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1. Stigma and efficacy beliefs regarding opioid use disorder treatment and naloxone in communities participating in the HEALing Communities Study intervention.

Author: Nicky Lewis, Barry Eggleston, Redonna K Chandler, Dawn Goddard-Eckrich, Jamie E Luster, Dacia D Beard, Emma Rodgers, Rouba Chahine, Philip M Westgate, Shoshana N Benjamin, JaNae Holloway, Thomas Clarke, R Craig Lefebvre, Michael D Stein, Donald W Helme, Jennifer Reynolds, Sharon L Walsh, Darcy Freedman, Nabila El-Bassel, Kara Stephens, Anita Silwal, Michelle Lofwall, Janet E Childerhose, Hilary L Surratt, Brooke N Crockett, Amy L Farmer, James L David, Laura Fanucchi, Judy Harness, Ben Wilburn, Kelli Bursey, Kristin Mattson, Sarah Mann, Rebecca D Jackson, Aimee Shadwick, Katherine Calver, Deborah Chassler, Jennifer Kimball, Nancy Regan, Jeffrey H Samet, Rachel Sword-Cruz, and Michael D Slater
Subjects: Medicine, Science
Abstract: BackgroundThe HEALing Communities Study (HCS) included health campaigns as part of a community-engaged intervention to reduce opioid-related overdose deaths in 67 highly impacted communities across Kentucky, Massachusetts, New York, and Ohio. Five campaigns were developed with community input to provide information on opioid use disorder (OUD) and overdose prevention, reduce stigma, and build demand for evidence-based practices (EBPs). An evaluation examined the recognition of campaign messages about naloxone and whether stigma and efficacy beliefs regarding OUD treatment and naloxone changed in HCS intervention communities.MethodsData were collected through surveys offered on Facebook/Instagram to members of communities participating in the HCS intervention and wait-list control communities.ResultsParticipants in HCS intervention communities reported a reduction in stigma regarding OUD and increased efficacy beliefs regarding naloxone associated with recognition of campaign messages. However, this finding is cautiously interpreted as there was no clear evidence for recognition differences between the treatment/control conditions.ConclusionStudy findings indicate associations between campaign message recognition and positive outcomes. Results also highlight possible challenges concerning evaluations of social media campaigns using conventional evaluation techniques.Trial registrationClinicalTrials.gov NCT04111939.
Published: 2024
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2. A phenome-wide association study (PheWAS) in the Population Architecture using Genomics and Epidemiology (PAGE) study reveals potential pleiotropy in African Americans.

Author: Sarah A Pendergrass, Steven Buyske, Janina M Jeff, Alex Frase, Scott Dudek, Yuki Bradford, Jose-Luis Ambite, Christy L Avery, Petra Buzkova, Ewa Deelman, Megan D Fesinmeyer, Christopher Haiman, Gerardo Heiss, Lucia A Hindorff, Chun-Nan Hsu, Rebecca D Jackson, Yi Lin, Loic Le Marchand, Tara C Matise, Kristine R Monroe, Larry Moreland, Kari E North, Sungshim L Park, Alex Reiner, Robert Wallace, Lynne R Wilkens, Charles Kooperberg, Marylyn D Ritchie, and Dana C Crawford
Subjects: Medicine, Science
Abstract: We performed a hypothesis-generating phenome-wide association study (PheWAS) to identify and characterize cross-phenotype associations, where one SNP is associated with two or more phenotypes, between thousands of genetic variants assayed on the Metabochip and hundreds of phenotypes in 5,897 African Americans as part of the Population Architecture using Genomics and Epidemiology (PAGE) I study. The PAGE I study was a National Human Genome Research Institute-funded collaboration of four study sites accessing diverse epidemiologic studies genotyped on the Metabochip, a custom genotyping chip that has dense coverage of regions in the genome previously associated with cardio-metabolic traits and outcomes in mostly European-descent populations. Here we focus on identifying novel phenome-genome relationships, where SNPs are associated with more than one phenotype. To do this, we performed a PheWAS, testing each SNP on the Metabochip for an association with up to 273 phenotypes in the participating PAGE I study sites. We identified 133 putative pleiotropic variants, defined as SNPs associated at an empirically derived p-value threshold of p
Published: 2019
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3. Correction: Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations.

Author: Jingjing Liang, Thu H Le, Digna R Velez Edwards, Bamidele O Tayo, Kyle J Gaulton, Jennifer A Smith, Yingchang Lu, Richard A Jensen, Guanjie Chen, Lisa R Yanek, Karen Schwander, Salman M Tajuddin, Tamar Sofer, Wonji Kim, James Kayima, Colin A McKenzie, Ervin Fox, Michael A Nalls, J Hunter Young, Yan V Sun, Jacqueline M Lane, Sylvia Cechova, Jie Zhou, Hua Tang, Myriam Fornage, Solomon K Musani, Heming Wang, Juyoung Lee, Adebowale Adeyemo, Albert W Dreisbach, Terrence Forrester, Pei-Lun Chu, Anne Cappola, Michele K Evans, Alanna C Morrison, Lisa W Martin, Kerri L Wiggins, Qin Hui, Wei Zhao, Rebecca D Jackson, Erin B Ware, Jessica D Faul, Alex P Reiner, Michael Bray, Joshua C Denny, Thomas H Mosley, Walter Palmas, Xiuqing Guo, George J Papanicolaou, Alan D Penman, Joseph F Polak, Kenneth Rice, Ken D Taylor, Eric Boerwinkle, Erwin P Bottinger, Kiang Liu, Neil Risch, Steven C Hunt, Charles Kooperberg, Alan B Zonderman, Cathy C Laurie, Diane M Becker, Jianwen Cai, Ruth J F Loos, Bruce M Psaty, David R Weir, Sharon L R Kardia, Donna K Arnett, Sungho Won, Todd L Edwards, Susan Redline, Richard S Cooper, D C Rao, Jerome I Rotter, Charles Rotimi, Daniel Levy, Aravinda Chakravarti, Xiaofeng Zhu, and Nora Franceschini
Subjects: Genetics, QH426-470
Abstract: [This corrects the article DOI: 10.1371/journal.pgen.1006728.].
Published: 2018
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4. Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations.

Author: Jingjing Liang, Thu H Le, Digna R Velez Edwards, Bamidele O Tayo, Kyle J Gaulton, Jennifer A Smith, Yingchang Lu, Richard A Jensen, Guanjie Chen, Lisa R Yanek, Karen Schwander, Salman M Tajuddin, Tamar Sofer, Wonji Kim, James Kayima, Colin A McKenzie, Ervin Fox, Michael A Nalls, J Hunter Young, Yan V Sun, Jacqueline M Lane, Sylvia Cechova, Jie Zhou, Hua Tang, Myriam Fornage, Solomon K Musani, Heming Wang, Juyoung Lee, Adebowale Adeyemo, Albert W Dreisbach, Terrence Forrester, Pei-Lun Chu, Anne Cappola, Michele K Evans, Alanna C Morrison, Lisa W Martin, Kerri L Wiggins, Qin Hui, Wei Zhao, Rebecca D Jackson, Erin B Ware, Jessica D Faul, Alex P Reiner, Michael Bray, Joshua C Denny, Thomas H Mosley, Walter Palmas, Xiuqing Guo, George J Papanicolaou, Alan D Penman, Joseph F Polak, Kenneth Rice, Ken D Taylor, Eric Boerwinkle, Erwin P Bottinger, Kiang Liu, Neil Risch, Steven C Hunt, Charles Kooperberg, Alan B Zonderman, Cathy C Laurie, Diane M Becker, Jianwen Cai, Ruth J F Loos, Bruce M Psaty, David R Weir, Sharon L R Kardia, Donna K Arnett, Sungho Won, Todd L Edwards, Susan Redline, Richard S Cooper, D C Rao, Jerome I Rotter, Charles Rotimi, Daniel Levy, Aravinda Chakravarti, Xiaofeng Zhu, and Nora Franceschini
Subjects: Genetics, QH426-470
Abstract: Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10-8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.
Published: 2017
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5. A systematic mapping approach of 16q12.2/FTO and BMI in more than 20,000 African Americans narrows in on the underlying functional variation: results from the Population Architecture using Genomics and Epidemiology (PAGE) study.

Author: Ulrike Peters, Kari E North, Praveen Sethupathy, Steve Buyske, Jeff Haessler, Shuo Jiao, Megan D Fesinmeyer, Rebecca D Jackson, Lew H Kuller, Aleksandar Rajkovic, Unhee Lim, Iona Cheng, Fred Schumacher, Lynne Wilkens, Rongling Li, Keri Monda, Georg Ehret, Khanh-Dung H Nguyen, Richard Cooper, Cora E Lewis, Mark Leppert, Marguerite R Irvin, C Charles Gu, Denise Houston, Petra Buzkova, Marylyn Ritchie, Tara C Matise, Loic Le Marchand, Lucia A Hindorff, Dana C Crawford, Christopher A Haiman, and Charles Kooperberg
Subjects: Genetics, QH426-470
Abstract: Genetic variants in intron 1 of the fat mass- and obesity-associated (FTO) gene have been consistently associated with body mass index (BMI) in Europeans. However, follow-up studies in African Americans (AA) have shown no support for some of the most consistently BMI-associated FTO index single nucleotide polymorphisms (SNPs). This is most likely explained by different race-specific linkage disequilibrium (LD) patterns and lower correlation overall in AA, which provides the opportunity to fine-map this region and narrow in on the functional variant. To comprehensively explore the 16q12.2/FTO locus and to search for second independent signals in the broader region, we fine-mapped a 646-kb region, encompassing the large FTO gene and the flanking gene RPGRIP1L by investigating a total of 3,756 variants (1,529 genotyped and 2,227 imputed variants) in 20,488 AAs across five studies. We observed associations between BMI and variants in the known FTO intron 1 locus: the SNP with the most significant p-value, rs56137030 (8.3 × 10(-6)) had not been highlighted in previous studies. While rs56137030was correlated at r(2)>0.5 with 103 SNPs in Europeans (including the GWAS index SNPs), this number was reduced to 28 SNPs in AA. Among rs56137030 and the 28 correlated SNPs, six were located within candidate intronic regulatory elements, including rs1421085, for which we predicted allele-specific binding affinity for the transcription factor CUX1, which has recently been implicated in the regulation of FTO. We did not find strong evidence for a second independent signal in the broader region. In summary, this large fine-mapping study in AA has substantially reduced the number of common alleles that are likely to be functional candidates of the known FTO locus. Importantly our study demonstrated that comprehensive fine-mapping in AA provides a powerful approach to narrow in on the functional candidate(s) underlying the initial GWAS findings in European populations.
Published: 2013
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6. Phenome-wide association study (PheWAS) for detection of pleiotropy within the Population Architecture using Genomics and Epidemiology (PAGE) Network.

Author: Sarah A Pendergrass, Kristin Brown-Gentry, Scott Dudek, Alex Frase, Eric S Torstenson, Robert Goodloe, Jose Luis Ambite, Christy L Avery, Steve Buyske, Petra Bůžková, Ewa Deelman, Megan D Fesinmeyer, Christopher A Haiman, Gerardo Heiss, Lucia A Hindorff, Chu-Nan Hsu, Rebecca D Jackson, Charles Kooperberg, Loic Le Marchand, Yi Lin, Tara C Matise, Kristine R Monroe, Larry Moreland, Sungshim L Park, Alex Reiner, Robert Wallace, Lynn R Wilkens, Dana C Crawford, and Marylyn D Ritchie
Subjects: Genetics, QH426-470
Abstract: Using a phenome-wide association study (PheWAS) approach, we comprehensively tested genetic variants for association with phenotypes available for 70,061 study participants in the Population Architecture using Genomics and Epidemiology (PAGE) network. Our aim was to better characterize the genetic architecture of complex traits and identify novel pleiotropic relationships. This PheWAS drew on five population-based studies representing four major racial/ethnic groups (European Americans (EA), African Americans (AA), Hispanics/Mexican-Americans, and Asian/Pacific Islanders) in PAGE, each site with measurements for multiple traits, associated laboratory measures, and intermediate biomarkers. A total of 83 single nucleotide polymorphisms (SNPs) identified by genome-wide association studies (GWAS) were genotyped across two or more PAGE study sites. Comprehensive tests of association, stratified by race/ethnicity, were performed, encompassing 4,706 phenotypes mapped to 105 phenotype-classes, and association results were compared across study sites. A total of 111 PheWAS results had significant associations for two or more PAGE study sites with consistent direction of effect with a significance threshold of p
Published: 2013
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7. Confirmation of the reported association of clonal chromosomal mosaicism with an increased risk of incident hematologic cancer.

Author: Ursula M Schick, Andrew McDavid, Paul K Crane, Noah Weston, Kelly Ehrlich, Katherine M Newton, Robert Wallace, Ebony Bookman, Tabitha Harrison, Aaron Aragaki, David R Crosslin, Sophia S Wang, Alex P Reiner, Rebecca D Jackson, Ulrike Peters, Eric B Larson, Gail P Jarvik, and Christopher S Carlson
Subjects: Medicine, Science
Abstract: Chromosomal abnormalities provide clinical utility in the diagnosis and treatment of hematologic malignancies, and may be predictive of malignant transformation in individuals without apparent clinical presentation of a hematologic cancer. In an effort to confirm previous reports of an association between clonal mosaicism and incident hematologic cancer, we applied the anomDetectBAF algorithm to call chromosomal anomalies in genotype data from previously conducted Genome Wide Association Studies (GWAS). The genotypes were initially collected from DNA derived from peripheral blood of 12,176 participants in the Group Health electronic Medical Records and Genomics study (eMERGE) and the Women's Health Initiative (WHI). We detected clonal mosaicism in 169 individuals (1.4%) and large clonal mosaic events (>2 mb) in 117 (1.0%) individuals. Though only 9.5% of clonal mosaic carriers had an incident diagnosis of hematologic cancer (multiple myeloma, myelodysplastic syndrome, lymphoma, or leukemia), the carriers had a 5.5-fold increased risk (95% CI: 3.3-9.3; p-value = 7.5×10(-11)) of developing these cancers subsequently. Carriers of large mosaic anomalies showed particularly pronounced risk of subsequent leukemia (HR = 19.2, 95% CI: 8.9-41.6; p-value = 7.3×10(-14)). Thus we independently confirm the association between detectable clonal mosaicism and hematologic cancer found previously in two recent publications.
Published: 2013
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8. HNF1B and endometrial cancer risk: results from the PAGE study.

Author: Veronica Wendy Setiawan, Jeffrey Haessler, Fredrick Schumacher, Michele L Cote, Ewa Deelman, Megan D Fesinmeyer, Brian E Henderson, Rebecca D Jackson, Jens-S Vöckler, Lynne R Wilkens, Shagufta Yasmeen, Christopher A Haiman, Ulrike Peters, Loïc Le Marchand, and Charles Kooperberg
Subjects: Medicine, Science
Abstract: We examined the association between HNF1B variants identified in a recent genome-wide association study and endometrial cancer in two large case-control studies nested in prospective cohorts: the Multiethnic Cohort Study (MEC) and the Women's Health Initiative (WHI) as part of the Population Architecture using Genomics and Epidemiology (PAGE) study. A total of 1,357 incident cases of invasive endometrial cancer and 7,609 controls were included in the analysis (MEC: 426 cases/3,854 controls; WHI: 931 cases/3,755 controls). The majority of women in the WHI were European American, while the MEC included sizable numbers of African Americans, Japanese and Latinos. We estimated the odds ratios (ORs) per allele and 95% confidence intervals (CIs) of each SNP using unconditional logistic regression adjusting for age, body mass index, and four principal components of ancestry informative markers. The combined ORs were estimated using fixed effect models. Rs4430796 and rs7501939 were associated with endometrial cancer risk in MEC and WHI with no heterogeneity observed across racial/ethnic groups (P ≥ 0.21) or between studies (P ≥ 0.70). The OR(per allele) was 0.82 (95% CI: 0.75, 0.89; P = 5.63 × 10(-6)) for rs4430796 (G allele) and 0.79 (95% CI: 0.73, 0.87; P = 3.77 × 10(-7)) for rs7501939 (A allele). The associations with the risk of Type I and Type II tumors were similar (P ≥ 0.19). Adjustment for additional endometrial cancer risk factors such as parity, oral contraceptive use, menopausal hormone use, and smoking status had little effect on the results. In conclusion, HNF1B SNPs are associated with risk of endometrial cancer and that the associated relative risks are similar for Type I and Type II tumors.
Published: 2012
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9. Genome-wide search for gene-gene interactions in colorectal cancer.

Author: Shuo Jiao, Li Hsu, Sonja Berndt, Stéphane Bézieau, Hermann Brenner, Daniel Buchanan, Bette J Caan, Peter T Campbell, Christopher S Carlson, Graham Casey, Andrew T Chan, Jenny Chang-Claude, Stephen Chanock, David V Conti, Keith R Curtis, David Duggan, Steven Gallinger, Stephen B Gruber, Tabitha A Harrison, Richard B Hayes, Brian E Henderson, Michael Hoffmeister, John L Hopper, Thomas J Hudson, Carolyn M Hutter, Rebecca D Jackson, Mark A Jenkins, Elizabeth D Kantor, Laurence N Kolonel, Sébastien Küry, Loic Le Marchand, Mathieu Lemire, Polly A Newcomb, John D Potter, Conghui Qu, Stephanie A Rosse, Robert E Schoen, Fred R Schumacher, Daniela Seminara, Martha L Slattery, Cornelia M Ulrich, Brent W Zanke, and Ulrike Peters
Subjects: Medicine, Science
Abstract: Genome-wide association studies (GWAS) have successfully identified a number of single-nucleotide polymorphisms (SNPs) associated with colorectal cancer (CRC) risk. However, these susceptibility loci known today explain only a small fraction of the genetic risk. Gene-gene interaction (GxG) is considered to be one source of the missing heritability. To address this, we performed a genome-wide search for pair-wise GxG associated with CRC risk using 8,380 cases and 10,558 controls in the discovery phase and 2,527 cases and 2,658 controls in the replication phase. We developed a simple, but powerful method for testing interaction, which we term the Average Risk Due to Interaction (ARDI). With this method, we conducted a genome-wide search to identify SNPs showing evidence for GxG with previously identified CRC susceptibility loci from 14 independent regions. We also conducted a genome-wide search for GxG using the marginal association screening and examining interaction among SNPs that pass the screening threshold (p
Published: 2012
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10. Genome-wide meta-analysis identified novel variant associated with hallux valgus in Caucasians

Author: Liubov Arbeeva, Michelle Yau, Braxton D. Mitchell, Rebecca D. Jackson, Kathleen Ryan, Yvonne M. Golightly, Marian T. Hannan, Amanda Nelson, Joanne M. Jordan, and Marc C. Hochberg
Subjects: Genome-wide, Muscle disease, Genetic epidemiology, Rheumatology, Diseases of the musculoskeletal system, RC925-935
Abstract: Abstract Background Hallux valgus, one of the most common structural foot deformities, is highly heritable. However, previous efforts to elucidate the genetic underpinnings of hallux valgus through a genome-wide association study (GWAS) conducted in 4409 Caucasians did not identify genome-wide significant associations with hallux valgus in both gender-specific and sex-combined GWAS meta-analyses. In this analysis, we add newly available data and more densely imputed genotypes to identify novel genetic variants associated with hallux valgus. Methods A total of 5925 individuals of European Ancestry were categorized into two groups: ‘hallux valgus present’ (n = 2314) or ‘no deformity’ (n = 3611) as determined by trained examiners or using the Manchester grading scale. Genotyping was performed using commercially available arrays followed by imputation to the Haplotype Reference Consortium (HRC) reference panel version 1.1. We conducted both sex-specific and sex-combined association analyses using logistic regression and generalized estimating equations as appropriate in each cohort. Results were then combined in a fixed-effects inverse-variance meta-analyses. Functional Mapping and Annotation web-based platform (FUMA) was used for positional mapping, gene and gene-set analyses. Results We identified a novel locus in the intronic region of CLCA2 on chromosome 1, rs55807512 (OR = 0.48, p = 2.96E-09), an expression quantitative trait locus for COL24A1, a member of the collagen gene family. Conclusion In this report of the largest GWAS of hallux valgus to date, we identified a novel genome-wide significant locus for hallux valgus. Additional replication and functional follow-up will be needed to determine the functional role of this locus in hallux valgus biology.
Published: 2020
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11. Community Coalitions' Perspectives on Engaging with Hospitals in Ohio to Address the Opioid Crisis

