was associated with ≈75 base pairs shorter mean telomere length equivalent to ≈3.6 years of age-related attrition of mean telomere length.
doi:10.1038/ng.532
PMCID: PMC3773906  PMID: 20139977
3.  GENETIC ARCHITECTURE OF AMBULATORY BLOOD PRESSURE IN THE GENERAL POPULATION – INSIGHTS FROM CARDIOVASCULAR GENE-CENTRIC ARRAY 
Hypertension  2010;56(6):1069-1076.
Genetic determinants of blood pressure are poorly defined. We undertook a large-scale gene-centric analysis to identify loci and pathways associated with ambulatory systolic and diastolic blood pressure.
We measured 24-hour ambulatory BP in 2020 individuals from 520 white European nuclear families (the GRAPHIC Study) and genotyped their DNA using the Illumina HumanCVD BeadChip array which contains approximately 50000 single nucleotide polymorphisms in >2000 cardiovascular candidate loci. We found a strong association between rs13306560 polymorphism in the promoter region of MTHFR and CLCN6 and mean 24-hour diastolic blood pressure - each minor allele copy of rs13306560 was associated with 2.6 mmHg lower mean 24-hour diastolic blood pressure (P=1.2×10−8). rs13306560 was also associated with clinic diastolic blood pressure in a combined analysis of 8129 subjects from the GRAPHIC Study, the CoLaus Study and the Silesian Cardiovascular Study (P=5.4×10−6). Additional analysis of associations between variants in Gene Ontology-defined pathways and mean 24-hour blood pressure in the GRAPHIC Study showed that cell survival control signalling cascades could play a role in blood pressure regulation. There was also a significant over-representation of rare variants (minor allele frequency <0.05) amongst polymorphisms showing at least nominal association with mean 24-hour blood pressure indicating that a considerable proportion of its heritability may be explained by uncommon alleles.
Through a large scale gene-centric analysis of ambulatory blood pressure, we identified an association of a novel variant at the MTHFR/CLNC6 locus with diastolic blood pressure and provided new insights into the genetic architecture of blood pressure.
doi:10.1161/HYPERTENSIONAHA.110.155721
PMCID: PMC3035934  PMID: 21060006
gene; genetics; blood pressure; single nucleotide polymorphism; association; heritability
4.  Design of the Coronary ARtery DIsease Genome-Wide Replication And Meta-Analysis (CARDIoGRAM) Study 
Background
Recent genome-wide association studies (GWAS) of myocardial infarction (MI) and other forms of coronary artery disease (CAD) have led to the discovery of at least 13 genetic loci. In addition to the effect size, power to detect associations is largely driven by sample size. Therefore, to maximize the chance of finding novel susceptibility loci for CAD and MI, the Coronary ARtery DIsease Genome-wide Replication And Meta-analysis (CARDIoGRAM) consortium was formed.
Methods and Results
CARDIoGRAM combines data from all published and several unpublished GWAS in individuals with European ancestry; includes >22 000 cases with CAD, MI, or both and >60 000 controls; and unifies samples from the Atherosclerotic Disease VAscular functioN and genetiC Epidemiology study, CADomics, Cohorts for Heart and Aging Research in Genomic Epidemiology, deCODE, the German Myocardial Infarction Family Studies I, II, and III, Ludwigshafen Risk and Cardiovascular Heath Study/AtheroRemo, MedStar, Myocardial Infarction Genetics Consortium, Ottawa Heart Genomics Study, PennCath, and the Wellcome Trust Case Control Consortium. Genotyping was carried out on Affymetrix or Illumina platforms followed by imputation of genotypes in most studies. On average, 2.2 million single nucleotide polymorphisms were generated per study. The results from each study are combined using meta-analysis. As proof of principle, we meta-analyzed risk variants at 9p21 and found that rs1333049 confers a 29% increase in risk for MI per copy (P=2×10−20).
Conclusion
CARDIoGRAM is poised to contribute to our understanding of the role of common genetic variation on risk for CAD and MI.
doi:10.1161/CIRCGENETICS.109.899443
PMCID: PMC3070269  PMID: 20923989
coronary artery disease; myocardial infarction; meta-analysis; genetics
5.  TELOMERE LENGTH VARIANTS ARE ASSOCIATED WITH HIGH-GRADE GLIOMA RISK: IDENTIFICATION OF A NOVEL GLIOMA RISK LOCUS BY GENOME-WIDE ASSOCIATION STUDY 
Neuro-Oncology  2014;16(Suppl 3):iii2.
BACKGROUND: Glioblastoma, the most common and aggressive form of glioma, has a median survival time of just 15 months. Both inherited and acquired genetic variation influence gliomagenesis. Previous genome-wide association studies (GWAS) have discovered seven glioma risk loci, including two in genes involved in telomere structure and function (TERT and RTEL1). METHODS: To identify novel high-grade glioma risk loci, we performed SNP imputation and meta-analysis of genome-wide array data from The University of California, San Francisco Adult Glioma Study (AGS), The Cancer Genome Atlas (TCGA) and the Wellcome Trust Case-Control Consortium (WTCCC) (1,013 cases and 6,595 controls). SNPs with P < 1.0x10-6 in the discovery meta-analysis underwent attempted replication in an additional 631 glioblastoma cases and 1141 controls from The Mayo Clinic and UCSF. To investigate potential functional mechanisms through which SNPs might promote gliomagenesis, we examined the relationship between mean leukocyte telomere length (LTL) and glioma risk loci using data from a recent GWAS of LTL (N = 37,684). RESULTS: One novel SNP association from the discovery phase meta-analysis met criteria for attempted replication. This SNP was significantly associated with high-grade glioma risk in the replication dataset (P = 3.4x10-3). The combined P-value for all 1644 cases and 7736 controls achieved genome-wide statistical significance (8.3x10-9). Glioma risk alleles in both our newly identified risk region and the known TERT risk locus were strongly associated with longer LTL (P < 5.0x10-8). In contrast, glioma risk alleles near RTEL1 were inconsistently associated with LTL and suggested the presence of distinct causal alleles underlying these two phenotypes. No other established glioma risk loci were associated with LTL. CONCLUSIONS: We identify a novel genome-wide significant association between a constitutive SNP and glioma risk. Because telomere maintenance is a universal requirement of oncogenic progression and telomere length displays substantial interindividual variability, telomere length is a promising epidemiologic risk factor for human cancers. We demonstrate that alleles in our novel locus and in TERT are associated with both longer mean LTL and with increased glioma risk. These results strongly implicate inherited variation near these two genes in facilitating gliomagenesis through a mechanism involving lengthened telomeres. SECONDARY CATEGORY: n/a.
