@article {1345, title = {A phenomics-based strategy identifies loci on APOC1, BRAP, and PLCG1 associated with metabolic syndrome phenotype domains.}, journal = {PLoS Genet}, volume = {7}, year = {2011}, month = {2011 Oct}, pages = {e1002322}, abstract = {

Despite evidence of the clustering of metabolic syndrome components, current approaches for identifying unifying genetic mechanisms typically evaluate clinical categories that do not provide adequate etiological information. Here, we used data from 19,486 European American and 6,287 African American Candidate Gene Association Resource Consortium participants to identify loci associated with the clustering of metabolic phenotypes. Six phenotype domains (atherogenic dyslipidemia, vascular dysfunction, vascular inflammation, pro-thrombotic state, central obesity, and elevated plasma glucose) encompassing 19 quantitative traits were examined. Principal components analysis was used to reduce the dimension of each domain such that >55\% of the trait variance was represented within each domain. We then applied a statistically efficient and computational feasible multivariate approach that related eight principal components from the six domains to 250,000 imputed SNPs using an additive genetic model and including demographic covariates. In European Americans, we identified 606 genome-wide significant SNPs representing 19 loci. Many of these loci were associated with only one trait domain, were consistent with results in African Americans, and overlapped with published findings, for instance central obesity and FTO. However, our approach, which is applicable to any set of interval scale traits that is heritable and exhibits evidence of phenotypic clustering, identified three new loci in or near APOC1, BRAP, and PLCG1, which were associated with multiple phenotype domains. These pleiotropic loci may help characterize metabolic dysregulation and identify targets for intervention.

}, keywords = {African Americans, Apolipoprotein C-I, Blood Glucose, Dyslipidemias, European Continental Ancestry Group, Genetic Association Studies, Genetic Predisposition to Disease, Genome, Human, Humans, Metabolic Syndrome, Obesity, Abdominal, Phenotype, Phospholipase C gamma, Polymorphism, Single Nucleotide, Quantitative Trait, Heritable, Ubiquitin-Protein Ligases, Vascular Diseases}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1002322}, author = {Avery, Christy L and He, Qianchuan and North, Kari E and Ambite, Jos{\'e} L and Boerwinkle, Eric and Fornage, Myriam and Hindorff, Lucia A and Kooperberg, Charles and Meigs, James B and Pankow, James S and Pendergrass, Sarah A and Psaty, Bruce M and Ritchie, Marylyn D and Rotter, Jerome I and Taylor, Kent D and Wilkens, Lynne R and Heiss, Gerardo and Lin, Dan Yu} } @article {6083, title = {Fine-mapping and initial characterization of QT interval loci in African Americans.}, journal = {PLoS Genet}, volume = {8}, year = {2012}, month = {2012}, pages = {e1002870}, abstract = {

The QT interval (QT) is heritable and its prolongation is a risk factor for ventricular tachyarrhythmias and sudden death. Most genetic studies of QT have examined European ancestral populations; however, the increased genetic diversity in African Americans provides opportunities to narrow association signals and identify population-specific variants. We therefore evaluated 6,670 SNPs spanning eleven previously identified QT loci in 8,644 African American participants from two Population Architecture using Genomics and Epidemiology (PAGE) studies: the Atherosclerosis Risk in Communities study and Women{\textquoteright}s Health Initiative Clinical Trial. Of the fifteen known independent QT variants at the eleven previously identified loci, six were significantly associated with QT in African American populations (P<=1.20{\texttimes}10(-4)): ATP1B1, PLN1, KCNQ1, NDRG4, and two NOS1AP independent signals. We also identified three population-specific signals significantly associated with QT in African Americans (P<=1.37{\texttimes}10(-5)): one at NOS1AP and two at ATP1B1. Linkage disequilibrium (LD) patterns in African Americans assisted in narrowing the region likely to contain the functional variants for several loci. For example, African American LD patterns showed that 0 SNPs were in LD with NOS1AP signal rs12143842, compared with European LD patterns that indicated 87 SNPs, which spanned 114.2 Kb, were in LD with rs12143842. Finally, bioinformatic-based characterization of the nine African American signals pointed to functional candidates located exclusively within non-coding regions, including predicted binding sites for transcription factors such as TBX5, which has been implicated in cardiac structure and conductance. In this detailed evaluation of QT loci, we identified several African Americans SNPs that better define the association with QT and successfully narrowed intervals surrounding established loci. These results demonstrate that the same loci influence variation in QT across multiple populations, that novel signals exist in African Americans, and that the SNPs identified as strong candidates for functional evaluation implicate gene regulatory dysfunction in QT prolongation.

}, keywords = {African Americans, Aged, Computational Biology, Electrocardiography, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Male, Metagenomics, Middle Aged, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Quantitative Trait, Heritable, Risk Factors, Tachycardia, United States}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1002870}, author = {Avery, Christy L and Sethupathy, Praveen and Buyske, Steven and He, Qianchuan and Lin, Dan-Yu and Arking, Dan E and Carty, Cara L and Duggan, David and Fesinmeyer, Megan D and Hindorff, Lucia A and Jeff, Janina M and Klein, Liviu and Patton, Kristen K and Peters, Ulrike and Shohet, Ralph V and Sotoodehnia, Nona and Young, Alicia M and Kooperberg, Charles and Haiman, Christopher A and Mohlke, Karen L and Whitsel, Eric A and North, Kari E} }