Author: Daniel M. Walker, Karen Shiu-Yee, Sadie Chen, Matthew J. DePuccio, Rebecca D. Jackson, and Ann Scheck McAlearney
Subjects: Leadership and Management, Health Policy, Public Health, Environmental and Occupational Health, Humans, Opioid Epidemic, Hospitals, Ohio
Abstract: Community coalitions have been leading the multisector response to the opioid epidemic in the Unites States. However, with the medicalization of opioid use disorder and changing health care policies, hospitals have moved to the forefront, becoming more active in collaborating with community coalitions. Little is currently known about how community coalitions view and approach collaborating with hospitals despite its importance for understanding and advancing interorganizational approaches to combating the opioid epidemic. Using data from semistructured interviews (
Published: 2022
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12. Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors

Author: Florian, Thibord, Derek, Klarin, Jennifer A, Brody, Ming-Huei, Chen, Michael G, Levin, Daniel I, Chasman, Ellen L, Goode, Kristian, Hveem, Maris, Teder-Laving, Angel, Martinez-Perez, Dylan, Aïssi, Delphine, Daian-Bacq, Kaoru, Ito, Pradeep, Natarajan, Pamela L, Lutsey, Girish N, Nadkarni, Paul S, de Vries, Gabriel, Cuellar-Partida, Brooke N, Wolford, Jack W, Pattee, Charles, Kooperberg, Sigrid K, Braekkan, Ruifang, Li-Gao, Noemie, Saut, Corriene, Sept, Marine, Germain, Renae L, Judy, Kerri L, Wiggins, Darae, Ko, Christopher J, O'Donnell, Kent D, Taylor, Franco, Giulianini, Mariza, De Andrade, Therese H, Nøst, Anne, Boland, Jean-Philippe, Empana, Satoshi, Koyama, Thomas, Gilliland, Ron, Do, Jennifer E, Huffman, Xin, Wang, Wei, Zhou, Jose, Manuel Soria, Juan, Carlos Souto, Nathan, Pankratz, Jeffery, Haessler, Kristian, Hindberg, Frits R, Rosendaal, Constance, Turman, Robert, Olaso, Rachel L, Kember, Traci M, Bartz, Julie A, Lynch, Susan R, Heckbert, Sebastian M, Armasu, Ben, Brumpton, David M, Smadja, Xavier, Jouven, Issei, Komuro, Katharine R, Clapham, Ruth J F, Loos, Cristen J, Willer, Maria, Sabater-Lleal, James S, Pankow, Alexander P, Reiner, Vania M, Morelli, Paul M, Ridker, Astrid van Hylckama, Vlieg, Jean-François, Deleuze, Peter, Kraft, Daniel J, Rader, Kyung, Min Lee, Bruce M, Psaty, Anne, Heidi Skogholt, Joseph, Emmerich, Pierre, Suchon, Stephen S, Rich, Ha My T, Vy, Weihong, Tang, Rebecca D, Jackson, John-Bjarne, Hansen, Pierre-Emmanuel, Morange, Christopher, Kabrhel, David-Alexandre, Trégouët, Scott M, Damrauer, Andrew D, Johnson, Nicholas L, Smith, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
Subjects: genome-wide association study, venous thromboembolism, Quantitative Trait Loci, Thrombosis, Genomics, Venous Thromboembolism, Polymorphism, Single Nucleotide, meta-analysis, Meta-analysis, Physiology (medical), Venous thrombosis, Genetics, Humans, genetics, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Genetic Predisposition to Disease, venous thrombosis, Cardiology and Cardiovascular Medicine, Genome-Wide Association Study
Abstract: Background: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources. Methods: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations. Results: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis. Conclusions: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.
Published: 2022
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13. Prevalence, Incidence, and Progression of Radiographic and Symptomatic Hand Osteoarthritis: The Osteoarthritis Initiative

Author: Charles B. Eaton, Lena F. Schaefer, Jeff Duryea, Jeff B. Driban, Grace H. Lo, Mary B. Roberts, Ida K. Haugen, Bing Lu, Michael C. Nevitt, Marc C. Hochberg, Rebecca D. Jackson, C. K. Kwoh, and Timothy McAlindon
Subjects: Male, Hand Joints, Incidence, Immunology, Middle Aged, Hand, Metacarpophalangeal Joint, Radiography, Rheumatology, Osteoarthritis, Prevalence, Humans, Immunology and Allergy, Female
Abstract: To describe the prevalence, incidence, and progression of radiographic and symptomatic hand osteoarthritis (OA), and to evaluate differences according to age, sex, race, and other risk factors.Participants were assessed for radiographic and symptomatic hand OA at baseline and year 4 to determine incident disease. A modified Poisson regression with a robust variance estimator was used to account for clustering of joints within fingers within persons to estimate the prevalence ratios and relative risk estimates associated with participant characteristics.Among 3,588 participants, the prevalence of radiographic hand OA was 41.4%, and the prevalence of symptomatic hand OA was 12.4%. The incidence over 48 months was 5.6% for radiographic hand OA and 16.9% for symptomatic hand OA. Over 48 months, 27.3% of the participants exhibited OA progression. We found complex differences by age, sex, and race, with increasing rates of prevalent hand OA with older age in both men and women, but with rates of incident disease peaking at ages 55-64 years in women. Women had higher rates of symptomatic hand OA, but only nonsignificantly higher rates of incident radiographic hand OA, than men. Women more frequently had distal interphalangeal joint disease, while men more frequently had metacarpophalangeal joint OA. Black men and women had lower rates of hand OA than White participants, but Black men had higher rates of prevalent hand OA than Black women at younger ages.Hand OA is a heterogeneous disease with complex differences by age, sex, race, hand symptoms, and patterns of specific joints affected. Further research investigating the mechanisms behind these differences, whether mechanical, metabolic, hormonal, or constitutional, is warranted.
Published: 2022
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14. Whole-Genome Sequencing Association Analyses of Stroke and Its Subtypes in Ancestrally Diverse Populations From Trans-Omics for Precision Medicine Project

Author: Regina Manansala, Jeffrey Haessler, Sandro Marini, Rebecca D. Jackson, Tanika N. Kelly, Ruth J. F. Loos, Quenna Wong, Jonathan Rosand, Sudha Seshadri, Charles Kooperberg, Adolfo Correa, Stephen S. Rich, Ron Do, Paul L. Auer, Xiao Sun, Kerri L. Wiggins, Bruce M. Psaty, Jerome I. Rotter, Alexander P. Reiner, Jaeyoon Chung, Arden Moscati, Chloé Sarnowski, Laura M. Raffield, William T. Longstreth, Themistocles L. Assimes, Christopher D. Anderson, Yao Hu, David L. Tirschwell, Joshua C. Bis, Braxton D. Mitchell, Simin Liu, Leslie A. Lange, Alexa S. Beiser, Brian Silver, Ramachandran S. Vasan, Huichun Xu, Nancy L. Heard-Costa, Sylvia Wassertheil-Smoller, and Myriam Fornage
Subjects: Male, Bioinformatics, Polymorphism, Single Nucleotide, Article, medicine, Humans, Genetic Predisposition to Disease, Precision Medicine, Stroke, Aged, Genetic association, Cause of death, Aged, 80 and over, Advanced and Specialized Nursing, Whole genome sequencing, Whole Genome Sequencing, business.industry, Racial Groups, Middle Aged, medicine.disease, Omics, Precision medicine, Embolic stroke, Genetic Loci, Female, Neurology (clinical), Cardiology and Cardiovascular Medicine, business, Genome-Wide Association Study
Abstract: Background and Purpose: Stroke is the leading cause of death and long-term disability worldwide. Previous genome-wide association studies identified 51 loci associated with stroke (mostly ischemic) and its subtypes among predominantly European populations. Using whole-genome sequencing in ancestrally diverse populations from the Trans-Omics for Precision Medicine (TOPMed) Program, we aimed to identify novel variants, especially low-frequency or ancestry-specific variants, associated with all stroke, ischemic stroke and its subtypes (large artery, cardioembolic, and small vessel), and hemorrhagic stroke and its subtypes (intracerebral and subarachnoid). Methods: Whole-genome sequencing data were available for 6833 stroke cases and 27 116 controls, including 22 315 European, 7877 Black, 2616 Hispanic/Latino, 850 Asian, 54 Native American, and 237 other ancestry participants. In TOPMed, we performed single variant association analysis examining 40 million common variants and aggregated association analysis focusing on rare variants. We also combined TOPMed European populations with over 28 000 additional European participants from the UK BioBank genome-wide array data through meta-analysis. Results: In the single variant association analysis in TOPMed, we identified one novel locus 13q33 for large artery at whole-genome-wide significance ( P −9 ) and 4 novel loci at genome-wide significance ( P −8 ), all of which need confirmation in independent studies. Lead variants in all 5 loci are low-frequency but are more common in non-European populations. An aggregation of synonymous rare variants within the gene C6orf26 demonstrated suggestive evidence of association for hemorrhagic stroke ( P −6 ). By meta-analyzing European ancestry samples in TOPMed and UK BioBank, we replicated several previously reported stroke loci including PITX2 , HDAC9 , ZFHX3 , and LRCH1 . Conclusions: We represent the first association analysis for stroke and its subtypes using whole-genome sequencing data from ancestrally diverse populations. While our findings suggest the potential benefits of combining whole-genome sequencing data with populations of diverse genetic backgrounds to identify possible low-frequency or ancestry-specific variants, they also highlight the need to increase genome coverage and sample sizes.
Published: 2022
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15. Racket or Bat Sports: No Association With Thumb-Base Osteoarthritis

Author: Jeffrey B. Driban, L.F. Schaefer, Timothy E. McAlindon, C. Kent Kwoh, Grace H. Lo, Michael C. Nevitt, Mary B. Roberts, Marc C. Hochberg, Bing Lu, Matthew S. Harkey, Ida K. Haugen, Jeffrey Duryea, Stacy E. Smith, Rebecca D. Jackson, and Charles B. Eaton
Subjects: Male, medicine.medical_specialty, sports, Physical Therapy, Sports Therapy and Rehabilitation, Context (language use), Osteoarthritis, Odds, Cohort Studies, Carpometacarpal joint, Chiroptera, medicine, Animals, Humans, Orthopedics and Sports Medicine, Risk factor, Child, Racquetball, business.industry, Carpometacarpal Joints, General Medicine, Odds ratio, medicine.disease, Hand, medicine.anatomical_structure, Thumb, Cohort, Physical therapy, sports.sport, Female, business
Abstract: Context Repetitive joint use is a risk factor for osteoarthritis, which is a leading cause of disability. Sports requiring a racket or bat to perform repetitive high-velocity impacts may increase the risk of thumb-base osteoarthritis. However, this hypothesis remains untested. Objective To determine if a history of participation in racket or bat sports was associated with the prevalence of thumb-base osteoarthritis. Design Descriptive epidemiologic study. Setting Four US clinical sites associated with the Osteoarthritis Initiative. Patients or Other Participants We recruited 2309 men and women from the community. Eligible participants had dominant-hand radiographic readings, hand symptom assessments, and historical physical activity survey data. Main Outcome Measure(s) A history of exposure to racket or bat sports (badminton, baseball or softball, racketball or squash, table tennis [or ping pong], tennis [doubles], or tennis [singles]) was based on self-reported recall data covering 3 age ranges (12–18, 19–34, and 35–49 years). Prevalent radiographic thumb-base osteoarthritis was defined as Kellgren-Lawrence grade >2 in the first carpometacarpal joint or scaphotrapezoidal joint at the Osteoarthritis Initiative baseline visit. Symptomatic thumb-base osteoarthritis was defined as radiographic osteoarthritis and hand or finger symptoms. Results Radiographic or symptomatic thumb-base osteoarthritis was present in 355 (34%) and 56 (5%), respectively, of men (total = 1049) and 535 (42%) and 170 (13%), respectively, of women (total = 1260). After adjusting for age, race, and education level, we found no significant associations between a history of any racket or bat sport participation and thumb-base osteoarthritis (radiographic or symptomatic; odds ratios ranged from 0.82 to 1.34). Conclusions In a community-based cohort, a self-reported history of participation in racket or bat sports was not associated with increased odds of having radiographic or symptomatic thumb-base osteoarthritis in the dominant hand.
Published: 2023

16. Supplementary Table 4 from Characterization of Gene–Environment Interactions for Colorectal Cancer Susceptibility Loci

Author: Ulrike Peters, Thomas J. Hudson, Andrew T. Chan, Stéphane Bézieau, Li Hsu, John D. Potter, Bette J. Caan, Richard B. Hayes, Sonja I. Berndt, Stephen J. Chanock, Robert E. Schoen, Rebecca D. Jackson, Ross L. Prentice, Andrea Z. LaCroix, Charles Kooperberg, Polly A. Newcomb, Emily White, Cornelia M. Ulrich, Jing Ma, Bernd Frank, Hermann Brenner, Brent W. Zanke, Steven Gallinger, David J. Hunter, Peter Kraft, Aditi Hazra, Edward Giovannucci, Charles S. Fuchs, Sébastien Küry, Michael Hoffmeister, Greg S. Warnick, Deanna L. Stelling, Lin S. Chen, Yan Liu, Tabitha A. Harrison, Shuo Jiao, Jane C. Figueiredo, Jagadish Rangrej, Mathieu Lemire, Hongmei Nan, David Duggan, Yi Lin, Bethann M. Pflugeisen, Martha L. Slattery, Jenny Chang-Claude, and Carolyn M. Hutter
Abstract: PDF file - 77K, All GxE interaction results.
Published: 2023
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17. Supplementary Table 2 from Characterization of Gene–Environment Interactions for Colorectal Cancer Susceptibility Loci

Author: Ulrike Peters, Thomas J. Hudson, Andrew T. Chan, Stéphane Bézieau, Li Hsu, John D. Potter, Bette J. Caan, Richard B. Hayes, Sonja I. Berndt, Stephen J. Chanock, Robert E. Schoen, Rebecca D. Jackson, Ross L. Prentice, Andrea Z. LaCroix, Charles Kooperberg, Polly A. Newcomb, Emily White, Cornelia M. Ulrich, Jing Ma, Bernd Frank, Hermann Brenner, Brent W. Zanke, Steven Gallinger, David J. Hunter, Peter Kraft, Aditi Hazra, Edward Giovannucci, Charles S. Fuchs, Sébastien Küry, Michael Hoffmeister, Greg S. Warnick, Deanna L. Stelling, Lin S. Chen, Yan Liu, Tabitha A. Harrison, Shuo Jiao, Jane C. Figueiredo, Jagadish Rangrej, Mathieu Lemire, Hongmei Nan, David Duggan, Yi Lin, Bethann M. Pflugeisen, Martha L. Slattery, Jenny Chang-Claude, and Carolyn M. Hutter
Abstract: PDF file - 55K, Study specific definitions of regular aspirin/NSAID use.
Published: 2023
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18. Supplementary Table 7 from Characterization of Gene–Environment Interactions for Colorectal Cancer Susceptibility Loci

Author: Ulrike Peters, Thomas J. Hudson, Andrew T. Chan, Stéphane Bézieau, Li Hsu, John D. Potter, Bette J. Caan, Richard B. Hayes, Sonja I. Berndt, Stephen J. Chanock, Robert E. Schoen, Rebecca D. Jackson, Ross L. Prentice, Andrea Z. LaCroix, Charles Kooperberg, Polly A. Newcomb, Emily White, Cornelia M. Ulrich, Jing Ma, Bernd Frank, Hermann Brenner, Brent W. Zanke, Steven Gallinger, David J. Hunter, Peter Kraft, Aditi Hazra, Edward Giovannucci, Charles S. Fuchs, Sébastien Küry, Michael Hoffmeister, Greg S. Warnick, Deanna L. Stelling, Lin S. Chen, Yan Liu, Tabitha A. Harrison, Shuo Jiao, Jane C. Figueiredo, Jagadish Rangrej, Mathieu Lemire, Hongmei Nan, David Duggan, Yi Lin, Bethann M. Pflugeisen, Martha L. Slattery, Jenny Chang-Claude, and Carolyn M. Hutter
Abstract: PDF file - 96K, All GxE interactions stratified by cancer site.
Published: 2023
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19. Supplementary Figure 1 from Characterization of Gene–Environment Interactions for Colorectal Cancer Susceptibility Loci

Author: Ulrike Peters, Thomas J. Hudson, Andrew T. Chan, Stéphane Bézieau, Li Hsu, John D. Potter, Bette J. Caan, Richard B. Hayes, Sonja I. Berndt, Stephen J. Chanock, Robert E. Schoen, Rebecca D. Jackson, Ross L. Prentice, Andrea Z. LaCroix, Charles Kooperberg, Polly A. Newcomb, Emily White, Cornelia M. Ulrich, Jing Ma, Bernd Frank, Hermann Brenner, Brent W. Zanke, Steven Gallinger, David J. Hunter, Peter Kraft, Aditi Hazra, Edward Giovannucci, Charles S. Fuchs, Sébastien Küry, Michael Hoffmeister, Greg S. Warnick, Deanna L. Stelling, Lin S. Chen, Yan Liu, Tabitha A. Harrison, Shuo Jiao, Jane C. Figueiredo, Jagadish Rangrej, Mathieu Lemire, Hongmei Nan, David Duggan, Yi Lin, Bethann M. Pflugeisen, Martha L. Slattery, Jenny Chang-Claude, and Carolyn M. Hutter
Abstract: PDF file - 52K, Forest plots for meta-analysis results with GxE interaction p < 0.01
Published: 2023
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20. Supplementary Table 3 from Characterization of Gene–Environment Interactions for Colorectal Cancer Susceptibility Loci

Author: Ulrike Peters, Thomas J. Hudson, Andrew T. Chan, Stéphane Bézieau, Li Hsu, John D. Potter, Bette J. Caan, Richard B. Hayes, Sonja I. Berndt, Stephen J. Chanock, Robert E. Schoen, Rebecca D. Jackson, Ross L. Prentice, Andrea Z. LaCroix, Charles Kooperberg, Polly A. Newcomb, Emily White, Cornelia M. Ulrich, Jing Ma, Bernd Frank, Hermann Brenner, Brent W. Zanke, Steven Gallinger, David J. Hunter, Peter Kraft, Aditi Hazra, Edward Giovannucci, Charles S. Fuchs, Sébastien Küry, Michael Hoffmeister, Greg S. Warnick, Deanna L. Stelling, Lin S. Chen, Yan Liu, Tabitha A. Harrison, Shuo Jiao, Jane C. Figueiredo, Jagadish Rangrej, Mathieu Lemire, Hongmei Nan, David Duggan, Yi Lin, Bethann M. Pflugeisen, Martha L. Slattery, Jenny Chang-Claude, and Carolyn M. Hutter
Abstract: PDF file - 67K, Descriptives for smoking, BMI, height, dietary variables, alcohol, sex, and NSAID use.
Published: 2023
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21. Supplementary Table 6 from Characterization of Gene–Environment Interactions for Colorectal Cancer Susceptibility Loci