doi:10.1093/neuonc/nou206.4
PMCID: PMC4144506
6.  Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation 
Horikoshi, Momoko | Mӓgi, Reedik | van de Bunt, Martijn | Surakka, Ida | Sarin, Antti-Pekka | Mahajan, Anubha | Marullo, Letizia | Thorleifsson, Gudmar | Hӓgg, Sara | Hottenga, Jouke-Jan | Ladenvall, Claes | Ried, Janina S. | Winkler, Thomas W. | Willems, Sara M. | Pervjakova, Natalia | Esko, Tõnu | Beekman, Marian | Nelson, Christopher P. | Willenborg, Christina | Wiltshire, Steven | Ferreira, Teresa | Fernandez, Juan | Gaulton, Kyle J. | Steinthorsdottir, Valgerdur | Hamsten, Anders | Magnusson, Patrik K. E. | Willemsen, Gonneke | Milaneschi, Yuri | Robertson, Neil R. | Groves, Christopher J. | Bennett, Amanda J. | Lehtimӓki, Terho | Viikari, Jorma S. | Rung, Johan | Lyssenko, Valeriya | Perola, Markus | Heid, Iris M. | Herder, Christian | Grallert, Harald | Müller-Nurasyid, Martina | Roden, Michael | Hypponen, Elina | Isaacs, Aaron | van Leeuwen, Elisabeth M. | Karssen, Lennart C. | Mihailov, Evelin | Houwing-Duistermaat, Jeanine J. | de Craen, Anton J. M. | Deelen, Joris | Havulinna, Aki S. | Blades, Matthew | Hengstenberg, Christian | Erdmann, Jeanette | Schunkert, Heribert | Kaprio, Jaakko | Tobin, Martin D. | Samani, Nilesh J. | Lind, Lars | Salomaa, Veikko | Lindgren, Cecilia M. | Slagboom, P. Eline | Metspalu, Andres | van Duijn, Cornelia M. | Eriksson, Johan G. | Peters, Annette | Gieger, Christian | Jula, Antti | Groop, Leif | Raitakari, Olli T. | Power, Chris | Penninx, Brenda W. J. H. | de Geus, Eco | Smit, Johannes H. | Boomsma, Dorret I. | Pedersen, Nancy L. | Ingelsson, Erik | Thorsteinsdottir, Unnur | Stefansson, Kari | Ripatti, Samuli | Prokopenko, Inga | McCarthy, Mark I. | Morris, Andrew P.
PLoS Genetics  2015;11(7):e1005230.
Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency ≥0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated.
Author Summary
Human genetic studies have demonstrated that quantitative human anthropometric and metabolic traits, including body mass index, waist-hip ratio, and plasma concentrations of glucose and insulin, are highly heritable, and are established risk factors for type 2 diabetes and cardiovascular diseases. Although many regions of the genome have been associated with these traits, the specific genes responsible have not yet been identified. By making use of advanced statistical “imputation” techniques applied to more than 87,000 individuals of European ancestry, and publicly available “reference panels” of more than 37 million genetic variants, we have been able to identify novel regions of the genome associated with these glycaemic and obesity-related traits and localise genes within these regions that are most likely to be causal. This improved understanding of the biological mechanisms underlying glycaemic and obesity-related traits is extremely important because it may advance drug development for downstream disease endpoints, ultimately leading to public health benefits.
doi:10.1371/journal.pgen.1005230
PMCID: PMC4488845  PMID: 26132169
7.  A Genome-Wide Association Study Identifies Variants in Casein Kinase II (CSNK2A2) to be Associated with Leukocyte Telomere Length in a Punjabi Sikh Diabetic Cohort 
Background
Telomere length is a heritable trait and short telomere length has been associated with multiple chronic diseases. We investigated the relationship of relative leukocyte telomere length (RTL) with cardiometabolic risk and performed the first GWAS and meta-analysis to identify variants influencing RTL in a population of Sikhs from South Asia.
Methods and Results
Our results revealed a significant independent association of shorter RTL with type 2 diabetes (T2D) and heart disease. Our discovery GWAS (n=1,616) was followed by Stage 1 replication of 25 top signals (P<10−6) in an additional Sikhs (n=2,397). On combined discovery and Stage 1 meta-analysis (n= 4013), we identified a novel RTL locus at chromosome 16q21 represented by an intronic variant (rs74019828) in the CSNK2A2 gene (β −0.38, P=4.5×10−8). We further tested 3 top variants by genotyping in UKCVD (Caucasians n=2,952) for Stage 2. Next we performed in silico replication of 139 top signals (p<10−5) in UKTWIN, NHS, PLCO and MDACC (n=10,033) and joint meta-analysis (n=16,998). The observed signal in CSNK2A2 was confined to South Asians and could not be replicated in Caucasians due to significant difference in allele frequencies (P<0.001). CSNK2A2 phosphorylates TRF1 and plays an important role for regulation of telomere length homoeostasis.
Conclusions
By identification of a novel signal in telomere pathway genes, our study provides new molecular insight into the underlying mechanism that may regulate telomere length and its association with human aging and cardiometabolic pathophysiology.
doi:10.1161/CIRCGENETICS.113.000412
PMCID: PMC4106467  PMID: 24795349
telomere genetics; type 2 diabetes mellitus; Genome Wide Association Study; cardiovascular disease
8.  Gene-centric meta-analyses for central adiposity traits in up to 57 412 individuals of European descent confirm known loci and reveal several novel associations 
Yoneyama, Sachiko | Guo, Yiran | Lanktree, Matthew B. | Barnes, Michael R. | Elbers, Clara C. | Karczewski, Konrad J | Padmanabhan, Sandosh | Bauer, Florianne | Baumert, Jens | Beitelshees, Amber | Berenson, Gerald S. | Boer, Jolanda M.A. | Burke, Gregory | Cade, Brian | Chen, Wei | Cooper-Dehoff, Rhonda M. | Gaunt, Tom R. | Gieger, Christian | Gong, Yan | Gorski, Mathias | Heard-Costa, Nancy | Johnson, Toby | Lamonte, Michael J. | Mcdonough, Caitrin | Monda, Keri L. | Onland-Moret, N. Charlotte | Nelson, Christopher P. | O'Connell, Jeffrey R. | Ordovas, Jose | Peter, Inga | Peters, Annette | Shaffer, Jonathan | Shen, Haiqinq | Smith, Erin | Speilotes, Liz | Thomas, Fridtjof | Thorand, Barbara | Monique Verschuren, W. M. | Anand, Sonia S. | Dominiczak, Anna | Davidson, Karina W. | Hegele, Robert A. | Heid, Iris | Hofker, Marten H. | Huggins, Gordon S. | Illig, Thomas | Johnson, Julie A. | Kirkland, Susan | König, Wolfgang | Langaee, Taimour Y. | Mccaffery, Jeanne | Melander, Olle | Mitchell, Braxton D. | Munroe, Patricia | Murray, Sarah S. | Papanicolaou, George | Redline, Susan | Reilly, Muredach | Samani, Nilesh J. | Schork, Nicholas J. | Van Der Schouw, Yvonne T. | Shimbo, Daichi | Shuldiner, Alan R. | Tobin, Martin D. | Wijmenga, Cisca | Yusuf, Salim | Hakonarson, Hakon | Lange, Leslie A. | Demerath, Ellen W | Fox, Caroline S. | North, Kari E | Reiner, Alex P. | Keating, Brendan | Taylor, Kira C.
Human Molecular Genetics  2013;23(9):2498-2510.
