TY - JOUR T1 - Best practices and joint calling of the HumanExome BeadChip: the CHARGE Consortium. JF - PLoS One Y1 - 2013 A1 - Grove, Megan L A1 - Yu, Bing A1 - Cochran, Barbara J A1 - Haritunians, Talin A1 - Bis, Joshua C A1 - Taylor, Kent D A1 - Hansen, Mark A1 - Borecki, Ingrid B A1 - Cupples, L Adrienne A1 - Fornage, Myriam A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Kathiresan, Sekar A1 - Kraaij, Robert A1 - Launer, Lenore J A1 - Levy, Daniel A1 - Liu, Yongmei A1 - Mosley, Thomas A1 - Peloso, Gina M A1 - Psaty, Bruce M A1 - Rich, Stephen S A1 - Rivadeneira, Fernando A1 - Siscovick, David S A1 - Smith, Albert V A1 - Uitterlinden, Andre A1 - van Duijn, Cornelia M A1 - Wilson, James G A1 - O'Donnell, Christopher J A1 - Rotter, Jerome I A1 - Boerwinkle, Eric KW - Aging KW - Alleles KW - Cluster Analysis KW - Cohort Studies KW - Continental Population Groups KW - Exome KW - Female KW - Gene Frequency KW - Genomics KW - Genotype KW - Heart KW - Humans KW - Male KW - Oligonucleotide Array Sequence Analysis KW - Polymorphism, Single Nucleotide KW - Sample Size KW - Self Report KW - Sequence Analysis, DNA AB -

Genotyping arrays are a cost effective approach when typing previously-identified genetic polymorphisms in large numbers of samples. One limitation of genotyping arrays with rare variants (e.g., minor allele frequency [MAF] <0.01) is the difficulty that automated clustering algorithms have to accurately detect and assign genotype calls. Combining intensity data from large numbers of samples may increase the ability to accurately call the genotypes of rare variants. Approximately 62,000 ethnically diverse samples from eleven Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium cohorts were genotyped with the Illumina HumanExome BeadChip across seven genotyping centers. The raw data files for the samples were assembled into a single project for joint calling. To assess the quality of the joint calling, concordance of genotypes in a subset of individuals having both exome chip and exome sequence data was analyzed. After exclusion of low performing SNPs on the exome chip and non-overlap of SNPs derived from sequence data, genotypes of 185,119 variants (11,356 were monomorphic) were compared in 530 individuals that had whole exome sequence data. A total of 98,113,070 pairs of genotypes were tested and 99.77% were concordant, 0.14% had missing data, and 0.09% were discordant. We report that joint calling allows the ability to accurately genotype rare variation using array technology when large sample sizes are available and best practices are followed. The cluster file from this experiment is available at www.chargeconsortium.com/main/exomechip.

VL - 8 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23874508?dopt=Abstract ER - TY - JOUR T1 - Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels. JF - Nat Commun Y1 - 2018 A1 - Tin, Adrienne A1 - Li, Yong A1 - Brody, Jennifer A A1 - Nutile, Teresa A1 - Chu, Audrey Y A1 - Huffman, Jennifer E A1 - Yang, Qiong A1 - Chen, Ming-Huei A1 - Robinson-Cohen, Cassianne A1 - Mace, Aurelien A1 - Liu, Jun A1 - Demirkan, Ayse A1 - Sorice, Rossella A1 - Sedaghat, Sanaz A1 - Swen, Melody A1 - Yu, Bing A1 - Ghasemi, Sahar A1 - Teumer, Alexanda A1 - Vollenweider, Peter A1 - Ciullo, Marina A1 - Li, Meng A1 - Uitterlinden, André G A1 - Kraaij, Robert A1 - Amin, Najaf A1 - van Rooij, Jeroen A1 - Kutalik, Zoltán A1 - Dehghan, Abbas A1 - McKnight, Barbara A1 - van Duijn, Cornelia M A1 - Morrison, Alanna A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - Fox, Caroline S A1 - Woodward, Owen M A1 - Köttgen, Anna KW - Exome KW - Genetic Predisposition to Disease KW - Glucose Transport Proteins, Facilitative KW - Humans KW - Kidney Function Tests KW - Meta-Analysis as Topic KW - Organic Anion Transporters KW - Organic Cation Transport Proteins KW - Protein Structure, Secondary KW - Uric Acid AB -