Author: Ulrike Peters, Thomas J. Hudson, Andrew T. Chan, Stéphane Bézieau, Li Hsu, John D. Potter, Bette J. Caan, Richard B. Hayes, Sonja I. Berndt, Stephen J. Chanock, Robert E. Schoen, Rebecca D. Jackson, Ross L. Prentice, Andrea Z. LaCroix, Charles Kooperberg, Polly A. Newcomb, Emily White, Cornelia M. Ulrich, Jing Ma, Bernd Frank, Hermann Brenner, Brent W. Zanke, Steven Gallinger, David J. Hunter, Peter Kraft, Aditi Hazra, Edward Giovannucci, Charles S. Fuchs, Sébastien Küry, Michael Hoffmeister, Greg S. Warnick, Deanna L. Stelling, Lin S. Chen, Yan Liu, Tabitha A. Harrison, Shuo Jiao, Jane C. Figueiredo, Jagadish Rangrej, Mathieu Lemire, Hongmei Nan, David Duggan, Yi Lin, Bethann M. Pflugeisen, Martha L. Slattery, Jenny Chang-Claude, and Carolyn M. Hutter
Abstract: PDF file - 55K, Further information about main finding
Published: 2023
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22. Supplementary Table 1 from Characterization of Gene–Environment Interactions for Colorectal Cancer Susceptibility Loci

Author: Ulrike Peters, Thomas J. Hudson, Andrew T. Chan, Stéphane Bézieau, Li Hsu, John D. Potter, Bette J. Caan, Richard B. Hayes, Sonja I. Berndt, Stephen J. Chanock, Robert E. Schoen, Rebecca D. Jackson, Ross L. Prentice, Andrea Z. LaCroix, Charles Kooperberg, Polly A. Newcomb, Emily White, Cornelia M. Ulrich, Jing Ma, Bernd Frank, Hermann Brenner, Brent W. Zanke, Steven Gallinger, David J. Hunter, Peter Kraft, Aditi Hazra, Edward Giovannucci, Charles S. Fuchs, Sébastien Küry, Michael Hoffmeister, Greg S. Warnick, Deanna L. Stelling, Lin S. Chen, Yan Liu, Tabitha A. Harrison, Shuo Jiao, Jane C. Figueiredo, Jagadish Rangrej, Mathieu Lemire, Hongmei Nan, David Duggan, Yi Lin, Bethann M. Pflugeisen, Martha L. Slattery, Jenny Chang-Claude, and Carolyn M. Hutter
Abstract: PDF file - 168K, SNP details by study.
Published: 2023
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23. Resiliency Among Women’s Health Initiative Women Aged 80 and Older by Race, Ethnicity, and Neighborhood Socioeconomic Status

Author: Jessica L Krok-Schoen, Michelle J Naughton, Ashley S Felix, Crystal Wiley Cené, Sparkle Springfield, Mengda Yu, Eric M McLaughlin, Aladdin H Shadyab, Timiya S Nolan, Candyce H Kroenke, Lorena Garcia, Shawna Follis, and Rebecca D Jackson
Subjects: Clinical Psychology, Social Psychology, Geriatrics and Gerontology, Gerontology
Abstract: Objectives A comprehensive examination of resilience by race, ethnicity, and neighborhood socioeconomic status (NSES) among women aged ≥80 is needed, given the aging of the U.S. population, increasing longevity, and growing racial and ethnic diversity. Methods Participants were women aged ≥80 enrolled in the Women’s Health Initiative. Resilience was assessed with a modified version of the Brief Resilience Scale. Descriptive statistics and multiple linear regression examined the association of demographic, health, and psychosocial variables with resilience by race, ethnicity, and NSES. Results Participants (n = 29,367, median age = 84.3) were White (91.4%), Black (3.7%), Hispanic (1.9%), and Asian (1.7%) women. There were no significant differences by race and ethnicity on mean resiliency scores (p = .06). Significant differences by NSES were observed regarding mean resiliency scores between those with low NSES (3.94 ± 0.83, out of 5) and high NSES (4.00 ± 0.81). Older age, higher education, higher self-rated health, lower stress, and living alone were significant positive correlates of resilience in the sample. Social support was correlated with resilience among White, Black, and Asian women, but not for Hispanic women. Depression was a significant correlate of lower resilience, except among Asian women. Living alone, smoking, and spirituality were significantly associated with higher resilience among women with moderate NSES. Discussion Multiple factors were associated with resilience among women aged ≥80 in the Women’s Health Initiative. Despite some differing correlates of resilience by race, ethnicity, and NSES, there were many similarities. These results may aid in the design of resilience interventions for the growing, increasingly diverse population of older women.
Published: 2023
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24. Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease

Author: William J. Young, Jeffrey Haessler, Jan-Walter Benjamins, Linda Repetto, Jie Yao, Aaron Isaacs, Andrew R. Harper, Julia Ramirez, Sophie Garnier, Stefan van Duijvenboden, Antoine R. Baldassari, Maria Pina Concas, ThuyVy Duong, Luisa Foco, Jonas L. Isaksen, Hao Mei, Raymond Noordam, Casia Nursyifa, Anne Richmond, Meddly L. Santolalla, Colleen M. Sitlani, Negin Soroush, Sébastien Thériault, Stella Trompet, Stefanie Aeschbacher, Fariba Ahmadizar, Alvaro Alonso, Jennifer A. Brody, Archie Campbell, Adolfo Correa, Dawood Darbar, Antonio De Luca, Jean-François Deleuze, Christina Ellervik, Christian Fuchsberger, Anuj Goel, Christopher Grace, Xiuqing Guo, Torben Hansen, Susan R. Heckbert, Rebecca D. Jackson, Jan A. Kors, Maria Fernanda Lima-Costa, Allan Linneberg, Peter W. Macfarlane, Alanna C. Morrison, Pau Navarro, David J. Porteous, Peter P. Pramstaller, Alexander P. Reiner, Lorenz Risch, Ulrich Schotten, Xia Shen, Gianfranco Sinagra, Elsayed Z. Soliman, Monika Stoll, Eduardo Tarazona-Santos, Andrew Tinker, Katerina Trajanoska, Eric Villard, Helen R. Warren, Eric A. Whitsel, Kerri L. Wiggins, Dan E. Arking, Christy L. Avery, David Conen, Giorgia Girotto, Niels Grarup, Caroline Hayward, J.Wouter Jukema, Dennis O. Mook-Kanamori, Morten Salling Olesen, Sandosh Padmanabhan, Bruce M. Psaty, Cristian Pattaro, Antonio Luiz P. Ribeiro, Jerome I. Rotter, Bruno H. Stricker, Pim van der Harst, Cornelia M. van Duijn, Niek Verweij, James G. Wilson, Michele Orini, Philippe Charron, Hugh Watkins, Charles Kooperberg, Henry J. Lin, James F. Wilson, Jørgen K. Kanters, Nona Sotoodehnia, Borbala Mifsud, Pier D. Lambiase, Larisa G. Tereshchenko, Patricia B. Munroe, Epidemiology, Department of Finance, Medical Informatics, Internal Medicine, Erasmus MC other, Cardiovascular Centre (CVC), Young, William J, Haessler, Jeffrey, Benjamins, Jan-Walter, Repetto, Linda, Yao, Jie, Isaacs, Aaron, Harper, Andrew R, Ramirez, Julia, Garnier, Sophie, van Duijvenboden, Stefan, Baldassari, Antoine R, Concas, Maria Pina, Duong, Thuyvy, Foco, Luisa, Isaksen, Jonas L, Mei, Hao, Noordam, Raymond, Nursyifa, Casia, Richmond, Anne, Santolalla, Meddly L, Sitlani, Colleen M, Soroush, Negin, Thériault, Sébastien, Trompet, Stella, Aeschbacher, Stefanie, Ahmadizar, Fariba, Alonso, Alvaro, Brody, Jennifer A, Campbell, Archie, Correa, Adolfo, Darbar, Dawood, De Luca, Antonio, Deleuze, Jean-Françoi, Ellervik, Christina, Fuchsberger, Christian, Goel, Anuj, Grace, Christopher, Guo, Xiuqing, Hansen, Torben, Heckbert, Susan R, Jackson, Rebecca D, Kors, Jan A, Lima-Costa, Maria Fernanda, Linneberg, Allan, Macfarlane, Peter W, Morrison, Alanna C, Navarro, Pau, Porteous, David J, Pramstaller, Peter P, Reiner, Alexander P, Risch, Lorenz, Schotten, Ulrich, Shen, Xia, Sinagra, Gianfranco, Soliman, Elsayed Z, Stoll, Monika, Tarazona-Santos, Eduardo, Tinker, Andrew, Trajanoska, Katerina, Villard, Eric, Warren, Helen R, Whitsel, Eric A, Wiggins, Kerri L, Arking, Dan E, Avery, Christy L, Conen, David, Girotto, Giorgia, Grarup, Niel, Hayward, Caroline, Jukema, J Wouter, Mook-Kanamori, Dennis O, Olesen, Morten Salling, Padmanabhan, Sandosh, Psaty, Bruce M, Pattaro, Cristian, Ribeiro, Antonio Luiz P, Rotter, Jerome I, Stricker, Bruno H, van der Harst, Pim, van Duijn, Cornelia M, Verweij, Niek, Wilson, James G, Orini, Michele, Charron, Philippe, Watkins, Hugh, Kooperberg, Charle, Lin, Henry J, Wilson, James F, Kanters, Jørgen K, Sotoodehnia, Nona, Mifsud, Borbala, Lambiase, Pier D, Tereshchenko, Larisa G, and Munroe, Patricia B
Subjects: Electrocardiography/methods, General Physics and Astronomy, 610 Medicine & health, Arrhythmias, Cardiovascular, General Biochemistry, Genetics and Molecular Biology, cardiac arrhythmia, Electrocardiography, SDG 3 - Good Health and Well-being, Risk Factors, Cardiovascular Diseases/genetics, Genetics, Humans, Arrhythmias, Cardiac/genetics, Atrioventricular Block, Multidisciplinary, Human Genome, General Chemistry, Heart Disease, Cardiovascular Diseases, Cardiac, Biomarkers, Genome-Wide Association Study
Abstract: The 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic influences with PR interval and QRS duration. Phenome-wide scanning indicate associations with atrial fibrillation, atrioventricular block and arterial embolism and genetically determined QRS-T angle measures are associated with fascicular and bundle branch block (and also atrioventricular block for the frontal QRS-T angle). We identify potential biology involved in the QRS-T angle and their genetic relationships with cardiovascular traits and diseases, may inform future research and risk prediction.
Published: 2023
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25. Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Author: Stavroula Kanoni, Sarah E. Graham, Yuxuan Wang, Ida Surakka, Shweta Ramdas, Xiang Zhu, Shoa L. Clarke, Konain Fatima Bhatti, Sailaja Vedantam, Thomas W. Winkler, Adam E. Locke, Eirini Marouli, Greg J. M. Zajac, Kuan-Han H. Wu, Ioanna Ntalla, Qin Hui, Derek Klarin, Austin T. Hilliard, Zeyuan Wang, Chao Xue, Gudmar Thorleifsson, Anna Helgadottir, Daniel F. Gudbjartsson, Hilma Holm, Isleifur Olafsson, Mi Yeong Hwang, Sohee Han, Masato Akiyama, Saori Sakaue, Chikashi Terao, Masahiro Kanai, Wei Zhou, Ben M. Brumpton, Humaira Rasheed, Aki S. Havulinna, Yogasudha Veturi, Jennifer Allen Pacheco, Elisabeth A. Rosenthal, Todd Lingren, QiPing Feng, Iftikhar J. Kullo, Akira Narita, Jun Takayama, Hilary C. Martin, Karen A. Hunt, Bhavi Trivedi, Jeffrey Haessler, Franco Giulianini, Yuki Bradford, Jason E. Miller, Archie Campbell, Kuang Lin, Iona Y. Millwood, Asif Rasheed, George Hindy, Jessica D. Faul, Wei Zhao, David R. Weir, Constance Turman, Hongyan Huang, Mariaelisa Graff, Ananyo Choudhury, Dhriti Sengupta, Anubha Mahajan, Michael R. Brown, Weihua Zhang, Ketian Yu, Ellen M. Schmidt, Anita Pandit, Stefan Gustafsson, Xianyong Yin, Jian’an Luan, Jing-Hua Zhao, Fumihiko Matsuda, Hye-Mi Jang, Kyungheon Yoon, Carolina Medina-Gomez, Achilleas Pitsillides, Jouke Jan Hottenga, Andrew R. Wood, Yingji Ji, Zishan Gao, Simon Haworth, Noha A. Yousri, Ruth E. Mitchell, Jin Fang Chai, Mette Aadahl, Anne A. Bjerregaard, Jie Yao, Ani Manichaikul, Chii-Min Hwu, Yi-Jen Hung, Helen R. Warren, Julia Ramirez, Jette Bork-Jensen, Line L. Kårhus, Anuj Goel, Maria Sabater-Lleal, Raymond Noordam, Pala Mauro, Floris Matteo, Aaron F. McDaid, Pedro Marques-Vidal, Matthias Wielscher, Stella Trompet, Naveed Sattar, Line T. Møllehave, Matthias Munz, Lingyao Zeng, Jianfeng Huang, Bin Yang, Alaitz Poveda, Azra Kurbasic, Claudia Lamina, Lukas Forer, Markus Scholz, Tessel E. Galesloot, Jonathan P. Bradfield, Sanni E. Ruotsalainen, EWarwick Daw, Joseph M. Zmuda, Jonathan S. Mitchell, Christian Fuchsberger, Henry Christensen, Jennifer A. Brody, Miguel Vazquez-Moreno, Mary F. Feitosa, Mary K. Wojczynski, Zhe Wang, Michael H. Preuss, Massimo Mangino, Paraskevi Christofidou, Niek Verweij, Jan W. Benjamins, Jorgen Engmann, Noah L. Tsao, Anurag Verma, Roderick C. Slieker, Ken Sin Lo, Nuno R. Zilhao, Phuong Le, Marcus E. Kleber, Graciela E. Delgado, Shaofeng Huo, Daisuke D. Ikeda, Hiroyuki Iha, Jian Yang, Jun Liu, Ayşe Demirkan, Hampton L. Leonard, Jonathan Marten, Mirjam Frank, Börge Schmidt, Laura J. Smyth, Marisa Cañadas-Garre, Chaolong Wang, Masahiro Nakatochi, Andrew Wong, Nina Hutri-Kähönen, Xueling Sim, Rui Xia, Alicia Huerta-Chagoya, Juan Carlos Fernandez-Lopez, Valeriya Lyssenko, Suraj S. Nongmaithem, Swati Bayyana, Heather M. Stringham, Marguerite R. Irvin, Christopher Oldmeadow, Han-Na Kim, Seungho Ryu, Paul R. H. J. Timmers, Liubov Arbeeva, Rajkumar Dorajoo, Leslie A. Lange, Gauri Prasad, Laura Lorés-Motta, Marc Pauper, Jirong Long, Xiaohui Li, Elizabeth Theusch, Fumihiko Takeuchi, Cassandra N. Spracklen, Anu Loukola, Sailalitha Bollepalli, Sophie C. Warner, Ya Xing Wang, Wen B. Wei, Teresa Nutile, Daniela Ruggiero, Yun Ju Sung, Shufeng Chen, Fangchao Liu, Jingyun Yang, Katherine A. Kentistou, Bernhard Banas, Giuseppe Giovanni Nardone, Karina Meidtner, Lawrence F. Bielak, Jennifer A. Smith, Prashantha Hebbar, Aliki-Eleni Farmaki, Edith Hofer, Maoxuan Lin, Maria Pina Concas, Simona Vaccargiu, Peter J. van der Most, Niina Pitkänen, Brian E. Cade, Sander W. van der Laan, Kumaraswamy Naidu Chitrala, Stefan Weiss, Amy R. Bentley, Ayo P. Doumatey, Adebowale A. Adeyemo, Jong Young Lee, Eva R. B. Petersen, Aneta A. Nielsen, Hyeok Sun Choi, Maria Nethander, Sandra Freitag-Wolf, Lorraine Southam, Nigel W. Rayner, Carol A. Wang, Shih-Yi Lin, Jun-Sing Wang, Christian Couture, Leo-Pekka Lyytikäinen, Kjell Nikus, Gabriel Cuellar-Partida, Henrik Vestergaard, Bertha Hidalgo, Olga Giannakopoulou, Qiuyin Cai, Morgan O. Obura, Jessica van Setten, Xiaoyin Li, Jingjing Liang, Hua Tang, Natalie Terzikhan, Jae Hun Shin, Rebecca D. Jackson, Alexander P. Reiner, Lisa Warsinger Martin, Zhengming Chen, Liming Li, Takahisa Kawaguchi, Joachim Thiery, Joshua C. Bis, Lenore J. Launer, Huaixing Li, Mike A. Nalls, Olli T. Raitakari, Sahoko Ichihara, Sarah H. Wild, Christopher P. Nelson, Harry Campbell, Susanne Jäger, Toru Nabika, Fahd Al-Mulla, Harri Niinikoski, Peter S. Braund, Ivana Kolcic, Peter Kovacs, Tota Giardoglou, Tomohiro Katsuya, Dominique de Kleijn, Gert J. de Borst, Eung Kweon Kim, Hieab H. H. Adams, M. Arfan Ikram, Xiaofeng Zhu, Folkert W. Asselbergs, Adriaan O. Kraaijeveld, Joline W. J. Beulens, Xiao-Ou Shu, Loukianos S. Rallidis, Oluf Pedersen, Torben Hansen, Paul Mitchell, Alex W. Hewitt, Mika Kähönen, Louis Pérusse, Claude Bouchard, Anke Tönjes, Yii-Der Ida Chen, Craig E. Pennell, Trevor A. Mori, Wolfgang Lieb, Andre Franke, Claes Ohlsson, Dan Mellström, Yoon Shin Cho, Hyejin Lee, Jian-Min Yuan, Woon-Puay Koh, Sang Youl Rhee, Jeong-Taek Woo, Iris M. Heid, Klaus J. Stark, Martina E. Zimmermann, Henry Völzke, Georg Homuth, Michele K. Evans, Alan B. Zonderman, Ozren Polasek, Gerard Pasterkamp, Imo E. Hoefer, Susan Redline, Katja Pahkala, Albertine J. Oldehinkel, Harold Snieder, Ginevra Biino, Reinhold Schmidt, Helena Schmidt, Stefania Bandinelli, George Dedoussis, Thangavel Alphonse Thanaraj, Sharon L. R. Kardia, Patricia A. Peyser, Norihiro Kato, Matthias B. Schulze, Giorgia Girotto, Carsten A. Böger, Bettina Jung, Peter K. Joshi, David A. Bennett, Philip L. De Jager, Xiangfeng Lu, Vasiliki Mamakou, Morris Brown, Mark J. Caulfield, Patricia B. Munroe, Xiuqing Guo, Marina Ciullo, Jost B. Jonas, Nilesh J. Samani, Jaakko Kaprio, Päivi Pajukanta, Teresa Tusié-Luna, Carlos A. Aguilar-Salinas, Linda S. Adair, Sonny Augustin Bechayda, H. Janaka de Silva, Ananda R. Wickremasinghe, Ronald M. Krauss, Jer-Yuarn Wu, Wei Zheng, Anneke Iden Hollander, Dwaipayan Bharadwaj, Adolfo Correa, James G. Wilson, Lars Lind, Chew-Kiat Heng, Amanda E. Nelson, Yvonne M. Golightly, James F. Wilson, Brenda Penninx, Hyung-Lae Kim, John Attia, Rodney J. Scott, D. C. Rao, Donna K. Arnett, Steven C. Hunt, Mark Walker, Heikki A. Koistinen, Giriraj R. Chandak, Josep M. Mercader, Maria C. Costanzo, Dongkeun Jang, Noël P. Burtt, Clicerio Gonzalez Villalpando, Lorena Orozco, Myriam Fornage, EShyong Tai, Rob M. van Dam, Terho Lehtimäki, Nish Chaturvedi, Mitsuhiro Yokota, Jianjun Liu, Dermot F. Reilly, Amy Jayne McKnight, Frank Kee, Karl-Heinz Jöckel, Mark I. McCarthy, Colin N. A. Palmer, Veronique Vitart, Caroline Hayward, Eleanor Simonsick, Cornelia M. van Duijn, Zi-Bing Jin, Jia Qu, Haretsugu Hishigaki, Xu Lin, Winfried März, Vilmundur Gudnason, Jean-Claude Tardif, Guillaume Lettre, Leen M.‘t Hart, Petra J. M. Elders, Scott M. Damrauer, Meena Kumari, Mika Kivimaki, Pim van der Harst, Tim D. Spector, Ruth J. F. Loos, Michael A. Province, Esteban J. Parra, Miguel Cruz, Bruce M. Psaty, Ivan Brandslund, Peter P. Pramstaller, Charles N. Rotimi, Kaare Christensen, Samuli Ripatti, Elisabeth Widén, Hakon Hakonarson, Struan F. A. Grant, Lambertus A. L. M. Kiemeney, Jacqueline de Graaf, Markus Loeffler, Florian Kronenberg, Dongfeng Gu, Jeanette Erdmann, Heribert Schunkert, Paul W. Franks, Allan Linneberg, J. Wouter Jukema, Amit V. Khera, Minna Männikkö, Marjo-Riitta Jarvelin, Zoltan Kutalik, Cucca Francesco, Dennis O. Mook-Kanamori, Ko Willems van Dijk, Hugh Watkins, David P. Strachan, Niels Grarup, Peter Sever, Neil Poulter, Lee-Ming Chuang, Jerome I. Rotter, Thomas M. Dantoft, Fredrik Karpe, Matt J. Neville, Nicholas J. Timpson, Ching-Yu Cheng, Tien-Yin Wong, Chiea Chuen Khor, Hengtong Li, Charumathi Sabanayagam, Annette Peters, Christian Gieger, Andrew T. Hattersley, Nancy L. Pedersen, Patrik K. E. Magnusson, Dorret I. Boomsma, Allegonda H. M. Willemsen, LAdrienne Cupples, Joyce B. J. van Meurs, Mohsen Ghanbari, Penny Gordon-Larsen, Wei Huang, Young Jin Kim, Yasuharu Tabara, Nicholas J. Wareham, Claudia Langenberg, Eleftheria Zeggini, Johanna Kuusisto, Markku Laakso, Erik Ingelsson, Goncalo Abecasis, John C. Chambers, Jaspal S. Kooner, Paul S. de Vries, Alanna C. Morrison, Scott Hazelhurst, Michèle Ramsay, Kari E. North, Martha Daviglus, Peter Kraft, Nicholas G. Martin, John B. Whitfield, Shahid Abbas, Danish Saleheen, Robin G. Walters, Michael V. Holmes, Corri Black, Blair H. Smith, Aris Baras, Anne E. Justice, Julie E. Buring, Paul M. Ridker, Daniel I. Chasman, Charles Kooperberg, Gen Tamiya, Masayuki Yamamoto, David A. van Heel, Richard C. Trembath, Wei-Qi Wei, Gail P. Jarvik, Bahram Namjou, M. Geoffrey Hayes, Marylyn D. Ritchie, Pekka Jousilahti, Veikko Salomaa, Kristian Hveem, Bjørn Olav Åsvold, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, Yoshinori Murakami, Bong-Jo Kim, Unnur Thorsteinsdottir, Kari Stefansson, Jifeng Zhang, YEugene Chen, Yuk-Lam Ho, Julie A. Lynch, Daniel J. Rader, Philip S. Tsao, Kyong-Mi Chang, Kelly Cho, Christopher J. O’Donnell, John M. Gaziano, Peter W. F. Wilson, Timothy M. Frayling, Joel N. Hirschhorn, Sekar Kathiresan, Karen L. Mohlke, Yan V. Sun, Andrew P. Morris, Michael Boehnke, Christopher D. Brown, Pradeep Natarajan, Panos Deloukas, Cristen J. Willer, Themistocles L. Assimes, Gina M. Peloso, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Amsterdam Reproduction & Development, APH - Mental Health, APH - Methodology, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Medicum, Institute for Molecular Medicine Finland, Complex Disease Genetics, Samuli Olli Ripatti / Principal Investigator, HUSLAB, Epigenetics of Complex Diseases and Traits, Department of Medicine, Helsinki University Hospital Area, Centre of Excellence in Complex Disease Genetics, Department of Public Health, Faculty Common Matters (Faculty of Social Sciences), Elisabeth Ingrid Maria Widen / Principal Investigator, Genomic Discoveries and Clinical Translation, Tampere University, Primary Health Care, Clinical Medicine, Department of Clinical Chemistry, TAYS Heart Centre, Department of Clinical Physiology and Nuclear Medicine, Epidemiology and Data Science, APH - Aging & Later Life, ACS - Diabetes & metabolism, ACS - Heart failure & arrhythmias, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, General practice, APH - Digital Health, Lee Kong Chian School of Medicine (LKCMedicine), Peloso, Gina M [0000-0002-5355-8636], Apollo - University of Cambridge Repository, Epidemiology, Department of Marketing Management, Erasmus MC other, Radiology & Nuclear Medicine, Kanoni, Stavroula, Graham, Sarah E, Wang, Yuxuan, Surakka, Ida, Ramdas, Shweta, Zhu, Xiang, Clarke, Shoa L, Bhatti, Konain Fatima, Vedantam, Sailaja, Winkler, Thomas W, Locke, Adam E, Marouli, Eirini, Zajac, Greg J M, Wu, Kuan-Han H, Ntalla, Ioanna, Hui, Qin, Klarin, Derek, Hilliard, Austin T, Wang, Zeyuan, Xue, Chao, Thorleifsson, Gudmar, Helgadottir, Anna, Gudbjartsson, Daniel F, Holm, Hilma, Olafsson, Isleifur, Hwang, Mi Yeong, Han, Sohee, Akiyama, Masato, Sakaue, Saori, Terao, Chikashi, Kanai, Masahiro, Zhou, Wei, Brumpton, Ben M, Rasheed, Humaira, Havulinna, Aki S, Veturi, Yogasudha, Pacheco, Jennifer Allen, Rosenthal, Elisabeth A, Lingren, Todd, Feng, Qiping, Kullo, Iftikhar J, Narita, Akira, Takayama, Jun, Martin, Hilary C, Hunt, Karen A, Trivedi, Bhavi, Haessler, Jeffrey, Giulianini, Franco, Bradford, Yuki, Miller, Jason E, Campbell, Archie, Lin, Kuang, Millwood, Iona Y, Rasheed, Asif, Hindy, George, Faul, Jessica D, Zhao, Wei, Weir, David R, Turman, Constance, Huang, Hongyan, Graff, Mariaelisa, Choudhury, Ananyo, Sengupta, Dhriti, Mahajan, Anubha, Brown, Michael R, Zhang, Weihua, Yu, Ketian, Schmidt, Ellen M, Pandit, Anita, Gustafsson, Stefan, Yin, Xianyong, Luan, Jian'An, Zhao, Jing-Hua, Matsuda, Fumihiko, Jang, Hye-Mi, Yoon, Kyungheon, Medina-Gomez, Carolina, Pitsillides, Achillea, Hottenga, Jouke Jan, Wood, Andrew R, Ji, Yingji, Gao, Zishan, Haworth, Simon, Yousri, Noha A, Mitchell, Ruth E, Chai, Jin Fang, Aadahl, Mette, Bjerregaard, Anne A, Yao, Jie, Manichaikul, Ani, Hwu, Chii-Min, Hung, Yi-Jen, Warren, Helen R, Ramirez, Julia, Bork-Jensen, Jette, Kårhus, Line L, Goel, Anuj, Sabater-Lleal, Maria, Noordam, Raymond, Mauro, Pala, Matteo, Flori, Mcdaid, Aaron F, Marques-Vidal, Pedro, Wielscher, Matthia, Trompet, Stella, Sattar, Naveed, Møllehave, Line T, Munz, Matthia, Zeng, Lingyao, Huang, Jianfeng, Yang, Bin, Poveda, Alaitz, Kurbasic, Azra, Lamina, Claudia, Forer, Luka, Scholz, Marku, Galesloot, Tessel E, Bradfield, Jonathan P, Ruotsalainen, Sanni E, Daw, Ewarwick, Zmuda, Joseph M, Mitchell, Jonathan S, Fuchsberger, Christian, Christensen, Henry, Brody, Jennifer A, Vazquez-Moreno, Miguel, Feitosa, Mary F, Wojczynski, Mary K, Wang, Zhe, Preuss, Michael H, Mangino, Massimo, Christofidou, Paraskevi, Verweij, Niek, Benjamins, Jan W, Engmann, Jorgen, Tsao, Noah L, Verma, Anurag, Slieker, Roderick C, Lo, Ken Sin, Zilhao, Nuno R, Le, Phuong, Kleber, Marcus E, Delgado, Graciela E, Huo, Shaofeng, Ikeda, Daisuke D, Iha, Hiroyuki, Yang, Jian, Liu, Jun, Demirkan, Ayşe, Leonard, Hampton L, Marten, Jonathan, Frank, Mirjam, Schmidt, Börge, Smyth, Laura J, Cañadas-Garre, Marisa, Wang, Chaolong, Nakatochi, Masahiro, Wong, Andrew, Hutri-Kähönen, Nina, Sim, Xueling, Xia, Rui, Huerta-Chagoya, Alicia, Fernandez-Lopez, Juan Carlo, Lyssenko, Valeriya, Nongmaithem, Suraj S, Bayyana, Swati, Stringham, Heather M, Irvin, Marguerite R, Oldmeadow, Christopher, Kim, Han-Na, Ryu, Seungho, Timmers, Paul R H J, Arbeeva, Liubov, Dorajoo, Rajkumar, Lange, Leslie A, Prasad, Gauri, Lorés-Motta, Laura, Pauper, Marc, Long, Jirong, Li, Xiaohui, Theusch, Elizabeth, Takeuchi, Fumihiko, Spracklen, Cassandra N, Loukola, Anu, Bollepalli, Sailalitha, Warner, Sophie C, Wang, Ya Xing, Wei, Wen B, Nutile, Teresa, Ruggiero, Daniela, Sung, Yun Ju, Chen, Shufeng, Liu, Fangchao, Yang, Jingyun, Kentistou, Katherine A, Banas, Bernhard, Nardone, Giuseppe Giovanni, Meidtner, Karina, Bielak, Lawrence F, Smith, Jennifer A, Hebbar, Prashantha, Farmaki, Aliki-Eleni, Hofer, Edith, Lin, Maoxuan, Concas, Maria Pina, Vaccargiu, Simona, van der Most, Peter J, Pitkänen, Niina, Cade, Brian E, van der Laan, Sander W, Chitrala, Kumaraswamy Naidu, Weiss, Stefan, Bentley, Amy R, Doumatey, Ayo P, Adeyemo, Adebowale A, Lee, Jong Young, Petersen, Eva R B, Nielsen, Aneta A, Choi, Hyeok Sun, Nethander, Maria, Freitag-Wolf, Sandra, Southam, Lorraine, Rayner, Nigel W, Wang, Carol A, Lin, Shih-Yi, Wang, Jun-Sing, Couture, Christian, Lyytikäinen, Leo-Pekka, Nikus, Kjell, Cuellar-Partida, Gabriel, Vestergaard, Henrik, Hidalgo, Bertha, Giannakopoulou, Olga, Cai, Qiuyin, Obura, Morgan O, van Setten, Jessica, Li, Xiaoyin, Liang, Jingjing, Tang, Hua, Terzikhan, Natalie, Shin, Jae Hun, Jackson, Rebecca D, Reiner, Alexander P, Martin, Lisa Warsinger, Chen, Zhengming, Li, Liming, Kawaguchi, Takahisa, Thiery, Joachim, Bis, Joshua C, Launer, Lenore J, Li, Huaixing, Nalls, Mike A, Raitakari, Olli T, Ichihara, Sahoko, Wild, Sarah H, Nelson, Christopher P, Campbell, Harry, Jäger, Susanne, Nabika, Toru, Al-Mulla, Fahd, Niinikoski, Harri, Braund, Peter S, Kolcic, Ivana, Kovacs, Peter, Giardoglou, Tota, Katsuya, Tomohiro, de Kleijn, Dominique, de Borst, Gert J, Kim, Eung Kweon, Adams, Hieab H H, Ikram, M Arfan, Zhu, Xiaofeng, Asselbergs, Folkert W, Kraaijeveld, Adriaan O, Beulens, Joline W J, Shu, Xiao-Ou, Rallidis, Loukianos S, Pedersen, Oluf, Hansen, Torben, Mitchell, Paul, Hewitt, Alex W, Kähönen, Mika, Pérusse, Loui, Bouchard, Claude, Tönjes, Anke, Chen, Yii-Der Ida, Pennell, Craig E, Mori, Trevor A, Lieb, Wolfgang, Franke, Andre, Ohlsson, Clae, Mellström, Dan, Cho, Yoon Shin, Lee, Hyejin, Yuan, Jian-Min, Koh, Woon-Puay, Rhee, Sang Youl, Woo, Jeong-Taek, Heid, Iris M, Stark, Klaus J, Zimmermann, Martina E, Völzke, Henry, Homuth, Georg, Evans, Michele K, Zonderman, Alan B, Polasek, Ozren, Pasterkamp, Gerard, Hoefer, Imo E, Redline, Susan, Pahkala, Katja, Oldehinkel, Albertine J, Snieder, Harold, Biino, Ginevra, Schmidt, Reinhold, Schmidt, Helena, Bandinelli, Stefania, Dedoussis, George, Thanaraj, Thangavel Alphonse, Kardia, Sharon L R, Peyser, Patricia A, Kato, Norihiro, Schulze, Matthias B, Girotto, Giorgia, Böger, Carsten A, Jung, Bettina, Joshi, Peter K, Bennett, David A, De Jager, Philip L, Lu, Xiangfeng, Mamakou, Vasiliki, Brown, Morri, Caulfield, Mark J, Munroe, Patricia B, Guo, Xiuqing, Ciullo, Marina, Jonas, Jost B, Samani, Nilesh J, Kaprio, Jaakko, Pajukanta, Päivi, Tusié-Luna, Teresa, Aguilar-Salinas, Carlos A, Adair, Linda S, Bechayda, Sonny Augustin, de Silva, H Janaka, Wickremasinghe, Ananda R, Krauss, Ronald M, Wu, Jer-Yuarn, Zheng, Wei, Hollander, Anneke Iden, Bharadwaj, Dwaipayan, Correa, Adolfo, Wilson, James G, Lind, Lar, Heng, Chew-Kiat, Nelson, Amanda E, Golightly, Yvonne M, Wilson, James F, Penninx, Brenda, Kim, Hyung-Lae, Attia, John, Scott, Rodney J, Rao, D C, Arnett, Donna K, Hunt, Steven C, Walker, Mark, Koistinen, Heikki A, Chandak, Giriraj R, Mercader, Josep M, Costanzo, Maria C, Jang, Dongkeun, Burtt, Noël P, Villalpando, Clicerio Gonzalez, Orozco, Lorena, Fornage, Myriam, Tai, Eshyong, van Dam, Rob M, Lehtimäki, Terho, Chaturvedi, Nish, Yokota, Mitsuhiro, Liu, Jianjun, Reilly, Dermot F, Mcknight, Amy Jayne, Kee, Frank, Jöckel, Karl-Heinz, Mccarthy, Mark I, Palmer, Colin N A, Vitart, Veronique, Hayward, Caroline, Simonsick, Eleanor, van Duijn, Cornelia M, Jin, Zi-Bing, Qu, Jia, Hishigaki, Haretsugu, Lin, Xu, März, Winfried, Gudnason, Vilmundur, Tardif, Jean-Claude, Lettre, Guillaume, Hart, Leen M 't, Elders, Petra J M, Damrauer, Scott M, Kumari, Meena, Kivimaki, Mika, van der Harst, Pim, Spector, Tim D, Loos, Ruth J F, Province, Michael A, Parra, Esteban J, Cruz, Miguel, Psaty, Bruce M, Brandslund, Ivan, Pramstaller, Peter P, Rotimi, Charles N, Christensen, Kaare, Ripatti, Samuli, Widén, Elisabeth, Hakonarson, Hakon, Grant, Struan F A, Kiemeney, Lambertus A L M, de Graaf, Jacqueline, Loeffler, Marku, Kronenberg, Florian, Gu, Dongfeng, Erdmann, Jeanette, Schunkert, Heribert, Franks, Paul W, Linneberg, Allan, Jukema, J Wouter, Khera, Amit V, Männikkö, Minna, Jarvelin, Marjo-Riitta, Kutalik, Zoltan, Francesco, Cucca, Mook-Kanamori, Dennis O, van Dijk, Ko Willem, Watkins, Hugh, Strachan, David P, Grarup, Niel, Sever, Peter, Poulter, Neil, Chuang, Lee-Ming, Rotter, Jerome I, Dantoft, Thomas M, Karpe, Fredrik, Neville, Matt J, Timpson, Nicholas J, Cheng, Ching-Yu, Wong, Tien-Yin, Khor, Chiea Chuen, Li, Hengtong, Sabanayagam, Charumathi, Peters, Annette, Gieger, Christian, Hattersley, Andrew T, Pedersen, Nancy L, Magnusson, Patrik K E, Boomsma, Dorret I, Willemsen, Allegonda H M, Cupples, Ladrienne, van Meurs, Joyce B J, Ghanbari, Mohsen, Gordon-Larsen, Penny, Huang, Wei, Kim, Young Jin, Tabara, Yasuharu, Wareham, Nicholas J, Langenberg, Claudia, Zeggini, Eleftheria, Kuusisto, Johanna, Laakso, Markku, Ingelsson, Erik, Abecasis, Goncalo, Chambers, John C, Kooner, Jaspal S, de Vries, Paul S, Morrison, Alanna C, Hazelhurst, Scott, Ramsay, Michèle, North, Kari E, Daviglus, Martha, Kraft, Peter, Martin, Nicholas G, Whitfield, John B, Abbas, Shahid, Saleheen, Danish, Walters, Robin G, Holmes, Michael V, Black, Corri, Smith, Blair H, Baras, Ari, Justice, Anne E, Buring, Julie E, Ridker, Paul M, Chasman, Daniel I, Kooperberg, Charle, Tamiya, Gen, Yamamoto, Masayuki, van Heel, David A, Trembath, Richard C, Wei, Wei-Qi, Jarvik, Gail P, Namjou, Bahram, Hayes, M Geoffrey, Ritchie, Marylyn D, Jousilahti, Pekka, Salomaa, Veikko, Hveem, Kristian, Åsvold, Bjørn Olav, Kubo, Michiaki, Kamatani, Yoichiro, Okada, Yukinori, Murakami, Yoshinori, Kim, Bong-Jo, Thorsteinsdottir, Unnur, Stefansson, Kari, Zhang, Jifeng, Chen, Yeugene, Ho, Yuk-Lam, Lynch, Julie A, Rader, Daniel J, Tsao, Philip S, Chang, Kyong-Mi, Cho, Kelly, O'Donnell, Christopher J, Gaziano, John M, Wilson, Peter W F, Frayling, Timothy M, Hirschhorn, Joel N, Kathiresan, Sekar, Mohlke, Karen L, Sun, Yan V, Morris, Andrew P, Boehnke, Michael, Brown, Christopher D, Natarajan, Pradeep, Deloukas, Pano, Willer, Cristen J, Assimes, Themistocles L, and Peloso, Gina M
Subjects: Genome-wide association study, Medizin, Polymorphism, Single Nucleotide, Humans, Genome-Wide Association Study, Genetic Predisposition to Disease, Sex Characteristics, Phenotype, Lipids/genetics, Genetic Pleiotropy, Cholesterol, GWAS, Genetics, Lipids, Genetic, SDG 3 - Good Health and Well-being, Medicine [Science], 112 Statistics and probability, Medicinsk genetik, Genome-wide Association Study, Gwas, 1184 Genetics, developmental biology, physiology, 3126 Surgery, anesthesiology, intensive care, radiology, 3142 Public health care science, environmental and occupational health, 3141 Health care science, FOS: Biological sciences, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 3111 Biomedicine, Medical Genetics
Abstract: Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry metaanalysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk., United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Heart Lung & Blood Institute (NHLBI) R01HL127564 R01HL142711, Wellcome Trust 201543/B/16/Z 202802/Z/16/Z, European Commission HEALTH-F2-2013-601456 608765 786833, TriPartite Immunometabolism Consortium [TrIC]-Novo Nordisk Foundation NNF15CC0018486, American Diabetes Association 1-19-ICTS-068, Academy of Finland 312062 Finnish Foundation for Cardiovascular Research, Sigrid Juselius Foundation, Finnish innovation fund Sitra (EW) Finska Lakaresallskapet, American Heart Association 15POST24470131 17POST33650016, University of Bristol NIHR Biomedical Research Centre BRC-1215-2001, MRC & WT 217065/Z/19/Z, UK Research & Innovation (UKRI), Medical Research Council UK (MRC) MC_UU_00011, CRUK Integrative Cancer Epidemiology Programme C18281/A19169, Medical Research Council UK (MRC) MC_UU_00011/1, UK National Institute for Health Research Academic Clinical Fellowship, American Heart Association 18CDA34110116, Miguel Servet contract from the ISCIII Spanish Health Institute CP17/00142, European Social Fund (ESF), Westlake Education Foundation, British Heart Foundation FS/14/66/3129 Z01HG200362 R01HL142302 R01HL105756
Published: 2022
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26. Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways

Author: William J. Young, Najim Lahrouchi, Aaron Isaacs, ThuyVy Duong, Luisa Foco, Farah Ahmed, Jennifer A. Brody, Reem Salman, Raymond Noordam, Jan-Walter Benjamins, Jeffrey Haessler, Leo-Pekka Lyytikäinen, Linda Repetto, Maria Pina Concas, Marten E. van den Berg, Stefan Weiss, Antoine R. Baldassari, Traci M. Bartz, James P. Cook, Daniel S. Evans, Rebecca Freudling, Oliver Hines, Jonas L. Isaksen, Honghuang Lin, Hao Mei, Arden Moscati, Martina Müller-Nurasyid, Casia Nursyifa, Yong Qian, Anne Richmond, Carolina Roselli, Kathleen A. Ryan, Eduardo Tarazona-Santos, Sébastien Thériault, Stefan van Duijvenboden, Helen R. Warren, Jie Yao, Dania Raza, Stefanie Aeschbacher, Gustav Ahlberg, Alvaro Alonso, Laura Andreasen, Joshua C. Bis, Eric Boerwinkle, Archie Campbell, Eulalia Catamo, Massimiliano Cocca, Michael J. Cutler, Dawood Darbar, Alessandro De Grandi, Antonio De Luca, Jun Ding, Christina Ellervik, Patrick T. Ellinor, Stephan B. Felix, Philippe Froguel, Christian Fuchsberger, Martin Gögele, Claus Graff, Mariaelisa Graff, Xiuqing Guo, Torben Hansen, Susan R. Heckbert, Paul L. Huang, Heikki V. Huikuri, Nina Hutri-Kähönen, M. Arfan Ikram, Rebecca D. Jackson, Juhani Junttila, Maryam Kavousi, Jan A. Kors, Thiago P. Leal, Rozenn N. Lemaitre, Henry J. Lin, Lars Lind, Allan Linneberg, Simin Liu, Peter W. MacFarlane, Massimo Mangino, Thomas Meitinger, Massimo Mezzavilla, Pashupati P. Mishra, Rebecca N. Mitchell, Nina Mononen, May E. Montasser, Alanna C. Morrison, Matthias Nauck, Victor Nauffal, Pau Navarro, Kjell Nikus, Guillaume Pare, Kristen K. Patton, Giulia Pelliccione, Alan Pittman, David J. Porteous, Peter P. Pramstaller, Michael H. Preuss, Olli T. Raitakari, Alexander P. Reiner, Antonio Luiz P. Ribeiro, Kenneth M. Rice, Lorenz Risch, David Schlessinger, Ulrich Schotten, Claudia Schurmann, Xia Shen, M. Benjamin Shoemaker, Gianfranco Sinagra, Moritz F. Sinner, Elsayed Z. Soliman, Monika Stoll, Konstantin Strauch, Kirill Tarasov, Kent D. Taylor, Andrew Tinker, Stella Trompet, André Uitterlinden, Uwe Völker, Henry Völzke, Melanie Waldenberger, Lu-Chen Weng, Eric A. Whitsel, James G. Wilson, Christy L. Avery, David Conen, Adolfo Correa, Francesco Cucca, Marcus Dörr, Sina A. Gharib, Giorgia Girotto, Niels Grarup, Caroline Hayward, Yalda Jamshidi, Marjo-Riitta Järvelin, J. Wouter Jukema, Stefan Kääb, Mika Kähönen, Jørgen K. Kanters, Charles Kooperberg, Terho Lehtimäki, Maria Fernanda Lima-Costa, Yongmei Liu, Ruth J. F. Loos, Steven A. Lubitz, Dennis O. Mook-Kanamori, Andrew P. Morris, Jeffrey R. O’Connell, Morten Salling Olesen, Michele Orini, Sandosh Padmanabhan, Cristian Pattaro, Annette Peters, Bruce M. Psaty, Jerome I. Rotter, Bruno Stricker, Pim van der Harst, Cornelia M. van Duijn, Niek Verweij, James F. Wilson, Dan E. Arking, Julia Ramirez, Pier D. Lambiase, Nona Sotoodehnia, Borbala Mifsud, Christopher Newton-Cheh, Patricia B. Munroe, Cardiology, ACS - Heart failure & arrhythmias, Epidemiology, Radiology & Nuclear Medicine, Medical Informatics, Internal Medicine, Young, William J, Lahrouchi, Najim, Isaacs, Aaron, Duong, Thuyvy, Foco, Luisa, Ahmed, Farah, Brody, Jennifer A, Salman, Reem, Noordam, Raymond, Benjamins, Jan-Walter, Haessler, Jeffrey, Lyytikäinen, Leo-Pekka, Repetto, Linda, Concas, Maria Pina, van den Berg, Marten E, Weiss, Stefan, Baldassari, Antoine R, Bartz, Traci M, Cook, James P, Evans, Daniel S, Freudling, Rebecca, Hines, Oliver, Isaksen, Jonas L, Lin, Honghuang, Mei, Hao, Moscati, Arden, Müller-Nurasyid, Martina, Nursyifa, Casia, Qian, Yong, Richmond, Anne, Roselli, Carolina, Ryan, Kathleen A, Tarazona-Santos, Eduardo, Thériault, Sébastien, van Duijvenboden, Stefan, Warren, Helen R, Yao, Jie, Raza, Dania, Aeschbacher, Stefanie, Ahlberg, Gustav, Alonso, Alvaro, Andreasen, Laura, Bis, Joshua C, Boerwinkle, Eric, Campbell, Archie, Catamo, Eulalia, Cocca, Massimiliano, Cutler, Michael J, Darbar, Dawood, De Grandi, Alessandro, De Luca, Antonio, Ding, Jun, Ellervik, Christina, Ellinor, Patrick T, Felix, Stephan B, Froguel, Philippe, Fuchsberger, Christian, Gögele, Martin, Graff, Clau, Graff, Mariaelisa, Guo, Xiuqing, Hansen, Torben, Heckbert, Susan R, Huang, Paul L, Huikuri, Heikki V, Hutri-Kähönen, Nina, Ikram, M Arfan, Jackson, Rebecca D, Junttila, Juhani, Kavousi, Maryam, Kors, Jan A, Leal, Thiago P, Lemaitre, Rozenn N, Lin, Henry J, Lind, Lar, Linneberg, Allan, Liu, Simin, Macfarlane, Peter W, Mangino, Massimo, Meitinger, Thoma, Mezzavilla, Massimo, Mishra, Pashupati P, Mitchell, Rebecca N, Mononen, Nina, Montasser, May E, Morrison, Alanna C, Nauck, Matthia, Nauffal, Victor, Navarro, Pau, Nikus, Kjell, Pare, Guillaume, Patton, Kristen K, Pelliccione, Giulia, Pittman, Alan, Porteous, David J, Pramstaller, Peter P, Preuss, Michael H, Raitakari, Olli T, Reiner, Alexander P, Ribeiro, Antonio Luiz P, Rice, Kenneth M, Risch, Lorenz, Schlessinger, David, Schotten, Ulrich, Schurmann, Claudia, Shen, Xia, Shoemaker, M Benjamin, Sinagra, Gianfranco, Sinner, Moritz F, Soliman, Elsayed Z, Stoll, Monika, Strauch, Konstantin, Tarasov, Kirill, Taylor, Kent D, Tinker, Andrew, Trompet, Stella, Uitterlinden, André, Völker, Uwe, Völzke, Henry, Waldenberger, Melanie, Weng, Lu-Chen, Whitsel, Eric A, Wilson, James G, Avery, Christy L, Conen, David, Correa, Adolfo, Cucca, Francesco, Dörr, Marcu, Gharib, Sina A, Girotto, Giorgia, Grarup, Niel, Hayward, Caroline, Jamshidi, Yalda, Järvelin, Marjo-Riitta, Jukema, J Wouter, Kääb, Stefan, Kähönen, Mika, Kanters, Jørgen K, Kooperberg, Charle, Lehtimäki, Terho, Lima-Costa, Maria Fernanda, Liu, Yongmei, Loos, Ruth J F, Lubitz, Steven A, Mook-Kanamori, Dennis O, Morris, Andrew P, O'Connell, Jeffrey R, Olesen, Morten Salling, Orini, Michele, Padmanabhan, Sandosh, Pattaro, Cristian, Peters, Annette, Psaty, Bruce M, Rotter, Jerome I, Stricker, Bruno, van der Harst, Pim, van Duijn, Cornelia M, Verweij, Niek, Wilson, James F, Arking, Dan E, Ramirez, Julia, Lambiase, Pier D, Sotoodehnia, Nona, Mifsud, Borbala, Newton-Cheh, Christopher, Munroe, Patricia B, Cardiovascular Centre (CVC), Tampere University, Department of Clinical Chemistry, Clinical Medicine, Department of Paediatrics, TAYS Heart Centre, Department of Clinical Physiology and Nuclear Medicine, Fysiologie, RS: Carim - B01 Blood proteins & engineering, RS: Carim - H08 Experimental atrial fibrillation, and Biochemie
Subjects: Male, Electrocardiography/methods, General Physics and Astronomy, 610 Medicine & health, Arrhythmias, 3121 Internal medicine, Genome-wide association studies, General Biochemistry, Genetics and Molecular Biology, Electrocardiography, Humans, Arrhythmias, Cardiac/genetics, Genetic Testing, Medicinsk genetik, Multidisciplinary, Death, Sudden, Cardiac, Arrhythmias, Cardiac, General Chemistry, Sudden, Electrocardiogram, Death, Genetic markers, 3111 Biomedicine, 610 Medizin und Gesundheit, Cardiac, Medical Genetics
Abstract: The QT interval is a heritable electrocardiographic measure associated with arrhythmia risk when prolonged. Here, the authors used a series of genetic analyses to identify genetic loci, pathways, therapeutic targets, and relationships with cardiovascular disease. The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.
Published: 2022
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27. Doris Duke Charitable Foundation Fund to Retain Clinical Scientists: innovating support for early-career family caregivers

Author: Reshma Jagsi, T. DeLene Beeland, Kevin Sia, Lauren A. Szczygiel, Matthew R. Allen, Vineet M. Arora, Megan Bair-Merritt, Melissa D. Bauman, Hillary R. Bogner, Gail Daumit, Esa Davis, Angela Fagerlin, Daniel E. Ford, Rasheed Gbadegesin, Kathy Griendling, Katherine Hartmann, S. Susan Hedayati, Rebecca D. Jackson, Susan Matulevicius, Michael J. Mugavero, Eric J. Nehl, Tuhina Neogi, Judith G. Regensteiner, Michael A. Rubin, Doris Rubio, Kanakadurga Singer, Brownsyne Tucker Edmonds, Anna Volerman, Sandra Laney, Carrie Patton, and Sindy Escobar Alvarez
Subjects: Caregivers, Financial Management, Physicians, Humans, General Medicine
Published: 2022

28. Template-based level set segmentation using anatomical information.

Author: Jeffrey W. Prescott, Mark S. Swanson, Kimerly A. Powell, Metin N. Gurcan, Furqan Haq, Thomas M. Best, and Rebecca D. Jackson
Published: 2009
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29. Pandemic-related barriers to the success of women in research: a framework for action

Author: Pamela B. Davis, Emma A. Meagher, Claire Pomeroy, William L. Lowe, Arthur H. Rubenstein, Joy Y. Wu, Anne B. Curtis, and Rebecca D. Jackson
Subjects: General Medicine, General Biochemistry, Genetics and Molecular Biology
Published: 2022
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30. Imputation of coding variants in African Americans: better performance using data from the exome sequencing project.

Author: Qing Duan, Eric Yi Liu, Paul L. Auer, Guosheng Zhang, Ethan M. Lange, Goo Jun, Chris Bizon, Shuo Jiao, Steven Buyske, Nora Franceschini, Chris S. Carlson, Li Hsu, Alex P. Reiner, Ulrike Peters, Jeffrey Haessler, Keith Curtis, Christina L. Wassel, Jennifer G. Robinson, Lisa W. Martin, Christopher A. Haiman, Loic Le Marchand, Tara Cox Matise, Lucia A. Hindorff, Dana C. Crawford, Themistocles L. Assimes, Hyun Min Kang, Gerardo Heiss, Rebecca D. Jackson, Charles Kooperberg, James G. Wilson, Gonçalo R. Abecasis, Kari E. North, Deborah A. Nickerson, Leslie A. Lange, and Yun Li
Published: 2013
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31. Multi-phenotype analyses of hemostatic traits with cardiovascular events reveal novel genetic associations