Waist circumference (WC) and waist-to-hip ratio (WHR) are surrogate measures of central adiposity that are associated with adverse cardiovascular events, type 2 diabetes and cancer independent of body mass index (BMI). WC and WHR are highly heritable with multiple susceptibility loci identified to date. We assessed the association between SNPs and BMI-adjusted WC and WHR and unadjusted WC in up to 57 412 individuals of European descent from 22 cohorts collaborating with the NHLBI's Candidate Gene Association Resource (CARe) project. The study population consisted of women and men aged 20–80 years. Study participants were genotyped using the ITMAT/Broad/CARE array, which includes ∼50 000 cosmopolitan tagged SNPs across ∼2100 cardiovascular-related genes. Each trait was modeled as a function of age, study site and principal components to control for population stratification, and we conducted a fixed-effects meta-analysis. No new loci for WC were observed. For WHR analyses, three novel loci were significantly associated (P < 2.4 × 10−6). Previously unreported rs2811337-G near TMCC1 was associated with increased WHR (β ± SE, 0.048 ± 0.008, P = 7.7 × 10−9) as was rs7302703-G in HOXC10 (β = 0.044 ± 0.008, P = 2.9 × 10−7) and rs936108-C in PEMT (β = 0.035 ± 0.007, P = 1.9 × 10−6). Sex-stratified analyses revealed two additional novel signals among females only, rs12076073-A in SHC1 (β = 0.10 ± 0.02, P = 1.9 × 10−6) and rs1037575-A in ATBDB4 (β = 0.046 ± 0.01, P = 2.2 × 10−6), supporting an already established sexual dimorphism of central adiposity-related genetic variants. Functional analysis using ENCODE and eQTL databases revealed that several of these loci are in regulatory regions or regions with differential expression in adipose tissue.
doi:10.1093/hmg/ddt626
PMCID: PMC3988452  PMID: 24345515
9.  A Novel Genetic Approach to Investigate the Role of Plasma Secretory Phospholipase A2 (sPLA2)-V Isoenzyme in Coronary Heart Disease: A Modified Mendelian Randomization Analysis Using PLA2G5 Expression Levels 
Background
Secretory phospholipase A2 (sPLA2) enzymes are considered to play a role in atherosclerosis. sPLA2 activity encompasses several sPLA2 isoenzymes, including sPLA2-V. While observational studies show strong association between elevated sPLA2 activity and CHD, no assay to measure sPLA2-V levels exists and the only evidence linking the sPLA2-V isoform to atherosclerosis progression comes from animal studies. In the absence of an assay that directly quantifies sPLA2-V levels, we used PLA2G5 mRNA levels in a novel, modified Mendelian randomization approach to investigate the hypothesized causal role of sPLA2-V in coronary heart disease (CHD) pathogenesis.
Methods and Results
Using data from the Advanced Study of Aortic Pathology, we identified the single nucleotide polymorphism (SNP) in PLA2G5 showing strongest association with PLA2G5 mRNA expression levels, as a proxy for sPLA2-V levels. We tested the association of this SNP with sPLA2 activity and CHD events in four prospective and 14 case-control studies with 27,230 events and 70,500 controls. rs525380C>A showed the strongest association with PLA2G5 mRNA expression (P=5.1×10−6). There was no association of rs525380C>A with plasma sPLA2 activity (difference in geometric mean of sPLA2 activity per rs525380 A-allele 0.4% (95%CI: −0.9%, 1.6%), P=0.56). In meta-analyses, the odds ratio for CHD per A allele was 1.02 (95% CI: 0.99, 1.04; P=0.20).
Conclusions
This novel approach for SNP selection for this modified Mendelian randomization analysis showed no association between rs525380 (the lead SNP for PLA2G5 expression, a surrogate for sPLA2-V levels) and CHD events. The evidence does not support a causal role for sPLA2-V in CHD.
doi:10.1161/CIRCGENETICS.113.000271
PMCID: PMC4212409  PMID: 24563418
Mendelian randomization; cardiovascular disease risk factors; DNA polymorphisms; GATA2; sPLA2-V; PLA2G5
10.  DCAF4, a novel gene associated with leucocyte telomere length 
Journal of Medical Genetics  2015;52(3):157-162.
Background
Leucocyte telomere length (LTL), which is fashioned by multiple genes, has been linked to a host of human diseases, including sporadic melanoma. A number of genes associated with LTL have already been identified through genome-wide association studies. The main aim of this study was to establish whether DCAF4 (DDB1 and CUL4-associated factor 4) is associated with LTL. In addition, using ingenuity pathway analysis (IPA), we examined whether LTL-associated genes in the general population might partially explain the inherently longer LTL in patients with sporadic melanoma, the risk for which is increased with ultraviolet radiation (UVR).
Results
Genome-wide association (GWA) meta-analysis and de novo genotyping of 20 022 individuals revealed a novel association (p=6.4×10−10) between LTL and rs2535913, which lies within DCAF4. Notably, eQTL analysis showed that rs2535913 is associated with decline in DCAF4 expressions in both lymphoblastoid cells and sun-exposed skin (p=4.1×10−3 and 2×10−3, respectively). Moreover, IPA revealed that LTL-associated genes, derived from GWA meta-analysis (N=9190), are over-represented among genes engaged in melanoma pathways. Meeting increasingly stringent p value thresholds (p<0.05, <0.01, <0.005, <0.001) in the LTL-GWA meta-analysis, these genes were jointly over-represented for melanoma at p values ranging from 1.97×10−169 to 3.42×10−24.
Conclusions
We uncovered a new locus associated with LTL in the general population. We also provided preliminary findings that suggest a link of LTL through genetic mechanisms with UVR and melanoma in the general population.
doi:10.1136/jmedgenet-2014-102681
PMCID: PMC4345921  PMID: 25624462
Complex traits; Telomere; cancer: skin; melanoma
11.  Analysis of Gene-Gene Interactions among Common Variants in Candidate Cardiovascular Genes in Coronary Artery Disease 
PLoS ONE  2015;10(2):e0117684.
Objective
Only a small fraction of coronary artery disease (CAD) heritability has been explained by common variants identified to date. Interactions between genes of importance to cardiovascular regulation may account for some of the missing heritability of CAD. This study aimed to investigate the role of gene-gene interactions in common variants in candidate cardiovascular genes in CAD.
Approach and Results
2,101 patients with CAD from the British Heart Foundation Family Heart Study and 2,426 CAD-free controls were included in the discovery cohort. All subjects were genotyped with the Illumina HumanCVD BeadChip enriched for genes and pathways relevant to the cardiovascular system and disease. The primary analysis in the discovery cohort examined pairwise interactions among 913 common (minor allele frequency >0.1) independent single nucleotide polymorphisms (SNPs) with at least nominal association with CAD in single locus analysis. A secondary exploratory interaction analysis was performed among all 11,332 independent common SNPs surviving quality control criteria. Replication analyses were conducted in 2,967 patients and 3,075 controls from the Myocardial Infarction Genetics Consortium. None of the interactions amongst 913 SNPs analysed in the primary analysis was statistically significant after correction for multiple testing (required P<1.2x10-7). Similarly, none of the pairwise gene-gene interactions in the secondary analysis reached statistical significance after correction for multiple testing (required P = 7.8x10-10). None of 36 suggestive interactions from the primary analysis or 31 interactions from the secondary analysis was significant in the replication cohort. Our study had 80% power to detect odds ratios > 1.7 for common variants in the primary analysis.
