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Whole Genome Sequencing Identifies Structural Variants Contributing To Hematologic Traits In The Nhlbi Topmed Program, Marsha M Wheeler, Adrienne M Stilp, Shuquan Rao, Bjarni V Halldórsson, Doruk Beyter, Jia Wen, Anna V Mihkaylova, Caitlin P Mchugh, John Lane, Min-Zhi Jiang, Laura M Raffield, Goo Jun, Fritz J Sedlazeck, Ginger Metcalf, Yao Yao, Joshua B Bis, Nathalie Chami, Paul S De Vries, Pinkal Desai, James S Floyd, Yan Gao, Kai Kammers, Wonji Kim, Jee-Young Moon, Aakrosh Ratan, Lisa R Yanek, Laura Almasy, Lewis C Becker, John Blangero, Michael H Cho, Joanne E Curran, Myriam Fornage, Robert C Kaplan, Joshua P Lewis, Ruth J F Loos, Braxton D Mitchell, Alanna C Morrison, Michael Preuss, Bruce M Psaty, Stephen S Rich, Jerome I Rotter, Hua Tang, Russell P Tracy, Eric Boerwinkle, Goncalo R Abecasis, Thomas W Blackwell, Albert V Smith, Andrew D Johnson, Rasika A Mathias, Deborah A Nickerson, Matthew P Conomos, Yun Li, Unnur Þorsteinsdóttir, Magnús K Magnússon, Kari Stefansson, Nathan D Pankratz, Daniel E Bauer, Paul L Auer, Alex P Reiner

Journal Articles

Genome-wide association studies have identified thousands of single nucleotide variants and small indels that contribute to variation in hematologic traits. While structural variants are known to cause rare blood or hematopoietic disorders, the genome-wide contribution of structural variants to quantitative blood cell trait variation is unknown. Here we utilized whole genome sequencing data in ancestrally diverse participants of the NHLBI Trans Omics for Precision Medicine program (N = 50,675) to detect structural variants associated with hematologic traits. Using single variant tests, we assessed the association of common and rare structural variants with red cell-, white cell-, and platelet-related quantitative traits …

Leveraging Pleiotropy To Discover And Interpret Gwas Results For Sleep-Associated Traits, Sung Chun, Sebastian Akle, Athanasios Teodosiadis, Brian E Cade, Heming Wang, Tamar Sofer, Daniel S Evans, Katie L Stone, Sina A Gharib, Sutapa Mukherjee, Lyle J Palmer, David Hillman, Jerome I Rotter, Craig L Hanis, John A Stamatoyannopoulos, Susan Redline, Chris Cotsapas, Shamil R Sunyaev

Journal Articles

Genetic association studies of many heritable traits resulting from physiological testing often have modest sample sizes due to the cost and burden of the required phenotyping. This reduces statistical power and limits discovery of multiple genetic associations. We present a strategy to leverage pleiotropy between traits to both discover new loci and to provide mechanistic hypotheses of the underlying pathophysiology. Specifically, we combine a colocalization test with a locus-level test of pleiotropy. In simulations, we show that this approach is highly selective for identifying true pleiotropy driven by the same causative variant, thereby improves the chance to replicate the associations …

A Framework For Detecting Noncoding Rare-Variant Associations Of Large-Scale Whole-Genome Sequencing Studies, Zilin Li, Xihao Li, Hufeng Zhou, Sheila M Gaynor, Margaret Sunitha Selvaraj, Theodore Arapoglou, Corbin Quick, Yaowu Liu, Han Chen, Ryan Sun, Rounak Dey, Donna K Arnett, Paul L Auer, Lawrence F Bielak, Joshua C Bis, Thomas W Blackwell, John Blangero, Eric Boerwinkle, Donald W Bowden, Jennifer A Brody, Brian E Cade, Matthew P Conomos, Adolfo Correa, L Adrienne Cupples, Joanne E Curran, Paul S De Vries, Ravindranath Duggirala, Nora Franceschini, Barry I Freedman, Harald H H Göring, Xiuqing Guo, Rita R Kalyani, Charles Kooperberg, Brian G Kral, Leslie A Lange, Bridget M Lin, Ani Manichaikul, Alisa K Manning, Lisa W Martin, Rasika A Mathias, James B Meigs, Braxton D Mitchell, May E Montasser, Alanna C Morrison, Take Naseri, Jeffrey R O'Connell, Nicholette D Palmer, Patricia A Peyser, Bruce M Psaty, Laura M Raffield, Susan Redline, Alexander P Reiner, Muagututi'a Sefuiva Reupena, Kenneth M Rice, Stephen S Rich, Jennifer A Smith, Kent D Taylor, Margaret A Taub, Ramachandran S Vasan, Daniel E Weeks, James G Wilson, Lisa R Yanek, Wei Zhao, Jerome I Rotter, Cristen J Willer, Pradeep Natarajan, Gina M Peloso, Xihong Lin