Author: Gerard Temprano‐Sagrera, Colleen M. Sitlani, William P. Bone, Miguel Martin‐Bornez, Benjamin F. Voight, Alanna C. Morrison, Scott M. Damrauer, Paul S. de Vries, Nicholas L. Smith, Maria Sabater‐Lleal, Abbas Dehghan, Adam S Heath, Alanna C Morrison, Alex P Reiner, Andrew Johnson, Anne Richmond, Annette Peters, Astrid van Hylckama Vlieg, Barbara McKnight, Bruce M Psaty, Caroline Hayward, Cavin Ward‐Caviness, Christopher O’Donnell, Daniel Chasman, David P Strachan, David A Tregouet, Dennis Mook‐Kanamori, Dipender Gill, Florian Thibord, Folkert W Asselbergs, Frank W.G. Leebeek, Frits R Rosendaal, Gail Davies, Georg Homuth, Gerard Temprano, Harry Campbell, Herman A Taylor, Jan Bressler, Jennifer E Huffman, Jerome I Rotter, Jie Yao, James F Wilson, Joshua C Bis, Julie M Hahn, Karl C Desch, Kerri L Wiggins, Laura M Raffield, Lawrence F Bielak, Lisa R Yanek, Marcus E Kleber, Martina Mueller, Maryam Kavousi, Massimo Mangino, Melissa Liu, Michael R Brown, Matthew P Conomos, Min‐A Jhun, Ming‐Huei Chen, Moniek P.M. de Maat, Nathan Pankratz, Nicholas L Smith, Patricia A Peyser, Paul Elliot, Paul S de Vries, Peng Wei, Philipp S Wild, Pierre E Morange, Pim van der Harst, Qiong Yang, Ngoc‐Quynh Le, Riccardo Marioni, Ruifang Li, Scott M Damrauer, Simon R Cox, Stella Trompet, Stephan B Felix, Uwe Völker, Weihong Tang, Wolfgang Koenig, J. Wouter Jukema, Xiuqing Guo, Sara Lindstrom, Lu Wang, Erin N Smith, William Gordon, Mariza de Andrade, Jennifer A Brody, Jack W Pattee, Jeffrey Haessler, Ben M Brumpton, Daniel I Chasman, Pierre Suchon, Constance Turman, Marine Germain, James MacDonald, Sigrid K Braekkan, Sebastian M Armasu, Rabecca D Jackson, Jonas B Nielsen, Franco Giulianini, Marja K Puurunen, Manal Ibrahim, Susan R Heckbert, Theo K Bammler, Kelly A Frazer, Bryan M McCauley, Kent Taylor, James S Pankow, Alexander P Reiner, Maiken E Gabrielsen, Jean‐François Deleuze, Chris J O’Donnell, Jihye Kim, Peter Kraft, John‐Bjarne Hansen, John A Heit, Charles Kooperberg, Kristian Hveem, Paul M Ridker, Pierre‐Emmanuel Morange, Andrew D Johnson, Christopher Kabrhel, David‐Alexandre Trégouët, Rainer Malik, Ganesh Chauhan, Matthew Traylor, Muralidharan Sargurupremraj, Yukinori Okada, Aniket Mishra, Loes Rutten‐Jacobs, Anne‐Katrin Giese, Sander W van der Laan, Solveig Gretarsdottir, Christopher D Anderson, Michael Chong, Hieab HH Adams, Tetsuro Ago, Peter Almgren, Philippe Amouyel, Hakan Ay, Traci M Bartz, Oscar R Benavente, Steve Bevan, Giorgio B Boncoraglio, Robert D Brown, Adam S Butterworth, Caty Carrera, Cara L Carty, Wei‐Min Chen, John W Cole, Adolfo Correa, Ioana Cotlarciuc, Carlos Cruchaga, John Danesh, Paul IW de Bakker, Anita L DeStefano, Marcel den Hoed, Qing Duan, Stefan T Engelter, Guido J Falcone, Rebecca F Gottesman, Raji P Grewal, Vilmundur Gudnason, Stefan Gustafsson, Tamara B Harris, Ahamad Hassan, Aki S Havulinna, Elizabeth G Holliday, George Howard, Fang‐Chi Hsu, Hyacinth I Hyacinth, M Arfan Ikram, Erik Ingelsson, Marguerite R Irvin, Xueqiu Jian, Jordi Jiménez‐Conde, Julie A Johnson, J Wouter Jukema, Masahiro Kanai, Keith L Keene, Brett M Kissela, Dawn O Kleindorfer, Michiaki Kubo, Leslie A Lange, Carl D Langefeld, Claudia Langenberg, Lenore J Launer, Jin‐Moo Lee, Robin Lemmens, Didier Leys, Cathryn M Lewis, Wei‐Yu Lin, Arne G Lindgren, Erik Lorentzen, Patrik K Magnusson, Jane Maguire, Ani Manichaikul, Patrick F McArdle, James F Meschia, Braxton D Mitchell, Thomas H Mosley, Michael A Nalls, Toshiharu Ninomiya, Martin J O’Donnell, Sara L Pulit, Kristiina Rannikmäe, Kathryn M Rexrode, Kenneth Rice, Stephen S Rich, Natalia S Rost, Peter M Rothwell, Tatjana Rundek, Ralph L Sacco, Saori Sakaue, Michele M Sale, Veikko Salomaa, Bishwa R Sapkota, Reinhold Schmidt, Carsten O Schmidt, Ulf Schminke, Pankaj Sharma, Agnieszka Slowik, Cathie LM Sudlow, Christian Tanislav, Turgut Tatlisumak, Kent D Taylor, Vincent NS Thijs, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Steffen Tiedt, Christophe Tzourio, Cornelia M van Duijn, Matthew Walters, Nicholas J Wareham, Sylvia Wassertheil‐Smoller, James G Wilson, Salim Yusuf, Najaf Amin, Hugo S Aparicio, Donna K Arnett, John Attia, Alexa S Beiser, Claudine Berr, Julie E Buring, Mariana Bustamante, Valeria Caso, Yu‐Ching Cheng, Seung Hoan Choi, Ayesha Chowhan, Natalia Cullell, Jean‐François Dartigues, Hossein Delavaran, Pilar Delgado, Marcus Dörr, Gunnar Engström, Ian Ford, Wander S Gurpreet, Anders Hamsten, Laura Heitsch, Atsushi Hozawa, Laura Ibanez, Andreea Ilinca, Martin Ingelsson, Motoki Iwasaki, Rebecca D Jackson, Katarina Jood, Pekka Jousilahti, Sara Kaffashian, Lalit Kalra, Masahiro Kamouchi, Takanari Kitazono, Olafur Kjartansson, Manja Kloss, Peter J Koudstaal, Jerzy Krupinski, Daniel L Labovitz, Cathy C Laurie, Christopher R Levi, Linxin Li, Lars Lind, Cecilia M Lindgren, Vasileios Lioutas, Yong Mei Liu, Oscar L Lopez, Hirata Makoto, Nicolas Martinez‐Majander, Koichi Matsuda, Naoko Minegishi, Joan Montaner, Andrew P Morris, Elena Muiño, Martina Müller‐Nurasyid, Bo Norrving, Soichi Ogishima, Eugenio A Parati, Leema Reddy Peddareddygari, Nancy L Pedersen, Joanna Pera, Markus Perola, Alessandro Pezzini, Silvana Pileggi, Raquel Rabionet, Iolanda Riba‐Llena, Marta Ribasés, Jose R Romero, Jaume Roquer, Anthony G Rudd, Antti‐Pekka Sarin, Ralhan Sarju, Chloe Sarnowski, Makoto Sasaki, Claudia L Satizabal, Mamoru Satoh, Naveed Sattar, Norie Sawada, Gerli Sibolt, Ásgeir Sigurdsson, Albert Smith, Kenji Sobue, Carolina Soriano‐Tárraga, Tara Stanne, O Colin Stine, David J Stott, Konstantin Strauch, Takako Takai, Hideo Tanaka, Kozo Tanno, Alexander Teumer, Liisa Tomppo, Nuria P Torres‐Aguila, Emmanuel Touze, Shoichiro Tsugane, Andre G Uitterlinden, Einar M Valdimarsson, Sven J van der Lee, Henry Völzke, Kenji Wakai, David Weir, Stephen R Williams, Charles DA Wolfe, Quenna Wong, Huichun Xu, Taiki Yamaji, Dharambir K Sanghera, Olle Melander, Christina Jern, Daniel Strbian, Israel Fernandez‐Cadenas, W T Longstreth, Arndt Rolfs, Jun Hata, Daniel Woo, Jonathan Rosand, Guillaume Pare, Jemma C Hopewell, Danish Saleheen, Kari Stefansson, Bradford B Worrall, Steven J Kittner, Sudha Seshadri, Myriam Fornage, Hugh S Markus, Joanna MM Howson, Yoichiro Kamatani, Stephanie Debette, Martin Dichgans, and VU University medical center
Subjects: Hemostasis, genome-wide association study, genetic pleiotropy, Hematology, Polymorphism, Single Nucleotide, Hemostatics, blood coagulation, cardiovascular diseases, Phenotype, Cardiovascular Diseases, Tissue Plasminogen Activator, hemostasis, Humans, Genetic Predisposition to Disease, Factor XI, Genome-Wide Association Study
Abstract: Background: Multi-phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes. Objectives: To discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events. Methods: Summary statistics from genome wide-association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen activator inhibitor 1 [PAI-1]) and three major cardiovascular (CV) events (venous thromboembolism [VTE], coronary artery disease [CAD], ischemic stroke [IS]), were combined in 27 multi-trait combinations using metaUSAT. Genetic correlations between phenotypes were calculated using Linkage Disequilibrium Score Regression (LDSC). Newly associated loci were investigated for colocalization. We considered a significance threshold of 1.85 × 10−9 obtained after applying Bonferroni correction for the number of multi-trait combinations performed (n = 27). Results: Across the 27 multi-trait analyses, we found 4 novel pleiotropic loci (XXYLT1, KNG1, SUGP1/MAU2, TBL2/MLXIPL) that were not significant in the original individual datasets, were not described in previous GWAS for the individual traits, and that presented a common associated variant between the studied phenotypes. Conclusions: The discovery of four novel loci contributes to the understanding of the relationship between hemostasis and CV events and elucidate common genetic factors between these traits.
Published: 2022
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32. Applying knowledge-anchored hypothesis discovery methods to advance clinical and translational research: the OAMiner project.

Author: Philip R. O. Payne, Rebecca D. Jackson, Thomas M. Best, Tara Borlawsky, Albert M. Lai, Stephen L. James, and Metin N. Gurcan
Published: 2012
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33. Anatomically Anchored Template-Based Level Set Segmentation: Application to Quadriceps Muscles in MR Images from the Osteoarthritis Initiative.

Author: Jeffrey W. Prescott, Thomas M. Best, Mark S. Swanson, Furqan Haq, Rebecca D. Jackson, and Metin N. Gurcan
Published: 2011
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34. Insulinemic and Inflammatory Dietary Patterns Show Enhanced Predictive Potential for Type 2 Diabetes Risk in Postmenopausal Women

Author: Darwin L. Conwell, Simin Liu, Lesley F. Tinker, Wei Bao, Rami Nassir, Theodore M. Brasky, Macarius Donneyong, Ni Shi, Phil A. Hart, Zobeida Cruz-Monserrate, Dong Hoon Lee, Lawrence S. Phillips, Qi Jin, Joshua J. Joseph, Xuehong Zhang, Desmond Aroke, Fred K. Tabung, Steven K. Clinton, Aladdin H. Shadyab, and Rebecca D. Jackson
Subjects: medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Type 2 diabetes, 03 medical and health sciences, 0302 clinical medicine, Diabetes mellitus, Internal medicine, Glycemic load, Dietary Carbohydrates, Internal Medicine, medicine, Hyperinsulinemia, Humans, 030212 general & internal medicine, Epidemiology/Health Services Research, Glycemic, Advanced and Specialized Nursing, business.industry, Absolute risk reduction, medicine.disease, Diet, Postmenopause, Postprandial, Glycemic index, Diabetes Mellitus, Type 2, Glycemic Index, Female, business
Abstract: OBJECTIVE The empirical dietary index for hyperinsulinemia (EDIH) and empirical dietary inflammatory pattern (EDIP) scores assess the insulinemic and inflammatory potentials of habitual dietary patterns, irrespective of the macronutrient content, and are based on plasma insulin response or inflammatory biomarkers, respectively. The glycemic index (GI) and glycemic load (GL) assess postprandial glycemic potential based on dietary carbohydrate content. We tested the hypothesis that dietary patterns promoting hyperinsulinemia, chronic inflammation, or hyperglycemia may influence type 2 diabetes risk. RESEARCH DESIGN AND METHODS We calculated dietary scores from baseline (1993–1998) food frequency questionnaires among 73,495 postmenopausal women in the Women’s Health Initiative, followed through March 2019. We used multivariable-adjusted Cox regression to estimate hazard ratios (HRs) and 95% CIs for type 2 diabetes risk. We also estimated multivariable-adjusted absolute risk of type 2 diabetes. RESULTS During a median 13.3 years of follow-up, 11,009 incident cases of type 2 diabetes were diagnosed. Participants consuming the most hyperinsulinemic or proinflammatory dietary patterns experienced greater risk of type 2 diabetes; HRs (95% CI) comparing highest to lowest dietary index quintiles were EDIH 1.49 (1.32–1.68; Ptrend < 0.0001) and EDIP 1.45 (1.29–1.63; Ptrend < 0.0001). The absolute excess incidence for the same comparison was 220 (EDIH) and 271 (EDIP) cases per 100,000 person-years. GI and GL were not associated with type 2 diabetes risk: GI 0.99 (0.88–1.12; Ptrend = 0.46) and GL 1.01 (0.89–1.16; Ptrend = 0.30). CONCLUSIONS Our findings in this diverse cohort of postmenopausal women suggest that lowering the insulinemic and inflammatory potentials of the diet may be more effective in preventing type 2 diabetes than focusing on glycemic foods.
Published: 2021
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35. A Meta‐Analysis of the Transferability of Bone Mineral Density Genetic Loci Associations From European to African Ancestry Populations

Author: Allison L. Kuipers, Michele K. Evans, Liubov Arbeeva, Ching-Ti Liu, Tamara B. Harris, Michelle S. Yau, Aude Nicolas, Salman M. Tajuddin, Joanne M. Jordan, Struan F.A. Grant, Ryan Price, Rebecca D. Jackson, Douglas P. Kiel, Babette S. Zemel, Samuel K. Handelman, Yi-Hsiang Hsu, David Karasik, Joseph M. Zmuda, and Alessandra Chesi
Subjects: Adult, Male, 0301 basic medicine, Adolescent, Genotype, Endocrinology, Diabetes and Metabolism, Osteoporosis, 030209 endocrinology & metabolism, Locus (genetics), Single-nucleotide polymorphism, Biology, Mannose-Binding Lectin, Mitochondrial Membrane Transport Proteins, Polymorphism, Single Nucleotide, Article, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Bone Density, medicine, Humans, SNP, Orthopedics and Sports Medicine, Child, Aged, Femoral neck, Femur Neck, Middle Aged, medicine.disease, Study heterogeneity, 030104 developmental biology, medicine.anatomical_structure, Genetic Loci, Meta-analysis, Cohort, Female, Genome-Wide Association Study, Demography
Abstract: Genetic studies of bone mineral density (BMD) largely have been conducted in European populations. We therefore conducted a meta-analysis of six independent African ancestry cohorts to determine whether previously reported BMD loci identified in European populations were transferable to African ancestry populations. We included nearly 5000 individuals with both genetic data and assessments of BMD. Genotype imputation was conducted using the 1000G reference panel. We assessed single-nucleotide polymorphism (SNP) associations with femoral neck and lumbar spine BMD in each cohort separately, then combined results in fixed effects (or random effects if study heterogeneity was high, I2 index >60) inverse variance weighted meta-analyses. In secondary analyses, we conducted locus-based analyses of rare variants using SKAT-O. Mean age ranged from 12 to 68 years. One cohort included only men and another cohort included only women; the proportion of women in the other four cohorts ranged from 52% to 63%. Of 56 BMD loci tested, one locus, 6q25 (C6orf97, p = 8.87 × 10-4 ), was associated with lumbar spine BMD and two loci, 7q21 (SLC25A13, p = 2.84 × 10-4 ) and 7q31 (WNT16, p = 2.96 × 10-5 ), were associated with femoral neck BMD. Effects were in the same direction as previously reported in European ancestry studies and met a Bonferroni-adjusted p value threshold, the criteria for transferability to African ancestry populations. We also found associations that met locus-specific Bonferroni-adjusted p value thresholds in 11q13 (LRP5, p
Published: 2020
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36. Examining the Impact of the 2019 Novel Coronavirus and Pandemic-Related Hardship on Adverse Pregnancy and Infant Outcomes: Design and Launch of the HOPE COVID-19 Study

Author: Xianhua Piao, Jean Costello, Elissa S. Epel, Rebecca D. Jackson, Ganapati Srinivasa, Jeffrey E. Olgin, Miriam Kuppermann, Nisha I. Parikh, Rebecca J. Baer, Brian D. Piening, Laura L. Jelliffe-Pawlowski, Allison O'Leary, Larry Rand, Fei Jiang, Charles E. McCulloch, Christina Lindan, Aric A. Prather, Alison G. Paquette, Nadia Diamond-Smith, Noah D. Peyser, Elizabeth E. Rogers, Karen A. Scott, Matt Pantell, Scott P. Oltman, Gretchen Bandoli, George W. Rutherford, April J. Bell, Jodi Stookey, Hollis Wright, Martina Steurer-Muller, Kelli K. Ryckman, Christina D. Chambers, and Deborah Karasek
Subjects: medicine.medical_specialty, Pregnancy, business.industry, Public health, Ethnic group, Geology, Ocean Engineering, Disease, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, 030225 pediatrics, Family medicine, Cohort, Pandemic, medicine, 030212 general & internal medicine, Social isolation, medicine.symptom, business, Socioeconomic status, Water Science and Technology
Abstract: The 2019 novel coronavirus disease (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread and worsen in many parts of the world. As the pandemic grows, it is especially important to understand how the virus and the pandemic are affecting pregnant women and infants. While early data suggested that being infected with the virus did not increase the risk of adverse pregnancy or infant outcomes, as more information has emerged, it has become clear that risks for some adverse pregnancy and infant outcomes are increased (e.g., preterm birth, cesarean section, respiratory distress, and hospitalization). The Healthy Outcomes of Pregnancy for Everyone in the time of novel coronavirus disease-19 (HOPE COVID-19) study is a multi-year, prospective investigation designed to better understand how the SARS-CoV-2 virus and COVID-19 impact adverse pregnancy and infant outcomes. The study also examines how the pandemic exacerbates existing hardships such as social isolation, economic destabilization, job loss, housing instability, and/or family member sickness or death among minoritized and marginalized communities. Specifically, the study examines how pandemic-related hardships impact clinical outcomes and characterizes the experiences of Black, Latinx and low-income groups compared to those in other race/ethnicity and socioeconomic stratum. The study includes two nested cohorts. The survey only cohort will enroll 7500 women over a two-year period. The survey+testing cohort will enroll 2500 women over this same time period. Participants in both cohorts complete short surveys daily using a mobile phone application about COVID-19-related symptoms (e.g., fever and cough) and complete longer surveys once during each trimester and at 6–8 weeks and 6, 12 and 18 months after delivery that focus on the health and well-being of mothers and, after birth, of infants. Participants in the survey+testing cohort also have testing for SARS-CoV-2 and related antibodies during pregnancy and after birth as well as testing that looks at inflammation and for the presence of other infections like Influenza and Rhinovirus. Study results are expected to be reported on a rolling basis and will include quarterly reporting for participants and public health partners as well as more traditional scientific reporting.
Published: 2020
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37. Cardiovascular Outcomes in Relation to Antihypertensive Medication Use in Women with and Without Cancer: Results from the Women's Health Initiative

Author: Sylvia Wassertheil-Smoller, Theodore M. Brasky, Mara Z. Vitolins, W. Gregory Hundley, Wendy E. Barrington, April Morgenroth, Eric J. Chow, Jessica Chubak, Marian C. Limacher, Ana Barac, Matthew Barnhart, Richard Cheng, Laurel A. Habel, Matthew P. Banegas, Rebecca D. Jackson, Aaron K. Aragaki, Kerryn W. Reding, Ralph B. D'Agostino, Rowan T. Chlebowski, and Chu Chen
Subjects: Cancer Research, medicine.medical_specialty, Population, Angiotensin-Converting Enzyme Inhibitors, 030204 cardiovascular system & hematology, Angiotensin Receptor Antagonists, 03 medical and health sciences, 0302 clinical medicine, Neoplasms, Internal medicine, medicine, Clinical endpoint, Humans, cardiovascular diseases, Prospective Studies, education, Prospective cohort study, Antihypertensive Agents, education.field_of_study, business.industry, Women's Health Initiative, Hazard ratio, medicine.disease, Clinical trial, Treatment Outcome, Oncology, Symptom Management and Supportive Care, 030220 oncology & carcinogenesis, Heart failure, Hypertension, Cohort, Women's Health, Female, business
Abstract: Background Recent clinical trials have evaluated angiotensin-converting enzyme (ACE) inhibitors (ACEis), angiotensin receptor blockers (ARBs), and beta blockers (BBs) in relation to cardiotoxicity in patients with cancer, typically defined by ejection fraction declines. However, these trials have not examined long-term, hard clinical endpoints. Within a prospective study, we examined the risk of heart failure (HF) and coronary heart disease (CHD) events in relation to use of commonly used antihypertensive medications, including ACEis/ARBs, BBs, calcium channel blockers (CCB), and diuretics, comparing women with and without cancer. Materials and Methods In a cohort of 56,997 Women's Health Initiative study participants free of cardiovascular disease who received antihypertensive treatment, we used multivariable-adjusted Cox regression models to calculate the hazard ratios (HRs) of developing CHD, HF, and a composite outcome of cardiac events (combining CHD and HF) in relation to use of ACEis/ARBs, CCBs, or diuretics versus BBs, separately in women with and without cancer. Results Whereas there was no difference in risk of cardiac events comparing ACEi/ARB with BB use among cancer-free women (HR = 0.99 [0.88–1.12]), among cancer survivors ACEi/ARB users were at a 2.24-fold risk of total cardiac events (1.18–4.24); p-interaction = .06). When investigated in relation to CHD only, an increased risk was similarly observed in ACEi/ARB versus BB use for cancer survivors (HR = 1.87 [0.88–3.95]) but not in cancer-free women (HR = 0.91 [0.79–1.06]; p-interaction = .04). A similar pattern was also seen in relation to HF but did not reach statistical significance (p-interaction = .23). Conclusion These results from this observational study suggest differing risks of cardiac events in relation to antihypertensive medications depending on history of cancer. Although these results require replication before becoming actionable in a clinical setting, they suggest the need for more rigorous examination of the effect of antihypertensive choice on long-term cardiac outcomes in cancer survivors. Implications for Practice Although additional research is needed to replicate these findings, these data from a large, nationally representative sample of postmenopausal women indicate that beta blockers are favorable to angiotensin-converting enzyme inhibitors in reducing the risk of cardiac events among cancer survivors. This differs from the patterns observed in a noncancer cohort, which largely mirrors what is found in the randomized clinical trials in the general population.
Published: 2020
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38. The Value of Rare Genetic Variation in the Prediction of Common Obesity in European Ancestry Populations