Conclusions
Moderately large additive interactions between common SNPs in genes relevant to cardiovascular disease do not appear to play a major role in genetic predisposition to CAD. The role of genetic interactions amongst less common SNPs and with medium and small magnitude effects remain to be investigated.
doi:10.1371/journal.pone.0117684
PMCID: PMC4320092  PMID: 25658981
12.  Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization 
Arking, Dan E. | Pulit, Sara L. | Crotti, Lia | van der Harst, Pim | Munroe, Patricia B. | Koopmann, Tamara T. | Sotoodehnia, Nona | Rossin, Elizabeth J. | Morley, Michael | Wang, Xinchen | Johnson, Andrew D. | Lundby, Alicia | Gudbjartsson, Daníel F. | Noseworthy, Peter A. | Eijgelsheim, Mark | Bradford, Yuki | Tarasov, Kirill V. | Dörr, Marcus | Müller-Nurasyid, Martina | Lahtinen, Annukka M. | Nolte, Ilja M. | Smith, Albert Vernon | Bis, Joshua C. | Isaacs, Aaron | Newhouse, Stephen J. | Evans, Daniel S. | Post, Wendy S. | Waggott, Daryl | Lyytikäinen, Leo-Pekka | Hicks, Andrew A. | Eisele, Lewin | Ellinghaus, David | Hayward, Caroline | Navarro, Pau | Ulivi, Sheila | Tanaka, Toshiko | Tester, David J. | Chatel, Stéphanie | Gustafsson, Stefan | Kumari, Meena | Morris, Richard W. | Naluai, Åsa T. | Padmanabhan, Sandosh | Kluttig, Alexander | Strohmer, Bernhard | Panayiotou, Andrie G. | Torres, Maria | Knoflach, Michael | Hubacek, Jaroslav A. | Slowikowski, Kamil | Raychaudhuri, Soumya | Kumar, Runjun D. | Harris, Tamara B. | Launer, Lenore J. | Shuldiner, Alan R. | Alonso, Alvaro | Bader, Joel S. | Ehret, Georg | Huang, Hailiang | Kao, W.H. Linda | Strait, James B. | Macfarlane, Peter W. | Brown, Morris | Caulfield, Mark J. | Samani, Nilesh J. | Kronenberg, Florian | Willeit, Johann | Smith, J. Gustav | Greiser, Karin H. | zu Schwabedissen, Henriette Meyer | Werdan, Karl | Carella, Massimo | Zelante, Leopoldo | Heckbert, Susan R. | Psaty, Bruce M. | Rotter, Jerome I. | Kolcic, Ivana | Polašek, Ozren | Wright, Alan F. | Griffin, Maura | Daly, Mark J. | Arnar, David O. | Hólm, Hilma | Thorsteinsdottir, Unnur | Denny, Joshua C. | Roden, Dan M. | Zuvich, Rebecca L. | Emilsson, Valur | Plump, Andrew S. | Larson, Martin G. | O'Donnell, Christopher J. | Yin, Xiaoyan | Bobbo, Marco | D'Adamo, Adamo P. | Iorio, Annamaria | Sinagra, Gianfranco | Carracedo, Angel | Cummings, Steven R. | Nalls, Michael A. | Jula, Antti | Kontula, Kimmo K. | Marjamaa, Annukka | Oikarinen, Lasse | Perola, Markus | Porthan, Kimmo | Erbel, Raimund | Hoffmann, Per | Jöckel, Karl-Heinz | Kälsch, Hagen | Nöthen, Markus M. | consortium, HRGEN | den Hoed, Marcel | Loos, Ruth J.F. | Thelle, Dag S. | Gieger, Christian | Meitinger, Thomas | Perz, Siegfried | Peters, Annette | Prucha, Hanna | Sinner, Moritz F. | Waldenberger, Melanie | de Boer, Rudolf A. | Franke, Lude | van der Vleuten, Pieter A. | Beckmann, Britt Maria | Martens, Eimo | Bardai, Abdennasser | Hofman, Nynke | Wilde, Arthur A.M. | Behr, Elijah R. | Dalageorgou, Chrysoula | Giudicessi, John R. | Medeiros-Domingo, Argelia | Barc, Julien | Kyndt, Florence | Probst, Vincent | Ghidoni, Alice | Insolia, Roberto | Hamilton, Robert M. | Scherer, Stephen W. | Brandimarto, Jeffrey | Margulies, Kenneth | Moravec, Christine E. | Fabiola Del, Greco M. | Fuchsberger, Christian | O'Connell, Jeffrey R. | Lee, Wai K. | Watt, Graham C.M. | Campbell, Harry | Wild, Sarah H. | El Mokhtari, Nour E. | Frey, Norbert | Asselbergs, Folkert W. | Leach, Irene Mateo | Navis, Gerjan | van den Berg, Maarten P. | van Veldhuisen, Dirk J. | Kellis, Manolis | Krijthe, Bouwe P. | Franco, Oscar H. | Hofman, Albert | Kors, Jan A. | Uitterlinden, André G. | Witteman, Jacqueline C.M. | Kedenko, Lyudmyla | Lamina, Claudia | Oostra, Ben A. | Abecasis, Gonçalo R. | Lakatta, Edward G. | Mulas, Antonella | Orrú, Marco | Schlessinger, David | Uda, Manuela | Markus, Marcello R.P. | Völker, Uwe | Snieder, Harold | Spector, Timothy D. | Ärnlöv, Johan | Lind, Lars | Sundström, Johan | Syvänen, Ann-Christine | Kivimaki, Mika | Kähönen, Mika | Mononen, Nina | Raitakari, Olli T. | Viikari, Jorma S. | Adamkova, Vera | Kiechl, Stefan | Brion, Maria | Nicolaides, Andrew N. | Paulweber, Bernhard | Haerting, Johannes | Dominiczak, Anna F. | Nyberg, Fredrik | Whincup, Peter H. | Hingorani, Aroon | Schott, Jean-Jacques | Bezzina, Connie R. | Ingelsson, Erik | Ferrucci, Luigi | Gasparini, Paolo | Wilson, James F. | Rudan, Igor | Franke, Andre | Mühleisen, Thomas W. | Pramstaller, Peter P. | Lehtimäki, Terho J. | Paterson, Andrew D. | Parsa, Afshin | Liu, Yongmei | van Duijn, Cornelia | Siscovick, David S. | Gudnason, Vilmundur | Jamshidi, Yalda | Salomaa, Veikko | Felix, Stephan B. | Sanna, Serena | Ritchie, Marylyn D. | Stricker, Bruno H. | Stefansson, Kari | Boyer, Laurie A. | Cappola, Thomas P. | Olsen, Jesper V. | Lage, Kasper | Schwartz, Peter J. | Kääb, Stefan | Chakravarti, Aravinda | Ackerman, Michael J. | Pfeufer, Arne | de Bakker, Paul I.W. | Newton-Cheh, Christopher
Nature genetics  2014;46(8):826-836.