Journal Articles

Large-scale whole-genome sequencing studies have enabled analysis of noncoding rare-variant (RV) associations with complex human diseases and traits. Variant-set analysis is a powerful approach to study RV association. However, existing methods have limited ability in analyzing the noncoding genome. We propose a computationally efficient and robust noncoding RV association detection framework, STAARpipeline, to automatically annotate a whole-genome sequencing study and perform flexible noncoding RV association analysis, including gene-centric analysis and fixed window-based and dynamic window-based non-gene-centric analysis by incorporating variant functional annotations. In gene-centric analysis, STAARpipeline uses STAAR to group noncoding variants based on functional categories of genes and incorporate …

Genetic Variations Mir-10aa>T, Mir-30ca>G, Mir-181at>C, And Mir-499ba>G And The Risk Of Recurrent Pregnancy Loss In Korean Women, Hui-Jeong An, Sung-Hwan Cho, Han-Sung Park, Ji-Hyang Kim, Young-Ran Kim, Woo-Sik Lee, Jung-Ryeol Lee, Seong-Soo Joo, Eun-Hee Ahn, Nam-Keun Kim

Journal Articles

This study investigated the genetic association between recurrent pregnancy loss (RPL) and microRNA (miRNA) polymorphisms in miR-10aA>T, miR-30cA>G, miR-181aT>C, and miR-499bA>G in Korean women. Blood samples were collected from 381 RPL patients and 281 control participants, and genotyping of miR-10aA>T, miR-30cA>G, miR-181aT>C, and miR-499bA>G was carried out by TaqMan miRNA RT-Real Time polymerase chain reaction (PCR). Four polymorphisms were identified, including miR-10aA>T, miR-30cA>G, miR-181aT>C, and miR-499bA>G. MiR-10a dominant model (AA vs. AT + TT) and miR-499bGG genotypes were associated with increased RPL risk (adjusted odds ratio [AOR] = …

Comparative Risks Of Initial Aortic Events Associated With Genetic Thoracic Aortic Disease, Ellen S Regalado, Shaine A Morris, Alan C Braverman, Ellen M Hostetler, Julie De Backer, Ruosha Li, Reed E Pyeritz, Anji T Yetman, Elena Cervi, Sherene Shalhub, Richmond Jeremy, Scott Lemaire, Maral Ouzounian, Arturo Evangelista, Catherine Boileau, Guillaume Jondeau, Dianna M Milewicz

Journal Articles

BACKGROUND: Pathogenic variants in 11 genes predispose individuals to heritable thoracic aortic disease (HTAD), but limited data are available to stratify the risk for aortic events associated with these genes.

OBJECTIVES: This study sought to compare the risk of first aortic event, specifically thoracic aortic aneurysm surgery or an aortic dissection, among 7 HTAD genes and variant types within each gene.

METHODS: A retrospective cohort of probands and relatives with rare variants in 7 genes for HTAD (n = 1,028) was assessed for the risk of first aortic events based on the gene altered, pathogenic variant type, sex, proband status, …

Top-Ld: A Tool To Explore Linkage Disequilibrium With Topmed Whole-Genome Sequence Data, Le Huang, Jonathan D Rosen, Quan Sun, Jiawen Chen, Marsha M Wheeler, Ying Zhou, Yuan-I Min, Charles Kooperberg, Matthew P Conomos, Adrienne M Stilp, Stephen S Rich, Jerome I Rotter, Ani Manichaikul, Ruth J F Loos, Eimear E Kenny, Thomas W Blackwell, Albert V Smith, Goo Jun, Fritz J Sedlazeck, Ginger Metcalf, Eric Boerwinkle, Laura M Raffield, Alex P Reiner, Paul L Auer, Yun Li

Journal Articles

Current publicly available tools that allow rapid exploration of linkage disequilibrium (LD) between markers (e.g., HaploReg and LDlink) are based on whole-genome sequence (WGS) data from 2,504 individuals in the 1000 Genomes Project. Here, we present toP-LD, an online tool to explore LD inferred with high-coverage (∼30×) WGS data from 15,578 individuals in the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. toP-LD provides a significant upgrade compared to current LD tools, as the toPMed WGS data provide a more comprehensive representation of genetic variation than the 1000 Genomes data, particularly for rare variants and in the specific populations that we …

Association Study Between Mucin 4 (Muc4) Polymorphisms And Idiopathic Recurrent Pregnancy Loss In A Korean Population, Ji-Hyang Kim, Han-Sung Park, Jeong-Yong Lee, Eun-Ju Ko, Young-Ran Kim, Hee-Young Cho, Woo-Sik Lee, Eun-Hee Ahn, Nam-Keun Kim

Journal Articles

Recurrent pregnancy loss (RPL) is the loss of two or more consecutive pregnancies before 20 weeks of gestational age. Our study investigated whether mucin 4 (MUC4) polymorphisms are associated with RPL. MUC polymorphisms (rs882605 C>A, rs1104760 A>G, rs2688513 A>G, rs2258447 C>T, and rs2291652 A>G) were genotyped in 374 women with RPL and 239 controls of Korean ethnicity using polymerase chain reaction-restriction fragment length polymorphism analysis and the TaqMan probe SNP genotyping assay. Differences in genotype frequencies between cases of RPL and the controls were compared. MUC4 rs882605 C>A and rs1104760 A>G polymorphisms were …