Author: Zhe Wang, Shing Wan Choi, Nathalie Chami, Eric Boerwinkle, Myriam Fornage, Susan Redline, Joshua C. Bis, Jennifer A. Brody, Bruce M. Psaty, Wonji Kim, Merry-Lynn N. McDonald, Elizabeth A. Regan, Edwin K. Silverman, Ching-Ti Liu, Ramachandran S. Vasan, Rita R. Kalyani, Rasika A. Mathias, Lisa R. Yanek, Donna K. Arnett, Anne E. Justice, Kari E. North, Robert Kaplan, Susan R. Heckbert, Mariza de Andrade, Xiuqing Guo, Leslie A. Lange, Stephen S. Rich, Jerome I. Rotter, Patrick T. Ellinor, Steven A. Lubitz, John Blangero, M. Benjamin Shoemaker, Dawood Darbar, Mark T. Gladwin, Christine M. Albert, Daniel I. Chasman, Rebecca D. Jackson, Charles Kooperberg, Alexander P. Reiner, Paul F. O’Reilly, and Ruth J. F. Loos
Subjects: burden score, Whole Genome Sequencing, Endocrinology, Diabetes and Metabolism, C+T, Genetic Variation, BMI - body mass index, lassosum, rare variants, PRS-CS, Gene Frequency, obesity risk, polygenic risk score, Humans, Obesity, Genome-Wide Association Study
Abstract: Polygenic risk scores (PRSs) aggregate the effects of genetic variants across the genome and are used to predict risk of complex diseases, such as obesity. Current PRSs only include common variants (minor allele frequency (MAF) ≥1%), whereas the contribution of rare variants in PRSs to predict disease remains unknown. Here, we examine whether augmenting the standard common variant PRS (PRScommon) with a rare variant PRS (PRSrare) improves prediction of obesity. We used genome-wide genotyped and imputed data on 451,145 European-ancestry participants of the UK Biobank, as well as whole exome sequencing (WES) data on 184,385 participants. We performed single variant analyses (for both common and rare variants) and gene-based analyses (for rare variants) for association with BMI (kg/m2), obesity (BMI ≥ 30 kg/m2), and extreme obesity (BMI ≥ 40 kg/m2). We built PRSscommon and PRSsrare using a range of methods (Clumping+Thresholding [C+T], PRS-CS, lassosum, gene-burden test). We selected the best-performing PRSs and assessed their performance in 36,757 European-ancestry unrelated participants with whole genome sequencing (WGS) data from the Trans-Omics for Precision Medicine (TOPMed) program. The best-performing PRScommon explained 10.1% of variation in BMI, and 18.3% and 22.5% of the susceptibility to obesity and extreme obesity, respectively, whereas the best-performing PRSrare explained 1.49%, and 2.97% and 3.68%, respectively. The PRSrare was associated with an increased risk of obesity and extreme obesity (ORobesity = 1.37 per SDPRS, Pobesity = 1.7x10-85; ORextremeobesity = 1.55 per SDPRS, Pextremeobesity = 3.8x10-40), which was attenuated, after adjusting for PRScommon (ORobesity = 1.08 per SDPRS, Pobesity = 9.8x10-6; ORextremeobesity= 1.09 per SDPRS, Pextremeobesity = 0.02). When PRSrare and PRScommon are combined, the increase in explained variance attributed to PRSrare was small (incremental Nagelkerke R2 = 0.24% for obesity and 0.51% for extreme obesity). Consistently, combining PRSrare to PRScommon provided little improvement to the prediction of obesity (PRSrare AUC = 0.591; PRScommon AUC = 0.708; PRScombined AUC = 0.710). In summary, while rare variants show convincing association with BMI, obesity and extreme obesity, the PRSrare provides limited improvement over PRScommon in the prediction of obesity risk, based on these large populations.
Published: 2022
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39. Association Between Walking for Exercise and Symptomatic and Structural Progression in Individuals With Knee Osteoarthritis: Data From the Osteoarthritis Initiative Cohort

Author: Grace H. Lo, Surabhi Vinod, Michael J. Richard, Matthew S. Harkey, Timothy E. McAlindon, Andrea M. Kriska, Bonny Rockette‐Wagner, Charles B. Eaton, Marc C. Hochberg, Rebecca D. Jackson, C. Kent Kwoh, Michael C. Nevitt, and Jeffrey B. Driban
Subjects: Male, Knee Joint, Immunology, Pain, Walking, Middle Aged, Osteoarthritis, Knee, Rheumatology, Disease Progression, Immunology and Allergy, Humans, Female, Exercise, Aged
Abstract: To assess the relationship between walking for exercise and symptomatic and structural disease progression in individuals with knee osteoarthritis (OA).We assessed a nested cohort of participants age 50 years or older within the Osteoarthritis Initiative, a community-based observational study in which subjects were enrolled between 2004 and 2006. We focused on 4 dichotomous outcomes from baseline to the 48-month visit, involving determination of the frequency of knee pain and radiographic severity of knee OA on posteroanterior semiflexed knee radiographs. The outcomes assessed included 1) new frequent knee pain, 2) worsening of radiographic severity of knee OA based on the Kellgren/Lawrence grade, 3) progression of medial joint space narrowing, and 4) improved frequent knee pain. We used a modified version of the Historical Physical Activity Survey Instrument to ascertain those subjects who reported walking for exercise after age 50 years. The survey was administered at the 96-month visit (2012-2014).Of 1,212 participants with knee OA, 45% were male and 73% reported walking for exercise. The mean ± SD age was 63.2 ± 7.9 years, and the mean ± SD body mass index was 29.4 ± 4.6 kg/mIn individuals with knee OA who were age 50 years or older, walking for exercise was associated with less frequent development of knee pain. These findings support the notion that walking for exercise should be encouraged for people with knee OA. Furthermore, we offer a proof of concept that walking for exercise could be disease modifying, which warrants further study.
Published: 2022

40. Exploring perspectives on changing opioid prescribing practices: A qualitative study of community stakeholders in the HEALing Communities Study

Author: Daniel M. Walker, Janet E. Childerhose, Sadie Chen, Nicolette Coovert, Rebecca D. Jackson, Natasha Kurien, Ann Scheck McAlearney, Jaclyn Volney, Daniel P. Alford, Julie Bosak, Douglas R. Oyler, Laura K. Stinson, Melika Behrooz, Mia-Cara Christopher, and Mari-Lynn Drainoni
Subjects: Pharmacology, Analgesics, Opioid, Psychiatry and Mental health, Humans, Pain, Pharmacology (medical), Opioid Epidemic, Practice Patterns, Physicians', Toxicology, Opioid-Related Disorders, Article
Abstract: BACKGROUND: Community-based perspectives are needed to more broadly inform policy-makers, public health practitioners, prescribers, and pharmacists about community-led and broader efforts to reduce opioid overprescribing, and ultimately reduce prescription opioid use disorder, overdoses and fatalities. The aim of this study is to explore community-based perspectives on efforts to change opioid prescribing practices in their communities. METHODS: Semi-structured interviews were conducted with 388 community stakeholders across four states (Kentucky, Massachusetts, New York, Ohio) from November 2019 to January 2020 about community approaches and goals of community-led responses to the opioid crisis. Data analysis combined deductive and inductive approaches to identify themes and sub-themes related to improving opioid prescribing practices. RESULTS: Three major themes and different subthemes were characterized: (1) acknowledging progress (i.e., healthcare providers being part of the solution, provider education, and prescription drug monitoring programs); (2) emergent challenges (i.e., physician nonadherence with safer opioid prescribing guidelines, difficulty identifying appropriate use of opioids, and concerns about accelerating the progression from opioid misuse to drug abuse); and (3) opportunities for change (i.e., educating patients about safer use and proper disposal of opioids, expanding prescriber and pharmacist education, changing unrealistic expectations around eliminating pain, expanding and increasing insurance coverage for alternative treatment options). CONCLUSIONS: Community stakeholders appeared to support specific opportunities to reduce prescription opioid misuse and improve safer prescribing. The opportunities included culture change around pain expectations, awareness of safe disposal, additional provider education, and increased coverage and acceptability of non-opioid treatments.
Published: 2022

41. Corrigendum to 'Altered gait mechanics are associated with severity of chondropathy after hip arthroscopy for femoroacetabular impingement syndrome' [Gait Posture 77 (2020) 175–181]

Author: Rebecca D. Jackson, Stephanie Di Stasi, Jennifer Perry, Lindsey Brown-Taylor, John Ryan, Jason E. Payne, Michael V. Knopp, Timothy E. Hewett, Jordan Wilson, and Michael P. McNally
Subjects: Chondropathy, medicine.medical_specialty, Gait (human), Physical medicine and rehabilitation, Femoroacetabular Impingement Syndrome, business.industry, Rehabilitation, Biophysics, medicine, Orthopedics and Sports Medicine, Hip arthroscopy, medicine.disease, business
Published: 2022
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42. Genetic Contributions to Early and Late Onset Ischemic Stroke

Author: Cristina Sanchez-Mora, Jie Hu, Philippe Amouyel, Annette Peters, Charles C Hong, Mary Cushman, Kathleen A. Ryan, Jiang Li, Liming Li, Thomas Jaworek, Sylvia Wassertheil-Smoller, Tiina Metso, Martin Soderholm, Kathryn M. Rexrode, Nicholas L. Smith, Jane Maguire, Martina Müller-Nurasyid, Agnieszka Slowik, Marguerite R. Irvin, Adam S. Butterworth, Martin O’Donnell, Leema Reddy Peddareddygari, Rainer Malik, Ralph L. Sacco, Brady Gaynor, Christian Geiger, Debashree Ray, Anne-Katrin Giese, John W. Cole, Jon Peter Durda, Vincent Thijs, Jukka Putaala, Michiaki Kubo, O. Colin Stine, Rebecca D. Jackson, Israel Fernandez-Cadenas, Reinhold Schmidt, Aki S. Havulinna, Kuang Lin, Christopher Levi, Steven Bell, Timothy O’Connor, Daniel Woo, Jara Cárcel-Márquez, Braxton D. Mitchell, Christina Jern, Jonathan Rosand, Sharon L.R. Kardia, Pankaj Sharma, Mina A. Jacob, Masaru Koido, Vida Abedi, Yoichiro Kamatani, Kristiina Rannikmäe, Michael Chong, Nuria P. Torres-Aguila, Cathie L. M. Sudlow, Ramin Zand, Elizabeth Holliday, Tatjana Rundek, Jessica D. Faul, Leslie Lange, Gunnar Engstrom, Marc C. Hochberg, Bradford B. Worrall, Hugh S. Markus, Joanna Pera, Jordi Jimenez-Conde, Caitrin W. McDonough, Raji P. Grewal, Owen Ross, Robin G. Walters, David J. Duggan, Guillaume Paré, Turgut Tatlisumak, Laura Heitsch, Jin-Moo Lee, Natalie Fecteau, Robin Lemmens, Jennifer A. Smith, Daniel Strbian, Patrick F. McArdle, Martin Dichgans, Jan H. Veldink, Liisa Tomppo, Arne G. Lindgren, Zhengming Chen, Chikashi Terao, Ulrike Grittner, Marta Ribasés, David R. Weir, James F. Meschia, Sothear Luke, Raquel Rabionet Janssen, Tara M. Stanne, Stephanie Debette, Nicole D. Armstrong, James A. Perry, Julie A. Johnson, Huichun Xu, Christopher D. Anderson, Giorgio B. Boncoraglio, Christian Enzinger, Haley Lopez, Anil Man Tuladhar, Oscar R. Benavente, Veikko Salomaa, David-Alexandre Trégouët, John Danesh, F-E de Leeuw, John Attia, Peter M. Rothwell, Steven J. Kittner, Andreea Ilinca, and Carlos Cruchaga
Subjects: 0303 health sciences, medicine.medical_specialty, business.industry, Late onset, Locus (genetics), 030204 cardiovascular system & hematology, medicine.disease, 3. Good health, 03 medical and health sciences, Venous thrombosis, 0302 clinical medicine, ABO blood group system, Internal medicine, Ischemic stroke, medicine, Cardiology, SNP, business, Stroke, 030304 developmental biology, Genetic association
Abstract: ObjectiveTo determine the contribution of common genetic variants to risk of early onset ischemic stroke (IS).MethodsWe performed a meta-analysis of genome-wide association studies of early onset IS, ages 18-59, using individual level data or summary statistics in 16,927 cases and 576,353 non-stroke controls from 48 different studies across North America, Europe, and Asia. We further compared effect sizes at our most genome-wide significant loci between early and late onset IS and compared polygenic risk scores for venous thromboembolism between early versus later onset IS.ResultsWe observed an association between early onset IS and ABO, a known stroke locus. The effect size of the peak ABO SNP, rs8176685, was significantly larger in early compared to late onset IS (OR 1.17 (95% C.I.: 1.11-1.22) vs 1.05 (0.99-1.12); p for interaction = 0.008). Analysis of genetically determined ABO blood groups revealed that early onset IS cases were more likely to have blood group A and less likely to have blood group O compared to both non-stroke controls and to late onset IS cases. Using polygenic risk scores, we observed that greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with early, compared to late, onset IS (p=0.008).ConclusionThe ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with early onset IS, compared with late onset IS, supporting a stronger role of prothrombotic factors in early onset IS.
Published: 2021
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43. Genetic analyses of the QT interval and its components in over 250K individuals identifies new loci and pathways affecting ventricular depolarization and repolarization

Author: Peter W. Macfarlane, Niels Grarup, Ruth J. F. Loos, Marcus Dörr, Peter P. Pramstaller, Torben Hansen, James F. Wilson, Lu-Chen Weng, Eduardo Tarazona-Santos, Honghuang Lin, Yong Qian, Jeffrey R. O'Connell, Maria Pina Concas, Claudia Schurmann, Michele Orini, Joshua C. Bis, Archie Campbell, Susan R. Heckbert, Jie Yao, Eulalia Catamo, Claus Graff, James G. Wilson, Pashupati P. Mishra, Massimo Mangino, Martina Müller-Nurasyid, Borbala Mifsud, Linda Repetto, Stephan B. Felix, Julia Ramirez, Rebecca D. Jackson, Eric Boerwinkle, Monika Stoll, Elsayed Z. Soliman, Maryam Kavousi, David J. Porteous, Nina Mononen, Dan E. Arking, Laura Andreasen, Lorenz Risch, Antonio Luiz Pinho Ribeiro, Pier D. Lambiase, Mika Kähönen, Xia Shen, Kenneth Rice, Eric A. Whitsel, Nona Sotoodehnia, Victor Nauffal, Konstantin Strauch, Jørgen K. Kanters, Henry Völzke, Daniel S. Evans, Jonas L. Isaksen, Alessandro De Grandi, Hao Mei, Alexander P. Reiner, Christy L. Avery, Thiago P. Leal, Alanna C. Morrison, Christian Fuchsberger, M. Arfan Ikram, Moritz Sinner, Yongmei Liu, Bruno H. Stricker, Francesco Cucca, Allan Linneberg, Patricia B. Munroe, Christina Ellervik, Olli T. Raitakari, Melanie Waldenberger, Reem Salman, Xiuqing Guo, Sandosh Padmanabhan, ThuyVy Duong, Dawood Darbar, Stefan Weiss, Arden Moscati, Alvaro Alonso, Cornelia M. van Duijn, Gianfranco Sinagra, Luisa Foco, Matthias Nauck, Kathleen A. Ryan, Kjell Nikus, Gustav Ahlberg, Helen R. Warren, Kent D. Taylor, Niek Verweij, Rebecca Freudling, Cristian Pattaro, Michael Preuss, Charles Kooperberg, Anne Richmond, David Conen, Oliver Hines, Juhani Junttila, Leo-Pekka Lyytikäinen, Nina Hutri-Kähönen, Kirill V. Tarasov, Ulrich Schotten, M. Benjamin Shoemaker, Marten E. van den Berg, Jerome I. Rotter, Michael J. Cutler, Adolfo Correa, Bruce M. Psaty, Caroline Hayward, Yalda Jamshidi, Pau Navarro, J W Benjamins, Patrick T. Ellinor, Massimo Mezzavilla, William J Young, Stefan Kääb, Lars Lind, Antonio De Luca, Heikki V. Huikuri, Marjo-Riitta Järvelin, Guillaume Paré, Stefan van Duijvenboden, Uwe Völker, Maria Fernanda Lima-Costa, Philippe Froguel, Jan A. Kors, Annette Peters, David Schlessinger, Christopher Newton-Cheh, J. Wouter Jukema, Andrew Tinker, Dennis O. Mook-Kanamori, Antoine R Baldassari, Stefanie Aeschbacher, Mariaelisa Graff, Najim Lahrouchi, Henry J. Lin, Giorgia Girotto, Giulia Pelliccione, Jeffrey Haessler, Aaron Isaacs, Rebecca N. Mitchell, Carolina Roselli, Massimiliano Cocca, Sina A. Gharib, Rozenn N. Lemaitre, Raymond Noordam, Morten S. Olesen, Steven A. Lubitz, Jun Ding, May E. Montasser, Jennifer A. Brody, Stella Trompet, Traci M. Bartz, Dania Raza, Thomas Meitinger, Andrew P. Morris, James P. Cook, Sébastien Thériault, Martin Gögele, André G. Uitterlinden, Pim van der Harst, Alan Pittman, Farah Ahmed, Simin Liu, Casia Nursyifa, Paul L. Huang, Kristen K. Patton, and Terho Lehtimäki
Subjects: medicine.medical_specialty, business.industry, Locus (genetics), Atrial fibrillation, medicine.disease, QT interval, Genetic architecture, Sudden cardiac death, QRS complex, Internal medicine, cardiovascular system, medicine, Cardiology, Repolarization, cardiovascular diseases, business, Ventricular depolarization
Abstract: The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization (QRS duration) and repolarization (JT interval). Abnormalities of the QT interval are associated with potentially fatal ventricular arrhythmia. We conducted genome-wide multi-ancestry analyses in >250,000 individuals and identified 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identified associations with Mendelian disease genes. Enrichments were observed in established pathways for QT and JT, with new genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast, connective tissue components and processes for cell growth and extracellular matrix interactions were significantly enriched for QRS. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlighted potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.
Published: 2021

44. KL2 scholars' perceptions of factors contributing to sustained translational science career success

Author: Susan S. Smyth, Barry S. Coller, Rebecca D. Jackson, Philip A. Kern, Scott McIntosh, Emma A. Meagher, Doris M. Rubio, Kathryn Sandberg, Joel Tsevat, Jason G. Umans, Jacqueline Attia, Heather L. Baker, Joan D. Nagel, Colleen A. McMullen, and Erica Rosemond
Subjects: General Medicine
Abstract: Introduction: Identifying the most effective ways to support career development of early stage investigators in clinical and translational science should yield benefits for the biomedical research community. Institutions with Clinical and Translational Science Awards (CTSA) offer KL2 programs to facilitate career development; however, the sustained impact has not been widely assessed. Methods: A survey comprised of quantitative and qualitative questions was sent to 2144 individuals that had previously received support through CTSA KL2 mechanisms. The 547 responses were analyzed with identifying information redacted. Results: Respondents held MD (47%), PhD (36%), and MD/PhD (13%) degrees. After KL2 support was completed, physicians’ time was divided 50% to research and 30% to patient care, whereas PhD respondents devoted 70% time to research. Funded research effort averaged 60% for the cohort. Respondents were satisfied with their career progression. More than 95% thought their current job was meaningful. Two-thirds felt confident or very confident in their ability to sustain a career in clinical and translational research. Factors cited as contributing to career success included protected time, mentoring, and collaborations. Conclusion: This first large systematic survey of KL2 alumni provides valuable insight into the group’s perceptions of the program and outcome information. Former scholars are largely satisfied with their career choice and direction, national recognition of their expertise, and impact of their work. Importantly, they identified training activities that contributed to success. Our results and future analysis of the survey data should inform the framework for developing platforms to launch sustaining careers of translational scientists.
Published: 2021

45. Inherited variants at 3q13.33 and 3p24.1 are associated with risk of diffuse large B-cell lymphoma and implicate immune pathways