The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal Mendelian Long QT Syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals we identified 35 common variant QT interval loci, that collectively explain ∼8-10% of QT variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 novel QT loci in 298 unrelated LQTS probands identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode for proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies novel candidate genes for ventricular arrhythmias, LQTS,and SCD.
doi:10.1038/ng.3014
PMCID: PMC4124521  PMID: 24952745
genome-wide association study; QT interval; Long QT Syndrome; sudden cardiac death; myocardial repolarization; arrhythmias
14.  Shared genetic susceptibility to ischemic stroke and coronary artery disease – a genome-wide analysis of common variants 
Summary
Background and Purpose
Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each have a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases.
Methods
Genome-wide association data were obtained from the METASTROKE, CARDIoGRAM, and C4D consortia. We first analyzed common variants reaching a nominal threshold of significance (p<0.01) for CAD for their association with IS and vice versa. We then examined specific overlap across phenotypes for variants that reached a high threshold of significance. Finally, we conducted a joint meta-analysis on the combined phenotype of IS or CAD. Corresponding analyses were performed restricted to the 2,167 individuals with the ischemic large artery stroke (LAS) subtype.
Results
Common variants associated with CAD at p<0.01 were associated with a significant excess risk for IS and for LAS and vice versa. Among the 42 known genome-wide significant loci for CAD, three and five loci were significantly associated with IS and LAS, respectively. In the joint meta-analyses, 15 loci passed genome-wide significance (p<5×10-8) for the combined phenotype of IS or CAD and 17 loci passed genome-wide significance for LAS or CAD. Since these loci had prior evidence for genome-wide significance for CAD we specifically analyzed the respective signals for IS and LAS and found evidence for association at chr12q24/SH2B3 (pIS=1.62×10-07) and ABO (pIS =2.6×10-4) as well as at HDAC9 (pLAS=2.32×10-12), 9p21 (pLAS =3.70×10-6), RAI1-PEMT-RASD1 (pLAS =2.69×10-5), EDNRA (pLAS =7.29×10-4), and CYP17A1-CNNM2-NT5C2 (pLAS =4.9×10-4).
Conclusions
Our results demonstrate substantial overlap in the genetic risk of ischemic stroke and particularly the large artery stroke subtype with coronary artery disease.
doi:10.1161/STROKEAHA.113.002707
PMCID: PMC4112102  PMID: 24262325
15.  Meta-analysis of telomere length in 19 713 subjects reveals high heritability, stronger maternal inheritance and a paternal age effect 
European Journal of Human Genetics  2013;21(10):1163-1168.
Telomere length (TL) has been associated with aging and mortality, but individual differences are also influenced by genetic factors, with previous studies reporting heritability estimates ranging from 34 to 82%. Here we investigate the heritability, mode of inheritance and the influence of parental age at birth on TL in six large, independent cohort studies with a total of 19 713 participants. The meta-analysis estimate of TL heritability was 0.70 (95% CI 0.64–0.76) and is based on a pattern of results that is highly similar for twins and other family members. We observed a stronger mother–offspring (r=0.42; P-value=3.60 × 10−61) than father–offspring correlation (r=0.33; P-value=7.01 × 10−5), and a significant positive association with paternal age at offspring birth (β=0.005; P-value=7.01 × 10−5). Interestingly, a significant and quite substantial correlation in TL between spouses (r=0.25; P-value=2.82 × 10−30) was seen, which appeared stronger in older spouse pairs (mean age ≥55 years; r=0.31; P-value=4.27 × 10−23) than in younger pairs (mean age<55 years; r=0.20; P-value=3.24 × 10−10). In summary, we find a high and very consistent heritability estimate for TL, evidence for a maternal inheritance component and a positive association with paternal age.
doi:10.1038/ejhg.2012.303
PMCID: PMC3778341  PMID: 23321625
telomere length; heritability; paternal age effect
16.  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
17.  Loci influencing blood pressure identified using a cardiovascular gene-centric array 
Ganesh, Santhi K. | Tragante, Vinicius | Guo, Wei | Guo, Yiran | Lanktree, Matthew B. | Smith, Erin N. | Johnson, Toby | Castillo, Berta Almoguera | Barnard, John | Baumert, Jens | Chang, Yen-Pei Christy | Elbers, Clara C. | Farrall, Martin | Fischer, Mary E. | Franceschini, Nora | Gaunt, Tom R. | Gho, Johannes M.I.H. | Gieger, Christian | Gong, Yan | Isaacs, Aaron | Kleber, Marcus E. | Leach, Irene Mateo | McDonough, Caitrin W. | Meijs, Matthijs F.L. | Mellander, Olle | Molony, Cliona M. | Nolte, Ilja M. | Padmanabhan, Sandosh | Price, Tom S. | Rajagopalan, Ramakrishnan | Shaffer, Jonathan | Shah, Sonia | Shen, Haiqing | Soranzo, Nicole | van der Most, Peter J. | Van Iperen, Erik P.A. | Van Setten, Jessica | Vonk, Judith M. | Zhang, Li | Beitelshees, Amber L. | Berenson, Gerald S. | Bhatt, Deepak L. | Boer, Jolanda M.A. | Boerwinkle, Eric | Burkley, Ben | Burt, Amber | Chakravarti, Aravinda | Chen, Wei | Cooper-DeHoff, Rhonda M. | Curtis, Sean P. | Dreisbach, Albert | Duggan, David | Ehret, Georg B. | Fabsitz, Richard R. | Fornage, Myriam | Fox, Ervin | Furlong, Clement E. | Gansevoort, Ron T. | Hofker, Marten H. | Hovingh, G. Kees | Kirkland, Susan A. | Kottke-Marchant, Kandice | Kutlar, Abdullah | LaCroix, Andrea Z. | Langaee, Taimour Y. | Li, Yun R. | Lin, Honghuang | Liu, Kiang | Maiwald, Steffi | Malik, Rainer | Murugesan, Gurunathan | Newton-Cheh, Christopher | O'Connell, Jeffery R. | Onland-Moret, N. Charlotte | Ouwehand, Willem H. | Palmas, Walter | Penninx, Brenda W. | Pepine, Carl J. | Pettinger, Mary | Polak, Joseph F. | Ramachandran, Vasan S. | Ranchalis, Jane | Redline, Susan | Ridker, Paul M. | Rose, Lynda M. | Scharnag, Hubert | Schork, Nicholas J. | Shimbo, Daichi | Shuldiner, Alan R. | Srinivasan, Sathanur R. | Stolk, Ronald P. | Taylor, Herman A. | Thorand, Barbara | Trip, Mieke D. | van Duijn, Cornelia M. | Verschuren, W. Monique | Wijmenga, Cisca | Winkelmann, Bernhard R. | Wyatt, Sharon | Young, J. Hunter | Boehm, Bernhard O. | Caulfield, Mark J. | Chasman, Daniel I. | Davidson, Karina W. | Doevendans, Pieter A. | FitzGerald, Garret A. | Gums, John G. | Hakonarson, Hakon | Hillege, Hans L. | Illig, Thomas | Jarvik, Gail P. | Johnson, Julie A. | Kastelein, John J.P. | Koenig, Wolfgang | März, Winfried | Mitchell, Braxton D. | Murray, Sarah S. | Oldehinkel, Albertine J. | Rader, Daniel J. | Reilly, Muredach P. | Reiner, Alex P. | Schadt, Eric E. | Silverstein, Roy L. | Snieder, Harold | Stanton, Alice V. | Uitterlinden, André G. | van der Harst, Pim | van der Schouw, Yvonne T. | Samani, Nilesh J. | Johnson, Andrew D. | Munroe, Patricia B. | de Bakker, Paul I.W. | Zhu, Xiaofeng | Levy, Daniel | Keating, Brendan J. | Asselbergs, Folkert W.