Elevated serum urate levels can cause gout, an excruciating disease with suboptimal treatment. Previous GWAS identified common variants with modest effects on serum urate. Here we report large-scale whole-exome sequencing association studies of serum urate and kidney function among ≤19,517 European ancestry and African-American individuals. We identify aggregate associations of low-frequency damaging variants in the urate transporters SLC22A12 (URAT1; p = 1.3 × 10) and SLC2A9 (p = 4.5 × 10). Gout risk in rare SLC22A12 variant carriers is halved (OR = 0.5, p = 4.9 × 10). Selected rare variants in SLC22A12 are validated in transport studies, confirming three as loss-of-function (R325W, R405C, and T467M) and illustrating the therapeutic potential of the new URAT1-blocker lesinurad. In SLC2A9, mapping of rare variants of large effects onto the predicted protein structure reveals new residues that may affect urate binding. These findings provide new insights into the genetic architecture of serum urate, and highlight molecular targets in SLC22A12 and SLC2A9 for lowering serum urate and preventing gout.

VL - 9 IS - 1 ER - TY - JOUR T1 - Whole exome sequencing of 14 389 individuals from the ESP and CHARGE consortia identifies novel rare variation associated with hemostatic factors. JF - Hum Mol Genet Y1 - 2022 A1 - Pankratz, Nathan A1 - Wei, Peng A1 - Brody, Jennifer A A1 - Chen, Ming-Huei A1 - Vries, Paul S A1 - Huffman, Jennifer E A1 - Stimson, Mary Rachel A1 - Auer, Paul L A1 - Boerwinkle, Eric A1 - Cushman, Mary A1 - Maat, Moniek P M A1 - Folsom, Aaron R A1 - Franco, Oscar H A1 - Gibbs, Richard A A1 - Haagenson, Kelly K A1 - Hofman, Albert A1 - Johnsen, Jill M A1 - Kovar, Christie L A1 - Kraaij, Robert A1 - McKnight, Barbara A1 - Metcalf, Ginger A A1 - Muzny, Donna A1 - Psaty, Bruce M A1 - Tang, Weihong A1 - Uitterlinden, André G A1 - Rooij, Jeroen G J A1 - Dehghan, Abbas A1 - O'Donnell, Christopher J A1 - Reiner, Alex P A1 - Morrison, Alanna C A1 - Smith, Nicholas L AB -

Plasma levels of fibrinogen, coagulation factors VII and VIII, and von Willebrand factor (vWF) are four intermediate phenotypes that are heritable and have been associated with the risk of clinical thrombotic events. To identify rare and low-frequency variants associated with these hemostatic factors, we conducted whole exome sequencing in 10 860 individuals of European ancestry (EA) and 3529 African Americans (AAs) from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium and the National Heart, Lung, and Blood Institute's Exome Sequencing Project (ESP). Gene-based tests demonstrated significant associations with rare variation (minor allele frequency < 5%) in FGG (with fibrinogen, p = 9.1x10-13), F7 (with factor VII, p = 1.3x10-72; seven novel variants), and VWF (with factor VIII and vWF; p = 3.2x10-14; one novel variant). These eight novel rare variant associations were independent of the known common variants at these loci and tended to have much larger effect sizes. In addition, one of the rare novel variants in F7 was significantly associated with an increased risk of venous thromboembolism in AAs (Ile200Ser; rs141219108; p = 4.2x10-5). After restricting gene-based analyses to only loss-of-function variants, a novel significant association was detected and replicated between factor VIII levels and a stop-gain mutation exclusive to African Americans (rs3211938) in CD36. This variant has previously been linked to dyslipidemia but not with levels of a hemostatic factor. These efforts represent the largest integration of whole exome sequence data from two national projects to identify genetic variation associated with plasma hemostatic factors.

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