Author: Qing Lan, Alexandra Nieters, Mark P. Purdue, Christine F. Skibola, Lauren R. Teras, Angela Brooks-Wilson, Kenneth Offit, Anne Zeleniuch-Jacquotte, Joseph Vijai, Simon Crouch, Vivekananda Sarangi, Graham G. Giles, James R. Cerhan, Sophia S. Wang, Nathaniel Rothman, James McKay, Mads Melbye, Karin E. Smedby, Yan W. Asmann, Xifeng Wu, Pierluigi Cocco, Gilles Salles, Hervé Ghesquières, Rebecca D. Jackson, Peter Kraft, Brenda M. Birmann, Huihuang Yan, Sonja I. Berndt, Stephen J. Chanock, Claire M. Vajdic, Demetrius Albanes, Michelle A.T. Hildebrandt, Susan L. Slager, Yuanqing Ye, Geffen Kleinstern, Alain Monnereau, Yawei Zhang, and Roel Vermeulen
Subjects: Linkage disequilibrium, Lymphoma, B-Cell, Genotype, Receptors, Cell Surface, Genome-wide association study, Single-nucleotide polymorphism, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Article, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Odds Ratio, Genetics, medicine, Genetic predisposition, Humans, SNP, Genetic Predisposition to Disease, Promoter Regions, Genetic, Molecular Biology, Genetics (clinical), 030304 developmental biology, 0303 health sciences, General Medicine, medicine.disease, Minor allele frequency, 030220 oncology & carcinogenesis, B7-2 Antigen, Chromosomes, Human, Pair 3, Diffuse large B-cell lymphoma, Genome-Wide Association Study
Abstract: We previously identified five single nucleotide polymorphisms (SNPs) at four susceptibility loci for diffuse large B-cell lymphoma (DLBCL) in individuals of European ancestry through a large genome-wide association study (GWAS). To further elucidate genetic susceptibility to DLBCL, we sought to validate two loci at 3q13.33 and 3p24.1 that were suggestive in the original GWAS with additional genotyping. In the meta-analysis (5662 cases and 9237 controls) of the four original GWAS discovery scans and three replication studies, the 3q13.33 locus (rs9831894; minor allele frequency [MAF] = 0.40) was associated with DLBCL risk [odds ratio (OR) = 0.83, P = 3.62 × 10−13]. rs9831894 is in linkage disequilibrium (LD) with additional variants that are part of a super-enhancer that physically interacts with promoters of CD86 and ILDR1. In the meta-analysis (5510 cases and 12 817 controls) of the four GWAS discovery scans and four replication studies, the 3p24.1 locus (rs6773363; MAF = 0.45) was also associated with DLBCL risk (OR = 1.20, P = 2.31 × 10−12). This SNP is 29 426-bp upstream of the nearest gene EOMES and in LD with additional SNPs that are part of a highly lineage-specific and tumor-acquired super-enhancer that shows long-range interaction with AZI2 promoter. These loci provide additional evidence for the role of immune function in the etiology of DLBCL, the most common lymphoma subtype.
Published: 2019
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46. Genome-wide association study of knee pain identifies associations with GDF5 and COL27A1 in UK Biobank

Author: Mark Adams, Rebecca D. Jackson, Adam Auton, Michelle S. Yau, Blair H. Smith, Kathleen A. Ryan, Weihua Meng, Braxton D. Mitchell, Andrew M. McIntosh, Colin N. A. Palmer, Joanne M. Jordan, and Jingchunzi Shi
Subjects: Male, 0301 basic medicine, Within the past 12 months, Knee Joint, Fibrillar Collagens, Medicine (miscellaneous), Genome-wide association study, Osteoarthritis, Genome-wide association studies, Linkage Disequilibrium, Cohort Studies, 0302 clinical medicine, Growth Differentiation Factor 5, lcsh:QH301-705.5, Biological Specimen Banks, Medical attention, Musculoskeletal system, Middle Aged, musculoskeletal system, Biobank, 3. Good health, Cohort, Female, medicine.symptom, General Agricultural and Biological Sciences, musculoskeletal diseases, medicine.medical_specialty, Pain, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, medicine, Humans, Genetic Predisposition to Disease, Author Correction, 030203 arthritis & rheumatology, business.industry, Genetic variants, medicine.disease, United Kingdom, 030104 developmental biology, Knee pain, Gene Expression Regulation, lcsh:Biology (General), Case-Control Studies, Physical therapy, business, human activities, Genome-Wide Association Study
Abstract: Knee pain is one of the most common musculoskeletal complaints that brings people to medical attention. Approximately 50% of individuals over the age of 50 report an experience of knee pain within the past 12 months. We sought to identify the genetic variants associated with knee pain in 171,516 subjects from the UK Biobank cohort and seek supporting evidence in cohorts from 23andMe, the Osteoarthritis Initiative, and the Johnston County Osteoarthritis Project. We identified two loci that reached genome-wide significance in the UK Biobank: rs143384, located in GDF5 (P = 1.32 × 10−12), a gene previously implicated in osteoarthritis; and rs2808772, located near COL27A1 (P = 1.49 × 10−8). These findings were supported in cohorts with self-reported osteoarthritis/radiographic knee osteoarthritis without pain information. In this report on genome-wide association of knee pain, we identified two loci in or near GDF5 and COL27A1 that are associated with knee pain., Weihua Meng, Mark Adams et al. report a genome-wide association study of knee pain in the UK Biobank, identifying two loci near GDF5 and COL27A1 as significantly associated. These findings are supported by association data in additional cohorts, using self-reported osteoarthritis or radiographic knee osteoarthritis as a proxy for knee pain.
Published: 2019
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47. Development and validation of risk stratification trees for incident slow gait speed in persons at high risk for knee osteoarthritis

Author: Leena Sharma, Jane A. Cauley, Alison H. Chang, Marc C. Hochberg, Orit Almagor, Michael C. Nevitt, Jing Song, Rebecca D. Jackson, Joan S. Chmiel, Jungwha Lee, Charles B. Eaton, and Kent Kwoh
Subjects: Male, Osteoarthritis, Disease, Logistic regression, Disability Evaluation, 0302 clinical medicine, prevention, Risk Factors, Immunology and Allergy, Medicine, 030212 general & internal medicine, Incidence, Middle Aged, Osteoarthritis, Knee, Area Under Curve, Risk stratification, Public Health and Health Services, Female, medicine.medical_specialty, WOMAC, Clinical Trials and Supportive Activities, Clinical Sciences, Immunology, Risk Assessment, knee osteoarthritis, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Physical medicine and rehabilitation, Rheumatology, Clinical Research, Neurologic, Humans, Knee, Gait Disorders, Gait Disorders, Neurologic, Aged, 030203 arthritis & rheumatology, Receiver operating characteristic, business.industry, Arthritis, Decision Trees, Reproducibility of Results, medicine.disease, Obesity, Arthritis & Rheumatology, Walking Speed, Gait speed, functional impairment, Good Health and Well Being, Logistic Models, disability, ROC Curve, Feasibility Studies, business
Abstract: Objectives Disability prevention strategies are more achievable before osteoarthritis disease drives impairment. It is critical to identify high-risk groups, for strategy implementation and trial eligibility. An established measure, gait speed is associated with disability and mortality. We sought to develop and validate risk stratification trees for incident slow gait in persons at high risk for knee osteoarthritis, feasible in community and clinical settings. Methods Osteoarthritis Initiative (derivation cohort) and Multicenter Osteoarthritis Study (validation cohort) participants at high risk for knee osteoarthritis were included. Outcome was incident slow gait over up to 10-year follow-up. Derivation cohort classification and regression tree analysis identified predictors from easily assessed variables and developed risk stratification models, then applied to the validation cohort. Logistic regression compared risk group predictive values; area under the receiver operating characteristic curves (AUCs) summarised discrimination ability. Results 1870 (derivation) and 1279 (validation) persons were included. The most parsimonious tree identified three risk groups, from stratification based on age and WOMAC Function. A 7-risk-group tree also included education, strenuous sport/recreational activity, obesity and depressive symptoms; outcome occurred in 11%, varying 0%–29 % (derivation) and 2%–23 % (validation) depending on risk group. AUCs were comparable in the two cohorts (7-risk-group tree, 0.75, 95% CI 0.72 to 0.78 (derivation); 0.72, 95% CI 0.68 to 0.76 (validation)). Conclusions In persons at high risk for knee osteoarthritis, easily acquired data can be used to identify those at high risk of incident functional impairment. Outcome risk varied greatly depending on tree-based risk group membership. These trees can inform individual awareness of risk for impaired function and define eligibility for prevention trials.
Published: 2019
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48. Sports with a Bat or Racket are Not Associated with Thumb-base Osteoarthritis

Author: Jeffrey B, Driban, Grace H, Lo, Mary B, Roberts, Matthew S, Harkey, Lena, Schaefer, Ida K, Haugen, Stacy E, Smith, Jeffrey, Duryea, Bing, Lu, Charles B, Eaton, Marc C, Hochberg, Rebecca D, Jackson, C Kent, Kwoh, Michael C, Nevitt, and Timothy E, McAlindon
Abstract: Repetitive joint use is a risk factor for osteoarthritis, which is a leading cause of disability. Sports requiring a bat or racket to perform repetitive high-velocity impacts may increase the risk of thumb-base osteoarthritis. However, this hypothesis remains untested.To determine if a history of participation in racket or bat sports is associated with the prevalence of thumb-base osteoarthritis.Descriptive epidemiology study.Osteoarthritis Initiative. Four clinical sites in the United States.We included men and women from the recruited from the community. Eligible participants had dominant hand radiographic readings, hand symptom assessments, and historical physical activity survey data.A history of exposure to racket or bat sports (baseball/softball, racquetball/squash, badminton, table tennis, tennis [doubles/singles]) was based on self-reported recall data covering 3 age ranges (12-18 years, 19-34 years, 35-49 years). Prevalent radiographic thumb-base osteoarthritis was defined as someone with Kellgren-Lawrence grade≥2 in the first carpometacarpal joint or scaphotrapezoidal joint at the OAI baseline visit. Symptomatic thumb-base osteoarthritis was defined as the presence of radiographic osteoarthritis and hand/finger symptoms.In total, we included 2309 participants. Among 1049 men, 355 (34%) and 56 (5%) had radiographic or symptomatic thumb-base osteoarthritis, respectively; and among 1260 women, 535 (42%) and 170 (13%), respectively. After adjusting for age, race, and education level, we found no statistically significant associations between a history of any racket or bat sport participation and thumb-base osteoarthritis (radiographic or symptomatic; odds ratios range from 0.82 to 1.34).Within a community-based cohort, a self-reported history of participation in racket or bat sports was not associated with an increased odds of having radiographic or symptomatic thumb-base osteoarthritis in the dominant hand.
Published: 2021

49. Genetic insights into biological mechanisms governing human ovarian ageing

Author: Unnur Styrkarsdottir, Lynda M. Rose, Rehannah Borup, Anne B. Newman, Georgia Chenevix-Trench, Chikashi Terao, Jeremy A. Daniel, Christa Meisinger, Albert V. Smith, Emil Peter Thrane Hertz, Raymond Noordam, Wei He, Jennifer A. Smith, Mikael Eriksson, Konstantin Strauch, Daniel I. Chasman, Nicholas J. Timpson, Melissa A. Troester, Claudia Langenberg, Montserrat Garcia-Closas, Mohammad Arfan Ikram, Sara Lindström, Gad Rennert, Pascal Guénel, Kristina W. Olsen, Pierre Fontanillas, Ozren Polasek, Daniel F. Gudbjartsson, Frank B. Hu, Archie Campbell, Celine M. Vachon, Sheila Ulivi, Robin N Beaumont, Robert Karlsson, Lenore J. Launer, Renée de Mutsert, Annette Peters, David Schlessinger, Stefania Bandinelli, Rico Rueedi, Joop S.E. Laven, Pascal Timshel, Joanne M. Murabito, Kuang Lin, Jazib Hussain, Dennis O. Mook-Kanamori, Manjeet K. Bolla, Catherine E. Aiken, Javier Martin Gonzalez, Simon S. Cross, Immaculata De Vivo, Paul M. Ridker, Christopher A. Haiman, Gerardo Heiss, Jessica Tyrrell, Paul R. H. J. Timmers, Hironori Abe, Mike A. Nalls, Luigi Ferrucci, Natalia Perjakova, Jouke J. Hottenga, Robin G. Walters, Reedik Mägi, Niclas Håkansson, Miriam Dwek, Barbara McKnight, Sandra Turon, Stasa Stankovic, Linda Broer, Stephen J. Chanock, Martina La Bianca, Jenny Chang-Claude, Loic Le Marchand, Hamdi Mbarek, Doris Stöckl, Andrew F. Olshan, Graham G. Giles, James F. Wilson, Micaella Joaquim, Amruta Shrikhande, Eva Hoffmann, Stefania Benonisdottir, Ana Martínez-Marchal, Anthony J. Swerdlow, David Karasik, Nicholas J. Wareham, Peter A. Fasching, Jane L. Tarry-Adkins, Charles Kooperberg, Peter Vollenweider, Douglas F. Easton, Paula Aguilera, Jessica D. Faul, Patrik K. E. Magnusson, Emmanouil Saloustros, Alpa V. Patel, Ellen W. Demerath, Qin Wang, Aditya Sankar, Christopher G. Scott, Iffat Rahman, Sharon L.R. Kardia, Peter K. Joshi, Caterina Barbieri, Claus Yding Andersen, Tõnu Esko, Massimo Mezzavilla, Nicholas G. Martin, Rebecca D. Jackson, Alison D. Murray, Marina Ciullo, Nicholas Bowker, Anna Murray, Patrick Deelen, Zoltán Kutalik, Alicja Wolk, Manuela Gago-Dominguez, Eleonora Porcu, Laura Crisponi, Michela Traglia, Katharina E. Schraut, Antonietta Robino, Chunyan He, Bruce H. R. Wolffenbuttel, Henry Völzke, Daniela Ruggiero, John R. B. Perry, Lude Franke, Igor Rudan, Angela Cox, Unnur Þorsteinsdottir, Christian Gieger, David R. Weir, Jodie N. Painter, Martha S. Linet, Massimo Mangino, Melissa C. Southey, Petr Solc, Tim D. Spector, Christiana Kartsonaki, Momoko Horikoshi, Meir J. Stampfer, Eulalia Catamo, Mònica Ferrer-Roda, Ko Willems van Dijk, Daniela Toniolo, Caroline Hayward, Lili Milani, Chloé Sarnowski, Jian'an Luan, Behrooz Z. Alizadeh, Jenny A. Visser, Stig E. Bojesen, Genevieve Lachance, Ulrike Peters, Antonella Mulas, John J. Spinelli, Elnaz Naderi, Andrew R. Wood, Paul D.P. Pharoah, Elinor J. Sawyer, Annique Claringbould, Saleh Shekari, David G. Hunter, Marie Louise Grøndahl, Vilmundur Gudnason, Nora Franceschini, Dale P. Sandler, Dale R. Nyholt, Jacques E. Rossouw, Amber N. Wilcox, Thomas U. Ahearn, Hedy S. Rennert, Olivier B. Bakker, Jingmei Li, Francesco Cucca, Eric Boerwinkle, Matthias W. Beckmann, Cristina Menni, Minouk J. Schoemaker, Esther M. John, Tune H. Pers, Andrés J. López-Contreras, Tanguy Corre, Jonathan Marten, Alice M. Arnold, N. Charlotte Onland-Moret, Lucie Knoblochova, Anna Pujol, Kathryn L. Lunetta, Marjanka K. Schmidt, Teresa Nutile, Serena Sanna, Gonneke Willemsen, Roger L. Milne, Kristan J. Aronson, Frits R. Rosendaal, Murielle Bochud, Ken K. Ong, Susan M. Ring, Nancy L. Pedersen, Blair H. Smith, Ivana Kolcic, Annelie Augustinsson, Jose E. Castelao, Alexander Teumer, Felix R. Day, Sven Bergmann, Timothy M. Frayling, Lauren R. Teras, George Davey Smith, Thomas Meitinger, Alison M. Dunning, Ignasi Roig, Dorret I. Boomsma, Harald Grallert, Toshiko Tanaka, Katherine S. Ruth, Julie E. Buring, Marek Zygmunt, Uwe Völker, Irene L. Andrulis, Håkan Olsson, Harry Campbell, Cari M. Kitahara, Annika Lindblom, Yvonne T. van der Schouw, Cinzia Sala, Debbie A Lawlor, Joe Dennis, Yongmei Liu, Yan Huang, Stephen Burgess, Brumat Marco, Veronique Vitart, Kari Stefansson, Susan E. Ozanne, Kamila Czene, Simin Liu, John L. Hopper, Joyce B. J. van Meurs, Satoshi H. Namekawa, Miya Kudo Høffding, Fergus J. Couch, Ajuna Azad, Eco J. C. de Geus, Liming Li, Grant W. Montgomery, Peter Kraft, André G. Uitterlinden, Arto Mannermaa, Heiko Becher, Allison W. Kurian, Vallari Shukla, Zhengming Chen, Per Hall, Jennifer A. Brody, Rossella Sorice, Wei Zhao, Andres Metspalu, Sarah E. Medland, Tricia Lindstrom, Clarice R. Weinberg, Bruce M. Psaty, Thérèse Truong, Anna Marie Mulligan, Deborah J. Thompson, Patrick Sulem, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Hoffmann, Eva R [0000-0002-2588-0652], Murray, Anna [0000-0002-2351-2522], Roig, Ignasi [0000-0003-0313-3581], Perry, John RB [0000-0001-6483-3771], Apollo - University of Cambridge Repository, Life Course Epidemiology (LCE), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Biological Psychology, APH - Mental Health, APH - Methodology, APH - Personalized Medicine, and APH - Health Behaviors & Chronic Diseases
Subjects: Gerontology, Aging, Far East, Endocrinology, Diabetes and Metabolism, Menopause, Premature, Genome-wide association study, VARIANTS, Primary Ovarian Insufficiency, Inbred C57BL, Bioinformatics, DISEASE, Healthy Aging, genetics of ovarian aging, Fragile X Mental Retardation Protein, Mice, Endocrinology, Medicine, EARLY MENOPAUSE, media_common, RISK, Multidisciplinary, Asia, Eastern, Reproduction, Longevity, Middle Aged, Europe, MENDELIAN RANDOMIZATION, Medical genetics, Female, ICEP, Menopause, Adult, Alleles, Animals, Bone and Bones, Checkpoint Kinase 1, Checkpoint Kinase 2, Diabetes Mellitus, Type 2, Diet, Fertility, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Mice, Inbred C57BL, Ovary, Uterus, Type 2, medicine.medical_specialty, media_common.quotation_subject, MEDLINE, Biology, Premature ovarian insufficiency, Article, genome-wide meta-analysis, SDG 3 - Good Health and Well-being, GERMLINE, Diabetes Mellitus, Genetic predisposition, Ovarian reserve, Premature, business.industry, Human genetics, CHROMOSOME SYNAPSIS, DNA-DAMAGE, Ageing, EXPRESSION ANALYSIS, business, MEIOTIC CELL-CYCLE
Abstract: Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease. Hundreds of genetic loci associated with age at menopause, combined with experimental evidence in mice, highlight mechanisms of reproductive ageing across the lifespan.
Published: 2021
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50. Immediate impact of the COVID-19 pandemic on CTSA TL1 and KL2 training and career development

Author: Joel Tsevat, Jason G. Umans, Kathryn Sandberg, H. William Schnaper, Joan D. Nagel, Rebecca D. Jackson, Cynthia D. Morris, Miriam A. Bredella, Emma A. Meagher, Susan N. Pusek, Doris M. Rubio, Scott McIntosh, David H. Ingbar, and Wayne T. McCormack
Subjects: Medical education, 2019-20 coronavirus outbreak, 030505 public health, Coronavirus disease 2019 (COVID-19), education, COVID-19, General Medicine, KL2, career development, Training (civil), humanities, research training, Education, 03 medical and health sciences, 0302 clinical medicine, TL1, Expedited Report, Pandemic, Clinical and Translational Science Award, Time management, 030212 general & internal medicine, 0305 other medical science, Psychology, Productivity, Career development
Abstract: Clinical and Translational Science Award (CTSA) TL1 trainees and KL2 scholars were surveyed to determine the immediate impact of the COVID-19 pandemic on training and career development. The most negative impact was lack of access to research facilities, clinics, and human subjects, plus for KL2 scholars lack of access to team members and need for homeschooling. TL1 trainees reported having more time to think and write. Common strategies to maintain research productivity involved time management, virtual connections with colleagues, and shifting to research activities not requiring laboratory/clinic settings. Strategies for mitigating the impact of the COVID-19 pandemic on training and career development are described.
Published: 2021

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