Human Molecular Genetics  2013;22(16):3394-3395.
doi:10.1093/hmg/ddt177
PMCID: PMC3888295
18.  Integrative Genomics Reveals Novel Molecular Pathways and Gene Networks for Coronary Artery Disease 
PLoS Genetics  2014;10(7):e1004502.
The majority of the heritability of coronary artery disease (CAD) remains unexplained, despite recent successes of genome-wide association studies (GWAS) in identifying novel susceptibility loci. Integrating functional genomic data from a variety of sources with a large-scale meta-analysis of CAD GWAS may facilitate the identification of novel biological processes and genes involved in CAD, as well as clarify the causal relationships of established processes. Towards this end, we integrated 14 GWAS from the CARDIoGRAM Consortium and two additional GWAS from the Ottawa Heart Institute (25,491 cases and 66,819 controls) with 1) genetics of gene expression studies of CAD-relevant tissues in humans, 2) metabolic and signaling pathways from public databases, and 3) data-driven, tissue-specific gene networks from a multitude of human and mouse experiments. We not only detected CAD-associated gene networks of lipid metabolism, coagulation, immunity, and additional networks with no clear functional annotation, but also revealed key driver genes for each CAD network based on the topology of the gene regulatory networks. In particular, we found a gene network involved in antigen processing to be strongly associated with CAD. The key driver genes of this network included glyoxalase I (GLO1) and peptidylprolyl isomerase I (PPIL1), which we verified as regulatory by siRNA experiments in human aortic endothelial cells. Our results suggest genetic influences on a diverse set of both known and novel biological processes that contribute to CAD risk. The key driver genes for these networks highlight potential novel targets for further mechanistic studies and therapeutic interventions.
Author Summary
Sudden death due to heart attack ranks among the top causes of death in the world, and family studies have shown that genetics has a substantial effect on heart disease risk. Recent studies suggest that multiple genetic factors each with modest effects are necessary for the development of CAD, but the genes and molecular processes involved remain poorly understood. We conducted an integrative genomics study where we used the information of gene-gene interactions to capture groups of genes that are most likely to increase heart disease risk. We not only confirmed the importance of several known CAD risk processes such as the metabolism and transport of cholesterol, immune response, and blood coagulation, but also revealed many novel processes such as neuroprotection, cell cycle, and proteolysis that were not previously implicated in CAD. In particular, we highlight several genes such as GLO1 with key regulatory roles within these processes not detected by the first wave of genetic analyses. These results highlight the value of integrating population genetic data with diverse resources that functionally annotate the human genome. Such integration facilitates the identification of novel molecular processes involved in the pathogenesis of CAD as well as potential novel targets for the development of efficacious therapeutic interventions.
doi:10.1371/journal.pgen.1004502
PMCID: PMC4102418  PMID: 25033284
19.  A sequence variant associated with sortilin-1 (SORT1) on 1p13.3 is independently associated with abdominal aortic aneurysm 
Human Molecular Genetics  2013;22(14):2941-2947.
Abdominal aortic aneurysm (AAA) is a common human disease with a high estimated heritability (0.7); however, only a small number of associated genetic loci have been reported to date. In contrast, over 100 loci have now been reproducibly associated with either blood lipid profile and/or coronary artery disease (CAD) (both risk factors for AAA) in large-scale meta-analyses. This study employed a staged design to investigate whether the loci for these two phenotypes are also associated with AAA. Validated CAD and dyslipidaemia loci underwent screening using the Otago AAA genome-wide association data set. Putative associations underwent staged secondary validation in 10 additional cohorts. A novel association between the SORT1 (1p13.3) locus and AAA was identified. The rs599839 G allele, which has been previously associated with both dyslipidaemia and CAD, reached genome-wide significance in 11 combined independent cohorts (meta-analysis with 7048 AAA cases and 75 976 controls: G allele OR 0.81, 95% CI 0.76–0.85, P = 7.2 × 10−14). Modelling for confounding interactions of concurrent dyslipidaemia, heart disease and other risk factors suggested that this marker is an independent predictor of AAA susceptibility. In conclusion, a genetic marker associated with cardiovascular risk factors, and in particular concurrent vascular disease, appeared to independently contribute to susceptibility for AAA. Given the potential genetic overlap between risk factor and disease phenotypes, the use of well-characterized case–control cohorts allowing for modelling of cardiovascular disease risk confounders will be an important component in the future discovery of genetic markers for conditions such as AAA.
doi:10.1093/hmg/ddt141
PMCID: PMC3690970  PMID: 23535823
20.  A Systems Biology Framework Identifies Molecular Underpinnings of Coronary Heart Disease 
Objective
Genetic approaches have identified numerous loci associated with coronary heart disease (CHD). The molecular mechanisms underlying CHD gene-disease associations, however, remain unclear. We hypothesized that genetic variants with both strong and subtle effects drive gene subnetworks that in turn affect CHD.
Approach and Results
We surveyed CHD-associated molecular interactions by constructing coexpression networks using whole blood gene expression profiles from 188 CHD cases and 188 age- and sex-matched controls. 24 coexpression modules were identified including one case-specific and one control-specific differential module (DM). The DMs were enriched for genes involved in B-cell activation, immune response, and ion transport. By integrating the DMs with altered gene expression associated SNPs (eSNPs) and with results of GWAS of CHD and its risk factors, the control-specific DM was implicated as CHD-causal based on its significant enrichment for both CHD and lipid eSNPs. This causal DM was further integrated with tissue-specific Bayesian networks and protein-protein interaction networks to identify regulatory key driver (KD) genes. Multi-tissue KDs (SPIB and TNFRSF13C) and tissue-specific KDs (e.g. EBF1) were identified.
Conclusions
Our network-driven integrative analysis not only identified CHD-related genes, but also defined network structure that sheds light on the molecular interactions of genes associated with CHD risk.
doi:10.1161/ATVBAHA.112.300112
PMCID: PMC3752786  PMID: 23539213
Gene expression; coronary heart disease; systems biology; coexpression network
21.  Exome sequencing and directed clinical phenotyping diagnose cholesterol ester storage disease presenting as autosomal recessive hypercholesterolemia 
Objective
Autosomal recessive hypercholesterolemia (ARH) is a rare inherited disorder characterized by extremely high total and low-density lipoprotein cholesterol levels that has been previously linked to mutations in LDLRAP1. We identified a family with ARH not explained by mutations in LDLRAP1 or other genes known to cause monogenic hypercholesterolemia. The aim of this study was to identify the molecular etiology of ARH in this family.
Approach and Results
We used exome sequencing to assess all protein coding regions of the genome in three family members and identified a homozygous exon 8 splice junction mutation (c.894G>A, also known as E8SJM) in LIPA that segregated with the diagnosis of hypercholesterolemia. Since homozygosity for mutations in LIPA is known to cause cholesterol ester storage disease (CESD), we performed directed follow-up phenotyping by non-invasively measuring hepatic cholesterol content. We observed abnormal hepatic accumulation of cholesterol in the homozygote individuals, supporting the diagnosis of CESD. Given previous suggestions of cardiovascular disease risk in heterozygous LIPA mutation carriers, we genotyped E8SJM in >27,000 individuals and found no association with plasma lipid levels or risk of myocardial infarction, confirming a true recessive mode of inheritance.
Conclusions
By integrating observations from Mendelian and population genetics along with directed clinical phenotyping, we diagnosed clinically unapparent CESD in the affected individuals from this kindred and addressed an outstanding question regarding risk of cardiovascular disease in LIPA E8SJM heterozygous carriers.
doi:10.1161/ATVBAHA.113.302426
PMCID: PMC4002172  PMID: 24072694
hypercholesterolemia; genetics; myocardial infarction
22.  Genetic predisposition to higher blood pressure increases coronary artery disease risk 
Hypertension  2013;61(5):10.1161/HYPERTENSIONAHA.111.00275.
Hypertension is a risk factor for coronary artery disease. Recent genome-wide association studies have identified 30 genetic variants associated with higher blood pressure at genome-wide significance (p<5×10−8). If elevated blood pressure is a causative factor for coronary artery disease, these variants should also increase coronary artery disease risk. Analyzing genome-wide association data from 22,233 coronary artery disease cases and 64,762 controls, we observed in the Coronary artery disease Genome-Wide Replication And Meta-Analysis (CARDIoGRAM) consortium that 88% of these blood pressure-associated polymorphisms were likewise positively associated with coronary artery disease, i.e. they had an odds ratio >1 for coronary artery disease, a proportion much higher than expected by chance (p=4.10−5). The average relative coronary artery disease risk increase per each of the multiple blood pressure-raising alleles observed in the consortium was 3.0% for systolic blood pressure-associated polymorphisms (95% confidence interval, 1.8 to 4.3%) and 2.9% for diastolic blood pressure-associated polymorphisms (95% confidence interval, 1.7 to 4.1%). In sub-studies, individuals carrying most systolic blood pressure- and diastolic blood pressure-related risk alleles (top quintile of a genetic risk score distribution) had 70% (95% confidence interval, 50-94%) and 59% (95% confidence interval, 40-81%) higher odds of having coronary artery disease, respectively, as compared to individuals in the bottom quintile. In conclusion, most blood pressure-associated polymorphisms also confer an increased risk for coronary artery disease. These findings are consistent with a causal relationship of increasing blood pressure to coronary artery disease. Genetic variants primarily affecting blood pressure contribute to the genetic basis of coronary artery disease.
doi:10.1161/HYPERTENSIONAHA.111.00275
PMCID: PMC3855241  PMID: 23478099
Blood pressure; polymorphism; genetics; coronary artery disease
23.  Identification of seven loci affecting mean telomere length and their association with disease 
Codd, Veryan | Nelson, Christopher P. | Albrecht, Eva | Mangino, Massimo | Deelen, Joris | Buxton, Jessica L. | Jan Hottenga, Jouke | Fischer, Krista | Esko, Tõnu | Surakka, Ida | Broer, Linda | Nyholt, Dale R. | Mateo Leach, Irene | Salo, Perttu | Hägg, Sara | Matthews, Mary K. | Palmen, Jutta | Norata, Giuseppe D. | O’Reilly, Paul F. | Saleheen, Danish | Amin, Najaf | Balmforth, Anthony J. | Beekman, Marian | de Boer, Rudolf A. | Böhringer, Stefan | Braund, Peter S. | Burton, Paul R. | de Craen, Anton J. M. | Denniff, Matthew | Dong, Yanbin | Douroudis, Konstantinos | Dubinina, Elena | Eriksson, Johan G. | Garlaschelli, Katia | Guo, Dehuang | Hartikainen, Anna-Liisa | Henders, Anjali K. | Houwing-Duistermaat, Jeanine J. | Kananen, Laura | Karssen, Lennart C. | Kettunen, Johannes | Klopp, Norman | Lagou, Vasiliki | van Leeuwen, Elisabeth M. | Madden, Pamela A. | Mägi, Reedik | Magnusson, Patrik K.E. | Männistö, Satu | McCarthy, Mark I. | Medland, Sarah E. | Mihailov, Evelin | Montgomery, Grant W. | Oostra, Ben A. | Palotie, Aarno | Peters, Annette | Pollard, Helen | Pouta, Anneli | Prokopenko, Inga | Ripatti, Samuli | Salomaa, Veikko | Suchiman, H. Eka D. | Valdes, Ana M. | Verweij, Niek | Viñuela, Ana | Wang, Xiaoling | Wichmann, H.-Erich | Widen, Elisabeth | Willemsen, Gonneke | Wright, Margaret J. | Xia, Kai | Xiao, Xiangjun | van Veldhuisen, Dirk J. | Catapano, Alberico L. | Tobin, Martin D. | Hall, Alistair S. | Blakemore, Alexandra I.F. | van Gilst, Wiek H. | Zhu, Haidong | Erdmann, Jeanette | Reilly, Muredach P. | Kathiresan, Sekar | Schunkert, Heribert | Talmud, Philippa J. | Pedersen, Nancy L. | Perola, Markus | Ouwehand, Willem | Kaprio, Jaakko | Martin, Nicholas G. | van Duijn, Cornelia M. | Hovatta, Iiris | Gieger, Christian | Metspalu, Andres | Boomsma, Dorret I. | Jarvelin, Marjo-Riitta | Slagboom, P. Eline | Thompson, John R. | Spector, Tim D. | van der Harst, Pim | Samani, Nilesh J.
Nature genetics  2013;45(4):422-427e2.
Inter-individual variation in mean leukocyte telomere length (LTL) is associated with cancer and several age-associated diseases. Here, in a genome-wide meta-analysis of 37,684 individuals with replication of selected variants in a further 10,739 individuals, we identified seven loci, including five novel loci, associated with mean LTL (P<5x10−8). Five of the loci contain genes (TERC, TERT, NAF1, OBFC1, RTEL1) that are known to be involved in telomere biology. Lead SNPs at two loci (TERC and TERT) associate with several cancers and other diseases, including idiopathic pulmonary fibrosis. Moreover, a genetic risk score analysis combining lead variants at all seven loci in 22,233 coronary artery disease cases and 64,762 controls showed an association of the alleles associated with shorter LTL with increased risk of CAD (21% (95% CI: 5–35%) per standard deviation in LTL, p=0.014). Our findings support a causal role of telomere length variation in some age-related diseases.
doi:10.1038/ng.2528
PMCID: PMC4006270  PMID: 23535734
24.  Loci influencing blood pressure identified using a cardiovascular gene-centric array 
Ganesh, Santhi K. | Tragante, Vinicius | Guo, Wei | Guo, Yiran | Lanktree, Matthew B. | Smith, Erin N. | Johnson, Toby | Castillo, Berta Almoguera | Barnard, John | Baumert, Jens | Chang, Yen-Pei Christy | Elbers, Clara C. | Farrall, Martin | Fischer, Mary E. | Franceschini, Nora | Gaunt, Tom R. | Gho, Johannes M.I.H. | Gieger, Christian | Gong, Yan | Isaacs, Aaron | Kleber, Marcus E. | Leach, Irene Mateo | McDonough, Caitrin W. | Meijs, Matthijs F.L. | Mellander, Olle | Molony, Cliona M. | Nolte, Ilja M. | Padmanabhan, Sandosh | Price, Tom S. | Rajagopalan, Ramakrishnan | Shaffer, Jonathan | Shah, Sonia | Shen, Haiqing | Soranzo, Nicole | van der Most, Peter J. | Van Iperen, Erik P.A. | Van Setten, Jessic A. | Vonk, Judith M. | Zhang, Li | Beitelshees, Amber L. | Berenson, Gerald S. | Bhatt, Deepak L. | Boer, Jolanda M.A. | Boerwinkle, Eric | Burkley, Ben | Burt, Amber | Chakravarti, Aravinda | Chen, Wei | Cooper-DeHoff, Rhonda M. | Curtis, Sean P. | Dreisbach, Albert | Duggan, David | Ehret, Georg B. | Fabsitz, Richard R. | Fornage, Myriam | Fox, Ervin | Furlong, Clement E. | Gansevoort, Ron T. | Hofker, Marten H. | Hovingh, G. Kees | Kirkland, Susan A. | Kottke-Marchant, Kandice | Kutlar, Abdullah | LaCroix, Andrea Z. | Langaee, Taimour Y. | Li, Yun R. | Lin, Honghuang | Liu, Kiang | Maiwald, Steffi | Malik, Rainer | Murugesan, Gurunathan | Newton-Cheh, Christopher | O'Connell, Jeffery R. | Onland-Moret, N. Charlotte | Ouwehand, Willem H. | Palmas, Walter | Penninx, Brenda W. | Pepine, Carl J. | Pettinger, Mary | Polak, Joseph F. | Ramachandran, Vasan S. | Ranchalis, Jane | Redline, Susan | Ridker, Paul M. | Rose, Lynda M. | Scharnag, Hubert | Schork, Nicholas J. | Shimbo, Daichi | Shuldiner, Alan R. | Srinivasan, Sathanur R. | Stolk, Ronald P. | Taylor, Herman A. | Thorand, Barbara | Trip, Mieke D. | van Duijn, Cornelia M. | Verschuren, W. Monique | Wijmenga, Cisca | Winkelmann, Bernhard R. | Wyatt, Sharon | Young, J. Hunter | Boehm, Bernhard O. | Caulfield, Mark J. | Chasman, Daniel I. | Davidson, Karina W. | Doevendans, Pieter A. | FitzGerald, Garret A. | Gums, John G. | Hakonarson, Hakon | Hillege, Hans L. | Illig, Thomas | Jarvik, Gail P. | Johnson, Julie A. | Kastelein, John J.P. | Koenig, Wolfgang | März, Winfried | Mitchell, Braxton D. | Murray, Sarah S. | Oldehinkel, Albertine J. | Rader, Daniel J. | Reilly, Muredach P. | Reiner, Alex P. | Schadt, Eric E. | Silverstein, Roy L. | Snieder, Harold | Stanton, Alice V. | Uitterlinden, André G. | van der Harst, Pim | van der Schouw, Yvonne T. | Samani, Nilesh J. | Johnson, Andrew D. | Munroe, Patricia B. | de Bakker, Paul I.W. | Zhu, Xiaofeng | Levy, Daniel | Keating, Brendan J. | Asselbergs, Folkert W.
Human Molecular Genetics  2013;22(8):1663-1678.
Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped ∼50 000 single-nucleotide polymorphisms (SNPs) that capture variation in ∼2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P < 2.4 × 10−6). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.
doi:10.1093/hmg/dds555
PMCID: PMC3657476  PMID: 23303523
25.  Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age 
Deelen, Joris | Beekman, Marian | Uh, Hae-Won | Broer, Linda | Ayers, Kristin L. | Tan, Qihua | Kamatani, Yoichiro | Bennet, Anna M. | Tamm, Riin | Trompet, Stella | Guðbjartsson, Daníel F. | Flachsbart, Friederike | Rose, Giuseppina | Viktorin, Alexander | Fischer, Krista | Nygaard, Marianne | Cordell, Heather J. | Crocco, Paolina | van den Akker, Erik B. | Böhringer, Stefan | Helmer, Quinta | Nelson, Christopher P. | Saunders, Gary I. | Alver, Maris | Andersen-Ranberg, Karen | Breen, Marie E. | van der Breggen, Ruud | Caliebe, Amke | Capri, Miriam | Cevenini, Elisa | Collerton, Joanna C. | Dato, Serena | Davies, Karen | Ford, Ian | Gampe, Jutta | Garagnani, Paolo | de Geus, Eco J.C. | Harrow, Jennifer | van Heemst, Diana | Heijmans, Bastiaan T. | Heinsen, Femke-Anouska | Hottenga, Jouke-Jan | Hofman, Albert | Jeune, Bernard | Jonsson, Palmi V. | Lathrop, Mark | Lechner, Doris | Martin-Ruiz, Carmen | Mcnerlan, Susan E. | Mihailov, Evelin | Montesanto, Alberto | Mooijaart, Simon P. | Murphy, Anne | Nohr, Ellen A. | Paternoster, Lavinia | Postmus, Iris | Rivadeneira, Fernando | Ross, Owen A. | Salvioli, Stefano | Sattar, Naveed | Schreiber, Stefan | Stefánsson, Hreinn | Stott, David J. | Tiemeier, Henning | Uitterlinden, André G. | Westendorp, Rudi G.J. | Willemsen, Gonneke | Samani, Nilesh J. | Galan, Pilar | Sørensen, Thorkild I.A. | Boomsma, Dorret I. | Jukema, J. Wouter | Rea, Irene Maeve | Passarino, Giuseppe | de Craen, Anton J.M. | Christensen, Kaare | Nebel, Almut | Stefánsson, Kári | Metspalu, Andres | Magnusson, Patrik | Blanché, Hélène | Christiansen, Lene | Kirkwood, Thomas B.L. | van Duijn, Cornelia M. | Franceschi, Claudio | Houwing-Duistermaat, Jeanine J. | Slagboom, P. Eline
Human Molecular Genetics  2014;23(16):4420-4432.
The genetic contribution to the variation in human lifespan is ∼25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality. We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (≥85 years) and 16 121 younger controls (<65 years) followed by replication in an additional set of 13 060 long-lived individuals and 61 156 controls. In addition, we performed a subset analysis in cases aged ≥90 years. We observed genome-wide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3 (OR = 1.10, P = 1.74 × 10−8). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR = 0.72, P = 3.40 × 10−36), representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis (n = 34 103), the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival (HR = 0.95, P = 0.003). This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decreased cardiovascular mortality risk, independent of blood pressure. We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure. Hence, the pleiotropic mechanisms by which this intragenic variation contributes to lifespan regulation have to be elucidated.
doi:10.1093/hmg/ddu139
PMCID: PMC4103672  PMID: 24688116

Results 1-25 (126)